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Sample records for genetic alterations contribute

  1. Genetic alterations in hepatocellular carcinoma: An update

    Science.gov (United States)

    Niu, Zhao-Shan; Niu, Xiao-Jun; Wang, Wen-Hong

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC. PMID:27895396

  2. Genetic and epigenetic alterations of the reduced folate carrier in untreated diffuse large B-cell lymphoma

    DEFF Research Database (Denmark)

    Kastrup, I.B.; Worm, J.; Ralfkiaer, E.

    2008-01-01

    The reduced folate carrier (RFC) is a transmembrane protein that mediates cellular uptake of reduced folates and antifolate drugs, including methotrexate (MTX). Acquired alterations of the RFC gene have been associated with resistance to MTX in cancer cell lines and primary osteosarcomas. Here, w...... with adverse outcome. In DLBCL, genetic and epigenetic alterations of RFC were detected at diagnosis in the absence of a selective MTX pressure, suggesting that these alterations may possibly contribute to the development of lymphoma Udgivelsesdato: 2008/1...

  3. Genetic Alterations in Glioma

    International Nuclear Information System (INIS)

    Bralten, Linda B. C.; French, Pim J.

    2011-01-01

    Gliomas are the most common type of primary brain tumor and have a dismal prognosis. Understanding the genetic alterations that drive glioma formation and progression may help improve patient prognosis by identification of novel treatment targets. Recently, two major studies have performed in-depth mutation analysis of glioblastomas (the most common and aggressive subtype of glioma). This systematic approach revealed three major pathways that are affected in glioblastomas: The receptor tyrosine kinase signaling pathway, the TP53 pathway and the pRB pathway. Apart from frequent mutations in the IDH1/2 gene, much less is known about the causal genetic changes of grade II and III (anaplastic) gliomas. Exceptions include TP53 mutations and fusion genes involving the BRAF gene in astrocytic and pilocytic glioma subtypes, respectively. In this review, we provide an update on all common events involved in the initiation and/or progression across the different subtypes of glioma and provide future directions for research into the genetic changes

  4. [Algorithm of toxigenic genetically altered Vibrio cholerae El Tor biovar strain identification].

    Science.gov (United States)

    Smirnova, N I; Agafonov, D A; Zadnova, S P; Cherkasov, A V; Kutyrev, V V

    2014-01-01

    Development of an algorithm of genetically altered Vibrio cholerae biovar El Tor strai identification that ensures determination of serogroup, serovar and biovar of the studied isolate based on pheno- and genotypic properties, detection of genetically altered cholera El Tor causative agents, their differentiation by epidemic potential as well as evaluation of variability of key pathogenicity genes. Complex analysis of 28 natural V. cholerae strains was carried out by using traditional microbiological methods, PCR and fragmentary sequencing. An algorithm of toxigenic genetically altered V. cholerae biovar El Tor strain identification was developed that includes 4 stages: determination of serogroup, serovar and biovar based on phenotypic properties, confirmation of serogroup and biovar based on molecular-genetic properties determination of strains as genetically altered, differentiation of genetically altered strains by their epidemic potential and detection of ctxB and tcpA key pathogenicity gene polymorphism. The algorithm is based on the use of traditional microbiological methods, PCR and sequencing of gene fragments. The use of the developed algorithm will increase the effectiveness of detection of genetically altered variants of the cholera El Tor causative agent, their differentiation by epidemic potential and will ensure establishment of polymorphism of genes that code key pathogenicity factors for determination of origins of the strains and possible routes of introduction of the infection.

  5. Genetic Alterations and Their Clinical Implications in High-Recurrence Risk Papillary Thyroid Cancer.

    Science.gov (United States)

    Lee, Min-Young; Ku, Bo Mi; Kim, Hae Su; Lee, Ji Yun; Lim, Sung Hee; Sun, Jong-Mu; Lee, Se-Hoon; Park, Keunchil; Oh, Young Lyun; Hong, Mineui; Jeong, Han-Sin; Son, Young-Ik; Baek, Chung-Hwan; Ahn, Myung-Ju

    2017-10-01

    Papillary thyroid carcinomas (PTCs) frequently involve genetic alterations. The objective of this study was to investigate genetic alterations and further explore the relationships between these genetic alterations and clinicopathological characteristics in a high-recurrence risk (node positive, N1) PTC group. Tumor tissue blocks were obtained from 240 surgically resected patients with histologically confirmed stage III/IV (pT3/4 or N1) PTCs. We screened gene fusions using NanoString's nCounter technology and mutational analysis was performed by direct DNA sequencing. Data describing the clinicopathological characteristics and clinical courses were retrospectively collected. Of the 240 PTC patients, 207 (86.3%) had at least one genetic alteration, including BRAF mutation in 190 patients (79.2%), PIK3CA mutation in 25 patients (10.4%), NTRK1/3 fusion in six patients (2.5%), and RET fusion in 24 patients (10.0%). Concomitant presence of more than two genetic alterations was seen in 36 patients (15%). PTCs harboring BRAF mutation were associated with RET wild-type expression (p=0.001). RET fusion genes have been found to occur with significantly higher frequency in N1b stage patients (p=0.003) or groups of patients aged 45 years or older (p=0.031); however, no significant correlation was found between other genetic alterations. There was no trend toward favorable recurrence-free survival or overall survival among patients lacking genetic alterations. In the selected high-recurrence risk PTC group, most patients had more than one genetic alteration. However, these known alterations could not entirely account for clinicopathological features of high-recurrence risk PTC.

  6. Genetic alterations and epigenetic changes in hepatocarcinogenesis

    Directory of Open Access Journals (Sweden)

    Luz Stella Hoyos Giraldo

    2007-02-01

    potent co-transactivator of viral and cellular promoters such as c-yuck and c-fos. Binding HBx protein to the p53 protein may interrupt p53 induced apoptosis and may inhibit DNA repair during hepatocarcinogenesis.

    Liver infection may lead to enhanced cell proliferation, in presence of DNA damage from AFB1, result in increased mutations. Genetic alterations and rearrangements are present in the early steps in hepatocarcinogenesis. Genetic alterations, including two different mechanisms relate to chromosomal instability (CIN and CpG island methylation.

    Genetic alterations and epigenetic changes in oncogenes and tumor suppressor genes may cause gain of functions or loss of functions respectively. HCC accumulate chromosome alterations such as chromosomal deletions, DNA rearrangements associated with HBV, DNA integration, aneuploidy, gene amplifications, mutations and microsatellite instability (MSI as well as epigenetic changes including modulation of DNA methylation. Mutation in p53 at the third base of codon 249 in exon 7, G to T transversion (arginine to serine linked with AFB1 exposure inactivates p53. The p53 gene may be the most important gene in human hepatocarcinogenesis. Then loss or inactivation of p53, which occurs in most of human cancer, may contribute to the genetic instability and allows genetically damaged and senescent cells to continue to replicate their DNA increasing the damage and it allow them to escape apoptosis. Studies of HCC have been identified in affecting chromosomal regions, (1p, 4q, 5q, 6q, 8p, 10q 11p, 16p, 16q, 17p and 22q. Later in hepatocarcinogenesis (HCC tumor cells undergo increasing levels of chromosomal aberrations including loss of gene heterozygosity (LOH of the TSG. Deletions have been reported in 8p, 17p, 4q, 1p, 13q, 16q, 6q, 16p, 1q, and 9p. For chromosome

  7. The genetic alteration of p53 in esophageal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Jae Il; Baik, Hee Jong; Kim, Chang Min; Kim, Mi Hee [Korea Cancer Center Hospital, Seoul (Korea, Republic of)

    1996-01-01

    Genetic alterations in the p53 gene have been detected in various human malignancies, and its alterations inactive the function of p53 as a tumor suppressor. Point mutation and gene deletion are the main mechanisms of p53 inactivation. To determine the incidence of genetic alteration of p53 and their clinical implications in Korean patients of esophageal cancer, we investigated p53 alterations in 26 esophageal cancer tissues paired with its normal tissue by Southern blot analysis, PCR-SSCP, and direct sequencing. Allelic loss of chromosome 17p occurred in 12 out of 21 informative cases(57%) by Southern blot analysis, and 16 cases showed mobility shift in PCR-SSCP, so overall incidence of p53 gene alterations was 77%(20/26). The mutations detected was randomly dispersed over exon4-8 and was frequently G-T transversion and C:T transitions. Three identical mutations were clustered at codon 213 suggested the same etiologic agents in this cases. The p53 gene alterations play a significant role in the development of esophageal cancers, however, no relationship between p53 mutation and clinical data was detected so far. 9 refs. (Author).

  8. Genetic alterations in head and neck squamous cell carcinomas

    Directory of Open Access Journals (Sweden)

    Nagai M.A.

    1999-01-01

    Full Text Available The genetic alterations observed in head and neck cancer are mainly due to oncogene activation (gain of function mutations and tumor suppressor gene inactivation (loss of function mutations, leading to deregulation of cell proliferation and death. These genetic alterations include gene amplification and overexpression of oncogenes such as myc, erbB-2, EGFR and cyclinD1 and mutations, deletions and hypermethylation leading to p16 and TP53 tumor suppressor gene inactivation. In addition, loss of heterozygosity in several chromosomal regions is frequently observed, suggesting that other tumor suppressor genes not yet identified could be involved in the tumorigenic process of head and neck cancers. The exact temporal sequence of the genetic alterations during head and neck squamous cell carcinoma (HNSCC development and progression has not yet been defined and their diagnostic or prognostic significance is controversial. Advances in the understanding of the molecular basis of head and neck cancer should help in the identification of new markers that could be used for the diagnosis, prognosis and treatment of the disease.

  9. Molecular genetic contributions to socioeconomic status and intelligence.

    Science.gov (United States)

    Marioni, Riccardo E; Davies, Gail; Hayward, Caroline; Liewald, Dave; Kerr, Shona M; Campbell, Archie; Luciano, Michelle; Smith, Blair H; Padmanabhan, Sandosh; Hocking, Lynne J; Hastie, Nicholas D; Wright, Alan F; Porteous, David J; Visscher, Peter M; Deary, Ian J

    2014-05-01

    Education, socioeconomic status, and intelligence are commonly used as predictors of health outcomes, social environment, and mortality. Education and socioeconomic status are typically viewed as environmental variables although both correlate with intelligence, which has a substantial genetic basis. Using data from 6815 unrelated subjects from the Generation Scotland study, we examined the genetic contributions to these variables and their genetic correlations. Subjects underwent genome-wide testing for common single nucleotide polymorphisms (SNPs). DNA-derived heritability estimates and genetic correlations were calculated using the 'Genome-wide Complex Trait Analyses' (GCTA) procedures. 21% of the variation in education, 18% of the variation in socioeconomic status, and 29% of the variation in general cognitive ability was explained by variation in common SNPs (SEs ~ 5%). The SNP-based genetic correlations of education and socioeconomic status with general intelligence were 0.95 (SE 0.13) and 0.26 (0.16), respectively. There are genetic contributions to intelligence and education with near-complete overlap between common additive SNP effects on these traits (genetic correlation ~ 1). Genetic influences on socioeconomic status are also associated with the genetic foundations of intelligence. The results are also compatible with substantial environmental contributions to socioeconomic status.

  10. Tissue culture-induced genetic and epigenetic alterations in rice pure-lines, F1 hybrids and polyploids.

    Science.gov (United States)

    Wang, Xiaoran; Wu, Rui; Lin, Xiuyun; Bai, Yan; Song, Congdi; Yu, Xiaoming; Xu, Chunming; Zhao, Na; Dong, Yuzhu; Liu, Bao

    2013-05-05

    Genetic and epigenetic alterations can be invoked by plant tissue culture, which may result in heritable changes in phenotypes, a phenomenon collectively termed somaclonal variation. Although extensive studies have been conducted on the molecular nature and spectrum of tissue culture-induced genomic alterations, the issue of whether and to what extent distinct plant genotypes, e.g., pure-lines, hybrids and polyploids, may respond differentially to the tissue culture condition remains poorly understood. We investigated tissue culture-induced genetic and epigenetic alterations in a set of rice genotypes including two pure-lines (different subspecies), a pair of reciprocal F1 hybrids parented by the two pure-lines, and a pair of reciprocal tetraploids resulted from the hybrids. Using two molecular markers, amplified fragment length polymorphism (AFLP) and methylation-sensitive amplified polymorphism (MSAP), both genetic and DNA methylation alterations were detected in calli and regenerants from all six genotypes, but genetic alteration is more prominent than epigenetic alteration. While significant genotypic difference was observed in frequencies of both types of alterations, only genetic alteration showed distinctive features among the three types of genomes, with one hybrid (N/9) being exceptionally labile. Surprisingly, difference in genetic alteration frequencies between the pair of reciprocal F1 hybrids is much greater than that between the two pure-line subspecies. Difference also exists in the pair of reciprocal tetraploids, but is to a less extent than that between the hybrids. The steady-state transcript abundance of genes involved in DNA repair and DNA methylation was significantly altered in both calli and regenerants, and some of which were correlated with the genetic and/or epigenetic alterations. Our results, based on molecular marker analysis of ca. 1,000 genomic loci, document that genetic alteration is the major cause of somaclonal variation in rice

  11. Rare endocrine cancers have novel genetic alterations

    Science.gov (United States)

    A molecular characterization of adrenocortical carcinoma, a rare cancer of the adrenal cortex, analyzed 91 cases for alterations in the tumor genomes and identified several novel genetic mutations as likely mechanisms driving the disease as well as whole genome doubling as a probable driver of the disease.

  12. Critical roles for a genetic code alteration in the evolution of the genus Candida.

    Science.gov (United States)

    Silva, Raquel M; Paredes, João A; Moura, Gabriela R; Manadas, Bruno; Lima-Costa, Tatiana; Rocha, Rita; Miranda, Isabel; Gomes, Ana C; Koerkamp, Marian J G; Perrot, Michel; Holstege, Frank C P; Boucherie, Hélian; Santos, Manuel A S

    2007-10-31

    During the last 30 years, several alterations to the standard genetic code have been discovered in various bacterial and eukaryotic species. Sense and nonsense codons have been reassigned or reprogrammed to expand the genetic code to selenocysteine and pyrrolysine. These discoveries highlight unexpected flexibility in the genetic code, but do not elucidate how the organisms survived the proteome chaos generated by codon identity redefinition. In order to shed new light on this question, we have reconstructed a Candida genetic code alteration in Saccharomyces cerevisiae and used a combination of DNA microarrays, proteomics and genetics approaches to evaluate its impact on gene expression, adaptation and sexual reproduction. This genetic manipulation blocked mating, locked yeast in a diploid state, remodelled gene expression and created stress cross-protection that generated adaptive advantages under environmental challenging conditions. This study highlights unanticipated roles for codon identity redefinition during the evolution of the genus Candida, and strongly suggests that genetic code alterations create genetic barriers that speed up speciation.

  13. A genetic code alteration is a phenotype diversity generator in the human pathogen Candida albicans.

    Directory of Open Access Journals (Sweden)

    Isabel Miranda

    Full Text Available BACKGROUND: The discovery of genetic code alterations and expansions in both prokaryotes and eukaryotes abolished the hypothesis of a frozen and universal genetic code and exposed unanticipated flexibility in codon and amino acid assignments. It is now clear that codon identity alterations involve sense and non-sense codons and can occur in organisms with complex genomes and proteomes. However, the biological functions, the molecular mechanisms of evolution and the diversity of genetic code alterations remain largely unknown. In various species of the genus Candida, the leucine CUG codon is decoded as serine by a unique serine tRNA that contains a leucine 5'-CAG-3'anticodon (tRNA(CAG(Ser. We are using this codon identity redefinition as a model system to elucidate the evolution of genetic code alterations. METHODOLOGY/PRINCIPAL FINDINGS: We have reconstructed the early stages of the Candida genetic code alteration by engineering tRNAs that partially reverted the identity of serine CUG codons back to their standard leucine meaning. Such genetic code manipulation had profound cellular consequences as it exposed important morphological variation, altered gene expression, re-arranged the karyotype, increased cell-cell adhesion and secretion of hydrolytic enzymes. CONCLUSION/SIGNIFICANCE: Our study provides the first experimental evidence for an important role of genetic code alterations as generators of phenotypic diversity of high selective potential and supports the hypothesis that they speed up evolution of new phenotypes.

  14. Genetic Alterations in Hungarian Patients with Papillary Thyroid Cancer.

    Science.gov (United States)

    Tobiás, Bálint; Halászlaki, Csaba; Balla, Bernadett; Kósa, János P; Árvai, Kristóf; Horváth, Péter; Takács, István; Nagy, Zsolt; Horváth, Evelin; Horányi, János; Járay, Balázs; Székely, Eszter; Székely, Tamás; Győri, Gabriella; Putz, Zsuzsanna; Dank, Magdolna; Valkusz, Zsuzsanna; Vasas, Béla; Iványi, Béla; Lakatos, Péter

    2016-01-01

    The incidence of thyroid cancers is increasing worldwide. Some somatic oncogene mutations (BRAF, NRAS, HRAS, KRAS) as well as gene translocations (RET/PTC, PAX8/PPAR-gamma) have been associated with the development of thyroid cancer. In our study, we analyzed these genetic alterations in 394 thyroid tissue samples (197 papillary carcinomas and 197 healthy). The somatic mutations and translocations were detected by Light Cycler melting method and Real-Time Polymerase Chain Reaction techniques, respectively. In tumorous samples, 86 BRAF (44.2%), 5 NRAS (3.1%), 2 HRAS (1.0%) and 1 KRAS (0.5%) mutations were found, as well as 9 RET/PTC1 (4.6%) and 1 RET/PTC3 (0.5%) translocations. No genetic alteration was seen in the non tumorous control thyroid tissues. No correlation was detected between the genetic variants and the pathological subtypes of papillary cancer as well as the severity of the disease. Our results are only partly concordant with the data found in the literature.

  15. Genetic alterations during radiation-induced carcinogenesis

    International Nuclear Information System (INIS)

    Kodama, Seiji

    1995-01-01

    This paper reviews radiation-induced genetic alterations and its carcinogenesis, focusing on the previous in vitro assay outcome. A colony formation assay using Syrian hamster fetal cells and focus formation assay using mouse C3H10T1/2 cells are currently available to find malignant transformation of cells. Such in vitro assays has proposed the hypothesis that radiation-induced carcinogenesis arises from at least two-stage processes; i.e., that an early step induced by irradiation plays an important role in promoting the potential to cause the subsequent mutation. A type of genetic instability induced by radiation results in a persistently elevated frequency of spontaneous mutations, so-called the phenomenon of delayed reproductive death. One possible mechanism by which genetic instability arises has been shown to be due to the development of abnormality in the gene group involved in the maintenance mechanism of genome stability. Another possibility has also been shown to stem from the loss of telomere (the extremities of a chromosome). The importance of search for radiation-induced genetic instability is emphasized in view of the elucidation of carcinogenesis. (N.K.)

  16. Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease.

    Directory of Open Access Journals (Sweden)

    Katrina Soderquest

    2017-02-01

    Full Text Available The polarization of CD4+ T cells into distinct T helper cell lineages is essential for protective immunity against infection, but aberrant T cell polarization can cause autoimmunity. The transcription factor T-bet (TBX21 specifies the Th1 lineage and represses alternative T cell fates. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs that may be causative for autoimmune diseases. The majority of these polymorphisms are located within non-coding distal regulatory elements. It is considered that these genetic variants contribute to disease by altering the binding of regulatory proteins and thus gene expression, but whether these variants alter the binding of lineage-specifying transcription factors has not been determined. Here, we show that SNPs associated with the mucosal inflammatory diseases Crohn's disease, ulcerative colitis (UC and celiac disease, but not rheumatoid arthritis or psoriasis, are enriched at T-bet binding sites. Furthermore, we identify disease-associated variants that alter T-bet binding in vitro and in vivo. ChIP-seq for T-bet in individuals heterozygous for the celiac disease-associated SNPs rs1465321 and rs2058622 and the IBD-associated SNPs rs1551398 and rs1551399, reveals decreased binding to the minor disease-associated alleles. Furthermore, we show that rs1465321 is an expression quantitative trait locus (eQTL for the neighboring gene IL18RAP, with decreased T-bet binding associated with decreased expression of this gene. These results suggest that genetic polymorphisms may predispose individuals to mucosal autoimmune disease through alterations in T-bet binding. Other disease-associated variants may similarly act by modulating the binding of lineage-specifying transcription factors in a tissue-selective and disease-specific manner.

  17. The contribution of genetics and environment to obesity.

    Science.gov (United States)

    Albuquerque, David; Nóbrega, Clévio; Manco, Licínio; Padez, Cristina

    2017-09-01

    Obesity is a global health problem mainly attributed to lifestyle changes such as diet, low physical activity or socioeconomics factors. However, several evidences consistently showed that genetics contributes significantly to the weight-gain susceptibility. A systematic literature search of most relevant original, review and meta-analysis, restricted to English was conducted in PubMed, Web of Science and Google scholar up to May 2017 concerning the contribution of genetics and environmental factors to obesity. Several evidences suggest that obesogenic environments contribute to the development of an obese phenotype. However, not every individual from the same population, despite sharing the same obesogenic environment, develop obesity. After more than 10 years of investigation on the genetics of obesity, the variants found associated with obesity represent only 3% of the estimated BMI-heritability, which is around 47-80%. Moreover, genetic factors per se were unable to explain the rapid spread of obesity prevalence. The integration of multi-omics data enables scientists having a better picture and to elucidate unknown pathways contributing to obesity. New studies based on case-control or gene candidate approach will be important to identify new variants associated with obesity susceptibility and consequently unveiling its genetic architecture. This will lead to an improvement of our understanding about underlying mechanisms involved in development and origin of the actual obesity epidemic. The integration of several omics will also provide insights about the interplay between genes and environments contributing to the obese phenotype. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  18. DNA Fingerprinting Techniques for the Analysis of Genetic and Epigenetic Alterations in Colorectal Cancer

    OpenAIRE

    Samuelsson, Johanna K.; Alonso, Sergio; Yamamoto, Fumiichiro; Perucho, Manuel

    2010-01-01

    Genetic somatic alterations are fundamental hallmarks of cancer. In addition to point and other small mutations targeting cancer genes, solid tumors often exhibit aneuploidy as well as multiple chromosomal rearrangements of large fragments of the genome. Whether somatic chromosomal alterations and aneuploidy are a driving force or a mere consequence of tumorigenesis remains controversial. Recently it became apparent that not only genetic but also epigenetic alterations play a major role in ca...

  19. Extensive genetic and DNA methylation variation contribute to heterosis in triploid loquat hybrids.

    Science.gov (United States)

    Liu, Chao; Wang, Mingbo; Wang, Lingli; Guo, Qigao; Liang, Guolu

    2018-04-24

    We aim to overcome the unclear origin of the loquat and elucidate the heterosis mechanism of the triploid loquat. Here we investigated the genetic and epigenetic variations between the triploid plant and its parental lines using amplified fragment length polymorphism (AFLP) and methylation-sensitive amplified fragment length polymorphism (MSAP) analyses. We show that in addition to genetic variations, extensive DNA methylation variation occurred during the formation process of triploid loquat, with the triploid hybrid having increased DNA methylation compared to the parents. Furthermore, a correlation existed between genetic variation and DNA methylation remodeling, suggesting that genome instability may lead to DNA methylation variation or vice versa. Sequence analysis of the MSAP bands revealed that over 53% of them overlap with protein-coding genes, which may indicate a functional role of the differential DNA methylation in gene regulation and hence heterosis phenotypes. Consistent with this, the genetic and epigenetic alterations were associated closely to the heterosis phenotypes of triploid loquat, and this association varied for different traits. Our results suggested that the formation of triploid is accompanied by extensive genetic and DNA methylation variation, and these changes contribute to the heterosis phenotypes of the triploid loquats from the two cross lines.

  20. [Epigenetic alterations in acute lymphoblastic leukemia].

    Science.gov (United States)

    Navarrete-Meneses, María Del Pilar; Pérez-Vera, Patricia

    Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. It is well-known that genetic alterations constitute the basis for the etiology of ALL. However, genetic abnormalities are not enough for the complete development of the disease, and additional alterations such as epigenetic modifications are required. Such alterations, like DNA methylation, histone modifications, and noncoding RNA regulation have been identified in ALL. DNA hypermethylation in promoter regions is one of the most frequent epigenetic modifications observed in ALL. This modification frequently leads to gene silencing in tumor suppressor genes, and in consequence, contributes to leukemogenesis. Alterations in histone remodeling proteins have also been detected in ALL, such as the overexpression of histone deacetylases enzymes, and alteration of acetyltransferases and methyltransferases. ALL also shows alteration in the expression of miRNAs, and in consequence, the modification in the expression of their target genes. All of these epigenetic modifications are key events in the malignant transformation since they lead to the deregulation of oncogenes as BLK, WNT5B and WISP1, and tumor suppressors such as FHIT, CDKN2A, CDKN2B, and TP53, which alter fundamental cellular processes and potentially lead to the development of ALL. Both genetic and epigenetic alterations contribute to the development and evolution of ALL. Copyright © 2017 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

  1. Parental Virtue and Prenatal Genetic Alteration Research.

    Science.gov (United States)

    Tonkens, Ryan

    2015-12-01

    Although the philosophical literature on the ethics of human prenatal genetic alteration (PGA) purports to inform us about how to act, it rarely explicitly recognizes the perspective of those who will be making the PGA decision in practice. Here I approach the ethics of PGA from a distinctly virtue-based perspective, taking seriously what it means to be a good parent making this decision for one's child. From this perspective, I generate a sound verdict on the moral standing of human PGA (research): given the current state of the art, good parents have compelling reason not to consent to PGA (research) for their child, especially as part of the first wave(s) of PGA research participants and especially for non-medically oriented purposes. This is because doing otherwise is inconsistent with a plausible and defensible understanding of virtuous parenting and parental virtues, founded on a genuine concern for promoting the overall flourishing of the eventual child. In essence, given the current and foreseeable state of the art, parents who allow prenatal genetic alteration of their children are less-than-virtuous parents to those children, even in cases where they have a right to do so and even if PGA turns out to be beneficial to the eventual child.

  2. Macro-environment of breast carcinoma: frequent genetic alterations in the normal appearing skins of patients with breast cancer.

    Science.gov (United States)

    Moinfar, Farid; Beham, Alfred; Friedrich, Gerhard; Deutsch, Alexander; Hrzenjak, Andelko; Luschin, Gero; Tavassoli, Fattaneh A

    2008-05-01

    Genetic abnormalities in microenvironmental tissues with subsequent alterations of reciprocal interactions between epithelial and mesenchymal cells play a key role in the breast carcinogenesis. Although a few reports have demonstrated abnormal fibroblastic functions in normal-appearing fibroblasts taken from the skins of breast cancer patients, the genetic basis of this phenomenon and its implication for carcinogenesis are unexplored. We analyzed 12 mastectomy specimens showing invasive ductal carcinomas. In each case, morphologically normal epidermis and dermis, carcinoma, normal stroma close to carcinoma, and stroma at a distant from carcinoma were microdissected. Metastatic-free lymphatic tissues from lymph nodes served as a control. Using PCR, DNA extracts were examined with 11 microsatellite markers known for a high frequency of allelic imbalances in breast cancer. Losses of heterozygosity and/or microsatellite instability were detected in 83% of the skin samples occurring either concurrently with or independently from the cancerous tissues. In 80% of these cases at least one microsatellite marker displayed loss of heterozygosity or microsatellite instability in the skin, which was absent in carcinoma. A total of 41% of samples showed alterations of certain loci observed exclusively in the carcinoma but not in the skin compartments. Our study suggests that breast cancer is not just a localized genetic disorder, but rather part of a larger field of genetic alterations/instabilities affecting multiple cell populations in the organ with various cellular elements, ultimately contributing to the manifestation of the more 'localized' carcinoma. These data indicate that more global assessment of tumor micro- and macro-environment is crucial for our understanding of breast carcinogenesis.

  3. [Colorectal cancer (CCR): genetic and molecular alterations].

    Science.gov (United States)

    Juárez-Vázquez, Clara Ibet; Rosales-Reynoso, Mónica Alejandra

    2014-01-01

    The aim of this review is to present a genetic and molecular overview of colorectal carcinogenesis (sporadic and hereditary origin) as a multistage process, where there are a number of molecular mechanisms associated with the development of colorectal cancer and genomic instability that allows the accumulation of mutations in proto-oncogenes and tumor suppressor genes, chromosomal instability, and methylation and microsatellite instability, and the involvement of altered expression of microRNAs' prognosis factors.

  4. DNA fingerprinting techniques for the analysis of genetic and epigenetic alterations in colorectal cancer.

    Science.gov (United States)

    Samuelsson, Johanna K; Alonso, Sergio; Yamamoto, Fumiichiro; Perucho, Manuel

    2010-11-10

    Genetic somatic alterations are fundamental hallmarks of cancer. In addition to point and other small mutations targeting cancer genes, solid tumors often exhibit aneuploidy as well as multiple chromosomal rearrangements of large fragments of the genome. Whether somatic chromosomal alterations and aneuploidy are a driving force or a mere consequence of tumorigenesis remains controversial. Recently it became apparent that not only genetic but also epigenetic alterations play a major role in carcinogenesis. Epigenetic regulation mechanisms underlie the maintenance of cell identity crucial for development and differentiation. These epigenetic regulatory mechanisms have been found substantially altered during cancer development and progression. In this review, we discuss approaches designed to analyze genetic and epigenetic alterations in colorectal cancer, especially DNA fingerprinting approaches to detect changes in DNA copy number and methylation. DNA fingerprinting techniques, despite their modest throughput, played a pivotal role in significant discoveries in the molecular basis of colorectal cancer. The aim of this review is to revisit the fingerprinting technologies employed and the oncogenic processes that they unveiled. 2010 Elsevier B.V. All rights reserved.

  5. Estimating the contribution of genetic variants to difference in incidence of disease between population groups

    Science.gov (United States)

    Moonesinghe, Ramal; Ioannidis, John PA; Flanders, W Dana; Yang, Quanhe; Truman, Benedict I; Khoury, Muin J

    2012-01-01

    Genome-wide association studies have identified multiple genetic susceptibility variants to several complex human diseases. However, risk-genotype frequency at loci showing robust associations might differ substantially among different populations. In this paper, we present methods to assess the contribution of genetic variants to the difference in the incidence of disease between different population groups for different scenarios. We derive expressions for the contribution of a single genetic variant, multiple genetic variants, and the contribution of the joint effect of a genetic variant and an environmental factor to the difference in the incidence of disease. The contribution of genetic variants to the difference in incidence increases with increasing difference in risk-genotype frequency, but declines with increasing difference in incidence between the two populations. The contribution of genetic variants also increases with increasing relative risk and the contribution of joint effect of genetic and environmental factors increases with increasing relative risk of the gene–environmental interaction. The contribution of genetic variants to the difference in incidence between two populations can be expressed as a function of the population attributable risks of the genetic variants in the two populations. The contribution of a group of genetic variants to the disparity in incidence of disease could change considerably by adding one more genetic variant to the group. Any estimate of genetic contribution to the disparity in incidence of disease between two populations at this stage seems to be an elusive goal. PMID:22333905

  6. Estimating the contribution of genetic variants to difference in incidence of disease between population groups.

    Science.gov (United States)

    Moonesinghe, Ramal; Ioannidis, John P A; Flanders, W Dana; Yang, Quanhe; Truman, Benedict I; Khoury, Muin J

    2012-08-01

    Genome-wide association studies have identified multiple genetic susceptibility variants to several complex human diseases. However, risk-genotype frequency at loci showing robust associations might differ substantially among different populations. In this paper, we present methods to assess the contribution of genetic variants to the difference in the incidence of disease between different population groups for different scenarios. We derive expressions for the contribution of a single genetic variant, multiple genetic variants, and the contribution of the joint effect of a genetic variant and an environmental factor to the difference in the incidence of disease. The contribution of genetic variants to the difference in incidence increases with increasing difference in risk-genotype frequency, but declines with increasing difference in incidence between the two populations. The contribution of genetic variants also increases with increasing relative risk and the contribution of joint effect of genetic and environmental factors increases with increasing relative risk of the gene-environmental interaction. The contribution of genetic variants to the difference in incidence between two populations can be expressed as a function of the population attributable risks of the genetic variants in the two populations. The contribution of a group of genetic variants to the disparity in incidence of disease could change considerably by adding one more genetic variant to the group. Any estimate of genetic contribution to the disparity in incidence of disease between two populations at this stage seems to be an elusive goal.

  7. Sporadic inclusion body myositis: the genetic contributions to the pathogenesis

    Science.gov (United States)

    2014-01-01

    Sporadic inclusion body myositis (sIBM) is the commonest idiopathic inflammatory muscle disease in people over 50 years old. It is characterized by slowly progressive muscle weakness and atrophy, with typical pathological changes of inflammation, degeneration and mitochondrial abnormality in affected muscle fibres. The cause(s) of sIBM are still unknown, but are considered complex, with the contribution of multiple factors such as environmental triggers, ageing and genetic susceptibility. This review summarizes the current understanding of the genetic contributions to sIBM and provides some insights for future research in this mysterious disease with the advantage of the rapid development of advanced genetic technology. An international sIBM genetic study is ongoing and whole-exome sequencing will be applied in a large cohort of sIBM patients with the aim of unravelling important genetic risk factors for sIBM. PMID:24948216

  8. Genetic and epigenetic alterations induced by different levels of rye genome integration in wheat recipient.

    Science.gov (United States)

    Zheng, X L; Zhou, J P; Zang, L L; Tang, A T; Liu, D Q; Deng, K J; Zhang, Y

    2016-06-17

    The narrow genetic variation present in common wheat (Triticum aestivum) varieties has greatly restricted the improvement of crop yield in modern breeding systems. Alien addition lines have proven to be an effective means to broaden the genetic diversity of common wheat. Wheat-rye addition lines, which are the direct bridge materials for wheat improvement, have been wildly used to produce new wheat cultivars carrying alien rye germplasm. In this study, we investigated the genetic and epigenetic alterations in two sets of wheat-rye disomic addition lines (1R-7R) and the corresponding triticales. We used expressed sequence tag-simple sequence repeat, amplified fragment length polymorphism, and methylation-sensitive amplification polymorphism analyses to analyze the effects of the introduction of alien chromosomes (either the entire genome or sub-genome) to wheat genetic background. We found obvious and diversiform variations in the genomic primary structure, as well as alterations in the extent and pattern of the genomic DNA methylation of the recipient. Meanwhile, these results also showed that introduction of different rye chromosomes could induce different genetic and epigenetic alterations in its recipient, and the genetic background of the parents is an important factor for genomic and epigenetic variation induced by alien chromosome addition.

  9. Estimating the relative contributions of maternal genetic, paternal genetic and intrauterine factors to offspring birth weight and head circumference.

    Science.gov (United States)

    Rice, Frances; Thapar, Anita

    2010-07-01

    Genetic factors and the prenatal environment contribute to birth weight. However, very few types of study design can disentangle their relative contribution. To examine maternal genetic and intrauterine contributions to offspring birth weight and head circumference. To compare the contribution of maternal and paternal genetic effects. Mothers and fathers were either genetically related or unrelated to their offspring who had been conceived by in vitro fertilization. 423 singleton full term offspring, of whom 262 were conceived via homologous IVF (both parents related), 66 via sperm donation (mother only related) and 95 via egg donation (father only related). Maternal weight at antenatal booking, current weight and maternal height. Paternal current weight and height were all predictors. Infant birth weight and head circumference were outcomes. Genetic relatedness was the main contributing factor between measures of parental weight and offspring birth weight as correlations were only significant when the parent was related to the child. However, there was a contribution of the intrauterine environment to the association between maternal height and both infant birth weight and infant head circumference as these were significant even when mothers were unrelated to their child. Both maternal and paternal genes made contributions to infant birth weight. Maternal height appeared to index a contribution of the intrauterine environment to infant growth and gestational age. Results suggested a possible biological interaction between the intrauterine environment and maternal inherited characteristics which suppresses the influence of paternal genes. 2010 Elsevier Ltd. All rights reserved.

  10. Genetic Variation in Choline-Metabolizing Enzymes Alters Choline Metabolism in Young Women Consuming Choline Intakes Meeting Current Recommendations

    Directory of Open Access Journals (Sweden)

    Ariel B. Ganz

    2017-01-01

    Full Text Available Single nucleotide polymorphisms (SNPs in choline metabolizing genes are associated with disease risk and greater susceptibility to organ dysfunction under conditions of dietary choline restriction. However, the underlying metabolic signatures of these variants are not well characterized and it is unknown whether genotypic differences persist at recommended choline intakes. Thus, we sought to determine if common genetic risk factors alter choline dynamics in pregnant, lactating, and non-pregnant women consuming choline intakes meeting and exceeding current recommendations. Women (n = 75 consumed 480 or 930 mg choline/day (22% as a metabolic tracer, choline-d9 for 10–12 weeks in a controlled feeding study. Genotyping was performed for eight variant SNPs and genetic differences in metabolic flux and partitioning of plasma choline metabolites were evaluated using stable isotope methodology. CHKA rs10791957, CHDH rs9001, CHDH rs12676, PEMT rs4646343, PEMT rs7946, FMO3 rs2266782, SLC44A1 rs7873937, and SLC44A1 rs3199966 altered the use of choline as a methyl donor; CHDH rs9001 and BHMT rs3733890 altered the partitioning of dietary choline between betaine and phosphatidylcholine synthesis via the cytidine diphosphate (CDP-choline pathway; and CHKA rs10791957, CHDH rs12676, PEMT rs4646343, PEMT rs7946 and SLC44A1 rs7873937 altered the distribution of dietary choline between the CDP-choline and phosphatidylethanolamine N-methyltransferase (PEMT denovo pathway. Such metabolic differences may contribute to disease pathogenesis and prognosis over the long-term.

  11. Generation of Infectious Poliovirus with Altered Genetic Information from Cloned cDNA.

    Science.gov (United States)

    Bujaki, Erika

    2016-01-01

    The effect of specific genetic alterations on virus biology and phenotype can be studied by a great number of available assays. The following method describes the basic protocol to generate infectious poliovirus with altered genetic information from cloned cDNA in cultured cells.The example explained here involves generation of a recombinant poliovirus genome by simply replacing a portion of the 5' noncoding region with a synthetic gene by restriction cloning. The vector containing the full length poliovirus genome and the insert DNA with the known mutation(s) are cleaved for directional cloning, then ligated and transformed into competent bacteria. The recombinant plasmid DNA is then propagated in bacteria and transcribed to RNA in vitro before RNA transfection of cultured cells is performed. Finally, viral particles are recovered from the cell culture.

  12. Genetic transformation of rare Verbascum eriophorum Godr. plants and metabolic alterations revealed by NMR-based metabolomics.

    Science.gov (United States)

    Marchev, Andrey; Yordanova, Zhenya; Alipieva, Kalina; Zahmanov, Georgi; Rusinova-Videva, Snezhana; Kapchina-Toteva, Veneta; Simova, Svetlana; Popova, Milena; Georgiev, Milen I

    2016-09-01

    To develop a protocol to transform Verbascum eriophorum and to study the metabolic differences between mother plants and hairy root culture by applying NMR and processing the datasets with chemometric tools. Verbascum eriophorum is a rare species with restricted distribution, which is poorly studied. Agrobacterium rhizogenes-mediated genetic transformation of V. eriophorum and hairy root culture induction are reported for the first time. To determine metabolic alterations, V. eriophorum mother plants and relevant hairy root culture were subjected to comprehensive metabolomic analyses, using NMR (1D and 2D). Metabolomics data, processed using chemometric tools (and principal component analysis in particular) allowed exploration of V. eriophorum metabolome and have enabled identification of verbascoside (by means of 2D-TOCSY NMR) as the most abundant compound in hairy root culture. Metabolomics data contribute to the elucidation of metabolic alterations after T-DNA transfer to the host V. eriophorum genome and the development of hairy root culture for sustainable bioproduction of high value verbascoside.

  13. The genetic alteration of retinoblastoma gene in esophageal cancer

    International Nuclear Information System (INIS)

    Cho, Jae Il; Shim, Yung Mok; Kim, Chang Min

    1994-12-01

    Retinoblastoma(RB) gene is the prototype of tumor suppressor gene and it's alteration have been frequently observed in a large number of human tumors. To investigate the role of RB in esophageal cancer, we studied 36 esophageal cancer tissues with Southern blot analysis to detect gross LOH and PCR-SSCP method to find minute LOH and mutation, if any. In the cases with abnormalities, the nucleotide sequence analysis was performed. Allelic loss of chromosome 13q14 occurred in 20 out of 32 informative cases (62.5%) by Southern analysis. Furthermore, PCR-LOH added three positive cases. Mobility shift by PCR-SSCP was observed in one case at exon 22, which showed 1 bp deletion in codon 771 of RB gene resulting in frame shift mutation. Besides, nine PCR-band alteration in tumor tissue compared with normal tissue were observed in exon 14 and 22, but mutation was not found on sequencing analysis suggesting the epigenetic alteration in tumor tissue. Analysis of the clinical data did not show any difference depending upon RB alteration. However, the total incidence of RB gene may play an important role in the development of esophageal cancer. The main genetic alteration of RB gene was deletion detected by Southern blot and one bp deletion leading to frame shift was also observed. 8 figs, 5 tabs. (Author)

  14. The genetic alteration of retinoblastoma gene in esophageal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Jae Il; Shim, Yung Mok; Kim, Chang Min [Korea Cancer Center Hospital of Korea Atomic Energy Research Institute, Taejon (Korea, Republic of)

    1994-12-01

    Retinoblastoma(RB) gene is the prototype of tumor suppressor gene and it`s alteration have been frequently observed in a large number of human tumors. To investigate the role of RB in esophageal cancer, we studied 36 esophageal cancer tissues with Southern blot analysis to detect gross LOH and PCR-SSCP method to find minute LOH and mutation, if any. In the cases with abnormalities, the nucleotide sequence analysis was performed. Allelic loss of chromosome 13q14 occurred in 20 out of 32 informative cases (62.5%) by Southern analysis. Furthermore, PCR-LOH added three positive cases. Mobility shift by PCR-SSCP was observed in one case at exon 22, which showed 1 bp deletion in codon 771 of RB gene resulting in frame shift mutation. Besides, nine PCR-band alteration in tumor tissue compared with normal tissue were observed in exon 14 and 22, but mutation was not found on sequencing analysis suggesting the epigenetic alteration in tumor tissue. Analysis of the clinical data did not show any difference depending upon RB alteration. However, the total incidence of RB gene may play an important role in the development of esophageal cancer. The main genetic alteration of RB gene was deletion detected by Southern blot and one bp deletion leading to frame shift was also observed. 8 figs, 5 tabs. (Author).

  15. Integrative analysis reveals relationships of genetic and epigenetic alterations in osteosarcoma.

    Directory of Open Access Journals (Sweden)

    Stine H Kresse

    Full Text Available BACKGROUND: Osteosarcomas are the most common non-haematological primary malignant tumours of bone, and all conventional osteosarcomas are high-grade tumours showing complex genomic aberrations. We have integrated genome-wide genetic and epigenetic profiles from the EuroBoNeT panel of 19 human osteosarcoma cell lines based on microarray technologies. PRINCIPAL FINDINGS: The cell lines showed complex patterns of DNA copy number changes, where genomic copy number gains were significantly associated with gene-rich regions and losses with gene-poor regions. By integrating the datasets, 350 genes were identified as having two types of aberrations (gain/over-expression, hypo-methylation/over-expression, loss/under-expression or hyper-methylation/under-expression using a recurrence threshold of 6/19 (>30% cell lines. The genes showed in general alterations in either DNA copy number or DNA methylation, both within individual samples and across the sample panel. These 350 genes are involved in embryonic skeletal system development and morphogenesis, as well as remodelling of extracellular matrix. The aberrations of three selected genes, CXCL5, DLX5 and RUNX2, were validated in five cell lines and five tumour samples using PCR techniques. Several genes were hyper-methylated and under-expressed compared to normal osteoblasts, and expression could be reactivated by demethylation using 5-Aza-2'-deoxycytidine treatment for four genes tested; AKAP12, CXCL5, EFEMP1 and IL11RA. Globally, there was as expected a significant positive association between gain and over-expression, loss and under-expression as well as hyper-methylation and under-expression, but gain was also associated with hyper-methylation and under-expression, suggesting that hyper-methylation may oppose the effects of increased copy number for detrimental genes. CONCLUSIONS: Integrative analysis of genome-wide genetic and epigenetic alterations identified dependencies and relationships between

  16. Population-based familial aggregation of eosinophilic esophagitis suggests a genetic contribution.

    Science.gov (United States)

    Allen-Brady, Kristina; Firszt, Rafael; Fang, John C; Wong, Jathine; Smith, Ken R; Peterson, Kathryn A

    2017-10-01

    Prior familial clustering studies have observed an increased risk of eosinophilic esophagitis (EoE) mostly among first-degree relatives, suggesting a genetic contribution to EoE, and twin studies have suggested a powerful contribution from environmental factors. This study sought to clarify the contribution of genetic factors to EoE through estimation of familial aggregation and risk of EoE in extended relatives. The Utah Population Database, a population-based genealogy resource linked to electronic medical records for health care systems across the state of Utah, was used to identify EoE cases and age, sex, and birthplace-matched controls at a 5:1 ratio. Logistic regression was used to determine the odds of EoE among relatives of EoE probands compared with the odds of EoE among relatives of controls. There were 4,423 EoE cases and 24,322 controls. The population-attributable risk of EoE was 31% (95% CI, 28% to 34%), suggesting a relatively strong genetic contribution. Risks of EoE were significantly increased among first-degree relatives (odds ratio [OR], 7.19; 95% CI, 5.65-9.14), particularly first-degree relatives of EoE cases diagnosed <18 years of age (OR, 16.3; 95% CI, 9.4-28.3); second-degree relatives (OR, 1.99; 95% CI, 1.49-2.65); and first cousins (OR, 1.35; 95% CI, 1.03-1.77), providing evidence of a genetic contribution. However, spouses of EoE probands were observed to be at increased risk of EoE (OR, 2.86; 95% CI, 1.31-6.25), suggesting either positive assortative mating or a shared environmental contribution to EoE. This study supports a significant genetic contribution to EoE as evidenced by increased risk of EoE in distant relatives. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  17. Genetic alterations of hepatocellular carcinoma by random amplified polymorphic DNA analysis and cloning sequencing of tumor differential DNA fragment

    Science.gov (United States)

    Xian, Zhi-Hong; Cong, Wen-Ming; Zhang, Shu-Hui; Wu, Meng-Chao

    2005-01-01

    AIM: To study the genetic alterations and their association with clinicopathological characteristics of hepatocellular carcinoma (HCC), and to find the tumor related DNA fragments. METHODS: DNA isolated from tumors and corresponding noncancerous liver tissues of 56 HCC patients was amplified by random amplified polymorphic DNA (RAPD) with 10 random 10-mer arbitrary primers. The RAPD bands showing obvious differences in tumor tissue DNA corresponding to that of normal tissue were separated, purified, cloned and sequenced. DNA sequences were analyzed and compared with GenBank data. RESULTS: A total of 56 cases of HCC were demonstrated to have genetic alterations, which were detected by at least one primer. The detestability of genetic alterations ranged from 20% to 70% in each case, and 17.9% to 50% in each primer. Serum HBV infection, tumor size, histological grade, tumor capsule, as well as tumor intrahepatic metastasis, might be correlated with genetic alterations on certain primers. A band with a higher intensity of 480 bp or so amplified fragments in tumor DNA relative to normal DNA could be seen in 27 of 56 tumor samples using primer 4. Sequence analysis of these fragments showed 91% homology with Homo sapiens double homeobox protein DUX10 gene. CONCLUSION: Genetic alterations are a frequent event in HCC, and tumor related DNA fragments have been found in this study, which may be associated with hepatocarcin-ogenesis. RAPD is an effective method for the identification and analysis of genetic alterations in HCC, and may provide new information for further evaluating the molecular mechanism of hepatocarcinogenesis. PMID:15996039

  18. Geology of gemstone deposit Ugljarevats (Central Serbia) and contributions to genetic model

    International Nuclear Information System (INIS)

    Kureshevicj, Lidija; Vushovicj, Olivera; Delicj-Nikolicj, Ivana

    2017-01-01

    Silica gemstone deposit Ugljarevats is situated within the ophiolite sequence of the Vardar zone central deep fault. Genetic processes of this deposit are connected to the Neogene calc-alkaline magmatic activity of the Vardar zone and hydrothermal activity triggered by it. Based on surface occurrences of listwenitized serpentinite containing silica mineralization, it can be inferred that the ore body is an elongated oval stock. Within the stock of hydrothermally altered serpentinite, the gemstone mineralization occurs as veins, stock works and irregular bodies. Present gemstone types include chalcedony varieties (jasper, colourless and greenish chalcedony, carnelian and sard) and opal (opalized serpentinite). Homogenous pieces are very rare. Most often, various types of silica are intimately intermixed and combined. The mineralization has formed in two distinct hydrothermal phases, apparently in close time succession. Jasper and coloured chalcedony (and rare magnesite) are the products of the first phase of hydro- thermal activity, while the colourless chalcedony is formed in the second phase. Newly discovered type of silica vein with central-symmetrical parallel banding gives new contributions to a genetic model, proving the precipitation process and its products are unpredictably changeable, heterogeneous and depending on the evolution of the local environment physico-chemical conditions, notably the contents of impurities and system's openness degree. (author)

  19. Network analysis of genomic alteration profiles reveals co-altered functional modules and driver genes for glioblastoma.

    Science.gov (United States)

    Gu, Yunyan; Wang, Hongwei; Qin, Yao; Zhang, Yujing; Zhao, Wenyuan; Qi, Lishuang; Zhang, Yuannv; Wang, Chenguang; Guo, Zheng

    2013-03-01

    The heterogeneity of genetic alterations in human cancer genomes presents a major challenge to advancing our understanding of cancer mechanisms and identifying cancer driver genes. To tackle this heterogeneity problem, many approaches have been proposed to investigate genetic alterations and predict driver genes at the individual pathway level. However, most of these approaches ignore the correlation of alteration events between pathways and miss many genes with rare alterations collectively contributing to carcinogenesis. Here, we devise a network-based approach to capture the cooperative functional modules hidden in genome-wide somatic mutation and copy number alteration profiles of glioblastoma (GBM) from The Cancer Genome Atlas (TCGA), where a module is a set of altered genes with dense interactions in the protein interaction network. We identify 7 pairs of significantly co-altered modules that involve the main pathways known to be altered in GBM (TP53, RB and RTK signaling pathways) and highlight the striking co-occurring alterations among these GBM pathways. By taking into account the non-random correlation of gene alterations, the property of co-alteration could distinguish oncogenic modules that contain driver genes involved in the progression of GBM. The collaboration among cancer pathways suggests that the redundant models and aggravating models could shed new light on the potential mechanisms during carcinogenesis and provide new indications for the design of cancer therapeutic strategies.

  20. Genetic and environmental contributions to hay fever among young adult twins

    DEFF Research Database (Denmark)

    Thomsen, Simon Francis; Suppli Ulrik, Charlotte; Kyvik, Kirsten Ohm

    2006-01-01

    environment, whereas the aetiology of 'sporadic' hay fever was mainly genetic. CONCLUSIONS: The susceptibility to develop hay fever is attributable to major genetic influences. However, effects of family environment and upbringing are also of importance in families where asthma is present. These results......BACKGROUND: The susceptibility to develop hay fever is putatively the result both of genetic and environmental causes. We estimated the significance and magnitude of genetic and environmental contributions to hay fever among young adult twins. METHODS: From the birth cohorts 1953-82 of The Danish...... effects accounted for 29% of the individual susceptibility to hay fever. The same genes contributed to the susceptibility to hay fever both in males and in females. In families with asthma, the susceptibility to develop hay fever was, in addition to genes, to a great extent ascribable to family...

  1. Genetic and Environmental Contributions to the Development of Childhood Aggression

    Science.gov (United States)

    Lubke, Gitta H.; McArtor, Daniel B.; Boomsma, Dorret I.; Bartels, Meike

    2018-01-01

    Longitudinal data from a large sample of twins participating in the Netherlands Twin Register (n = 42,827, age range 3-16) were analyzed to investigate the genetic and environmental contributions to childhood aggression. Genetic auto-regressive (simplex) models were used to assess whether the same genes are involved or whether new genes come into…

  2. Argentine Population Genetic Structure: Large Variance in Amerindian Contribution

    Science.gov (United States)

    Seldin, Michael F.; Tian, Chao; Shigeta, Russell; Scherbarth, Hugo R.; Silva, Gabriel; Belmont, John W.; Kittles, Rick; Gamron, Susana; Allevi, Alberto; Palatnik, Simon A.; Alvarellos, Alejandro; Paira, Sergio; Caprarulo, Cesar; Guillerón, Carolina; Catoggio, Luis J.; Prigione, Cristina; Berbotto, Guillermo A.; García, Mercedes A.; Perandones, Carlos E.; Pons-Estel, Bernardo A.; Alarcon-Riquelme, Marta E.

    2011-01-01

    Argentine population genetic structure was examined using a set of 78 ancestry informative markers (AIMs) to assess the contributions of European, Amerindian, and African ancestry in 94 individuals members of this population. Using the Bayesian clustering algorithm STRUCTURE, the mean European contribution was 78%, the Amerindian contribution was 19.4%, and the African contribution was 2.5%. Similar results were found using weighted least mean square method: European, 80.2%; Amerindian, 18.1%; and African, 1.7%. Consistent with previous studies the current results showed very few individuals (four of 94) with greater than 10% African admixture. Notably, when individual admixture was examined, the Amerindian and European admixture showed a very large variance and individual Amerindian contribution ranged from 1.5 to 84.5% in the 94 individual Argentine subjects. These results indicate that admixture must be considered when clinical epidemiology or case control genetic analyses are studied in this population. Moreover, the current study provides a set of informative SNPs that can be used to ascertain or control for this potentially hidden stratification. In addition, the large variance in admixture proportions in individual Argentine subjects shown by this study suggests that this population is appropriate for future admixture mapping studies. PMID:17177183

  3. Whole-genome and Transcriptome Sequencing of Prostate Cancer Identify New Genetic Alterations Driving Disease Progression

    DEFF Research Database (Denmark)

    Ren, Shancheng; Wei, Gong-Hong; Liu, Dongbing

    2018-01-01

    BACKGROUND: Global disparities in prostate cancer (PCa) incidence highlight the urgent need to identify genomic abnormalities in prostate tumors in different ethnic populations including Asian men. OBJECTIVE: To systematically explore the genomic complexity and define disease-driven genetic......-scale and comprehensive genomic data of prostate cancer from Asian population. Identification of these genetic alterations may help advance prostate cancer diagnosis, prognosis, and treatment....... alterations in PCa. DESIGN, SETTING, AND PARTICIPANTS: The study sequenced whole-genome and transcriptome of tumor-benign paired tissues from 65 treatment-naive Chinese PCa patients. Subsequent targeted deep sequencing of 293 PCa-relevant genes was performed in another cohort of 145 prostate tumors. OUTCOME...

  4. Additive Genetic Effects on Circulating Periostin Contribute to the Heritability of Bone Microstructure.

    Science.gov (United States)

    Bonnet, N; Biver, E; Durosier, C; Chevalley, T; Rizzoli, R; Ferrari, S

    2015-07-01

    Genetic factors account for 60-80% of the areal bone mineral density (aBMD) variance, whereas the heritability of bone microstructure is not clearly established. aBMD and microstructure are under the control of osteocytes, which regulate bone formation through the expression of molecules such as sclerostin (SOST) and periostin (POSTN). We hypothesized that additive genetic effects contribute to serum levels of SOST and POSTN and thereby to the individual variance of bone microstructure. In a retrospective analysis of 432 subjects from the Geneva Retiree Cohort age 64.9 ± 1.4 years and 96 of their offspring age 37.9 ± 5.7 years, we measured serum SOST (sSOST) and serum POSTN (sPOSTN), distal radius and tibia microstructure, hip and lumbar spine aBMD, and bone turnover markers, Heritability (h(2), %) was calculated as twice the slope of the regression (β) between parents and offspring. cPOSTN levels were significantly higher in men than women and in offspring than parents. h(2) values for bone microstructural traits ranged from 22-64% depending on the envelope (trabecular [Tb] or cortical [Ct]) and skeletal site (radius or tibia), whereas h(2) for sPOSTN and sSOST was 50% and 40%, respectively. sPOSTN was positively associated with Tb bone volume on total volume and Ct thickness, and negatively with Ct porosity. The associations for Ct parameters remain significant after adjustment for propetide of type-I procollagen, cross-linked telopeptide of type I collagen, femoral neck aBMD, sex or age. After adjustment of bone traits for sPOSTN, h(2) values decreased for several Tb and Ct bone parameters, but not for aBMD. In contrast, adjusting for sSOST did not alter h(2) values for bone traits. Additive genetic effects account for a substantial proportion of the individual variance of bone microstructure, sPOSTN, and sSOST. sPOSTN is largely inherited as a sex-related trait and carries an important contribution to the heritability of bone microstructure, indicating that

  5. Analysis of Genetic Diversity of Two Mangrove Species with Morphological Alterations in a Natural Environment

    Directory of Open Access Journals (Sweden)

    Catarina Fonseca Lira-Medeiros

    2015-04-01

    Full Text Available Mangrove is an ecosystem subjected to tide, salinity and nutrient variations. These conditions are stressful to most plants, except to mangrove plants that are well-adapted. However, many mangrove areas have extremely stressful conditions, such as salt marshes, and the plants nearby usually present morphological alterations. In Sepetiba Bay, two species of mangrove plants, Avicennia schaueriana and Laguncularia racemosa, have poor development near a salt marsh (SM compared to plants at the riverside (RS, which is considered a favorable habitat in mangroves. The level of genetic diversity and its possible correlation with the morphological divergence of SM and RS plants of both species were assessed by AFLP molecular markers. We found moderate genetic differentiation between A. schaueriana plants from SM and RS areas and depleted genetic diversity on SM plants. On the other hand, Laguncularia racemosa plants had no genetic differentiation between areas. It is possible that a limited gene flow among the studied areas might be acting more intensely on A. schaueriana plants, resulting in the observed genetic differentiation. The populations of Laguncularia racemosa appear to be well connected, as genetic differentiation was not significant between the SM and RS populations. Gene flow and genetic drift are acting on neutral genetic diversity of these two mangrove species in the studied areas, and the observed genetic differentiation of A. schaueriana plants might be correlated with its morphological variation. For L. racemosa, morphological alterations could be related to epigenetic phenomena or adaptive loci polymorphism that should be further investigated.

  6. Genetic and metabolic signals during acute enteric bacterial infection alter the microbiota and drive progression to chronic inflammatory disease

    Energy Technology Data Exchange (ETDEWEB)

    Kamdar, Karishma; Khakpour, Samira; Chen, Jingyu; Leone, Vanessa; Brulc, Jennifer; Mangatu, Thomas; Antonopoulos, Dionysios A.; Chang, Eugene B; Kahn, Stacy A.; Kirschner, Barbara S; Young, Glenn; DePaolo, R. William

    2016-01-13

    Chronic inflammatory disorders are thought to arise due to an interplay between predisposing host genetics and environmental factors. For example, the onset of inflammatory bowel disease is associated with enteric proteobacterial infection, yet the mechanistic basis for this association is unclear. We have shown previously that genetic defiency in TLR1 promotes acute enteric infection by the proteobacteria Yersinia enterocolitica. Examining that model further, we uncovered an altered cellular immune response that promotes the recruitment of neutrophils which in turn increases metabolism of the respiratory electron acceptor tetrathionate by Yersinia. These events drive permanent alterations in anti-commensal immunity, microbiota composition, and chronic inflammation, which persist long after Yersinia clearence. Deletion of the bacterial genes involved in tetrathionate respiration or treatment using targeted probiotics could prevent microbiota alterations and inflammation. Thus, acute infection can drive long term immune and microbiota alterations leading to chronic inflammatory disease in genetically predisposed individuals.

  7. Relationships between parenting and adolescent adjustment over time: genetic and environmental contributions.

    Science.gov (United States)

    Neiderhiser, J M; Reiss, D; Hetherington, E M; Plomin, R

    1999-05-01

    The predictive association between parenting and adolescent adjustment has been assumed to be environmental; however, genetic and environmental contributions have not been examined. This article represents one effort to examine these associations in which a genetically informative design was used. Participants were 395 families with adolescent siblings who participated in the Nonshared Environment in Adolescent Development (D. Reiss et al., 1994) project at 2 times of assessment, 3 years apart. There were 5 sibling types in 2 types of families: 63 identical twins, 75 fraternal twins, and 58 full siblings in nondivorced families and 95 full, 60 half, and 44 genetically unrelated siblings in stepfamilies. Results indicate that the cross-lagged associations between parental conflict-negativity and adolescent antisocial behavior and depressive symptoms can be explained primarily by genetic factors. These findings emphasize the need to recognize and examine the impact that adolescents have on parenting and the contribution of genetic factors to developmental change.

  8. [Gene geography of Chile: regional distribution of American, European and African genetic contributions].

    Science.gov (United States)

    Fuentes, Macarena; Pulgar, Iván; Gallo, Carla; Bortolini, María-Cátira; Canizales-Quinteros, Samuel; Bedoya, Gabriel; González-José, Rolando; Ruiz-Linares, Andrés; Rothhammer, Francisco

    2014-03-01

    The geographical distribution of genes plays a key role in genetic epidemiology. The Chilean population has three major stem groups (Native American, European and African). To estimate the regional rate of American, European and African admixture of the Chilean population. Forty single nucleotide polymorphisms (SNP´s) which exhibit substantially different frequencies between Amerindian populations (ancestry-informative markers or AIM´s), were genotyped in a sample of 923 Chilean participants to estimate individual genetic ancestry. The American, European and African individual average admixture estimates for the 15 Chilean Regions were relatively homogeneous and not statistically different. However, higher American components were found in northern and southern Chile and higher European components were found in central Chile. A negative correlation between African admixture and latitude was observed. On the average, American and European genetic contributions were similar and significantly higher than the African contribution. Weighted mean American, European and African genetic contributions of 44.34% ± 3 9%, 51.85% ± 5.44% and 3.81% ± 0.45%, were estimated. Fifty two percent of subjects harbor African genes. Individuals with Aymara and Mapuche surnames have an American admixture of 58.64% and 68.33%, respectively. Half of the Chilean population harbors African genes. Participants with Aymara and Mapuche surnames had a higher American genetic contribution than the general Chilean population. These results confirm the usefulness of surnames as a first approximation to determine genetic ancestry.

  9. Genetic alterations in B-cell non-Hodgkin's lymphoma

    Directory of Open Access Journals (Sweden)

    Magić Zvonko

    2005-01-01

    Full Text Available Background. Although the patients with diagnosed B-NHL are classified into the same disease stage on the basis of clinical, histopathological, and immunological parameters, they respond significantly different to the applied treatment. This points out the possibility that within the same group of lymphoma there are different diseases at molecular level. For that reason many studies deal with the detection of gene alterations in lymphomas to provide a better framework for diagnosis and treatment of these hematological malignancies. Aim. To define genetic alterations in the B-NHL with highest possibilities for diagnostic purposes and molecular detection of MRD. Methods. Formalin fixed and paraffin embedded lymph node tissues from 45 patients were examined by different PCR techniques for the presence of IgH and TCR γ gene rearrangement; K-ras and H-ras mutations; c-myc amplification and bcl-2 translocation. There were 34 cases of B-cell non-Hodgkin’s lymphoma (B-NHL, 5 cases of T-cell non-Hodgkin’s lymphoma (T-NHL and 6 cases of chronic lymphadenitis (CL. The mononuclear cell fraction of the peripheral blood of 12 patients with B-NHL was analyzed for the presence of monoclonality at the time of diagnosis and in 3 to 6 months time intervals after an autologous bone marrow transplantation (BMT. Results. The monoclonality of B-lymphocytes, as evidenced by DNA fragment length homogeneity, was detected in 88 % (30/34 of B-NHL, but never in CL, T-NHL, or in normal PBL. Bcl-2 translocation was detected in 7/31 (22.6% B-NHL specimens, c-myc amplification 9/31 (29%, all were more than doubled, K-ras mutations in 1/31 (3.23% and H-ras mutations in 2/31 (6.45% of the examined B-NHL samples. In the case of LC and normal PBL, however, these gene alterations were not detected. All the patients (12 with B-NHL had dominant clone of B-lymphocyte in the peripheral blood at the time of diagnosis while only in 2 of 12 patients MRD was detected 3 or 6 months after

  10. Genetic alterations during the progression of squamous cell carcinomas of the uterine cervix

    NARCIS (Netherlands)

    Kersemaekers, A. M.; van de Vijver, M. J.; Kenter, G. G.; Fleuren, G. J.

    1999-01-01

    Most cervical carcinomas appear to arise from cervical intraepithelial neoplasia (CIN) lesions. In addition to infection with high-risk human papilloma viruses, which is indicative of an increased risk of progression, alterations of oncogenes and tumor suppressor genes play a role. Genetic studies

  11. The Protective Effect of Minocycline in a Paraquat-Induced Parkinson's Disease Model in Drosophila is Modified in Altered Genetic Backgrounds

    Directory of Open Access Journals (Sweden)

    Arati A. Inamdar

    2012-01-01

    Full Text Available Epidemiological studies link the herbicide paraquat to increased incidence of Parkinson's disease (PD. We previously reported that Drosophila exposed to paraquat recapitulate PD symptoms, including region-specific degeneration of dopaminergic neurons. Minocycline, a tetracycline derivative, exerts ameliorative effects in neurodegenerative disease models, including Drosophila. We investigated whether our environmental toxin-based PD model could contribute to an understanding of cellular and genetic mechanisms of minocycline action and whether we could assess potential interference with these drug effects in altered genetic backgrounds. Cofeeding of minocycline with paraquat prolonged survival, rescued mobility defects, blocked generation of reactive oxygen species, and extended dopaminergic neuron survival, as has been reported previously for a genetic model of PD in Drosophila. We then extended this study to identify potential interactions of minocycline with genes regulating dopamine homeostasis that might modify protection against paraquat and found that deficits in GTP cyclohydrolase adversely affect minocycline rescue. We further performed genetic studies to identify signaling pathways that are necessary for minocycline protection against paraquat toxicity and found that mutations in the Drosophila genes that encode c-Jun N-terminal kinase (JNK and Akt/Protein kinase B block minocycline rescue.

  12. Population genetic dynamics of three-spined sticklebacks (Gasterosteus aculeatus) in anthropogenic altered habitats.

    Science.gov (United States)

    Scharsack, Joern P; Schweyen, Hannah; Schmidt, Alexander M; Dittmar, Janine; Reusch, Thorsten Bh; Kurtz, Joachim

    2012-06-01

    In industrialized and/or agriculturally used landscapes, inhabiting species are exposed to a variety of anthropogenic changes in their environments. Genetic diversity may be reduced if populations encounter founder events, bottlenecks, or isolation. Conversely, genetic diversity may increase if populations adapt to changes in selective regimes in newly created habitats. With the present study, genetic variability of 918 sticklebacks from 43 samplings (21.3 ± 3.8 per sample) at 36 locations from cultivated landscapes in Northwest Germany was analyzed at nine neutral microsatellite loci. To test if differentiation is influenced by habitat alterations, sticklebacks were collected from ancient running waters and adjacent artificial stagnant waters, from brooks with salt water inflow of anthropogenic and natural origin and adjacent freshwater sites. Overall population structure was dominated by isolation by distance (IBD), which was significant across all populations, and analysis of molecular variance (AMOVA) revealed that 10.6% of the variation was explained by river catchment area. Populations in anthropogenic modified habitats deviated from the general IBD structure and in the AMOVA, grouping by habitat type running/stagnant water explained 4.9% of variation and 1.4% of the variation was explained by salt-/freshwater habitat. Sticklebacks in salt-polluted water systems seem to exhibit elevated migratory activity between fresh- and saltwater habitats, reducing IBD. In other situations, populations showed distinct signs of genetic isolation, which in some locations was attributed to mechanical migration barriers, but in others to potential anthropogenic induced bottleneck or founder effects. The present study shows that anthropogenic habitat alterations may have diverse effects on the population genetic structure of inhabiting species. Depending on the type of habitat change, increased genetic differentiation, diversification, or isolation are possible consequences.

  13. A review of genetic factors contributing to the etiopathogenesis of anorectal malformations.

    Science.gov (United States)

    Khanna, Kashish; Sharma, Shilpa; Pabalan, Noel; Singh, Neetu; Gupta, D K

    2018-01-01

    Anorectal malformation (ARM) is a common congenital anomaly with a wide clinical spectrum. Recently, many genetic and molecular studies have been conducted worldwide highlighting the contribution of genetic factors in its etiology. We summarize the current literature on such genetic factors. Literature search was done using different combinations of terms related to genetics in anorectal malformations. From 2012 to June 2017, articles published in the English literature and studies conducted on human population were included. A paradigm shift was observed from the earlier studies concentrating on genetic aberrations in specific pathways to genome wide arrays exploring single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) in ARM patients. Rare CNVs (including 79 genes) and SNPs have been found to genetically contribute to ARM. Out of disrupted 79 genes one such putative gene is DKK4. Down regulation of CDX-1 gene has also been implicated in isolated ARM patients. In syndromic ARM de novo microdeletion at 17q12 and a few others have been identified. Major genetic aberrations proposed in the pathogenesis of ARM affect members of the Wnt, Hox (homebox) genes, Sonic hedgehog (Shh) and Gli2, Bmp4, Fgf and CDX1 signalling pathways; probable targets of future molecular gene therapy.

  14. Genetic Variant in Flavin-Containing Monooxygenase 3 Alters Lipid Metabolism in Laying Hens in a Diet-Specific Manner

    OpenAIRE

    Wang, Jing; Long, Cheng; Zhang, Haijun; Zhang, Yanan; Wang, Hao; Yue, Hongyuan; Wang, Xiaocui; Wu, Shugeng; Qi, Guanghai

    2016-01-01

    Genetic variant T329S in flavin-containing monooxygenase 3 (FMO3) impairs trimethylamine (TMA) metabolism in birds. The TMA metabolism that under complex genetic and dietary regulation, closely linked to cardiovascular disease risk. We determined whether the genetic defects in TMA metabolism may change other metabolic traits in birds, determined whether the genetic effects depend on diets, and to identify genes or gene pathways that underlie the metabolic alteration induced by genetic and die...

  15. Genetic contribution to patent ductus arteriosus in the premature newborn.

    Science.gov (United States)

    Bhandari, Vineet; Zhou, Gongfu; Bizzarro, Matthew J; Buhimschi, Catalin; Hussain, Naveed; Gruen, Jeffrey R; Zhang, Heping

    2009-02-01

    The most common congenital heart disease in the newborn population, patent ductus arteriosus, accounts for significant morbidity in preterm newborns. In addition to prematurity and environmental factors, we hypothesized that genetic factors play a significant role in this condition. The objective of this study was to quantify the contribution of genetic factors to the variance in liability for patent ductus arteriosus in premature newborns. A retrospective study (1991-2006) from 2 centers was performed by using zygosity data from premature twins born at Patent ductus arteriosus was diagnosed by echocardiography at each center. Mixed-effects logistic regression was used to assess the effect of specific covariates. Latent variable probit modeling was then performed to estimate the heritability of patent ductus arteriosus, and mixed-effects probit modeling was used to quantify the genetic component. We obtained data from 333 dizygotic twin pairs and 99 monozygotic twin pairs from 2 centers (Yale University and University of Connecticut). Data on chorioamnionitis, antenatal steroids, gestational age, body weight, gender, respiratory distress syndrome, patent ductus arteriosus, necrotizing enterocolitis, oxygen supplementation, and bronchopulmonary dysplasia were comparable between monozygotic and dizygotic twins. We found that gestational age, respiratory distress syndrome, and institution were significant covariates for patent ductus arteriosus. After controlling for specific covariates, genetic factors or the shared environment accounted for 76.1% of the variance in liability for patent ductus arteriosus. Preterm patent ductus arteriosus is highly familial (contributed to by genetic and environmental factors), with the effect being mainly environmental, after controlling for known confounders.

  16. Phytoplasmal infection derails genetically preprogrammed meristem fate and alters plant architecture

    OpenAIRE

    Wei, Wei; Davis, Robert Edward; Nuss, Donald L.; Zhao, Yan

    2013-01-01

    In higher plants, the destiny of apical meristems (stem cells) is specific organogenesis, which determines the pattern of plant growth, and therefore morphotype and fertility. We found that bacterial infection can derail the meristems from their genetically preprogrammed destiny, altering plant morphogenesis. We identified four abnormal growth patterns, symptoms, in tomato infected with a cell wall-less bacterium, and found that each symptom corresponds to a distinct phase in meristem fate de...

  17. Genetic Alterations of the Thrombopoietin/MPL/JAK2 Axis Impacting Megakaryopoiesis

    OpenAIRE

    Plo, Isabelle; Bellanné-Chantelot, Christine; Mosca, Matthieu; Mazzi, Stefania; Marty, Caroline; Vainchenker, William

    2017-01-01

    Megakaryopoiesis is an original and complex cell process which leads to the formation of platelets. The homeostatic production of platelets is mainly regulated and controlled by thrombopoietin (TPO) and the TPO receptor (MPL)/JAK2 axis. Therefore, any hereditary or acquired abnormality affecting this signaling axis can result in thrombocytosis or thrombocytopenia. Thrombocytosis can be due to genetic alterations that affect either the intrinsic MPL signaling through gain-of-function (GOF) act...

  18. The wild life at Chernobyl. Analysis of a prosperous but genetically altered fauna

    International Nuclear Information System (INIS)

    Chesser, R.; Baker, R.

    1996-01-01

    The ecological study of zones contaminated by Chernobyl accident reveals that the wild life abounds, because of inhabitants absence, evacuated. On the other hand, significant genetical alterations are observed, whom functional consequences, low visible, stay, at term, unknown. This kind of studies illustrates the development of a new discipline, the evolving toxicology

  19. Image-based computational quantification and visualization of genetic alterations and tumour heterogeneity.

    Science.gov (United States)

    Zhong, Qing; Rüschoff, Jan H; Guo, Tiannan; Gabrani, Maria; Schüffler, Peter J; Rechsteiner, Markus; Liu, Yansheng; Fuchs, Thomas J; Rupp, Niels J; Fankhauser, Christian; Buhmann, Joachim M; Perner, Sven; Poyet, Cédric; Blattner, Miriam; Soldini, Davide; Moch, Holger; Rubin, Mark A; Noske, Aurelia; Rüschoff, Josef; Haffner, Michael C; Jochum, Wolfram; Wild, Peter J

    2016-04-07

    Recent large-scale genome analyses of human tissue samples have uncovered a high degree of genetic alterations and tumour heterogeneity in most tumour entities, independent of morphological phenotypes and histopathological characteristics. Assessment of genetic copy-number variation (CNV) and tumour heterogeneity by fluorescence in situ hybridization (ISH) provides additional tissue morphology at single-cell resolution, but it is labour intensive with limited throughput and high inter-observer variability. We present an integrative method combining bright-field dual-colour chromogenic and silver ISH assays with an image-based computational workflow (ISHProfiler), for accurate detection of molecular signals, high-throughput evaluation of CNV, expressive visualization of multi-level heterogeneity (cellular, inter- and intra-tumour heterogeneity), and objective quantification of heterogeneous genetic deletions (PTEN) and amplifications (19q12, HER2) in diverse human tumours (prostate, endometrial, ovarian and gastric), using various tissue sizes and different scanners, with unprecedented throughput and reproducibility.

  20. Contribution of FKBP5 genetic variation to gemcitabine treatment and survival in pancreatic adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Katarzyna A Ellsworth

    Full Text Available FKBP51, (FKBP5, is a negative regulator of Akt. Variability in FKBP5 expression level is a major factor contributing to variation in response to chemotherapeutic agents including gemcitabine, a first line treatment for pancreatic cancer. Genetic variation in FKBP5 could influence its function and, ultimately, treatment response of pancreatic cancer.We set out to comprehensively study the role of genetic variation in FKBP5 identified by Next Generation DNA resequencing on response to gemcitabine treatment of pancreatic cancer by utilizing both tumor and germline DNA samples from 43 pancreatic cancer patients, including 19 paired normal-tumor samples. Next, genotype-phenotype association studies were performed with overall survival as well as with FKBP5 gene expression in tumor using the same samples in which resequencing had been performed, followed by functional genomics studies.In-depth resequencing identified 404 FKBP5 single nucleotide polymorphisms (SNPs in normal and tumor DNA. SNPs with the strongest associations with survival or FKBP5 expression were subjected to functional genomic study. Electromobility shift assay showed that the rs73748206 "A(T" SNP altered DNA-protein binding patterns, consistent with significantly increased reporter gene activity, possibly through its increased binding to Glucocorticoid Receptor (GR. The effect of rs73748206 was confirmed on the basis of its association with FKBP5 expression by affecting the binding to GR in lymphoblastoid cell lines derived from the same patients for whom DNA was used for resequencing.This comprehensive FKBP5 resequencing study provides insights into the role of genetic variation in variation of gemcitabine response.

  1. Contribution and perspectives of quantitative genetics to plant breeding in Brazil

    Directory of Open Access Journals (Sweden)

    Fernando Henrique Ribeiro Barrozo Toledo

    2012-12-01

    Full Text Available The purpose of this article is to show how quantitative genetics has contributed to the huge genetic progress obtained inplant breeding in Brazil in the last forty years. The information obtained through quantitative genetics has given Brazilian breedersthe possibility of responding to innumerable questions in their work in a much more informative way, such as the use or not of hybridcultivars, which segregating population to use, which breeding method to employ, alternatives for improving the efficiency of selectionprograms, and how to handle the data of progeny and/or cultivars evaluations to identify the most stable ones and thus improverecommendations.

  2. Targeted molecular profiling of rare genetic alterations in colorectal cancer using next-generation sequencing.

    Science.gov (United States)

    Jauhri, Mayank; Bhatnagar, Akanksha; Gupta, Satish; Shokeen, Yogender; Minhas, Sachin; Aggarwal, Shyam

    2016-10-01

    Mutation frequencies of common genetic alterations in colorectal cancer have been in the spotlight for many years. This study highlights few rare somatic mutations, which possess the attributes of a potential CRC biomarker yet are often neglected. Next-generation sequencing was performed over 112 tumor samples to detect genetic alterations in 31 rare genes in colorectal cancer. Mutations were detected in 26/31 (83.9 %) uncommon genes, which together contributed toward 149 gene mutations in 67/112 (59.8 %) colorectal cancer patients. The most frequent mutations include KDR (19.6 %), PTEN (17 %), FBXW7 (10.7 %), SMAD4 (10.7 %), VHL (8 %), KIT (8 %), MET (7.1 %), ATM (6.3 %), CTNNB1 (4.5 %) and CDKN2A (4.5 %). RB1, ERBB4 and ERBB2 mutations were persistent in 3.6 % patients. GNAS, FGFR2 and FGFR3 mutations were persistent in 1.8 % patients. Ten genes (EGFR, NOTCH1, SMARCB1, ABL1, STK11, SMO, RET, GNAQ, CSF1R and FLT3) were found mutated in 0.9 % patients. Lastly, no mutations were observed in AKT, HRAS, MAP2K1, PDGFR and JAK2. Significant associations were observed between VHL with tumor site, ERBB4 and SMARCB1 with tumor invasion, CTNNB1 with lack of lymph node involvement and CTNNB1, FGFR2 and FGFR3 with TNM stage. Significantly coinciding mutation pairs include PTEN and SMAD4, PTEN and KDR, EGFR and RET, EGFR and RB1, FBXW7 and CTNNB1, KDR and FGFR2, FLT3 and CTNNB1, RET and RB1, ATM and SMAD4, ATM and CDKN2A, ERBB4 and SMARCB1. This study elucidates few potential colorectal cancer biomarkers, specifically KDR, PTEN, FBXW7 and SMAD4, which are found mutated in more than 10 % patients.

  3. Dynamics of ASXL1 mutation and other associated genetic alterations during disease progression in patients with primary myelodysplastic syndrome

    International Nuclear Information System (INIS)

    Chen, T-C; Hou, H-A; Chou, W-C; Tang, J-L; Kuo, Y-Y; Chen, C-Y; Tseng, M-H; Huang, C-F; Lai, Y-J; Chiang, Y-C; Lee, F-Y; Liu, M-C; Liu, C-W; Liu, C-Y; Yao, M; Huang, S-Y; Ko, B-S; Hsu, S-C; Wu, S-J; Tsay, W; Chen, Y-C; Tien, H-F

    2014-01-01

    Recently, mutations of the additional sex comb-like 1 (ASXL1) gene were identified in patients with myelodysplastic syndrome (MDS), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, ASXL1 mutations were identified in 106 (22.7%) of the 466 patients with primary MDS based on the French-American-British (FAB) classification and 62 (17.1%) of the 362 patients based on the World Health Organization (WHO) classification. ASXL1 mutation was closely associated with trisomy 8 and mutations of RUNX1, EZH2, IDH, NRAS, JAK2, SETBP1 and SRSF2, but was negatively associated with SF3B1 mutation. Most ASXL1-mutated patients (85%) had concurrent other gene mutations at diagnosis. ASXL1 mutation was an independent poor prognostic factor for survival. Sequential studies showed that the original ASXL1 mutation remained unchanged at disease progression in all 32 ASXL1-mutated patients but were frequently accompanied with acquisition of mutations of other genes, including RUNX1, NRAS, KRAS, SF3B1, SETBP1 and chromosomal evolution. On the other side, among the 80 ASXL1-wild patients, only one acquired ASXL1 mutation at leukemia transformation. In conclusion, ASXL1 mutations in association with other genetic alterations may have a role in the development of MDS but contribute little to disease progression

  4. Persistent Genetic and Family-Wide Environmental Contributions to Early Number Knowledge and Later Achievement in Mathematics.

    Science.gov (United States)

    Garon-Carrier, Gabrielle; Boivin, Michel; Kovas, Yulia; Feng, Bei; Brendgen, Mara; Vitaro, Frank; Séguin, Jean R; Tremblay, Richard E; Dionne, Ginette

    2017-12-01

    This study investigated the stable and transient genetic and environmental contributions to individual differences in number knowledge in the transition from preschool (age 5) to Grade 1 (age 7) and to the predictive association between early number knowledge and later math achievement (age 10-12). We conducted genetic simplex modeling across these three time points. Genetic variance was transmitted from preschool number knowledge to late-elementary math achievement; in addition, significant genetic innovation (i.e., new influence) occurred at ages 10 through 12 years. The shared and nonshared environmental contributions decreased during the transition from preschool to school entry, but shared and nonshared environment contributed to the continuity across time from preschool number knowledge to subsequent number knowledge and math achievement. There was no new environmental contribution at time points subsequent to preschool. Results are discussed in light of their practical implications for children who have difficulties with mathematics, as well as for preventive intervention.

  5. Males and females contribute unequally to offspring genetic diversity in the polygynandrous mating system of wild boar.

    Directory of Open Access Journals (Sweden)

    Javier Pérez-González

    Full Text Available The maintenance of genetic diversity across generations depends on both the number of reproducing males and females. Variance in reproductive success, multiple paternity and litter size can all affect the relative contributions of male and female parents to genetic variation of progeny. The mating system of the wild boar (Sus scrofa has been described as polygynous, although evidence of multiple paternity in litters has been found. Using 14 microsatellite markers, we evaluated the contribution of males and females to genetic variation in the next generation in independent wild boar populations from the Iberian Peninsula and Hungary. Genetic contributions of males and females were obtained by distinguishing the paternal and maternal genetic component inherited by the progeny. We found that the paternally inherited genetic component of progeny was more diverse than the maternally inherited component. Simulations showed that this finding might be due to a sampling bias. However, after controlling for the bias by fitting both the genetic diversity in the adult population and the number of reproductive individuals in the models, paternally inherited genotypes remained more diverse than those inherited maternally. Our results suggest new insights into how promiscuous mating systems can help maintain genetic variation.

  6. The Landscape of Somatic Genetic Alterations in Breast Cancers From ATM Germline Mutation Carriers.

    Science.gov (United States)

    Weigelt, Britta; Bi, Rui; Kumar, Rahul; Blecua, Pedro; Mandelker, Diana L; Geyer, Felipe C; Pareja, Fresia; James, Paul A; Couch, Fergus J; Eccles, Diana M; Blows, Fiona; Pharoah, Paul; Li, Anqi; Selenica, Pier; Lim, Raymond S; Jayakumaran, Gowtham; Waddell, Nic; Shen, Ronglai; Norton, Larry; Wen, Hannah Y; Powell, Simon N; Riaz, Nadeem; Robson, Mark E; Reis-Filho, Jorge S; Chenevix-Trench, Georgia

    2018-02-28

    Pathogenic germline variants in ataxia-telangiectasia mutated (ATM), a gene that plays a role in DNA damage response and cell cycle checkpoints, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic characteristics and landscape of somatic genetic alterations in 24 BCs from ATM germline mutation carriers by whole-exome and targeted sequencing. ATM-associated BCs were consistently hormone receptor positive and largely displayed minimal immune infiltrate. Although 79.2% of these tumors exhibited loss of heterozygosity of the ATM wild-type allele, none displayed high activity of mutational signature 3 associated with defective homologous recombination DNA (HRD) repair. No TP53 mutations were found in the ATM-associated BCs. Analysis of an independent data set confirmed that germline ATM variants and TP53 somatic mutations are mutually exclusive. Our findings indicate that ATM-associated BCs often harbor bi-allelic inactivation of ATM, are phenotypically distinct from BRCA1/2-associated BCs, lack HRD-related mutational signatures, and that TP53 and ATM genetic alterations are likely epistatic.

  7. Genetic Alterations of the Thrombopoietin/MPL/JAK2 Axis Impacting Megakaryopoiesis.

    Science.gov (United States)

    Plo, Isabelle; Bellanné-Chantelot, Christine; Mosca, Matthieu; Mazzi, Stefania; Marty, Caroline; Vainchenker, William

    2017-01-01

    Megakaryopoiesis is an original and complex cell process which leads to the formation of platelets. The homeostatic production of platelets is mainly regulated and controlled by thrombopoietin (TPO) and the TPO receptor (MPL)/JAK2 axis. Therefore, any hereditary or acquired abnormality affecting this signaling axis can result in thrombocytosis or thrombocytopenia. Thrombocytosis can be due to genetic alterations that affect either the intrinsic MPL signaling through gain-of-function (GOF) activity ( MPL, JAK2, CALR ) and loss-of-function (LOF) activity of negative regulators ( CBL, LNK ) or the extrinsic MPL signaling by THPO GOF mutations leading to increased TPO synthesis. Alternatively, thrombocytosis may paradoxically result from mutations of MPL leading to an abnormal MPL trafficking, inducing increased TPO levels by alteration of its clearance. In contrast, thrombocytopenia can also result from LOF THPO or MPL mutations, which cause a complete defect in MPL trafficking to the cell membrane, impaired MPL signaling or stability, defects in the TPO/MPL interaction, or an absence of TPO production.

  8. Contribution of Large Region Joint Associations to Complex Traits Genetics

    Science.gov (United States)

    Paré, Guillaume; Asma, Senay; Deng, Wei Q.

    2015-01-01

    A polygenic model of inheritance, whereby hundreds or thousands of weakly associated variants contribute to a trait’s heritability, has been proposed to underlie the genetic architecture of complex traits. However, relatively few genetic variants have been positively identified so far and they collectively explain only a small fraction of the predicted heritability. We hypothesized that joint association of multiple weakly associated variants over large chromosomal regions contributes to complex traits variance. Confirmation of such regional associations can help identify new loci and lead to a better understanding of known ones. To test this hypothesis, we first characterized the ability of commonly used genetic association models to identify large region joint associations. Through theoretical derivation and simulation, we showed that multivariate linear models where multiple SNPs are included as independent predictors have the most favorable association profile. Based on these results, we tested for large region association with height in 3,740 European participants from the Health and Retirement Study (HRS) study. Adjusting for SNPs with known association with height, we demonstrated clustering of weak associations (p = 2x10-4) in regions extending up to 433.0 Kb from known height loci. The contribution of regional associations to phenotypic variance was estimated at 0.172 (95% CI 0.063-0.279; p < 0.001), which compared favorably to 0.129 explained by known height variants. Conversely, we showed that suggestively associated regions are enriched for known height loci. To extend our findings to other traits, we also tested BMI, HDLc and CRP for large region associations, with consistent results for CRP. Our results demonstrate the presence of large region joint associations and suggest these can be used to pinpoint weakly associated SNPs. PMID:25856144

  9. Genetic variations in the serotoninergic system contribute to body-mass index in Chinese adolescents.

    Directory of Open Access Journals (Sweden)

    Chunhui Chen

    Full Text Available OBJECTIVE: Obesity has become a worldwide health problem in the past decades. Human and animal studies have implicated serotonin in appetite regulation, and behavior genetic studies have shown that body mass index (BMI has a strong genetic component. However, the roles of genes related to the serotoninergic (5-hydroxytryptamine,5-HT system in obesity/BMI are not well understood, especially in Chinese subjects. SUBJECTS AND DESIGN: With a sample of 478 healthy Chinese volunteers, this study investigated the relation between BMI and genetic variations of the serotoninergic system as characterized by 136 representative polymorphisms. We used a system-level approach to identify SNPs associated with BMI, then estimated their overall contribution to BMI by multiple regression and verified it by permutation. RESULTS: We identified 12 SNPs that made statistically significant contributions to BMI. After controlling for gender and age, four of these SNPs accounted for 7.7% additional variance of BMI. Permutation analysis showed that the probability of obtaining these findings by chance was low (p = 0.015, permuted for 1000 times. CONCLUSION: These results showed that genetic variations in the serotoninergic system made a moderate contribution to individual differences in BMI among a healthy Chinese sample, suggesting that a similar approach can be used to study obesity.

  10. Genetic architecture of gene expression in ovine skeletal muscle

    DEFF Research Database (Denmark)

    Kogelman, Lisette Johanna Antonia; Byrne, Keren; Vuocolo, Tony

    2011-01-01

    architecture to the gene expression data, which also discriminated the sire-based Estimated Breeding Value for the trait. An integrated systems biology approach was then used to identify the major functional pathways contributing to the genetics of enhanced muscling by using both Estimated Breeding Value...... has potential, amongst other mechanisms, to alter gene expression via cis- or trans-acting mechanisms in a manner that impacts the functional activities of specific pathways that contribute to muscling traits. By integrating sire-based genetic merit information for a muscling trait with progeny...

  11. Contribution of genetics to ecological restoration.

    Science.gov (United States)

    Mijangos, Jose Luis; Pacioni, Carlo; Spencer, Peter B S; Craig, Michael D

    2015-01-01

    Ecological restoration of degraded ecosystems has emerged as a critical tool in the fight to reverse and ameliorate the current loss of biodiversity and ecosystem services. Approaches derived from different genetic disciplines are extending the theoretical and applied frameworks on which ecological restoration is based. We performed a search of scientific articles and identified 160 articles that employed a genetic approach within a restoration context to shed light on the links between genetics and restoration. These articles were then classified on whether they examined association between genetics and fitness or the application of genetics in demographic studies, and on the way the studies informed restoration practice. Although genetic research in restoration is rapidly growing, we found that studies could make better use of the extensive toolbox developed by applied fields in genetics. Overall, 41% of reviewed studies used genetic information to evaluate or monitor restoration, and 59% provided genetic information to guide prerestoration decision-making processes. Reviewed studies suggest that restoration practitioners often overlook the importance of including genetic aspects within their restoration goals. Even though there is a genetic basis influencing the provision of ecosystem services, few studies explored this relationship. We provide a view of research gaps, future directions and challenges in the genetics of restoration. © 2014 John Wiley & Sons Ltd.

  12. Evaluation of inbreeding in laying hens by applying optimum genetic contribution and gene flow theory.

    Science.gov (United States)

    König, S; Tsehay, F; Sitzenstock, F; von Borstel, U U; Schmutz, M; Preisinger, R; Simianer, H

    2010-04-01

    Due to consistent increases of inbreeding of on average 0.95% per generation in layer populations, selection tools should consider both genetic gain and genetic relationships in the long term. The optimum genetic contribution theory using official estimated breeding values for egg production was applied for 3 different lines of a layer breeding program to find the optimal allocations of hens and sires. Constraints in different scenarios encompassed restrictions related to additive genetic relationships, the increase of inbreeding, the number of selected sires and hens, and the number of selected offspring per mating. All these constraints enabled higher genetic gain up to 10.9% at the same level of additive genetic relationships or in lower relationships at the same gain when compared with conventional selection schemes ignoring relationships. Increases of inbreeding and genetic gain were associated with the number of selected sires. For the lowest level of the allowed average relationship at 10%, the optimal number of sires was 70 and the estimated breeding value for egg production of the selected group was 127.9. At the highest relationship constraint (16%), the optimal number of sires decreased to 15, and the average genetic value increased to 139.7. Contributions from selected sires and hens were used to develop specific mating plans to minimize inbreeding in the following generation by applying a simulated annealing algorithm. The additional reduction of average additive genetic relationships for matings was up to 44.9%. An innovative deterministic approach to estimate kinship coefficients between and within defined selection groups based on gene flow theory was applied to compare increases of inbreeding from random matings with layer populations undergoing selection. Large differences in rates of inbreeding were found, and they underline the necessity to establish selection tools controlling long-term relationships. Furthermore, it was suggested to use

  13. Merging data from genetic and epigenetic approaches to better understand autistic spectrum disorder.

    Science.gov (United States)

    Grayson, Dennis R; Guidotti, Alessandro

    2016-01-01

    Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is characterized by a wide range of cognitive and behavioral abnormalities. Genetic research has identified large numbers of genes that contribute to ASD phenotypes. There is compelling evidence that environmental factors contribute to ASD through influences that differentially impact the brain through epigenetic mechanisms. Both genetic mutations and epigenetic influences alter gene expression in different cell types of the brain. Mutations impact the expression of large numbers of genes and also have downstream consequences depending on specific pathways associated with the mutation. Environmental factors impact the expression of sets of genes by altering methylation/hydroxymethylation patterns, local histone modification patterns and chromatin remodeling. Herein, we discuss recent developments in the research of ASD with a focus on epigenetic pathways as a complement to current genetic screening.

  14. Parkinson's disease and pesticides: A meta-analysis of disease connection and genetic alterations.

    Science.gov (United States)

    Ahmed, Hussien; Abushouk, Abdelrahman Ibrahim; Gabr, Mohamed; Negida, Ahmed; Abdel-Daim, Mohamed M

    2017-06-01

    Parkinson's disease (PD) is a globally prevalent, multifactorial disorder that occurs due to interactions between genetic and environmental factors. Observational studies have shown a link between exposure to pesticides and the risk of PD. We performed this study to systemically review published case-control studies and estimate quantitatively the association between pesticide exposure and PD. We searched Medline (through PubMed) for eligible case-control studies. The association between pesticide exposure and PD risk or occurrence of certain genetic alterations, related to the pathogenesis of PD was presented as odds ratios (OR) and pooled under the random effects model, using the statistical add-in (MetaXL, version 5.0). The pooled result showed that exposure to pesticides is linked to PD (OR 1.46, 95% CI [1.21, 1.77]), but there was a significant heterogeneity among included studies. Exposure to pesticides increased the risk of alterations in different PD pathogenesis-related genes, such as GST (OR 1.97, 95% CI [1.41, 2.76]), PON-1 (OR 1.32, 95% CI [1.09, 1.6]), MDR1 (OR 2.06, 95% CI [1.58, 2.68]), and SNCA genes (OR 1.28, 95% CI [1.02, 1.37]). There was no statistically significant association between exposure to pesticides and alteration of CYP2D6 (OR 1.19, 95% CI [0.91, 1.54]), SLC6A3 (OR 0.74, 95% CI [0.55, 1]), MnSOD (OR 1.45, 95% CI [0.97, 2.16]), NQO1 (OR 1.35, 95% CI [0.91, 2.01]), and PON-2 genes (OR 0.88, 95% CI [0.53, 1.45]). In conclusion, this meta-analysis provides evidence that pesticide exposure is significantly associated with the risk of PD and alterations in genes involved in PD pathogenesis. However, the underlying mechanism of this association and the effect of the duration of exposure or the type of pesticides should be addressed by future research. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  15. Altering length and velocity feedback during a neuro-musculoskeletal simulation of normal gait contributes to hemiparetic gait characteristics.

    Science.gov (United States)

    Jansen, Karen; De Groote, Friedl; Aerts, Wouter; De Schutter, Joris; Duysens, Jacques; Jonkers, Ilse

    2014-04-30

    Spasticity is an important complication after stroke, especially in the anti-gravity muscles, i.e. lower limb extensors. However the contribution of hyperexcitable muscle spindle reflex loops to gait impairments after stroke is often disputed. In this study a neuro-musculoskeletal model was developed to investigate the contribution of an increased length and velocity feedback and altered reflex modulation patterns to hemiparetic gait deficits. A musculoskeletal model was extended with a muscle spindle model providing real-time length and velocity feedback of gastrocnemius, soleus, vasti and rectus femoris during a forward dynamic simulation (neural control model). By using a healthy subject's base muscle excitations, in combination with increased feedback gains and altered reflex modulation patterns, the effect on kinematics was simulated. A foot-ground contact model was added to account for the interaction effect between the changed kinematics and the ground. The qualitative effect i.e. the directional effect and the specific gait phases where the effect is present, on the joint kinematics was then compared with hemiparetic gait deviations reported in the literature. Our results show that increased feedback in combination with altered reflex modulation patterns of soleus, vasti and rectus femoris muscle can contribute to excessive ankle plantarflexion/inadequate dorsiflexion, knee hyperextension/inadequate flexion and increased hip extension/inadequate flexion during dedicated gait cycle phases. Increased feedback of gastrocnemius can also contribute to excessive plantarflexion/inadequate dorsiflexion, however in combination with excessive knee and hip flexion. Increased length/velocity feedback can therefore contribute to two types of gait deviations, which are both in accordance with previously reported gait deviations in hemiparetic patients. Furthermore altered modulation patterns, in particular the reduced suppression of the muscle spindle feedback during

  16. Genetic and epigenetic alteration among three homoeologous genes of a class E MADS box gene in hexaploid wheat.

    Science.gov (United States)

    Shitsukawa, Naoki; Tahira, Chikako; Kassai, Ken-Ichiro; Hirabayashi, Chizuru; Shimizu, Tomoaki; Takumi, Shigeo; Mochida, Keiichi; Kawaura, Kanako; Ogihara, Yasunari; Murai, Koji

    2007-06-01

    Bread wheat (Triticum aestivum) is a hexaploid species with A, B, and D ancestral genomes. Most bread wheat genes are present in the genome as triplicated homoeologous genes (homoeologs) derived from the ancestral species. Here, we report that both genetic and epigenetic alterations have occurred in the homoeologs of a wheat class E MADS box gene. Two class E genes are identified in wheat, wheat SEPALLATA (WSEP) and wheat LEAFY HULL STERILE1 (WLHS1), which are homologs of Os MADS45 and Os MADS1 in rice (Oryza sativa), respectively. The three wheat homoeologs of WSEP showed similar genomic structures and expression profiles. By contrast, the three homoeologs of WLHS1 showed genetic and epigenetic alterations. The A genome WLHS1 homoeolog (WLHS1-A) had a structural alteration that contained a large novel sequence in place of the K domain sequence. A yeast two-hybrid analysis and a transgenic experiment indicated that the WLHS1-A protein had no apparent function. The B and D genome homoeologs, WLHS1-B and WLHS1-D, respectively, had an intact MADS box gene structure, but WLHS1-B was predominantly silenced by cytosine methylation. Consequently, of the three WLHS1 homoeologs, only WLHS1-D functions in hexaploid wheat. This is a situation where three homoeologs are differentially regulated by genetic and epigenetic mechanisms.

  17. GENETICS ASPECTS OF DIABETIC NEPHROPATHY

    Directory of Open Access Journals (Sweden)

    Oana-Elena Sauca

    2010-09-01

    Full Text Available Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria, a relentless decline in GFR, raised arterial blood pressure, and increased relative mortality for cardiovascular diseases. The pathogenesis of diabetic nephropathy is multifactorial, with contributions from metabolic abnormalities, hemodynamic alteration, and various growth and genetic factors. The identification of the main genes would allow the detection of those individuals at high risk for diabetic nephropathy and better understanding of its pathophysiologyas well.The present review discusses the main information available in literature regarding some genetic variants (involved in the renin-angiotensin system, glucose and lipid metabolism and some cytoskeleton proteins that reaffirms the importance of genetic factors in diabetic nephropathy.

  18. Genetic and Environmental Contributions to General Cognitive Ability through the First 16 Years of Life

    Science.gov (United States)

    Petrill, Stephen A.; Lipton, Paul A.; Hewitt, John K.; Plomin, Robert; Cherny, Stacey S.; Corley, Robin; DeFries, John C.

    2004-01-01

    The genetic and environmental contributions to the development of general cognitive ability throughout the first 16 years of life were examined using sibling data from the Colorado Adoption Project. Correlations were analyzed along with structural equation models to characterize the genetic and environmental influences on longitudinal stability…

  19. Production of extracellular nucleic acids by genetically altered bacteria in aquatic-environment microcosms

    International Nuclear Information System (INIS)

    Paul, J.H.; David, A.W.

    1989-01-01

    The factors which affect the production of extracellular DNA by genetically altered strains of Escherichia coli, Pseudomonas aeruginosa, Pseudomonas cepacia, and Bradyrhizobium japonicum in aquatic environments were investigated. Cellular nucleic acids were labeled in vivo by incubation with [ 3 H]thymidine or [ 3 H]adenine, and production of extracellular DNA in marine waters, artificial seawater, or minimal salts media was determined by detecting radiolabeled macromolecules in incubation filtrates. The presence or absence of the ambient microbial community had little effect on the production of extracellular DNA. Three of four organisms produced the greatest amounts of extracellular nucleic acids when incubated in low-salinity media (2% artificial seawater) rather than high-salinity media (10 to 50% artificial seawater). The greatest production of extracellular nucleic acids by P. cepacia occurred at pH 7 and 37 degree C, suggesting that extracellular-DNA production may be a normal physiologic function of the cell. Incubation of labeled P. cepacia cells in water from Bimini Harbor, Bahamas, resulted in labeling of macromolecules of the ambient microbial population. Collectively these results indicate that (i) extracellular-DNA production by genetically altered bacteria released into aquatic environments is more strongly influenced by physicochemical factors than biotic factors, (ii) extracellular-DNA production rates are usually greater for organisms released in freshwater than marine environments, and (iii) ambient microbial populations can readily utilize materials released by these organisms

  20. Genetic Alterations in Intervertebral Disc Disease

    Directory of Open Access Journals (Sweden)

    Nikolay L. Martirosyan

    2016-11-01

    Full Text Available Background: Intervertebral disc degeneration (IVDD is considered a multifactorial disease. The last two decades of research strongly demonstrate that genetic factors contribute about 75% of the IVDD etiology. Recent total genome sequencing studies have shed light on the various single nucleotide polymorphisms (SNPs that are associated with IVDD.Aim: This review explores and presents updated information about the diversity of genetic factors in the inflammatory, degradative, homeostatic, and structural systems involved in the IVDD.Results: SNPs in the genes coding for structural proteins linked with IVDD or disc bulging include the Sp1 polymorphism of COL1A1, Trp3 polymorphism of COL9A3, several polymorphisms of COL11A1 and COL11A2, and a variable number tandem repeat polymorphism of ACAN. The rs4148941 SNP of CHST3 coding for an aggrecan sulfation enzyme is also associated with IVDD. The FokI, TaqI, and ApaI SNPs of the vitamin D receptor gene that is involved in chondrocyte functioning are also associated with IVDD. SNPs relevant to cytokine imbalance in IVDD include 889C/T of IL1a and 15T/A, as well as other SNPs (rs1800795, rs1800796, and rs1800797, of IL6, with effects limited to certain genders and populations. SNPs in collagenase genes include -1605G/D (guanine insertion/deletion of MMP1, -1306C/T of MMP2, -1562C/T and a 5-adenosine (5A variant (in the promotor region of MMP3, -1562C/T of MMP9, and -378T/C of MMP-14. SNPs in aggrecanase genes include 1877T/U of ADAMTS-4 and rs162509 of ADAMTS-5. Among the apoptosis-mediating genes, 1595T/C of the caspase 9 gene, 1525A/G and 1595T/C of the TRAIL gene, and 626C/G of the death receptor 4 gene (DR4 are SNPs associated with IVDD. Among the growth factors involved in disc homeostasis, the rs4871857 SNP of GDF5 was associated with IVDD. VEGF SNPs -2578C/A and -634G/C could foster neovascularization observed in IVDD.Conclusion: Improved understanding of the numerous genetic variants behind various

  1. Acquisition of Genetic Aberrations by Activation-Induced Cytidine Deaminase (AID) during Inflammation-Associated Carcinogenesis

    International Nuclear Information System (INIS)

    Takai, Atsushi; Marusawa, Hiroyuki; Chiba, Tsutomu

    2011-01-01

    Genetic abnormalities such as nucleotide alterations and chromosomal disorders that accumulate in various tumor-related genes have an important role in cancer development. The precise mechanism of the acquisition of genetic aberrations, however, remains unclear. Activation-induced cytidine deaminase (AID), a nucleotide editing enzyme, is essential for the diversification of antibody production. AID is expressed only in activated B lymphocytes under physiologic conditions and induces somatic hypermutation and class switch recombination in immunoglobulin genes. Inflammation leads to aberrant AID expression in various gastrointestinal organs and increased AID expression contributes to cancer development by inducing genetic alterations in epithelial cells. Studies of how AID induces genetic disorders are expected to elucidate the mechanism of inflammation-associated carcinogenesis

  2. Do alterations in follicular fluid proteases contribute to human infertility?

    Science.gov (United States)

    Cookingham, Lisa Marii; Van Voorhis, Bradley J; Ascoli, Mario

    2015-05-01

    Cathepsin L and ADAMTS-1 are known to play critical roles in follicular rupture, ovulation, and fertility in mice. Similar studies in humans are limited; however, both are known to increase during the periovulatory period. No studies have examined either protease in the follicular fluid of women with unexplained infertility or infertility related to advanced maternal age (AMA). We sought to determine if alterations in cathepsin L and/or ADAMTS-1 existed in these infertile populations. Patients undergoing in vitro fertilization (IVF) for unexplained infertility or AMA-related infertility were prospectively recruited for the study; patients with tubal or male factor infertility were recruited as controls. Follicular fluid was collected to determine gene expression (via quantitative polymerase chain reaction), enzyme concentrations (via enzyme-linked immunosorbent assays), and enzymatic activities (via fluorogenic enzyme cleavage assay or Western blot analysis) of cathepsin L and ADAMTS-1. The analysis included a total of 42 patients (14 per group). We found no statistically significant difference in gene expression, enzyme concentration, or enzymatic activity of cathepsin L or ADAMTS-1 in unexplained infertility or AMA-related infertility as compared to controls. We also found no statistically significant difference in expression or concentration with advancing age. Cathepsin L and ADAMTS-1 are not altered in women with unexplained infertility or AMA-related infertility undergoing IVF, and they do not decline with advancing age. It is possible that differences exist in natural cycles, contributing to infertility; however, our findings do not support a role for protease alterations as a common cause of infertility.

  3. Minimal Contribution of APOBEC3-Induced G-to-A Hypermutation to HIV-1 Recombination and Genetic Variation.

    Science.gov (United States)

    Delviks-Frankenberry, Krista A; Nikolaitchik, Olga A; Burdick, Ryan C; Gorelick, Robert J; Keele, Brandon F; Hu, Wei-Shau; Pathak, Vinay K

    2016-05-01

    Although the predominant effect of host restriction APOBEC3 proteins on HIV-1 infection is to block viral replication, they might inadvertently increase retroviral genetic variation by inducing G-to-A hypermutation. Numerous studies have disagreed on the contribution of hypermutation to viral genetic diversity and evolution. Confounding factors contributing to the debate include the extent of lethal (stop codon) and sublethal hypermutation induced by different APOBEC3 proteins, the inability to distinguish between G-to-A mutations induced by APOBEC3 proteins and error-prone viral replication, the potential impact of hypermutation on the frequency of retroviral recombination, and the extent to which viral recombination occurs in vivo, which can reassort mutations in hypermutated genomes. Here, we determined the effects of hypermutation on the HIV-1 recombination rate and its contribution to genetic variation through recombination to generate progeny genomes containing portions of hypermutated genomes without lethal mutations. We found that hypermutation did not significantly affect the rate of recombination, and recombination between hypermutated and wild-type genomes only increased the viral mutation rate by 3.9 × 10-5 mutations/bp/replication cycle in heterozygous virions, which is similar to the HIV-1 mutation rate. Since copackaging of hypermutated and wild-type genomes occurs very rarely in vivo, recombination between hypermutated and wild-type genomes does not significantly contribute to the genetic variation of replicating HIV-1. We also analyzed previously reported hypermutated sequences from infected patients and determined that the frequency of sublethal mutagenesis for A3G and A3F is negligible (4 × 10-21 and1 × 10-11, respectively) and its contribution to viral mutations is far below mutations generated during error-prone reverse transcription. Taken together, we conclude that the contribution of APOBEC3-induced hypermutation to HIV-1 genetic

  4. Evidence suggesting a genetic contribution to kidney stone in northeastern Thai population.

    Science.gov (United States)

    Sritippayawan, Suchai; Borvornpadungkitti, Sombat; Paemanee, Atchara; Predanon, Chagkrapan; Susaengrat, Wattanachai; Chuawattana, Duangporn; Sawasdee, Nunghathai; Nakjang, Sirintra; Pongtepaditep, Suttikarn; Nettuwakul, Choochai; Rungroj, Nanyawan; Vasuvattakul, Somkiat; Malasit, Prida; Yenchitsomanus, Pa-thai

    2009-06-01

    Genetic factor may play a role in the pathogenesis of kidney stone that is found in the northeastern (NE) Thai population. Herein, we report initial evidence suggesting genetic contribution to the disease in this population. We examined 1,034 subjects including 135 patients with kidney stone, 551 family members, and 348 villagers by radiography of kidney-ureter-bladder (KUB) and other methods, and also analyzed stones removed by surgical operations. One hundred and sixteen of 551 family members (21.05%) and 23 of the 348 villagers (6.61%) were affected with kidney stone. The relative risk (lambda(R)) of the disease among family members was 3.18. Calcium stones (whewellite, dahllite, and weddellite) were observed in about 88% of stones analyzed. Our data indicate familial aggregation of kidney stone in this population supporting that genetic factor should play some role in its pathogenesis. Genetic and genomic studies will be conducted to identify the genes associated with the disease.

  5. Linking neocortical, cognitive, and genetic variability in autism with alterations of brain plasticity: the Trigger-Threshold-Target model.

    Science.gov (United States)

    Mottron, Laurent; Belleville, Sylvie; Rouleau, Guy A; Collignon, Olivier

    2014-11-01

    The phenotype of autism involves heterogeneous adaptive traits (strengths vs. disabilities), different domains of alterations (social vs. non-social), and various associated genetic conditions (syndromic vs. nonsyndromic autism). Three observations suggest that alterations in experience-dependent plasticity are an etiological factor in autism: (1) the main cognitive domains enhanced in autism are controlled by the most plastic cortical brain regions, the multimodal association cortices; (2) autism and sensory deprivation share several features of cortical and functional reorganization; and (3) genetic mutations and/or environmental insults involved in autism all appear to affect developmental synaptic plasticity, and mostly lead to its upregulation. We present the Trigger-Threshold-Target (TTT) model of autism to organize these findings. In this model, genetic mutations trigger brain reorganization in individuals with a low plasticity threshold, mostly within regions sensitive to cortical reallocations. These changes account for the cognitive enhancements and reduced social expertise associated with autism. Enhanced but normal plasticity may underlie non-syndromic autism, whereas syndromic autism may occur when a triggering mutation or event produces an altered plastic reaction, also resulting in intellectual disability and dysmorphism in addition to autism. Differences in the target of brain reorganization (perceptual vs. language regions) account for the main autistic subgroups. In light of this model, future research should investigate how individual and sex-related differences in synaptic/regional brain plasticity influence the occurrence of autism. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  6. Conservation priorities for Ethiopian sheep breeds combining threat status, breed merits and contributions to genetic diversity

    NARCIS (Netherlands)

    Gizaw, S.; Komen, J.; Windig, J.J.; Hanotte, O.; Arendonk, van J.A.M.

    2008-01-01

    Prioritizing livestock breeds for conservation needs to incorporate both genetic and non-genetic aspects important for the survival of the breeds. Here, we apply a maximum-utility-strategy to prioritize 14 traditional Ethiopian sheep breeds based on their threat status, contributions to farmer

  7. The genetic alteration of MTS1/CDKN2 gene in esophageal cancer

    International Nuclear Information System (INIS)

    Zo, Jae Ill; Paik, Hee Jong; Park, Jong Ho; Kim, Mi Hee

    1996-12-01

    MTS1/CDKN2 gene plays a key role in cell cycle regulation, and there have been many studies about the significance of this gene in tumorigenesis. To investigate the frequency of MTS1/CDKN2 gene alteration in Korean esophageal cancer, we studied 36 esophageal cancer tissues with paired PCR analysis to detect homozygous deletion and PCR-SSCP methods to find minute mutations, if any. In the cases with abnormalities, the nucleotide sequence analysis was performed. And in cases without RB gene a alterations, direct sequence analysis was also done. There was no homozygous deletions. Mobility shift by PCR-SSCP was observed in four cases at exon 2, which showed 1 bp deletion in codon 97 of mutation in codon 100 which changed TAT (Tyr) from GAT (Asp). But there were not MTS1/CDKN2 gene alterations in cases without Rb gene alterations. Analysis of clinical data did not show any differences depending upon MTS1/CDKN2 gene alterations. Therefore the MTS1/CDKN2 gene mutations were infrequent events and do not play a major role in the group of patients examined. More study for contribution of methylation in MTS1/CDKN2 gene for inactivation of p16 should be done before evaluation and application of MTS1/CDKN2 gene in tumorigenesis and as an candidate of gene therapy. (author). 15 refs

  8. The genetic alteration of MTS1/CDKN2 gene in esophageal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Zo, Jae Ill; Paik, Hee Jong; Park, Jong Ho; Kim, Mi Hee [Korea Cancer Center Hospital, Seoul (Korea, Republic of)

    1996-12-01

    MTS1/CDKN2 gene plays a key role in cell cycle regulation, and there have been many studies about the significance of this gene in tumorigenesis. To investigate the frequency of MTS1/CDKN2 gene alteration in Korean esophageal cancer, we studied 36 esophageal cancer tissues with paired PCR analysis to detect homozygous deletion and PCR-SSCP methods to find minute mutations, if any. In the cases with abnormalities, the nucleotide sequence analysis was performed. And in cases without RB gene a alterations, direct sequence analysis was also done. There was no homozygous deletions. Mobility shift by PCR-SSCP was observed in four cases at exon 2, which showed 1 bp deletion in codon 97 of mutation in codon 100 which changed TAT (Tyr) from GAT (Asp). But there were not MTS1/CDKN2 gene alterations in cases without Rb gene alterations. Analysis of clinical data did not show any differences depending upon MTS1/CDKN2 gene alterations. Therefore the MTS1/CDKN2 gene mutations were infrequent events and do not play a major role in the group of patients examined. More study for contribution of methylation in MTS1/CDKN2 gene for inactivation of p16 should be done before evaluation and application of MTS1/CDKN2 gene in tumorigenesis and as an candidate of gene therapy. (author). 15 refs.

  9. Expansive phenotypic landscape of Botrytis cinerea shows differential contribution of genetic diversity and plasticity

    DEFF Research Database (Denmark)

    Corwin, Jason A; Subedy, Anushriya; Eshbaugh, Robert

    2016-01-01

    and genetic diversity for virulence-associated phenotypes in a generalist plant pathogen, we grew a population of 15 isolates of Botrytis cinerea from throughout the world, under a variety of in vitro and in planta conditions. Under in planta conditions, phenotypic differences between the isolates were......The modern evolutionary synthesis suggests that both environmental variation and genetic diversity are critical determinants of pathogen success. However, the relative contribution of these two sources of variation is not routinely measured. To estimate the relative contribution of plasticity...... determined by the combination of genotypic variation within the pathogen and environmental variation. In contrast, phenotypic differences between the isolates under in vitro conditions were predominantly determined by genetic variation in the pathogen. Using a correlation network approach, we link...

  10. GENETIC CONTRIBUTION OF RAM ON LITTER SIZE IN ŠUMAVA SHEEP

    Directory of Open Access Journals (Sweden)

    Jitka Schmidová

    2015-09-01

    Full Text Available The objective of the present study was to quantify the service sire effect in terms of (co variance components of born and weaned lambs number and to propose models for the potential inclusion of this effect in the linear equations for breeding value estimation. The database with 21,324 lambings in Šumava sheep from 1992- 2013 was used. The basic model equation for the analysis of variance of litter size contained effects of ewe´s age at lambing, contemporary group, permanent environmental effect of ewe and direct additive genetic effect of ewe. Two modifications of the basic model were used for estimation of service sire effect. The proportions of variance for the service sire effect for number of born and weaned lambs were 2.1% and 2.0%, when service sire was not included into relationship matrix; while included into the relationship matrix and dividing effect into genetic contribution and permanent environment effect refer that nongenetic effect seems to be bigger than genetic (0.013 vs. 0.009 for number of born and 0.017 vs. 0.004 for number of weaned. Changes in other variance components were relatively low, except of contemporary group. Model including service sire effect as a simple random effect without genetic relationship matrix inclusion is recommended for genetic evaluation of litter size traits.

  11. Genetic and environmental contributions to pro-social attitudes: a twin study of social responsibility.

    Science.gov (United States)

    Rushton, J Philippe

    2004-12-22

    Although 51 twin and adoption studies have been performed on the genetic architecture of antisocial behaviour, only four previous studies have examined a genetic contribution to pro-social behaviour. Earlier work by the author with the University of London Institute of Psychiatry Adult Twin Register found that genes contributed approximately half of the variance to measures of self-report altruism, empathy, nurturance and aggression, including acts of violence. The present study extends those results by using a 22-item Social Responsibility Questionnaire with 174 pairs of monozygotic twins and 148 pairs of dizygotic twins. Forty-two per cent of the reliable variance was due to the twins' genes, 23% to the twins' common environment and the remainder to the twins' non-shared environment.

  12. Circadian rhythms and metabolic syndrome: from experimental genetics to human disease

    OpenAIRE

    Maury, Eleonore; Ramsey, Kathryn Moynihan; Bass, Joseph

    2010-01-01

    The incidence of the metabolic syndrome represents a spectrum of disorders that continue to increase across the industrialized world. Both genetic and environmental factors contribute to metabolic syndrome and recent evidence has emerged to suggest that alterations in circadian systems and sleep participate in the pathogenesis of the disease. In this review, we highlight studies at the intersection of clinical medicine and experimental genetics that pinpoint how perturbations of the internal ...

  13. Nonverbal communication and conversational contribution in breast cancer genetic counseling: are counselors' nonverbal communication and conversational contribution associated with counselees' satisfaction, needs fulfillment and state anxiety in breast cancer genetic counseling?

    NARCIS (Netherlands)

    Dijkstra, H.; Albada, A.; Klöckner Cronauer, C.; Ausems, M.G.E.M.; Dulmen, S. van

    2013-01-01

    Objective: The current study aimed to examine how counselors’ nonverbal communication (i.e. nonverbal encouragements and counselee-directed eye gaze) and conversational contribution (i.e. verbal dominance and interactivity) during the final visit within breast cancer genetic counseling relate to

  14. Shared genetic contribution to ischemic stroke and Alzheimer's disease

    Science.gov (United States)

    Adib‐Samii, Poneh; Harold, Denise; Dichgans, Martin; Williams, Julie; Lewis, Cathryn M.; Markus, Hugh S.; Fornage, Myriam; Holliday, Elizabeth G; Sharma, Pankaj; Bis, Joshua C; Psaty, Bruce M; Seshadri, Sudha; Nalls, Mike A; Devan, William J; Boncoraglio, Giorgio; Malik, Rainer; Mitchell, Braxton D; Kittner, Steven J; Ikram, M Arfan; Clarke, Robert; Rosand, Jonathan; Meschia, James F; Sudlow, Cathie; Rothwell, Peter M; Levi, Christopher; Bevan, Steve; Kilarski, Laura L; Walters, Matthew; Thijs, Vincent; Slowik, Agnieszka; Lindgren, Arne; de Bakker, Paul I W; Lambert, Jean‐Charles; Ibrahim‐Verbaas, Carla A; Harold, Denise; Naj, Adam C; Sims, Rebecca; Bellenguez, Céline; Jun, Gyungah; DeStefano, Anita L; Bis, Joshua C; Beecham, Gary W; Grenier‐Boley, Benjamin; Russo, Giancarlo; Thornton‐Wells, Tricia A; Jones, Nicola; Smith, Albert V; Chouraki, Vincent; Thomas, Charlene; Ikram, M Arfan; Zelenika, Diana; Vardarajan, Badri N; Kamatani, Yoichiro; Lin, Chiao‐Feng; Gerrish, Amy; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L; Ruiz, Agustin; Bihoreau, Marie‐Thçrèse; Choi, Seung‐Hoan; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; Ramirez, Alfredo; Hanon, Olivier; Fitzpatrick, Annette L; Buxbaum, Joseph D; Campion, Dominique; Crane, Paul K; Baldwin, Clinton; Becker, Tim; Gudnason, Vilmundur; Cruchaga, Carlos; Craig, David; Amin, Najaf; Berr, Claudine; Lopez, Oscar L; De Jager, Philip L; Deramecourt, Vincent; Johnston, Janet A; Evans, Denis; Lovestone, Simon; Letenneur, Luc; Morón, Francisco J; Rubinsztein, David C; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M; Fiçvet, Nathalie; Huentelman, Matthew J; Gill, Michael; Brown, Kristelle; Kamboh, M Ilyas; Keller, Lina; Barberger‐Gateau, Pascale; McGuinness, Bernadette; Larson, Eric B; Green, Robert; Myers, Amanda J; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Rogaeva, Ekaterina; Gallacher, John; St George‐Hyslop, Peter; Clarimon, Jordi; Lleo, Alberto; Bayer, Anthony; Tsuang, Debby W; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petroula; Collinge, John; Sorbi, Sandro; Sanchez‐Garcia, Florentino; Fox, Nick C; Hardy, John; Deniz Naranjo, Maria Candida; Bosco, Paolo; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Mancuso, Michelangelo; Matthews, Fiona; Moebus, Susanne; Mecocci, Patrizia; Del Zompo, Maria; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Bullido, Maria; Panza, Francesco; Caffarra, Paolo; Nacmias, Benedetta; Gilbert, John R; Mayhaus, Manuel; Lannfelt, Lars; Hakonarson, Hakon; Pichler, Sabrina; Carrasquillo, Minerva M; Ingelsson, Martin; Beekly, Duane; Alvarez, Victoria; Zou, Fanggeng; Valladares, Otto; Younkin, Steven G; Coto, Eliecer; Hamilton‐Nelson, Kara L; Gu, Wei; Razquin, Cristina; Pastor, Pau; Mateo, Ignacio; Owen, Michael J; Faber, Kelley M; Jonsson, Palmi V; Combarros, Onofre; O'Donovan, Michael C; Cantwell, Laura B; Soininen, Hilkka; Blacker, Deborah; Mead, Simon; Mosley, Thomas H; Bennett, David A; Harris, Tamara B; Fratiglioni, Laura; Holmes, Clive; de Bruijn, Renee F A G; Passmore, Peter; Montine, Thomas J; Bettens, Karolien; Rotter, Jerome I; Brice, Alexis; Morgan, Kevin; Foroud, Tatiana M; Kukull, Walter A; Hannequin, Didier; Powell, John F; Nalls, Michael A; Ritchie, Karen; Lunetta, Kathryn L; Kauwe, John S K; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, Mercè; Hiltunen, Mikko; Martin, Eden R; Schmidt, Reinhold; Rujescu, Dan; Wang, Li‐San; Dartigues, Jean‐François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M; Graff, Caroline; Psaty, Bruce M; Jones, Lesley; Haines, Jonathan L; Holmans, Peter A; Lathrop, Mark; Pericak‐Vance, Margaret A; Launer, Lenore J; Farrer, Lindsay A; van Duijn, Cornelia M; Van Broeckhoven, Christine; Moskvina, Valentina; Seshadri, Sudha; Williams, Julie; Schellenberg, Gerard D; Amouyel, Philippe

    2016-01-01

    Objective Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and ischemic stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases. Methods Using genome‐wide association study (GWAS) data from METASTROKE + (15,916 IS cases and 68,826 controls) and the International Genomics of Alzheimer's Project (IGAP; 17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype‐level data (4,610 IS cases, 1,281 AD cases, and 14,320 controls), we estimated the genome‐wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, and large vessel), using genome‐wide single‐nucleotide polymorphism (SNP) data. We then performed a meta‐analysis and pathway analysis in the combined AD and small vessel stroke data sets to identify the SNPs and molecular pathways through which disease risk may be conferred. Results We found evidence of a shared genetic contribution between AD and small vessel stroke (rG [standard error] = 0.37 [0.17]; p = 0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta‐analysis of AD IGAP and METASTROKE + small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1) associated with both diseases (p = 1.8 × 10−8). A pathway analysis identified four associated pathways involving cholesterol transport and immune response. Interpretation Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. Ann Neurol 2016;79:739–747 PMID:26913989

  15. The contribution of additive genetic variation to personality variation: heritability of personality.

    Science.gov (United States)

    Dochtermann, Ned A; Schwab, Tori; Sih, Andrew

    2015-01-07

    Individual animals frequently exhibit repeatable differences from other members of their population, differences now commonly referred to as 'animal personality'. Personality differences can arise, for example, from differences in permanent environmental effects--including parental and epigenetic contributors--and the effect of additive genetic variation. Although several studies have evaluated the heritability of behaviour, less is known about general patterns of heritability and additive genetic variation in animal personality. As overall variation in behaviour includes both the among-individual differences that reflect different personalities and temporary environmental effects, it is possible for personality to be largely genetically influenced even when heritability of behaviour per se is quite low. The relative contribution of additive genetic variation to personality variation can be estimated whenever both repeatability and heritability are estimated for the same data. Using published estimates to address this issue, we found that approximately 52% of animal personality variation was attributable to additive genetic variation. Thus, while the heritability of behaviour is often moderate or low, the heritability of personality is much higher. Our results therefore (i) demonstrate that genetic differences are likely to be a major contributor to variation in animal personality and (ii) support the phenotypic gambit: that evolutionary inferences drawn from repeatability estimates may often be justified. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  16. Impact of genetic polymorphisms of four cytokine genes on treatment ...

    African Journals Online (AJOL)

    Background: Many factors contribute for viral clearance and response to antiviral therapy. Genetic polymorphisms of cytokines, chemokines, and their receptors can alter the immune response against Hepatitis C virus (HCV). Aim of the study: The aim of the current study is to assess single nucleotide polymorphism (SNP) in ...

  17. The devil is in the details: genetic variation in introduced populations and its contributions to invasion.

    Science.gov (United States)

    Dlugosch, Katrina M; Anderson, Samantha R; Braasch, Joseph; Cang, F Alice; Gillette, Heather D

    2015-05-01

    The influence of genetic variation on invasion success has captivated researchers since the start of the field of invasion genetics 50 years ago. We review the history of work on this question and conclude that genetic variation-as surveyed with molecular markers-appears to shape invasion rarely. Instead, there is a significant disconnect between marker assays and ecologically relevant genetic variation in introductions. We argue that the potential for adaptation to facilitate invasion will be shaped by the details of genotypes affecting phenotypes, and we highlight three areas in which we see opportunities to make powerful new insights. (i) The genetic architecture of adaptive variation. Traits shaped by large-effect alleles may be strongly impacted by founder events yet more likely to respond to selection when genetic drift is strong. Large-effect loci may be especially relevant for traits involved in biotic interactions. (ii) Cryptic genetic variation exposed during invasion. Introductions have strong potential to uncover masked variation due to alterations in genetic and ecological environments. (iii) Genetic interactions during admixture of multiple source populations. As divergence among sources increases, positive followed by increasingly negative effects of admixture should be expected. Although generally hypothesized to be beneficial during invasion, admixture is most often reported among sources of intermediate divergence, supporting the possibility that incompatibilities among divergent source populations might be limiting their introgression. Finally, we note that these details of invasion genetics can be coupled with comparative demographic analyses to link genetic changes to the evolution of invasiveness itself. © 2015 John Wiley & Sons Ltd.

  18. Viva la Familia Study: genetic and environmental contributions to childhood obesity and its comorbidities in the Hispanic population.

    Science.gov (United States)

    Butte, Nancy F; Cai, Guowen; Cole, Shelley A; Comuzzie, Anthony G

    2006-09-01

    Genetic and environmental contributions to childhood obesity are poorly delineated. The Viva la Familia Study was designed to genetically map childhood obesity and its comorbidities in the Hispanic population. The objectives of this report were to describe the study design and to summarize genetic and environmental contributions to the phenotypic variation in obesity and risk factors for metabolic diseases in Hispanic children. The Viva la Familia cohort consisted of 1030 children from 319 families selected based on an overweight proband between the ages of 4 and 19 y. In-depth phenotyping to characterize the overweight children and their siblings included anthropometric and body-composition traits by dual-energy X-ray absorptiometry and assessments of diet by 24-h recalls, physical activity by accelerometry, and risk factors for metabolic diseases by standard biochemical methods. Univariate quantitative genetic analysis was used to partition phenotypic variance into additive genetic and environmental components by using the computer program SOLAR. Sex, age, and environmental covariates explained 1-91% of the phenotypic variance. Heritabilities of anthropometric indexes ranged from 0.24 to 0.75. Heritability coefficients for the body-composition traits ranged from 0.18 to 0.35. Diet and physical activity presented heritabilities of 0.32 to 0.69. Risk factors for metabolic diseases were heritable with coefficients ranging from 0.25 to 0.73. Significant genetic correlations between obesity traits and risk factors for metabolic diseases substantiated pleiotropy between traits. The Viva la Familia Study provides evidence of a strong genetic contribution to the high prevalence of obesity and its comorbidities in Hispanic children.

  19. Genetic and Environmental Contributions to the Relationship between Violent Victimization and Criminal Behavior

    Science.gov (United States)

    Vaske, Jamie; Boisvert, Danielle; Wright, John Paul

    2012-01-01

    Studies have shown that there is a significant association between violent victimization and criminal behavior. One potential explanation for this association is that genetically mediated processes contribute to both violent victimization and criminal behavior. The current study uses data from the twin sample of the National Longitudinal Study of…

  20. Distinct genetic alteration profiles of acute myeloid leukemia between Caucasian and Eastern Asian population.

    Science.gov (United States)

    Wei, Hui; Wang, Ying; Zhou, Chunlin; Lin, Dong; Liu, Bingcheng; Liu, Kaiqi; Qiu, Shaowei; Gong, Benfa; Li, Yan; Zhang, Guangji; Wei, Shuning; Gong, Xiaoyuan; Liu, Yuntao; Zhao, Xingli; Gu, Runxia; Mi, Yingchang; Wang, Jianxiang

    2018-02-10

    Racial and ethnic disparities in malignancies attract extensive attention. To investigate whether there are racial and ethnic disparities in genetic alteration between Caucasian and Eastern Asian population, data from several prospective AML trials were retrospectively analyzed in this study. We found that there were more patients with core binding factor (CBF) leukemia in Eastern Asian cohorts and there were different CBF leukemia constitutions between them. The ratios of CBF leukemia are 27.7, 22.1, 21.1, and 23.4%, respectively, in our (ChiCTR-TRC-10001202), another Chinese, Korean, and Japanese Eastern Asian cohorts, which are significantly higher than those in ECOG1900, MRC AML15, UK NCRI AML17, HOVON/SAKK AML-42, and German AML2003 (15.5, 12.5, 9.3, 10.2, and 12%, respectively). And CBFbeta-MYH11 occurred more prevalently in HOVON/SAKK AML- 42 and ECOG1900 trials (50.0 and 54.3% of CBF leukemia, respectively) than in Chinese and Japanese trials (20.1 and 20.8%, respectively). The proportion of FLT3-ITD mutation is 11.2% in our cohort, which is lower than that in MRC AML15 and UK NCRI AML17 (24.6 and 17.9%, respectively). Even after excluding the age bias, there are still different incidence rates of mutation between Caucasian and Eastern Asian population. These data suggest that there are racial and ethnic disparities in genetic alteration between Caucasian and Eastern Asian population.

  1. Hypothesis: Genetic and epigenetic risk factors interact to modulate vulnerability and resilience to FASD

    Directory of Open Access Journals (Sweden)

    Elif eTunc-Ozcan

    2014-08-01

    Full Text Available Fetal alcohol spectrum disorder (FASD presents a collection of symptoms representing physiological and behavioral phenotypes caused by maternal alcohol consumption. Symptom severity is modified by genetic differences in fetal susceptibility and resistance as well as maternal genetic factors such as maternal alcohol sensitivity. Animal models demonstrate that both maternal and paternal genetics contribute to the variation in the fetus’ vulnerability to alcohol exposure. Maternal and paternal genetics define the variations in these phenotypes even without the effect of alcohol in utero, as most of these traits are polygenic, non-Mendelian, in their inheritance. In addition, the epigenetic alterations that instigate the alcohol induced neurodevelopmental deficits can interact with the polygenic inheritance of respective traits. Here, based on specific examples, we present the hypothesis that the principles of non-Mendelian inheritance, or ‘exceptions’ to Mendelian genetics, can be the driving force behind the severity of the prenatal alcohol-exposed individual’s symptomology. One such exception is when maternal alleles lead to an altered intrauterine hormonal environment and, therefore, produce variations in the long-term consequences on the development of the alcohol-exposed fetus. Another exception is when epigenetic regulation of allele-specific gene expression generates disequilibrium between the maternal versus paternal genetic contributions, and thereby, modifies the effect of prenatal alcohol exposure on the fetus. We propose that these situations in which one parent has an exaggerated influence over the offspring’s vulnerability to prenatal alcohol are major contributing mechanisms responsible for the variations in the symptomology of FASD in the exposed generation and beyond.

  2. A novel nuclear genetic code alteration in yeasts and the evolution of codon reassignment in eukaryotes.

    Science.gov (United States)

    Mühlhausen, Stefanie; Findeisen, Peggy; Plessmann, Uwe; Urlaub, Henning; Kollmar, Martin

    2016-07-01

    The genetic code is the cellular translation table for the conversion of nucleotide sequences into amino acid sequences. Changes to the meaning of sense codons would introduce errors into almost every translated message and are expected to be highly detrimental. However, reassignment of single or multiple codons in mitochondria and nuclear genomes, although extremely rare, demonstrates that the code can evolve. Several models for the mechanism of alteration of nuclear genetic codes have been proposed (including "codon capture," "genome streamlining," and "ambiguous intermediate" theories), but with little resolution. Here, we report a novel sense codon reassignment in Pachysolen tannophilus, a yeast related to the Pichiaceae. By generating proteomics data and using tRNA sequence comparisons, we show that Pachysolen translates CUG codons as alanine and not as the more usual leucine. The Pachysolen tRNACAG is an anticodon-mutated tRNA(Ala) containing all major alanine tRNA recognition sites. The polyphyly of the CUG-decoding tRNAs in yeasts is best explained by a tRNA loss driven codon reassignment mechanism. Loss of the CUG-tRNA in the ancient yeast is followed by gradual decrease of respective codons and subsequent codon capture by tRNAs whose anticodon is not part of the aminoacyl-tRNA synthetase recognition region. Our hypothesis applies to all nuclear genetic code alterations and provides several testable predictions. We anticipate more codon reassignments to be uncovered in existing and upcoming genome projects. © 2016 Mühlhausen et al.; Published by Cold Spring Harbor Laboratory Press.

  3. Implications of Genetic and Epigenetic Alterations of CDKN2A (p16INK4a in Cancer

    Directory of Open Access Journals (Sweden)

    Ran Zhao

    2016-06-01

    Full Text Available Aberrant gene silencing is highly associated with altered cell cycle regulation during carcinogenesis. In particular, silencing of the CDKN2A tumor suppressor gene, which encodes the p16INK4a protein, has a causal link with several different types of cancers. The p16INK4a protein plays an executional role in cell cycle and senescence through the regulation of the cyclin-dependent kinase (CDK 4/6 and cyclin D complexes. Several genetic and epigenetic aberrations of CDKN2A lead to enhanced tumorigenesis and metastasis with recurrence of cancer and poor prognosis. In these cases, the restoration of genetic and epigenetic reactivation of CDKN2A is a practical approach for the prevention and therapy of cancer. This review highlights the genetic status of CDKN2A as a prognostic and predictive biomarker in various cancers.

  4. Impact of genetic variations in C-C chemokine receptors and ligands on infectious diseases.

    Science.gov (United States)

    Qidwai, Tabish; Khan, M Y

    2016-10-01

    Chemokine receptors and ligands are crucial for extensive immune response against infectious diseases such as malaria, leishmaniasis, HIV and tuberculosis and a wide variety of other diseases. Role of chemokines are evidenced in the activation and regulation of immune cell migration which is important for immune response against diseases. Outcome of disease is determined by complex interaction among pathogen, host genetic variability and surrounding milieu. Variation in expression or function of chemokines caused by genetic polymorphisms could be associated with attenuated immune responses. Exploration of chemokine genetic polymorphisms in therapeutic response, gene regulation and disease outcome is important. Infectious agents in human host alter the expression of chemokines via epigenetic alterations and thus contribute to disease pathogenesis. Although some fragmentary data are available on chemokine genetic variations and their contribution in diseases, no unequivocal conclusion has been arrived as yet. We therefore, aim to investigate the association of CCR5-CCL5 and CCR2-CCL2 genetic polymorphisms with different infectious diseases, transcriptional regulation of gene, disease severity and response to therapy. Furthermore, the role of epigenetics in genes related to chemokines and infectious disease are also discussed. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  5. Why do some like it hot? Genetic and environmental contributions to the pleasantness of oral pungency.

    Science.gov (United States)

    Törnwall, Outi; Silventoinen, Karri; Kaprio, Jaakko; Tuorila, Hely

    2012-10-10

    Although potential environmental influences on hedonic responses to oral pungency have been identified, little is known of the possible role of genetics underlying these responses. We explored the contribution of genetic and environmental influences on the pleasantness of oral pungency and spicy foods. Respondents were young adult Finnish twins (n=331, 21-25 years), including 47 complete monozygotic and 93 dizygotic twin pairs and 51 twin individuals without their co-twin. Pleasantness and intensity of strawberry jelly spiked with capsaicin (0.0001% w/v) relative to untainted strawberry jelly were rated. Furthermore, pleasantness of spicy foods and oral pungency caused by spices were rated based on food names in a questionnaire. Respondents were grouped as non-likers, medium-likers, and likers by their pleasantness responses to capsaicin spiked jelly. The contribution of genetic and environmental factors to variation and co-variation of the pleasantness traits was analyzed using quantitative genetic modeling. The non-likers perceived oral pungency as more intense (sensory) and rated pleasantness of spicy foods and pungent sensations caused by spices (questionnaire) as less pleasant than the likers. Genetic factors accounted for 18-58% of the variation in the pleasantness of oral pungency, spicy foods and pungent sensations. The rest was due to environmental factors. All pleasantness traits (sensory and questionnaire based) were shown to share a common genetic variance. This indicates that an underlying genetic aptitude to like oral pungency, and spicy foods exists and it is expressed in these measures. The findings broaden the understanding of the diverse nature of individual food preferences and motivate further search for the underlying genetic components of oral pungency. Copyright © 2012. Published by Elsevier Inc.

  6. Contribution of silent mutations to thermal adaptation of RNA bacteriophage Qβ.

    Science.gov (United States)

    Kashiwagi, Akiko; Sugawara, Ryu; Sano Tsushima, Fumie; Kumagai, Tomofumi; Yomo, Tetsuya

    2014-10-01

    Changes in protein function and other biological properties, such as RNA structure, are crucial for adaptation of organisms to novel or inhibitory environments. To investigate how mutations that do not alter amino acid sequence may be positively selected, we performed a thermal adaptation experiment using the single-stranded RNA bacteriophage Qβ in which the culture temperature was increased from 37.2°C to 41.2°C and finally to an inhibitory temperature of 43.6°C in a stepwise manner in three independent lines. Whole-genome analysis revealed 31 mutations, including 14 mutations that did not result in amino acid sequence alterations, in this thermal adaptation. Eight of the 31 mutations were observed in all three lines. Reconstruction and fitness analyses of Qβ strains containing only mutations observed in all three lines indicated that five mutations that did not result in amino acid sequence changes but increased the amplification ratio appeared in the course of adaptation to growth at 41.2°C. Moreover, these mutations provided a suitable genetic background for subsequent mutations, altering the fitness contribution from deleterious to beneficial. These results clearly showed that mutations that do not alter the amino acid sequence play important roles in adaptation of this single-stranded RNA virus to elevated temperature. Recent studies using whole-genome analysis technology suggested the importance of mutations that do not alter the amino acid sequence for adaptation of organisms to novel environmental conditions. It is necessary to investigate how these mutations may be positively selected and to determine to what degree such mutations that do not alter amino acid sequences contribute to adaptive evolution. Here, we report the roles of these silent mutations in thermal adaptation of RNA bacteriophage Qβ based on experimental evolution during which Qβ showed adaptation to growth at an inhibitory temperature. Intriguingly, four synonymous mutations and

  7. Contribution of VPS35 genetic variability to LBD in the Flanders-Belgian population

    NARCIS (Netherlands)

    Verstraeten, Aline; Wauters, Eline; Crosiers, David; Meeus, Bram; Corsmit, Ellen; Elinck, Ellen; Mattheijssens, Maria; Peeters, Karin; Cras, Patrick; Pickut, Barbara; Vandenberghe, Rik; Engelborghs, Sebastiaan; De Deyn, Peter Paul; Van Broeckhoven, Christine; Theuns, Jessie

    VPS35 was recently identified as a novel autosomal dominant gene for Parkinson disease. In this study, we aimed to determine the contribution of simple and complex VPS35 variations to the genetic etiology of the spectrum of Lewy body disorders (LBD) in a Flanders-Belgian patient cohort (n = 677). We

  8. Relations of mitochondrial genetic variants to measures of vascular function.

    Science.gov (United States)

    Fetterman, Jessica L; Liu, Chunyu; Mitchell, Gary F; Vasan, Ramachandran S; Benjamin, Emelia J; Vita, Joseph A; Hamburg, Naomi M; Levy, Daniel

    2018-05-01

    Mitochondrial genetic variation with resultant alterations in oxidative phosphorylation may influence vascular function and contribute to cardiovascular disease susceptibility. We assessed relations of peptide-encoding variants in the mitochondrial genome with measures of vascular function in Framingham Heart Study participants. Of 258 variants assessed, 40 were predicted to have functional consequences by bioinformatics programs. A maternal pattern of heritability was estimated to contribute to the variability of aortic stiffness. A putative association with a microvascular function measure was identified that requires replication. The methods we have developed can be applied to assess the relations of mitochondrial genetic variation to other phenotypes. Copyright © 2017 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

  9. Epigenetic Alterations in Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Johannes eGräff

    2015-12-01

    Full Text Available Alzheimer’s disease (AD is the major cause of dementia in Western societies. It progresses asymptomatically during decades before being belatedly diagnosed when therapeutic strategies have become unviable. Although several genetic alterations have been associated with AD, the vast majority of AD cases do not show strong genetic underpinnings and are thus considered a consequence of non-genetic factors. Epigenetic mechanisms allow for the integration of long-lasting non-genetic inputs on specific genetic backgrounds, and recently, a growing number of epigenetic alterations in AD have been described. For instance, an accumulation of dysregulated epigenetic mechanisms in aging, the predominant risk factor of AD, might facilitate the onset of the disease. Likewise, mutations in several enzymes of the epigenetic machinery have been associated with neurodegenerative processes that are altered in AD such as impaired learning and memory formation. Genome-wide and locus-specific epigenetic alterations have also been reported, and several epigenetically dysregulated genes validated by independent groups. From these studies, a picture emerges of AD as being associated with DNA hypermethylation and histone deacetylation, suggesting a general repressed chromatin state and epigenetically reduced plasticity in AD. Here we review these recent findings and discuss several technical and methodological considerations that are imperative for their correct interpretation. We also pay particular focus on potential implementations and theoretical frameworks that we expect will help to better direct future studies aimed to unravel the epigenetic participation in AD.

  10. Epigenetic Alterations in Alzheimer's Disease.

    Science.gov (United States)

    Sanchez-Mut, Jose V; Gräff, Johannes

    2015-01-01

    Alzheimer's disease (AD) is the major cause of dementia in Western societies. It progresses asymptomatically during decades before being belatedly diagnosed when therapeutic strategies have become unviable. Although several genetic alterations have been associated with AD, the vast majority of AD cases do not show strong genetic underpinnings and are thus considered a consequence of non-genetic factors. Epigenetic mechanisms allow for the integration of long-lasting non-genetic inputs on specific genetic backgrounds, and recently, a growing number of epigenetic alterations in AD have been described. For instance, an accumulation of dysregulated epigenetic mechanisms in aging, the predominant risk factor of AD, might facilitate the onset of the disease. Likewise, mutations in several enzymes of the epigenetic machinery have been associated with neurodegenerative processes that are altered in AD such as impaired learning and memory formation. Genome-wide and locus-specific epigenetic alterations have also been reported, and several epigenetically dysregulated genes validated by independent groups. From these studies, a picture emerges of AD as being associated with DNA hypermethylation and histone deacetylation, suggesting a general repressed chromatin state and epigenetically reduced plasticity in AD. Here we review these recent findings and discuss several technical and methodological considerations that are imperative for their correct interpretation. We also pay particular focus on potential implementations and theoretical frameworks that we expect will help to better direct future studies aimed to unravel the epigenetic participation in AD.

  11. Genetic Alterations in Pesticide Exposed Bolivian Farmers

    DEFF Research Database (Denmark)

    Jørs, Erik; González, Ana Rosa; Ascarrunz, Maria Eugenia

    2007-01-01

    : Questionnaires were applied and blood tests taken from 81 volunteers from La Paz County, of whom 48 were pesticide exposed farmers and 33 non-exposed controls. Sixty males and 21 females participated with a mean age of 37.3 years (range 17-76). Data of exposure and possible genetic damage were collected...... and evaluated by well known statistical methods, controlling for relevant confounders. To measure genetic damage chromosomal aberrations and the comet assay analysis were performed. Results: Pesticide exposed farmers had a higher degree of genetic damage compared to the control group. The number of chromosomal......, probably related to exposure to pesticides. Due to the potentially negative long term health effects of genetic damage on reproduction and the development of cancer, preventive measures are recommended. Effective control with imports and sales, banning of the most toxic pesticides, education...

  12. Paternal genetic contribution influences fetal vulnerability to maternal alcohol consumption in a rat model of fetal alcohol spectrum disorder.

    Directory of Open Access Journals (Sweden)

    Laura J Sittig

    2010-04-01

    Full Text Available Fetal alcohol exposure causes in the offspring a collection of permanent physiological and neuropsychological deficits collectively termed Fetal Alcohol Spectrum Disorder (FASD. The timing and amount of exposure cannot fully explain the substantial variability among affected individuals, pointing to genetic influences that mediate fetal vulnerability. However, the aspects of vulnerability that depend on the mother, the father, or both, are not known.Using the outbred Sprague-Dawley (SD and inbred Brown Norway (BN rat strains as well as their reciprocal crosses, we administered ethanol (E, pair-fed (PF, or control (C diets to the pregnant dams. The dams' plasma levels of free thyroxine (fT4, triiodothyronine (T3, free T3 (fT3, and thyroid stimulating hormone (TSH were measured to elucidate potential differences in maternal thyroid hormonal environment, which affects specific aspects of FASD. We then compared alcohol-exposed, pair fed, and control offspring of each fetal strain on gestational day 21 (G21 to identify maternal and paternal genetic effects on bodyweight and placental weight of male and female fetuses.SD and BN dams exhibited different baseline hypothalamic-pituitary-thyroid function. Moreover, the thyroid function of SD dams was more severely affected by alcohol consumption while that of BN dams was relatively resistant. This novel finding suggests that genetic differences in maternal thyroid function are one source of maternal genetic effects on fetal vulnerability to FASD. The fetal vulnerability to decreased bodyweight after alcohol exposure depended on the genetic contribution of both parents, not only maternal contribution as previously thought. In contrast, the effect of maternal alcohol consumption on placental weight was consistent and not strain-dependent. Interestingly, placental weight in fetuses with different paternal genetic contributions exhibited opposite responses to caloric restriction (pair feeding. In summary

  13. Estimating host genetic effects on susceptibility and infectivity to infectious diseases and their contribution to response to selection

    NARCIS (Netherlands)

    Anche, M.T.

    2016-01-01

    Mahlet Teka Anche. (2016). Estimating host genetic effects on susceptibility and infectivity to infectious diseases and their contribution to response to selection. PhD thesis, Wageningen University, the Netherlands

    Genetic approaches aiming to reduce the prevalence of an infection in a

  14. Altered TGF-β endocytic trafficking contributes to the increased signaling in Marfan syndrome.

    Science.gov (United States)

    Siegert, Anna-Maria; Serra-Peinado, Carla; Gutiérrez-Martínez, Enric; Rodríguez-Pascual, Fernando; Fabregat, Isabel; Egea, Gustavo

    2018-02-01

    The main cardiovascular alteration in Marfan syndrome (MFS) is the formation of aortic aneurysms in which augmented TGF-β signaling is reported. However, the primary role of TGF-β signaling as a molecular link between the genetic mutation of fibrillin-1 and disease onset is controversial. The compartmentalization of TGF-β endocytic trafficking has been shown to determine a signaling response in which clathrin-dependent internalization leads to TGF-β signal propagation, and caveolin-1 (CAV-1) associated internalization leads to signal abrogation. We here studied the contribution of endocytic trafficking compartmentalization to increased TGF-β signaling in vascular smooth muscle cells (VSMC) from MFS patients. We examined molecular components involved in clathrin- (SARA, SMAD2) and caveolin-1- (SMAD7, SMURF2) dependent endocytosis. Marfan VSMC showed higher recruitment of SARA and SMAD2 to membranes and their increased interaction with TGF-β receptor II, as well as higher colocalization of SARA with the early endosome marker EEA1. We assessed TGF-β internalization using a biotinylated ligand (b-TGF-β), which colocalized equally with either EEA1 or CAV-1 in VSMC from Marfan patients and controls. However, in Marfan cells, colocalization of b-TGF-β with SARA and EEA1 was increased and accompanied by decreased colocalization with CAV-1 at EEA1-positive endosomes. Moreover, Marfan VSMC showed higher transcriptional levels and membrane enrichment of RAB5. Our results indicate that increased RAB5-associated SARA localization to early endosomes facilitates its TGF-β receptor binding and phosphorylation of signaling mediator SMAD2 in Marfan VSMC. This is accompanied by a reduction of TGF-β sorting into multifunctional vesicles containing cargo from both internalization pathways. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Introgression from cultivated rice alters genetic structures of wild relative populations: implications for in situ conservation

    Science.gov (United States)

    Jin, Xin; Chen, Yu; Liu, Ping; Li, Chen; Cai, Xingxing; Rong, Jun

    2018-01-01

    Abstract Maintaining genetic integrity is essential for in situ and ex situ conservation of crop wild relative (CWR) species. However, introgression of crop alleles into CWR species/populations may change their genetic structure and diversity, resulting in more invasive weeds or, in contrast, the extinction of endangered populations. To determine crop-wild introgression and its consequences, we examined the genetic structure and diversity of six wild rice (Oryza rufipogon) populations under in situ conservation in China. Thirty-four simple sequence repeat (SSR) and 34 insertion/deletion markers were used to genotype the wild rice populations and two sets of rice cultivars (O. sativa), corresponding to the two types of molecular markers. Shared alleles and STRUCTURE analyses suggested a variable level of crop-wild introgression and admixture. Principal coordinates and cluster analyses indicated differentiation of wild rice populations, which was associated with the spatial distances to cultivated rice fields. The level of overall genetic diversity was comparable between wild rice populations and rice cultivars, but a great number of wild-specific alleles was detected in the wild populations. We conclude based on the results that crop-wild introgression can considerably alter the pattern of genetic structure and relationships of CWR populations. Appropriate measures should be taken for effective in situ conservation of CWR species under the scenario of crop-wild introgression. PMID:29308123

  16. Genetic and Environmental Contributions to Covariation Between DHEA and Testosterone in Adolescent Twins.

    Science.gov (United States)

    Van Hulle, Carol A; Moore, Mollie N; Shirtcliff, Elizabeth A; Lemery-Chalfant, Kathryn; Goldsmith, H Hill

    2015-05-01

    Although several studies have shown that pubertal tempo and timing are shaped by genetic and environmental factors, few studies consider to what extent endocrine triggers of puberty are shaped by genetic and environmental factors. Doing so moves the field from examining correlated developmentally-sensitive biomarkers toward understanding what drives those associations. Two puberty related hormones, dehydroepiandrosterone and testosterone, were assayed from salivary samples in 118 MZ (62 % female), 111 same sex DZ (46 % female) and 103 opposite-sex DZ twin pairs, aged 12-16 years (M = 13.1, SD = 1.3). Pubertal status was assessed with a composite of mother- and self-reports. We used biometric models to estimate the genetic and environmental influences on the variance and covariance in testosterone and DHEA, with and without controlling for their association with puberty, and to test for sex differences. In males, the variance in testosterone and pubertal status was due to shared and non-shared environmental factors; variation in DHEA was due to genetic and non-shared environmental factors. In females, variance in testosterone was due to genetic and non-shared environmental factors; genetic, shared, and non-shared environmental factors contributed equally to variation in DHEA. In males, the testosterone-DHEA covariance was primarily due to shared environmental factors that overlapped with puberty as well as shared and non-shared environmental covariation specific to testosterone and DHEA. In females, the testosterone-DHEA covariance was due to genetic factors overlapping with pubertal status, and shared and non-shared environmental covariation specific to testosterone and DHEA.

  17. Keloid Scarring: Understanding the Genetic Basis, Advances, and Prospects

    Directory of Open Access Journals (Sweden)

    Ahmad Sukari Halim

    2012-05-01

    Full Text Available Keloid disease is a fibroproliferative dermal tumor with an unknown etiology that occurs after a skin injury in genetically susceptible individuals. Increased familial aggregation, a higher prevalence in certain races, parallelism in identical twins, and alteration in gene expression all favor a remarkable genetic contribution to keloid pathology. It seems that the environment triggers the disease in genetically susceptible individuals. Several genes have been implicated in the etiology of keloid disease, but no single gene mutation has thus far been found to be responsible. Therefore, a combination of methods such as association, gene-gene interaction, epigenetics, linkage, gene expression, and protein analysis should be applied to determine keloid etiology.

  18. Contributions of Function-Altering Variants in Genes Implicated in Pubertal Timing and Body Mass for Self-Limited Delayed Puberty.

    Science.gov (United States)

    Howard, Sasha R; Guasti, Leonardo; Poliandri, Ariel; David, Alessia; Cabrera, Claudia P; Barnes, Michael R; Wehkalampi, Karoliina; O'Rahilly, Stephen; Aiken, Catherine E; Coll, Anthony P; Ma, Marcella; Rimmington, Debra; Yeo, Giles S H; Dunkel, Leo

    2018-02-01

    Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females and voice break in males, particularly in pathways controlling energy balance. We sought to assess the contribution of rare variants in such genes to the phenotype of familial DP. We performed whole-exome sequencing in 67 pedigrees (125 individuals with DP and 35 unaffected controls) from our unique cohort of familial self-limited DP. Using a whole-exome sequencing filtering pipeline one candidate gene [fat mass and obesity-associated gene (FTO)] was identified. In silico, in vitro, and mouse model studies were performed to investigate the pathogenicity of FTO variants and timing of puberty in FTO+/- mice. We identified potentially pathogenic, rare variants in genes in linkage disequilibrium with genome-wide association studies of age at menarche loci in 283 genes. Of these, five genes were implicated in the control of body mass. After filtering for segregation with trait, one candidate, FTO, was retained. Two FTO variants, found in 14 affected individuals from three families, were also associated with leanness in these patients with DP. One variant (p.Leu44Val) demonstrated altered demethylation activity of the mutant protein in vitro. Fto+/- mice displayed a significantly delayed timing of pubertal onset (P puberty in the general population may contribute to the pathogenesis of self-limited DP. Copyright © 2017 Endocrine Society

  19. Alterations of social interaction through genetic and environmental manipulation of the 22q11.2 gene Sept5 in the mouse brain.

    Science.gov (United States)

    Harper, Kathryn M; Hiramoto, Takeshi; Tanigaki, Kenji; Kang, Gina; Suzuki, Go; Trimble, William; Hiroi, Noboru

    2012-08-01

    Social behavior dysfunction is a symptomatic element of schizophrenia and autism spectrum disorder (ASD). Although altered activities in numerous brain regions are associated with defective social cognition and perception, the causative relationship between these altered activities and social cognition and perception-and their genetic underpinnings-are not known in humans. To address these issues, we took advantage of the link between hemizygous deletion of human chromosome 22q11.2 and high rates of social behavior dysfunction, schizophrenia and ASD. We genetically manipulated Sept5, a 22q11.2 gene, and evaluated its role in social interaction in mice. Sept5 deficiency, against a high degree of homogeneity in a congenic genetic background, selectively impaired active affiliative social interaction in mice. Conversely, virally guided overexpression of Sept5 in the hippocampus or, to a lesser extent, the amygdala elevated levels of active affiliative social interaction in C57BL/6J mice. Congenic knockout mice and mice overexpressing Sept5 in the hippocampus or amygdala were indistinguishable from control mice in novelty and olfactory responses, anxiety or motor activity. Moreover, post-weaning individual housing, an environmental condition designed to reduce stress in male mice, selectively raised levels of Sept5 protein in the amygdala and increased active affiliative social interaction in C57BL/6J mice. These findings identify this 22q11.2 gene in the hippocampus and amygdala as a determinant of social interaction and suggest that defective social interaction seen in 22q11.2-associated schizophrenia and ASD can be genetically and environmentally modified by altering this 22q11.2 gene.

  20. Genetic KCa3.1-deficiency produces locomotor hyperactivity and alterations in cerebral monoamine levels

    DEFF Research Database (Denmark)

    Lambertsen, Kate Lykke; Gramsbergen, Jan Bert; Sivasaravanaparan, Mithula

    2012-01-01

    The calmodulin/calcium-activated K(+) channel KCa3.1 is expressed in red and white blood cells, epithelia and endothelia, and possibly central and peripheral neurons. However, our knowledge about its contribution to neurological functions and behavior is incomplete. Here, we investigated whether...... genetic deficiency or pharmacological activation of KCa3.1 change behavior and cerebral monoamine levels in mice....

  1. Genetic contributions to human brain morphology and intelligence

    DEFF Research Database (Denmark)

    Hulshoff Pol, HE; Schnack, HG; Posthuma, D

    2006-01-01

    Variation in gray matter (GM) and white matter (WM) volume of the adult human brain is primarily genetically determined. Moreover, total brain volume is positively correlated with general intelligence, and both share a common genetic origin. However, although genetic effects on morphology...... of specific GM areas in the brain have been studied, the heritability of focal WM is unknown. Similarly, it is unresolved whether there is a common genetic origin of focal GM and WM structures with intelligence. We explored the genetic influence on focal GM and WM densities in magnetic resonance brain images...

  2. Altered amygdalar resting-state connectivity in depression is explained by both genes and environment.

    Science.gov (United States)

    Córdova-Palomera, Aldo; Tornador, Cristian; Falcón, Carles; Bargalló, Nuria; Nenadic, Igor; Deco, Gustavo; Fañanás, Lourdes

    2015-10-01

    Recent findings indicate that alterations of the amygdalar resting-state fMRI connectivity play an important role in the etiology of depression. While both depression and resting-state brain activity are shaped by genes and environment, the relative contribution of genetic and environmental factors mediating the relationship between amygdalar resting-state connectivity and depression remain largely unexplored. Likewise, novel neuroimaging research indicates that different mathematical representations of resting-state fMRI activity patterns are able to embed distinct information relevant to brain health and disease. The present study analyzed the influence of genes and environment on amygdalar resting-state fMRI connectivity, in relation to depression risk. High-resolution resting-state fMRI scans were analyzed to estimate functional connectivity patterns in a sample of 48 twins (24 monozygotic pairs) informative for depressive psychopathology (6 concordant, 8 discordant and 10 healthy control pairs). A graph-theoretical framework was employed to construct brain networks using two methods: (i) the conventional approach of filtered BOLD fMRI time-series and (ii) analytic components of this fMRI activity. Results using both methods indicate that depression risk is increased by environmental factors altering amygdalar connectivity. When analyzing the analytic components of the BOLD fMRI time-series, genetic factors altering the amygdala neural activity at rest show an important contribution to depression risk. Overall, these findings show that both genes and environment modify different patterns the amygdala resting-state connectivity to increase depression risk. The genetic relationship between amygdalar connectivity and depression may be better elicited by examining analytic components of the brain resting-state BOLD fMRI signals. © 2015 Wiley Periodicals, Inc.

  3. Epigenetic Alterations in Alzheimer’s Disease

    Science.gov (United States)

    Sanchez-Mut, Jose V.; Gräff, Johannes

    2015-01-01

    Alzheimer’s disease (AD) is the major cause of dementia in Western societies. It progresses asymptomatically during decades before being belatedly diagnosed when therapeutic strategies have become unviable. Although several genetic alterations have been associated with AD, the vast majority of AD cases do not show strong genetic underpinnings and are thus considered a consequence of non-genetic factors. Epigenetic mechanisms allow for the integration of long-lasting non-genetic inputs on specific genetic backgrounds, and recently, a growing number of epigenetic alterations in AD have been described. For instance, an accumulation of dysregulated epigenetic mechanisms in aging, the predominant risk factor of AD, might facilitate the onset of the disease. Likewise, mutations in several enzymes of the epigenetic machinery have been associated with neurodegenerative processes that are altered in AD such as impaired learning and memory formation. Genome-wide and locus-specific epigenetic alterations have also been reported, and several epigenetically dysregulated genes validated by independent groups. From these studies, a picture emerges of AD as being associated with DNA hypermethylation and histone deacetylation, suggesting a general repressed chromatin state and epigenetically reduced plasticity in AD. Here we review these recent findings and discuss several technical and methodological considerations that are imperative for their correct interpretation. We also pay particular focus on potential implementations and theoretical frameworks that we expect will help to better direct future studies aimed to unravel the epigenetic participation in AD. PMID:26734709

  4. Altering BDNF expression by genetics and/or environment: impact for emotional and depression-like behaviour in laboratory mice.

    Science.gov (United States)

    Chourbaji, Sabine; Brandwein, Christiane; Gass, Peter

    2011-01-01

    According to the "neurotrophin hypothesis", brain-derived neurotrophic factor (BDNF) is an important candidate gene in depression. Moreover, environmental stress is known to represent a risk factor in the pathophysiology and treatment of this disease. To elucidate, whether changes of BDNF availability signify cause or consequence of depressive-like alterations, it is essential to look for endophenotypes under distinct genetic conditions (e.g. altered BDNF expression). Furthermore it is crucial to examine environment-driven BDNF regulation and its effect on depressive-linked features. Consequently, gene × environment studies investigating prospective genetic mouse models of depression in different environmental contexts become increasingly important. The present review summarizes recent findings in BDNF-mutant mice, which have been controversially discussed as models of depression and anxiety. It furthermore illustrates the potential of environment to serve as naturalistic stressor with the potential to modulate the phenotype in wildtype and mutant mice. Moreover, environment may exert protective effects by regulating BDNF levels as attributed to "environmental enrichment". The effect of this beneficial condition will also be discussed with regard to probable "curative/therapeutic" approaches. Copyright © 2010 Elsevier Ltd. All rights reserved.

  5. Contribution of the genetic improvement to the development of the cultivation of Colombian coffee

    International Nuclear Information System (INIS)

    Moreno Ruiz, German

    1994-01-01

    After several years of study trying to obtain a variety of resistant coffee to the Rust, the variety Colombia was obtained, which is considered as the contribution more important that has made the genetic improvement to the cultivation of Colombian coffee and consequently to optimize the cultivations and to improve the environment

  6. Genetic alterations in lung cancer: Assessing limitations in routine clinical use

    Directory of Open Access Journals (Sweden)

    Joana Espiga Macedo

    2007-01-01

    Full Text Available Lung cancer is the most frequent cause of cancer mortality worldwide, responsible for approximately 1.1 million deaths per year. Median survival is short, both as most tumours are diagnosed at an advanced stage and because of the limited efficacy of available treatments. The development of tumour molecular genetics carries the promise of altering this state of affairs, as it should lead to a more precise classification of tumours, identify specific molecular targets for therapy and, above all, allow the development of new methods for early diagnosis. Despite numerous studies demonstrating the usefulness of molecular genetic techniques in the study of lung cancer, its routine clinical use in Portugal has, however, been limited.In this study, we used a p53 mutation screen in multiple clinical samples from a series of lung cancer patients to attempt to identify the main practical limitations to the integration of molecular genetics in routine clinical practice. Our results suggest that the main limiting factor is the availability of samples with good quality DNA; a problem that could be overcome by alterations in common sample collection and storage procedures. Resumo: O cancro do pulmão é a causa mais frequente de mortalidade por cancro no mundo, sendo responsável por cerca de 1,1 milhões de mortes por ano. A sobrevivência média dos doentes é geralmente curta, por a doença se encontrar em estádios avançados na altura do diagnóstico, mas também devido à falta de eficácia dos tratamentos disponíveis. O advento da genética molecular dos tumores trouxe consigo a possibilidade de modificar esta situação, quer através do refinamento do diagnóstico, quer da identificação de alvos terapêuticos específicos, quer sobretudo por – pelo menos em teoria – permitir o diagnóstico precoce da doença. No entanto, e apesar de numerosos trabalhos terem já demonstrado a utilidade

  7. Genetic deletion of Mst1 alters T cell function and protects against autoimmunity.

    Directory of Open Access Journals (Sweden)

    Konstantin V Salojin

    Full Text Available Mammalian sterile 20-like kinase 1 (Mst1 is a MAPK kinase kinase kinase which is involved in a wide range of cellular responses, including apoptosis, lymphocyte adhesion and trafficking. The contribution of Mst1 to Ag-specific immune responses and autoimmunity has not been well defined. In this study, we provide evidence for the essential role of Mst1 in T cell differentiation and autoimmunity, using both genetic and pharmacologic approaches. Absence of Mst1 in mice reduced T cell proliferation and IL-2 production in vitro, blocked cell cycle progression, and elevated activation-induced cell death in Th1 cells. Mst1 deficiency led to a CD4+ T cell development path that was biased toward Th2 and immunoregulatory cytokine production with suppressed Th1 responses. In addition, Mst1-/- B cells showed decreased stimulation to B cell mitogens in vitro and deficient Ag-specific Ig production in vivo. Consistent with altered lymphocyte function, deletion of Mst1 reduced the severity of experimental autoimmune encephalomyelitis (EAE and protected against collagen-induced arthritis development. Mst1-/- CD4+ T cells displayed an intrinsic defect in their ability to respond to encephalitogenic antigens and deletion of Mst1 in the CD4+ T cell compartment was sufficient to alleviate CNS inflammation during EAE. These findings have prompted the discovery of novel compounds that are potent inhibitors of Mst1 and exhibit desirable pharmacokinetic properties. In conclusion, this report implicates Mst1 as a critical regulator of adaptive immune responses, Th1/Th2-dependent cytokine production, and as a potential therapeutic target for immune disorders.

  8. Genetic Contributions to Clinical Pain and Analgesia: Avoiding Pitfalls in Genetic Research

    Science.gov (United States)

    Kim, Hyungsuk; Clark, David; Dionne, Raymond A.

    2010-01-01

    Understanding the genetic basis of human variations in pain is critical to elucidating the molecular basis of pain sensitivity, variable responses to analgesic drugs, and, ultimately, to individualized treatment of pain and improved public health. With the help of recently accumulated knowledge and advanced technologies, pain researchers hope to gain insight into genetic mechanisms of pain and eventually apply this knowledge to pain treatment. Perspective We critically reviewed the published literature to examine the strength of evidence supporting genetic influences on clinical and human experimental pain. Based on this evidence and the experience of false associations that have occurred in other related disciplines, we provide recommendations for avoiding pitfalls in pain genetic research. PMID:19559388

  9. Drug-induced and genetic alterations in stress-responsive systems: Implications for specific addictive diseases.

    Science.gov (United States)

    Zhou, Yan; Proudnikov, Dmitri; Yuferov, Vadim; Kreek, Mary Jeanne

    2010-02-16

    From the earliest work in our laboratory, we hypothesized, and with studies conducted in both clinical research and animal models, we have shown that drugs of abuse, administered or self-administered, on a chronic basis, profoundly alter stress-responsive systems. Alterations of expression of specific genes involved in stress responsivity, with increases or decreases in mRNA levels, receptor, and neuropeptide levels, and resultant changes in hormone levels, have been documented to occur after chronic intermittent exposure to heroin, morphine, other opiates, cocaine, other stimulants, and alcohol in animal models and in human molecular genetics. The best studied of the stress-responsive systems in humans and mammalian species in general is undoubtedly the HPA axis. In addition, there are stress-responsive systems in other parts in the brain itself, and some of these include components of the HPA axis, such as CRF and CRF receptors, along with POMC gene and gene products. Several other stress-responsive systems are known to influence the HPA axis, such as the vasopressin-vasopressin receptor system. Orexin-hypocretin, acting at its receptors, may effect changes which suggest that it should be properly categorized as a stress-responsive system. However, less is known about the interactions and connectivity of some of these different neuropeptide and receptor systems, and in particular, about the possible connectivity of fast-acting (e.g., glutamate and GABA) and slow-acting (including dopamine, serotonin, and norepinephrine) neurotransmitters with each of these stress-responsive components and the resultant impact, especially in the setting of chronic exposure to drugs of abuse. Several of these stress-responsive systems and components, primarily based on our laboratory-based and human molecular genetics research of addictive diseases, will be briefly discussed in this review. Copyright 2009 Elsevier B.V. All rights reserved.

  10. Genetic Alterations in the Molecular Subtypes of Bladder Cancer: Illustration in the Cancer Genome Atlas Dataset.

    Science.gov (United States)

    Choi, Woonyoung; Ochoa, Andrea; McConkey, David J; Aine, Mattias; Höglund, Mattias; Kim, William Y; Real, Francisco X; Kiltie, Anne E; Milsom, Ian; Dyrskjøt, Lars; Lerner, Seth P

    2017-09-01

    Recent whole genome mRNA expression profiling studies revealed that bladder cancers can be grouped into molecular subtypes, some of which share clinical properties and gene expression patterns with the intrinsic subtypes of breast cancer and the molecular subtypes found in other solid tumors. The molecular subtypes in other solid tumors are enriched with specific mutations and copy number aberrations that are thought to underlie their distinct progression patterns, and biological and clinical properties. The availability of comprehensive genomic data from The Cancer Genome Atlas (TCGA) and other large projects made it possible to correlate the presence of DNA alterations with tumor molecular subtype membership. Our overall goal was to determine whether specific DNA mutations and/or copy number variations are enriched in specific molecular subtypes. We used the complete TCGA RNA-seq dataset and three different published classifiers developed by our groups to assign TCGA's bladder cancers to molecular subtypes, and examined the prevalence of the most common DNA alterations within them. We interpreted the results against the background of what was known from the published literature about the prevalence of these alterations in nonmuscle-invasive and muscle-invasive bladder cancers. The results confirmed that alterations involving RB1 and NFE2L2 were enriched in basal cancers, whereas alterations involving FGFR3 and KDM6A were enriched in luminal tumors. The results further reinforce the conclusion that the molecular subtypes of bladder cancer are distinct disease entities with specific genetic alterations. Our observation showed that some of subtype-enriched mutations and copy number aberrations are clinically actionable, which has direct implications for the clinical management of patients with bladder cancer. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  11. Disease and genetic contributions toward local tissue volume disturbances in schizophrenia: a tensor-based morphometry study.

    Science.gov (United States)

    Yang, Yaling; Nuechterlein, Keith H; Phillips, Owen R; Gutman, Boris; Kurth, Florian; Dinov, Ivo; Thompson, Paul M; Asarnow, Robert F; Toga, Arthur W; Narr, Katherine L

    2012-09-01

    Structural brain deficits, especially frontotemporal volume reduction and ventricular enlargement, have been repeatedly reported in patients with schizophrenia. However, it remains unclear whether brain structural deformations may be attributable to disease-related or genetic factors. In this study, the structural magnetic resonance imaging data of 48 adult-onset schizophrenia patients, 65 first-degree nonpsychotic relatives of schizophrenia patients, 27 community comparison (CC) probands, and 73 CC relatives were examined using tensor-based morphometry (TBM) to isolate global and localized differences in tissue volume across the entire brain between groups. We found brain tissue contractions most prominently in frontal and temporal regions and expansions in the putamen/pallidum, and lateral and third ventricles in schizophrenia patients when compared with unrelated CC probands. Results were similar, though less prominent when patients were compared with their nonpsychotic relatives. Structural deformations observed in unaffected patient relatives compared to age-similar CC relatives were suggestive of schizophrenia-related genetic liability and were pronounced in the putamen/pallidum and medial temporal regions. Schizophrenia and genetic liability effects for the putamen/pallidum were confirmed by regions-of-interest analysis. In conclusion, TBM findings complement reports of frontal, temporal, and ventricular dysmorphology in schizophrenia and further indicate that putamen/pallidum enlargements, originally linked mainly with medication exposure in early studies, also reflect a genetic predisposition for schizophrenia. Thus, brain deformation profiles revealed in this study may help to clarify the role of specific genetic or environmental risk factors toward altered brain morphology in schizophrenia.

  12. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability.

    Science.gov (United States)

    Colotta, Francesco; Allavena, Paola; Sica, Antonio; Garlanda, Cecilia; Mantovani, Alberto

    2009-07-01

    Inflammatory conditions in selected organs increase the risk of cancer. An inflammatory component is present also in the microenvironment of tumors that are not epidemiologically related to inflammation. Recent studies have begun to unravel molecular pathways linking inflammation and cancer. In the tumor microenvironment, smoldering inflammation contributes to proliferation and survival of malignant cells, angiogenesis, metastasis, subversion of adaptive immunity, reduced response to hormones and chemotherapeutic agents. Recent data suggest that an additional mechanism involved in cancer-related inflammation (CRI) is induction of genetic instability by inflammatory mediators, leading to accumulation of random genetic alterations in cancer cells. In a seminal contribution, Hanahan and Weinberg [(2000) Cell, 100, 57-70] identified the six hallmarks of cancer. We surmise that CRI represents the seventh hallmark.

  13. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

    Science.gov (United States)

    Whitcomb, David C.; LaRusch, Jessica; Krasinskas, Alyssa M.; Klei, Lambertus; Smith, Jill P.; Brand, Randall E.; Neoptolemos, John P.; Lerch, Markus M.; Tector, Matt; Sandhu, Bimaljit S.; Guda, Nalini M.; Orlichenko, Lidiya; Alkaade, Samer; Amann, Stephen T.; Anderson, Michelle A.; Baillie, John; Banks, Peter A.; Conwell, Darwin; Coté, Gregory A.; Cotton, Peter B.; DiSario, James; Farrer, Lindsay A.; Forsmark, Chris E.; Johnstone, Marianne; Gardner, Timothy B.; Gelrud, Andres; Greenhalf, William; Haines, Jonathan L.; Hartman, Douglas J.; Hawes, Robert A.; Lawrence, Christopher; Lewis, Michele; Mayerle, Julia; Mayeux, Richard; Melhem, Nadine M.; Money, Mary E.; Muniraj, Thiruvengadam; Papachristou, Georgios I.; Pericak-Vance, Margaret A.; Romagnuolo, Joseph; Schellenberg, Gerard D.; Sherman, Stuart; Simon, Peter; Singh, Vijay K.; Slivka, Adam; Stolz, Donna; Sutton, Robert; Weiss, Frank Ulrich; Wilcox, C. Mel; Zarnescu, Narcis Octavian; Wisniewski, Stephen R.; O'Connell, Michael R.; Kienholz, Michelle L.; Roeder, Kathryn; Barmada, M. Michael; Yadav, Dhiraj; Devlin, Bernie; Albert, Marilyn S.; Albin, Roger L.; Apostolova, Liana G.; Arnold, Steven E.; Baldwin, Clinton T.; Barber, Robert; Barnes, Lisa L.; Beach, Thomas G.; Beecham, Gary W.; Beekly, Duane; Bennett, David A.; Bigio, Eileen H.; Bird, Thomas D.; Blacker, Deborah; Boxer, Adam; Burke, James R.; Buxbaum, Joseph D.; Cairns, Nigel J.; Cantwell, Laura B.; Cao, Chuanhai; Carney, Regina M.; Carroll, Steven L.; Chui, Helena C.; Clark, David G.; Cribbs, David H.; Crocco, Elizabeth A.; Cruchaga, Carlos; DeCarli, Charles; Demirci, F. Yesim; Dick, Malcolm; Dickson, Dennis W.; Duara, Ranjan; Ertekin-Taner, Nilufer; Faber, Kelley M.; Fallon, Kenneth B.; Farlow, Martin R.; Ferris, Steven; Foroud, Tatiana M.; Frosch, Matthew P.; Galasko, Douglas R.; Ganguli, Mary; Gearing, Marla; Geschwind, Daniel H.; Ghetti, Bernardino; Gilbert, John R.; Gilman, Sid; Glass, Jonathan D.; Goate, Alison M.; Graff-Radford, Neill R.; Green, Robert C.; Growdon, John H.; Hakonarson, Hakon; Hamilton-Nelson, Kara L.; Hamilton, Ronald L.; Harrell, Lindy E.; Head, Elizabeth; Honig, Lawrence S.; Hulette, Christine M.; Hyman, Bradley T.; Jicha, Gregory A.; Jin, Lee-Way; Jun, Gyungah; Kamboh, M. Ilyas; Karydas, Anna; Kaye, Jeffrey A.; Kim, Ronald; Koo, Edward H.; Kowall, Neil W.; Kramer, Joel H.; Kramer, Patricia; Kukull, Walter A.; LaFerla, Frank M.; Lah, James J.; Leverenz, James B.; Levey, Allan I.; Li, Ge; Lin, Chiao-Feng; Lieberman, Andrew P.; Lopez, Oscar L.; Lunetta, Kathryn L.; Lyketsos, Constantine G.; Mack, Wendy J.; Marson, Daniel C.; Martin, Eden R.; Martiniuk, Frank; Mash, Deborah C.; Masliah, Eliezer; McKee, Ann C.; Mesulam, Marsel; Miller, Bruce L.; Miller, Carol A.; Miller, Joshua W.; Montine, Thomas J.; Morris, John C.; Murrell, Jill R.; Naj, Adam C.; Olichney, John M.; Parisi, Joseph E.; Peskind, Elaine; Petersen, Ronald C.; Pierce, Aimee; Poon, Wayne W.; Potter, Huntington; Quinn, Joseph F.; Raj, Ashok; Raskind, Murray; Reiman, Eric M.; Reisberg, Barry; Reitz, Christiane; Ringman, John M.; Roberson, Erik D.; Rosen, Howard J.; Rosenberg, Roger N.; Sano, Mary; Saykin, Andrew J.; Schneider, Julie A.; Schneider, Lon S.; Seeley, William W.; Smith, Amanda G.; Sonnen, Joshua A.; Spina, Salvatore; Stern, Robert A.; Tanzi, Rudolph E.; Trojanowski, John Q.; Troncoso, Juan C.; Tsuang, Debby W.; Valladares, Otto; Van Deerlin, Vivianna M.; Van Eldik, Linda J.; Vardarajan, Badri N.; Vinters, Harry V.; Vonsattel, Jean Paul; Wang, Li-San; Weintraub, Sandra; Welsh-Bohmer, Kathleen A.; Williamson, Jennifer; Woltjer, Randall L.; Wright, Clinton B.; Younkin, Steven G.; Yu, Chang-En; Yu, Lei

    2012-01-01

    Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07. PMID:23143602

  14. Distinct genetic alterations in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Hassan Ashktorab

    Full Text Available BACKGROUND: Colon cancer (CRC development often includes chromosomal instability (CIN leading to amplifications and deletions of large DNA segments. Epidemiological, clinical, and cytogenetic studies showed that there are considerable differences between CRC tumors from African Americans (AAs and Caucasian patients. In this study, we determined genomic copy number aberrations in sporadic CRC tumors from AAs, in order to investigate possible explanations for the observed disparities. METHODOLOGY/PRINCIPAL FINDINGS: We applied genome-wide array comparative genome hybridization (aCGH using a 105k chip to identify copy number aberrations in samples from 15 AAs. In addition, we did a population comparative analysis with aCGH data in Caucasians as well as with a widely publicized list of colon cancer genes (CAN genes. There was an average of 20 aberrations per patient with more amplifications than deletions. Analysis of DNA copy number of frequently altered chromosomes revealed that deletions occurred primarily in chromosomes 4, 8 and 18. Chromosomal duplications occurred in more than 50% of cases on chromosomes 7, 8, 13, 20 and X. The CIN profile showed some differences when compared to Caucasian alterations. CONCLUSIONS/SIGNIFICANCE: Chromosome X amplification in male patients and chromosomes 4, 8 and 18 deletions were prominent aberrations in AAs. Some CAN genes were altered at high frequencies in AAs with EXOC4, EPHB6, GNAS, MLL3 and TBX22 as the most frequently deleted genes and HAPLN1, ADAM29, SMAD2 and SMAD4 as the most frequently amplified genes. The observed CIN may play a distinctive role in CRC in AAs.

  15. DNA methylation alters transcriptional rates of differentially expressed genes and contributes to pathophysiology in mice fed a high fat diet

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    Pili Zhang

    2017-04-01

    Full Text Available Objective: Overnutrition can alter gene expression patterns through epigenetic mechanisms that may persist through generations. However, it is less clear if overnutrition, for example a high fat diet, modifies epigenetic control of gene expression in adults, or by what molecular mechanisms, or if such mechanisms contribute to the pathology of the metabolic syndrome. Here we test the hypothesis that a high fat diet alters hepatic DNA methylation, transcription and gene expression patterns, and explore the contribution of such changes to the pathophysiology of obesity. Methods: RNA-seq and targeted high-throughput bisulfite DNA sequencing were used to undertake a systematic analysis of the hepatic response to a high fat diet. RT-PCR, chromatin immunoprecipitation and in vivo knockdown of an identified driver gene, Phlda1, were used to validate the results. Results: A high fat diet resulted in the hypermethylation and decreased transcription and expression of Phlda1 and several other genes. A subnetwork of genes associated with Phlda1 was identified from an existing Bayesian gene network that contained numerous hepatic regulatory genes involved in lipid and body weight homeostasis. Hepatic-specific depletion of Phlda1 in mice decreased expression of the genes in the subnetwork, and led to increased oil droplet size in standard chow-fed mice, an early indicator of steatosis, validating the contribution of this gene to the phenotype. Conclusions: We conclude that a high fat diet alters the epigenetics and transcriptional activity of key hepatic genes controlling lipid homeostasis, contributing to the pathophysiology of obesity. Author Video: Author Video Watch what authors say about their articles Keywords: DNA methylation, RNA-seq, Transcription, High fat diet, Liver, Phlda1

  16. Altered expression of MGMT in high-grade gliomas results from the combined effect of epigenetic and genetic aberrations.

    Directory of Open Access Journals (Sweden)

    João Ramalho-Carvalho

    Full Text Available MGMT downregulation in high-grade gliomas (HGG has been mostly attributed to aberrant promoter methylation and is associated with increased sensitivity to alkylating agent-based chemotherapy. However, HGG harboring 10q deletions also benefit from treatment with alkylating agents. Because the MGMT gene is mapped at 10q26, we hypothesized that both epigenetic and genetic alterations might affect its expression and predict response to chemotherapy. To test this hypothesis, promoter methylation and mRNA levels of MGMT were determined by quantitative methylation-specific PCR (qMSP or methylation-specific multiplex ligation dependent probe amplification (MS-MLPA and quantitative RT-PCR, respectively, in a retrospective series of 61 HGG. MGMT/chromosome 10 copy number variations were determined by FISH or MS-MLPA analysis. Molecular findings were correlated with clinical parameters to assess their predictive value. Overall, MGMT methylation ratios assessed by qMSP and MS-MLPA were inversely correlated with mRNA expression levels (best coefficient value obtained with MS-MLPA. By FISH analysis in 68.3% of the cases there was loss of 10q26.1 and in 15% of the cases polysomy was demonstrated; the latter displayed the highest levels of transcript. When genetic and epigenetic data were combined, cases with MGMT promoter methylation and MGMT loss depicted the lowest transcript levels, although an impact in response to alkylating agent chemotherapy was not apparent. Cooperation between epigenetic (promoter methylation and genetic (monosomy, locus deletion changes affecting MGMT in HGG is required for effective MGMT silencing. Hence, evaluation of copy number alterations might add relevant prognostic and predictive information concerning response to alkylating agent-based chemotherapy.

  17. Genetic alterations in syndromes with oral manifestations

    Directory of Open Access Journals (Sweden)

    Krishnamurthy Anuthama

    2013-01-01

    Full Text Available Ever since Gregor Johan Mendel proposed the law of inheritance, genetics has transcended the field of health and has entered all walks of life in its application. Thus, the gene is the pivoting factor for all happenings revolving around it. Knowledge of gene mapping in various diseases would be a valuable tool in prenatally diagnosing the condition and averting the future disability and stigma for the posterity. This article includes an array of genetically determined conditions in patients seen at our college out-patient department with complete manifestation, partial manifestation and array of manifestations not fitting into a particular syndrome.

  18. Genetic Influences on Conduct Disorder

    Science.gov (United States)

    Salvatore, Jessica E.; Dick, Danielle M.

    2016-01-01

    Conduct disorder (CD) is a moderately heritable psychiatric disorder of childhood and adolescence characterized by aggression toward people and animals, destruction of property, deceitfulness or theft, and serious violation of rules. Genome-wide scans using linkage and association methods have identified a number of suggestive genomic regions that are pending replication. A small number of candidate genes (e.g., GABRA2, MAOA, SLC6A4, AVPR1A) are associated with CD related phenotypes across independent studies; however, failures to replicate also exist. Studies of gene-environment interplay show that CD genetic predispositions also contribute to selection into higher-risk environments, and that environmental factors can alter the importance of CD genetic factors and differentially methylate CD candidate genes. The field’s understanding of CD etiology will benefit from larger, adequately powered studies in gene identification efforts; the incorporation of polygenic approaches in gene-environment interplay studies; attention to the mechanisms of risk from genes to brain to behavior; and the use of genetically informative data to test quasi-causal hypotheses about purported risk factors. PMID:27350097

  19. Genetic and caregiving-based contributions to infant attachment: unique associations with distress reactivity and attachment security.

    Science.gov (United States)

    Raby, K Lee; Cicchetti, Dante; Carlson, Elizabeth A; Cutuli, J J; Englund, Michelle M; Egeland, Byron

    2012-09-01

    In the longitudinal study reported here, we examined genetic and caregiving-based contributions to individual differences in infant attachment classifications. For 154 mother-infant pairs, we rated mothers' responsiveness to their 6-month-old infants during naturalistic interactions and classified infants' attachment organization at 12 and 18 months using the Strange Situation procedure. These infants were later genotyped with respect to the serotonin-transporter-linked polymorphic region (5-HTTLPR). Maternal responsiveness uniquely predicted infants' attachment security. Infants' 5-HTTLPR variation uniquely predicted their subtype of attachment security at 12 months and their subtype of attachment insecurity at 12 and 18 months. The short allele for 5-HTTLPR was associated with attachment classifications characterized by higher emotional distress. These findings suggest that 5-HTTLPR variation contributes to infants' emotional reactivity and that the degree to which caregivers are responsive influences how effectively infants use their caregivers for emotion regulation. Theoretical implications for the study of genetic and caregiving influences are discussed.

  20. Dietary Modulation of Gut Microbiota Contributes to Alleviation of Both Genetic and Simple Obesity in Children.

    Science.gov (United States)

    Zhang, Chenhong; Yin, Aihua; Li, Hongde; Wang, Ruirui; Wu, Guojun; Shen, Jian; Zhang, Menghui; Wang, Linghua; Hou, Yaping; Ouyang, Haimei; Zhang, Yan; Zheng, Yinan; Wang, Jicheng; Lv, Xiaofei; Wang, Yulan; Zhang, Feng; Zeng, Benhua; Li, Wenxia; Yan, Feiyan; Zhao, Yufeng; Pang, Xiaoyan; Zhang, Xiaojun; Fu, Huaqing; Chen, Feng; Zhao, Naisi; Hamaker, Bruce R; Bridgewater, Laura C; Weinkove, David; Clement, Karine; Dore, Joel; Holmes, Elaine; Xiao, Huasheng; Zhao, Guoping; Yang, Shengli; Bork, Peer; Nicholson, Jeremy K; Wei, Hong; Tang, Huiru; Zhang, Xiaozhuang; Zhao, Liping

    2015-08-01

    Gut microbiota has been implicated as a pivotal contributing factor in diet-related obesity; however, its role in development of disease phenotypes in human genetic obesity such as Prader-Willi syndrome (PWS) remains elusive. In this hospitalized intervention trial with PWS (n = 17) and simple obesity (n = 21) children, a diet rich in non-digestible carbohydrates induced significant weight loss and concomitant structural changes of the gut microbiota together with reduction of serum antigen load and alleviation of inflammation. Co-abundance network analysis of 161 prevalent bacterial draft genomes assembled directly from metagenomic datasets showed relative increase of functional genome groups for acetate production from carbohydrates fermentation. NMR-based metabolomic profiling of urine showed diet-induced overall changes of host metabotypes and identified significantly reduced trimethylamine N-oxide and indoxyl sulfate, host-bacteria co-metabolites known to induce metabolic deteriorations. Specific bacterial genomes that were correlated with urine levels of these detrimental co-metabolites were found to encode enzyme genes for production of their precursors by fermentation of choline or tryptophan in the gut. When transplanted into germ-free mice, the pre-intervention gut microbiota induced higher inflammation and larger adipocytes compared with the post-intervention microbiota from the same volunteer. Our multi-omics-based systems analysis indicates a significant etiological contribution of dysbiotic gut microbiota to both genetic and simple obesity in children, implicating a potentially effective target for alleviation. Poorly managed diet and genetic mutations are the two primary driving forces behind the devastating epidemic of obesity-related diseases. Lack of understanding of the molecular chain of causation between the driving forces and the disease endpoints retards progress in prevention and treatment of the diseases. We found that children

  1. Recent and projected increases in atmospheric CO2 concentration can enhance gene flow between wild and genetically altered rice (Oryza sativa.

    Directory of Open Access Journals (Sweden)

    Lewis H Ziska

    Full Text Available Although recent and projected increases in atmospheric carbon dioxide can alter plant phenological development, these changes have not been quantified in terms of floral outcrossing rates or gene transfer. Could differential phenological development in response to rising CO(2 between genetically modified crops and wild, weedy relatives increase the spread of novel genes, potentially altering evolutionary fitness? Here we show that increasing CO(2 from an early 20(th century concentration (300 µmol mol(-1 to current (400 µmol mol(-1 and projected, mid-21(st century (600 µmol mol(-1 values, enhanced the flow of genes from wild, weedy rice to the genetically altered, herbicide resistant, cultivated population, with outcrossing increasing from 0.22% to 0.71% from 300 to 600 µmol mol(-1. The increase in outcrossing and gene transfer was associated with differential increases in plant height, as well as greater tiller and panicle production in the wild, relative to the cultivated population. In addition, increasing CO(2 also resulted in a greater synchronicity in flowering times between the two populations. The observed changes reported here resulted in a subsequent increase in rice dedomestication and a greater number of weedy, herbicide-resistant hybrid progeny. Overall, these data suggest that differential phenological responses to rising atmospheric CO(2 could result in enhanced flow of novel genes and greater success of feral plant species in agroecosystems.

  2. Recent and projected increases in atmospheric CO2 concentration can enhance gene flow between wild and genetically altered rice (Oryza sativa).

    Science.gov (United States)

    Ziska, Lewis H; Gealy, David R; Tomecek, Martha B; Jackson, Aaron K; Black, Howard L

    2012-01-01

    Although recent and projected increases in atmospheric carbon dioxide can alter plant phenological development, these changes have not been quantified in terms of floral outcrossing rates or gene transfer. Could differential phenological development in response to rising CO(2) between genetically modified crops and wild, weedy relatives increase the spread of novel genes, potentially altering evolutionary fitness? Here we show that increasing CO(2) from an early 20(th) century concentration (300 µmol mol(-1)) to current (400 µmol mol(-1)) and projected, mid-21(st) century (600 µmol mol(-1)) values, enhanced the flow of genes from wild, weedy rice to the genetically altered, herbicide resistant, cultivated population, with outcrossing increasing from 0.22% to 0.71% from 300 to 600 µmol mol(-1). The increase in outcrossing and gene transfer was associated with differential increases in plant height, as well as greater tiller and panicle production in the wild, relative to the cultivated population. In addition, increasing CO(2) also resulted in a greater synchronicity in flowering times between the two populations. The observed changes reported here resulted in a subsequent increase in rice dedomestication and a greater number of weedy, herbicide-resistant hybrid progeny. Overall, these data suggest that differential phenological responses to rising atmospheric CO(2) could result in enhanced flow of novel genes and greater success of feral plant species in agroecosystems.

  3. Diet- and genetically-induced obesity differentially affect the fecal microbiome and metabolome in Apc1638N mice

    Science.gov (United States)

    Obesity is a risk factor for colorectal cancer (CRC), and alterations in the colonic microbiome and metabolome may be mechanistically involved in this relationship. The relative contribution of diet and obesity per se are unclear. We compared the effect of diet- and genetically-induced obesity on th...

  4. Genetic and Epigenetic Alterations of Brassica nigra Introgression Lines from Somatic Hybridization: A Resource for Cauliflower Improvement.

    Science.gov (United States)

    Wang, Gui-Xiang; Lv, Jing; Zhang, Jie; Han, Shuo; Zong, Mei; Guo, Ning; Zeng, Xing-Ying; Zhang, Yue-Yun; Wang, You-Ping; Liu, Fan

    2016-01-01

    Broad phenotypic variations were obtained previously in derivatives from the asymmetric somatic hybridization of cauliflower "Korso" (Brassica oleracea var. botrytis, 2n = 18, CC genome) and black mustard "G1/1" (Brassica nigra, 2n = 16, BB genome). However, the mechanisms underlying these variations were unknown. In this study, 28 putative introgression lines (ILs) were pre-selected according to a series of morphological (leaf shape and color, plant height and branching, curd features, and flower traits) and physiological (black rot/club root resistance) characters. Multi-color fluorescence in situ hybridization revealed that these plants contained 18 chromosomes derived from "Korso." Molecular marker (65 simple sequence repeats and 77 amplified fragment length polymorphisms) analysis identified the presence of "G1/1" DNA segments (average 7.5%). Additionally, DNA profiling revealed many genetic and epigenetic differences among the ILs, including sequence alterations, deletions, and variation in patterns of cytosine methylation. The frequency of fragments lost (5.1%) was higher than presence of novel bands (1.4%), and the presence of fragments specific to Brassica carinata (BBCC 2n = 34) were common (average 15.5%). Methylation-sensitive amplified polymorphism analysis indicated that methylation changes were common and that hypermethylation (12.4%) was more frequent than hypomethylation (4.8%). Our results suggested that asymmetric somatic hybridization and alien DNA introgression induced genetic and epigenetic alterations. Thus, these ILs represent an important, novel germplasm resource for cauliflower improvement that can be mined for diverse traits of interest to breeders and researchers.

  5. Towards a genetic architecture of cryptic genetic variation

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 84; Issue 3. Towards a genetic architecture of cryptic genetic variation and genetic assimilation: the contribution of K. G. Bateman. Ian Dworkin. Commentary on J. Genet. Classic Volume 84 Issue 3 December 2005 pp 223-226 ...

  6. Genetic variations in the serotoninergic system contribute to amygdala volume in humans

    Directory of Open Access Journals (Sweden)

    Jin eLi

    2015-10-01

    Full Text Available The amygdala plays a critical role in emotion processing and psychiatric disorders associated with emotion dysfunction. Accumulating evidence suggests that amygdala structure is modulated by serotonin-related genes. However, there is a gap between the small contributions of single loci (less than 1% and the reported 63-65% heritability of amygdala structure. To understand the missing heritability, we systematically explored the contribution of serotonin genes on amygdala structure at the gene set level. The present study of 417 healthy Chinese volunteers examined 129 representative polymorphisms in genes from multiple biological mechanisms in the regulation of serotonin neurotransmission. A system-level approach using multiple regression analyses identified that nine SNPs collectively accounted for approximately 8% of the variance in amygdala volume. Permutation analyses showed that the probability of obtaining these findings by chance was low (p=0.043, permuted for 1000 times. Findings showed that serotonin genes contribute moderately to individual differences in amygdala volume in a healthy Chinese sample. These results indicate that the system-level approach can help us to understand the genetic basis of a complex trait such as amygdala structure.

  7. Adults' perceptions of genetic counseling and genetic testing.

    Science.gov (United States)

    Houfek, Julia Fisco; Soltis-Vaughan, Brigette S; Atwood, Jan R; Reiser, Gwendolyn M; Schaefer, G Bradley

    2015-02-01

    This study described the perceptions of genetic counseling and testing of adults (N = 116) attending a genetic education program. Understanding perceptions of genetic counseling, including the importance of counseling topics, will contribute to patient-focused care as clinical genetic applications for common, complex disorders evolve. Participants completed a survey addressing: the importance of genetic counseling topics, benefits and negative effects of genetic testing, and sharing test results. Topics addressing practical information about genetic conditions were rated most important; topics involving conceptual genetic/genomic principles were rated least important. The most frequently identified benefit and negative effect of testing were prevention/early detection/treatment and psychological distress. Participants perceived that they were more likely to share test results with first-degree than other relatives. Findings suggest providing patients with practical information about genetic testing and genetic contributions to disease, while also determining whether their self-care abilities would be enhanced by teaching genetic/genomic principles. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Neuroanatomic alterations and social and communication deficits in monozygotic twins discordant for autism disorder.

    Science.gov (United States)

    Mitchell, Shanti R; Reiss, Allan L; Tatusko, Danielle H; Ikuta, Ichiro; Kazmerski, Dana B; Botti, Jo-Anna C; Burnette, Courtney P; Kates, Wendy R

    2009-08-01

    Investigating neuroanatomic differences in monozygotic twins who are discordant for autism can help unravel the relative contributions of genetics and environment to this pervasive developmental disorder. The authors used magnetic resonance imaging (MRI) to investigate several brain regions of interest in monozygotic twins who varied in degree of phenotypic discordance for narrowly defined autism. The subjects were 14 pairs of monozygotic twins between the ages of 5 and 14 years old and 14 singleton age- and gender-matched typically developing comparison subjects. The monozygotic twin group was a cohort of children with narrowly defined autistic deficits and their co-twins who presented with varying levels of autistic deficits. High-resolution MRIs were acquired and volumetric/area measurements obtained for the frontal lobe, amygdala, and hippocampus and subregions of the prefrontal cortex, corpus callosum, and cerebellar vermis. No neurovolumetric/area differences were found between twin pairs. Relative to typically developing comparison subjects, dorsolateral prefrontal cortex volumes and anterior areas of the corpus callosum were significantly altered in autistic twins, and volumes of the posterior vermis were altered in both autistic twins and co-twins. Intraclass correlation analysis of brain volumes between children with autism and their co-twins indicated that the degree of within-pair neuroanatomic concordance varied with brain region. In the group of subjects with narrowly defined autism only, dorsolateral prefrontal cortex, amygdala, and posterior vermis volumes were significantly associated with the severity of autism based on scores from the Autism Diagnostic Observation Schedule-Generic. These findings support previous research demonstrating alterations in the prefrontal cortex, corpus callosum, and posterior vermis in children with autism and further suggest that alterations are associated with the severity of the autism phenotype. Continued research

  9. Epilepsy in patients with GRIN2A alterations

    DEFF Research Database (Denmark)

    von Stülpnagel, Celina; Ensslen, M; Møller, R S

    2017-01-01

    indicate that children with epilepsy due to pathogenic GRIN2A mutations present with different clinical phenotypes and a spectrum of seizure types in the context of a pharmacoresistant epilepsy providing information for clinicians treating children with this form of genetically determined epileptic......OBJECTIVE: To delineate the genetic, neurodevelopmental and epileptic spectrum associated with GRIN2A alterations with emphasis on epilepsy treatment. METHODS: Retrospective study of 19 patients (7 females; age: 1-38 years; mean 10.1 years) with epilepsy and GRIN2A alteration. Genetic variants were...... classified according to the guidelines and recommendations of the American College of Medical Genetics (ACMG). Clinical findings including epilepsy classification, treatment, EEG findings, early childhood development and neurodevelopmental outcome were collected with an electronic questionnaire. RESULTS: 7...

  10. Salmonella enterica serovars Enteritidis infection alters the indigenous microbiota diversity in young layer chicks

    Directory of Open Access Journals (Sweden)

    Khin Khine Zar Mon

    2015-11-01

    Full Text Available Avian gastrointestinal tracts are highly populated with a diverse array of microorganisms that share a symbiotic relationship with their hosts and contribute to the overall health and disease state of the intestinal tract. The microbiome of the young chick is easily prone to alteration in its composition by both exogenous and endogenous factors especially during the early post-hatch period. The genetic background of the host and exposure to pathogens can impact the diversity of the microbial profile that consequently contributes to the disease progression in the host. The objective of this study was to profile the composition and structure of the gut microbiota in young chickens from two genetically distinct highly inbred lines. Furthermore, the effect of the Salmonella Enteritidis infection on altering the composition makeup of the chicken microbiome was evaluated through the 16S rRNA gene sequencing analysis. One-day-old layer chicks were challenged with S. Enteritidis and the host cecal microbiota profile as well as the degree of susceptibility to Salmonella infection was examined at 2 and 7 days post-infection. Our result indicated that host genotype had a limited effect on resistance to S. Enteritidis infection. Alpha diversity, beta diversity, and overall microbiota composition were analyzed for four factors: host genotype, age, treatment, and post-infection time-points. S. Enteritidis infection in young chicks was found to significantly reduce the overall diversity of the microbiota population with expansion of Enterobacteriaceae family. These changes indicated that Salmonella colonization in the gastrointestinal tract of the chickens has a direct effect on altering the natural development of the gastrointestinal microbiota. The impact of S. Enteritidis infection on microbial communities was also more substantial in late stage of infection. Significant inverse correlation between Enterobacteriaceae and Lachnospiraceae family in both non

  11. Advances in asthma and allergy genetics in 2007.

    Science.gov (United States)

    Vercelli, Donata

    2008-08-01

    This review discusses the main advances in the genetics of asthma and allergy published in the Journal in 2007. The association studies discussed herein addressed 3 main topics: the effect of the environment and gene-environment interactions on asthma/allergy susceptibility, the contribution of T(H)2 immunity gene variants to allergic inflammation, and the role of filaggrin mutations in atopic dermatitis and associated phenotypes. Other articles revealed novel, potentially important candidate genes or confirmed known ones. Collectively, the works published in 2007 reiterate that allergy and asthma are typical complex diseases; that is, they are disorders in which intricate interactions among environmental and genetic factors modify disease susceptibility by altering the fundamental structural and functional properties of target organs at critical developmental windows.

  12. Transforming growth factor-β and breast cancer: Lessons learned from genetically altered mouse models

    International Nuclear Information System (INIS)

    Wakefield, Lalage M; Yang, Yu-an; Dukhanina, Oksana

    2000-01-01

    Transforming growth factor (TGF)-βs are plausible candidate tumor suppressors in the breast. They also have oncogenic activities under certain circumstances, however. Genetically altered mouse models provide powerful tools to analyze the complexities of TGF-βaction in the context of the whole animal. Overexpression of TGF-β can suppress tumorigenesis in the mammary gland, raising the possibility that use of pharmacologic agents to enhance TGF-β function locally might be an effective method for the chemoprevention of breast cancer. Conversely, loss of TGF-β response increases spontaneous and induced tumorigenesis in the mammary gland. This confirms that endogenous TGF-βs have tumor suppressor activity in the mammary gland, and suggests that the loss of TGF-β receptors seen in some human breast hyperplasias may play a causal role in tumor development

  13. Altered Immune Regulation in Type 1 Diabetes

    Science.gov (United States)

    Zóka, András; Műzes, Györgyi; Somogyi, Anikó; Varga, Tímea; Szémán, Barbara; Al-Aissa, Zahra; Hadarits, Orsolya; Firneisz, Gábor

    2013-01-01

    Research in genetics and immunology was going on separate strands for a long time. Type 1 diabetes mellitus might not be characterized with a single pathogenetic factor. It develops when a susceptible individual is exposed to potential triggers in a given sequence and timeframe that eventually disarranges the fine-tuned immune mechanisms that keep autoimmunity under control in health. Genomewide association studies have helped to understand the congenital susceptibility, and hand-in-hand with the immunological research novel paths of immune dysregulation were described in central tolerance, apoptotic pathways, or peripheral tolerance mediated by regulatory T-cells. Epigenetic factors are contributing to the immune dysregulation. The interplay between genetic susceptibility and potential triggers is likely to play a role at a very early age and gradually results in the loss of balanced autotolerance and subsequently in the development of the clinical disease. Genetic susceptibility, the impaired elimination of apoptotic β-cell remnants, altered immune regulatory functions, and environmental factors such as viral infections determine the outcome. Autoreactivity might exist under physiologic conditions and when the integrity of the complex regulatory process is damaged the disease might develop. We summarized the immune regulatory mechanisms that might have a crucial role in disease pathology and development. PMID:24285974

  14. Altered Immune Regulation in Type 1 Diabetes

    Directory of Open Access Journals (Sweden)

    András Zóka

    2013-01-01

    Full Text Available Research in genetics and immunology was going on separate strands for a long time. Type 1 diabetes mellitus might not be characterized with a single pathogenetic factor. It develops when a susceptible individual is exposed to potential triggers in a given sequence and timeframe that eventually disarranges the fine-tuned immune mechanisms that keep autoimmunity under control in health. Genomewide association studies have helped to understand the congenital susceptibility, and hand-in-hand with the immunological research novel paths of immune dysregulation were described in central tolerance, apoptotic pathways, or peripheral tolerance mediated by regulatory T-cells. Epigenetic factors are contributing to the immune dysregulation. The interplay between genetic susceptibility and potential triggers is likely to play a role at a very early age and gradually results in the loss of balanced autotolerance and subsequently in the development of the clinical disease. Genetic susceptibility, the impaired elimination of apoptotic β-cell remnants, altered immune regulatory functions, and environmental factors such as viral infections determine the outcome. Autoreactivity might exist under physiologic conditions and when the integrity of the complex regulatory process is damaged the disease might develop. We summarized the immune regulatory mechanisms that might have a crucial role in disease pathology and development.

  15. Genetic and Clinical Characteristics of Phyllodes Tumors of the Breast

    Directory of Open Access Journals (Sweden)

    Ji-Yeon Kim

    2018-02-01

    Full Text Available PURPOSE: Phyllodes tumors (PTs of the breast are rare, accounting for less than 1% of all breast tumors. Among PTs, malignant PTs (MPTs have malignant characteristics and distant metastases occur in about 20% to 30% of MPTs. However, there is no effective treatment for MPTs with distant metastasis, resulting in an abject prognosis. We performed targeted deep sequencing on PTs to identify the associations between genetic alterations and clinical prognosis. METHODS: We performed targeted deep sequencing to evaluate the genetic characteristics of PTs and analyzed the relationships between clinical and genetic characteristics. RESULTS: A total of 17 PTs were collected between 2001 and 2012. Histologic review was performed by pathologists. The samples included three benign PTs, one borderline PT, and 13 MPTs. The most frequently detected genetic alteration occurred in the TERT promoter region (70.6%, followed by MED12 (64.7%. EGFR amplification and TP53 alteration were detected in four MPTs without genetic alterations in MED12 and TERT promoter regions. Genetic alterations of RARA and ZNF703 were repeatedly found in PTs with local recurrence, and genetic alterations of SETD2, BRCA2, and TSC1 were detected in PTs with distant metastasis. Especially, MPT harboring PTEN and RB1 copy number deletion showed rapid disease progression. CONCLUSIONS: In this study, we provide genetic characterization and potential therapeutic target for this rare, potentially lethal disease. Further large-scale comprehensive genetic study and functional validation are warranted.

  16. Genetic Diversity of Toll-Like Receptors and Immunity to M. leprae Infection

    Directory of Open Access Journals (Sweden)

    Bryan E. Hart

    2012-01-01

    Full Text Available Genetic association studies of leprosy cohorts across the world have identified numerous polymorphisms which alter susceptibility and outcome to infection with Mycobacterium leprae. As expected, many of the polymorphisms reside within genes that encode components of the innate and adaptive immune system. Despite the preponderance of these studies, our understanding of the mechanisms that underlie these genetic associations remains sparse. Toll-like receptors (TLRs have emerged as an essential family of innate immune pattern recognition receptors which play a pivotal role in host defense against microbes, including pathogenic strains of mycobacteria. This paper will highlight studies which have uncovered the association of specific TLR gene polymorphisms with leprosy or tuberculosis: two important diseases resulting from mycobacterial infection. This analysis will focus on the potential influence these polymorphic variants have on TLR expression and function and how altered TLR recognition or signaling may contribute to successful antimycobacterial immunity.

  17. Dietary Modulation of Gut Microbiota Contributes to Alleviation of Both Genetic and Simple Obesity in Children

    Directory of Open Access Journals (Sweden)

    Chenhong Zhang

    2015-08-01

    Research in context: Poorly managed diet and genetic mutations are the two primary driving forces behind the devastating epidemic of obesity-related diseases. Lack of understanding of the molecular chain of causation between the driving forces and the disease endpoints retards progress in prevention and treatment of the diseases. We found that children genetically obese with Prader–Willi syndrome shared a similar dysbiosis in their gut microbiota with those having diet-related obesity. A diet rich in non-digestible but fermentable carbohydrates significantly promoted beneficial groups of bacteria and reduced toxin-producers, which contributes to the alleviation of metabolic deteriorations in obesity regardless of the primary driving forces.

  18. Maternal Inflammation Contributes to Brain Overgrowth and Autism-Associated Behaviors through Altered Redox Signaling in Stem and Progenitor Cells

    Directory of Open Access Journals (Sweden)

    Janel E. Le Belle

    2014-11-01

    Full Text Available A period of mild brain overgrowth with an unknown etiology has been identified as one of the most common phenotypes in autism. Here, we test the hypothesis that maternal inflammation during critical periods of embryonic development can cause brain overgrowth and autism-associated behaviors as a result of altered neural stem cell function. Pregnant mice treated with low-dose lipopolysaccharide at embryonic day 9 had offspring with brain overgrowth, with a more pronounced effect in PTEN heterozygotes. Exposure to maternal inflammation also enhanced NADPH oxidase (NOX-PI3K pathway signaling, stimulated the hyperproliferation of neural stem and progenitor cells, increased forebrain microglia, and produced abnormal autism-associated behaviors in affected pups. Our evidence supports the idea that a prenatal neuroinflammatory dysregulation in neural stem cell redox signaling can act in concert with underlying genetic susceptibilities to affect cellular responses to environmentally altered cellular levels of reactive oxygen species.

  19. Touch imprint cytology with massively parallel sequencing (TIC-seq): a simple and rapid method to snapshot genetic alterations in tumors.

    Science.gov (United States)

    Amemiya, Kenji; Hirotsu, Yosuke; Goto, Taichiro; Nakagomi, Hiroshi; Mochizuki, Hitoshi; Oyama, Toshio; Omata, Masao

    2016-12-01

    Identifying genetic alterations in tumors is critical for molecular targeting of therapy. In the clinical setting, formalin-fixed paraffin-embedded (FFPE) tissue is usually employed for genetic analysis. However, DNA extracted from FFPE tissue is often not suitable for analysis because of its low levels and poor quality. Additionally, FFPE sample preparation is time-consuming. To provide early treatment for cancer patients, a more rapid and robust method is required for precision medicine. We present a simple method for genetic analysis, called touch imprint cytology combined with massively paralleled sequencing (touch imprint cytology [TIC]-seq), to detect somatic mutations in tumors. We prepared FFPE tissues and TIC specimens from tumors in nine lung cancer patients and one patient with breast cancer. We found that the quality and quantity of TIC DNA was higher than that of FFPE DNA, which requires microdissection to enrich DNA from target tissues. Targeted sequencing using a next-generation sequencer obtained sufficient sequence data using TIC DNA. Most (92%) somatic mutations in lung primary tumors were found to be consistent between TIC and FFPE DNA. We also applied TIC DNA to primary and metastatic tumor tissues to analyze tumor heterogeneity in a breast cancer patient, and showed that common and distinct mutations among primary and metastatic sites could be classified into two distinct histological subtypes. TIC-seq is an alternative and feasible method to analyze genomic alterations in tumors by simply touching the cut surface of specimens to slides. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  20. Melanoma genetics

    DEFF Research Database (Denmark)

    Read, Jazlyn; Wadt, Karin A W; Hayward, Nicholas K

    2015-01-01

    Approximately 10% of melanoma cases report a relative affected with melanoma, and a positive family history is associated with an increased risk of developing melanoma. Although the majority of genetic alterations associated with melanoma development are somatic, the underlying presence of herita......Approximately 10% of melanoma cases report a relative affected with melanoma, and a positive family history is associated with an increased risk of developing melanoma. Although the majority of genetic alterations associated with melanoma development are somatic, the underlying presence...... in a combined total of approximately 50% of familial melanoma cases, the underlying genetic basis is unexplained for the remainder of high-density melanoma families. Aside from the possibility of extremely rare mutations in a few additional high penetrance genes yet to be discovered, this suggests a likely...... polygenic component to susceptibility, and a unique level of personal melanoma risk influenced by multiple low-risk alleles and genetic modifiers. In addition to conferring a risk of cutaneous melanoma, some 'melanoma' predisposition genes have been linked to other cancers, with cancer clustering observed...

  1. Legumain Regulates Differentiation Fate of Human Bone Marrow Stromal Cells and Is Altered in Postmenopausal Osteoporosis

    Directory of Open Access Journals (Sweden)

    Abbas Jafari

    2017-02-01

    Full Text Available Secreted factors are a key component of stem cell niche and their dysregulation compromises stem cell function. Legumain is a secreted cysteine protease involved in diverse biological processes. Here, we demonstrate that legumain regulates lineage commitment of human bone marrow stromal cells and that its expression level and cellular localization are altered in postmenopausal osteoporotic patients. As shown by genetic and pharmacological manipulation, legumain inhibited osteoblast (OB differentiation and in vivo bone formation through degradation of the bone matrix protein fibronectin. In addition, genetic ablation or pharmacological inhibition of legumain activity led to precocious OB differentiation and increased vertebral mineralization in zebrafish. Finally, we show that localized increased expression of legumain in bone marrow adipocytes was inversely correlated with adjacent trabecular bone mass in a cohort of patients with postmenopausal osteoporosis. Our data suggest that altered proteolytic activity of legumain in the bone microenvironment contributes to decreased bone mass in postmenopausal osteoporosis.

  2. Genetic Contributions to Continuity and Change in Attachment Security: A Prospective, Longitudinal Investigation from Infancy to Young Adulthood

    Science.gov (United States)

    Raby, K. Lee; Cicchetti, Dante; Carlson, Elizabeth A.; Egeland, Byron; Collins, W. Andrew

    2013-01-01

    Background Longitudinal research has demonstrated that individual differences in attachment security show only modest continuity from infancy to adulthood. Recent findings based on retrospective reports suggest that individuals’ genetic variation may moderate the developmental associations between early attachment-relevant relationship experiences and adult attachment security. The purpose of this study was to use a prospective, longitudinal design to investigate genetic contributions to continuity and changes in attachment security from infancy to young adulthood in a higher risk sample. Methods Infant attachment security was assessed using the Strange Situation Procedure at 12 and 18 months. Adults’ general attachment representations were assessed using the Adult Attachment Interview at age 19 and age 26. Romantic attachment representations were assessed with the Current Relationship Interview at ages 20–21 and ages 26–28. Individuals were genotyped for variants within the oxytocin receptor (OXTR), dopamine D4 receptor (DRD4), and serotonin transporter linked polymorphic region (5-HTTLPR). Results The continuity of attachment security from infancy into young adulthood was consistently moderated by OXTR genetic variation. Infant attachment security predicted the security of adults’ general and romantic attachment representations only for individuals with the OXTR G/G genotype. This interaction was significant when predicting adult attachment security as measured by the Adult Attachment Interview at age 19 and 26 and the Current Relationship Interview at ages 26–28. DRD4 and 5-HTTLPR genetic variation did not consistently moderate the longitudinal associations between attachment security during infancy and adulthood. Conclusions This study provides initial longitudinal evidence for genetic contributions to continuity and change in attachment security from infancy to young adulthood. Genetic variation related to the oxytocin system may moderate the

  3. Genetic contribution to neurodevelopmental outcomes in congenital heart disease: are some patients predetermined to have developmental delay?

    Science.gov (United States)

    Rollins, Caitlin K; Newburger, Jane W; Roberts, Amy E

    2017-10-01

    Neurodevelopmental impairment is common in children with moderate to severe congenital heart disease (CHD). As children live longer and healthier lives, research has focused on identifying causes of neurodevelopmental morbidity that significantly impact long-term quality of life. This review will address the role of genetic factors in predicting neurodevelopmental outcome in CHD. A robust literature suggests that among children with various forms of CHD, those with known genetic/extracardiac anomalies are at highest risk of neurodevelopmental impairment. Advances in genetic technology have identified genetic causes of CHD in an increasing percentage of patients. Further, emerging data suggest substantial overlap between mutations in children with CHD and those that have previously been associated with neurodevelopmental disorders. Innate and patient factors appear to be more important in predicting neurodevelopmental outcome than medical/surgical variables. Future research is needed to establish a broader understanding of the mutations that contribute to neurodevelopmental disorders and the variations in expressivity and penetrance.

  4. VHL genetic alteration in CCRCC does not determine de-regulation of HIF, CAIX, hnRNP A2/B1 and osteopontin.

    LENUS (Irish Health Repository)

    Nyhan, Michelle J

    2012-01-31

    BACKGROUND: von Hippel-Lindau (VHL) tumour suppressor gene inactivation is associated with clear cell renal cell carcinoma (CCRCC) development. The VHL protein (pVHL) has been proposed to regulate the expression of several proteins including Hypoxia Inducible Factor-alpha (HIF-alpha), carbonic anhydrase (CA)IX, heterogeneous nuclear ribonucleoprotein (hnRNP) A2\\/B1 and osteopontin. pVHL has been characterized in vitro, however, clinical studies are limited. We evaluated the impact of VHL genetic alterations on the expression of several pVHL protein targets in paired normal and tumor tissue. METHODS: The VHL gene was sequenced in 23 CCRCC patients and VHL transcript levels were evaluated by real-time RT-PCR. Expression of pVHL\\'s protein targets were determined by Western blotting in 17 paired patient samples. RESULTS: VHL genetic alterations were identified in 43.5% (10\\/23) of CCRCCs. HIF-1alpha, HIF-2alpha and CAIX were up-regulated in 88.2% (15\\/17), 100% (17\\/17) and 88.2% (15\\/17) of tumors respectively and their expression is independent of VHL status. hnRNP A2\\/B1 and osteopontin expression was variable in CCRCCs and had no association with VHL genetic status. CONCLUSION: As expression of these proposed pVHL targets can be achieved independently of VHL mutation (and possibly by hypoxia alone), these data suggests that other pVHL targets may be more crucial in renal carcinogenesis.

  5. Genetic and epigenetic alterations of Brassica nigra introgression lines from somatic hybridization: a resource for cauliflower improvement

    Directory of Open Access Journals (Sweden)

    Guixiang Wang

    2016-08-01

    Full Text Available Broad phenotypic variations were obtained previously in derivatives from the asymmetric somatic hybridization of cauliflower ‘Korso’ (Brassica oleracea var. botrytis, 2n = 18, CC genome and black mustard ‘G1/1’ (Brassica nigra, 2n = 16, BB genome. However, the mechanisms underlying these variations were unknown. In this study, 28 putative introgression lines (ILs were pre-selected according to a series of morphological (leaf shape and color, plant height and branching, curd features, and flower traits and physiological (black rot/club root resistance characters. Multi-color fluorescence in situ hybridization revealed that these plants contained 18 chromosomes derived from ‘Korso’. Molecular marker (65 simple sequence repeats and 77 amplified fragment length polymorphisms analysis identified the presence of ‘G1/1’ DNA segments (average 7.5%. Additionally, DNA profiling revealed many genetic and epigenetic differences among the ILs, including sequence alterations, deletions, and variation in patterns of cytosine methylation. The frequency of fragments lost (5.1% was significantly higher than presence of novel bands (1.4%, and the presence of fragments specific to B. carinata (BBCC 2n = 34 were common (average 15.5%. Methylation-sensitive amplified polymorphism analysis indicated that methylation changes were common and that hypermethylation (12.4% was more frequent than hypomethylation (4.8%. Our results suggested that asymmetric somatic hybridization and alien DNA introgression induced genetic and epigenetic alterations. Thus, these ILs represent an important, novel germplasm resource for cauliflower improvement that can be mined for diverse traits of interest to breeders and researchers.

  6. Early warm-rewarding parenting moderates the genetic contributions to callous-unemotional traits in childhood.

    Science.gov (United States)

    Henry, Jeffrey; Dionne, Ginette; Viding, Essi; Vitaro, Frank; Brendgen, Mara; Tremblay, Richard E; Boivin, Michel

    2018-04-23

    Previous gene-environment interaction studies of CU traits have relied on the candidate gene approach, which does not account for the entire genetic load of complex phenotypes. Moreover, these studies have not examined the role of positive environmental factors such as warm/rewarding parenting. The aim of the present study was to determine whether early warm/rewarding parenting moderates the genetic contributions (i.e., heritability) to callous-unemotional (CU) traits at school age. Data were collected in a population sample of 662 twin pairs (Quebec Newborn Twin Study - QNTS). Mothers reported on their warm/rewarding parenting. Teachers assessed children's CU traits. These reports were subjected to twin modeling. Callous-unemotional traits were highly heritable, with the remaining variance accounted for by nonshared environmental factors. Warm/rewarding parenting significantly moderated the role of genes in CU traits; heritability was lower when children received high warm/rewarding parenting than when they were exposed to low warm/rewarding parenting. High warm/rewarding parenting may partly impede the genetic expression of CU traits. Developmental models of CU traits need to account for such gene-environment processes. © 2018 Association for Child and Adolescent Mental Health.

  7. Indirect genetic effects contribute substantially to heritable variation in aggression-related traits in group-housed mink (Neovison vison)

    DEFF Research Database (Denmark)

    Alemu, Setegn Worku; Bijma, Peter; Møller, Steen Henrik

    2014-01-01

    Background Since the recommendations on group housing of mink (Neovison vison) were adopted by the Council of Europe in 1999, it has become common in mink production in Europe. Group housing is advantageous from a production perspective, but can lead to aggression between animals and thus raises...... a welfare issue. Bite marks on the animals are an indicator of this aggressive behaviour and thus selection against frequency of bite marks should reduce aggression and improve animal welfare. Bite marks on one individual reflect the aggression of its group members, which means that the number of bite marks...... genetic effects contribute to variation in number of bite marks in group-housed mink. Thus, a genetic selection design that includes both direct genetic and indirect genetic effects could reduce the frequency of bite marks and probably aggression behaviour in group-housed mink....

  8. Combined M-FISH and CGH analysis allows comprehensive description of genetic alterations in neuroblastoma cell lines.

    Science.gov (United States)

    Van Roy, N; Van Limbergen, H; Vandesompele, J; Van Gele, M; Poppe, B; Salwen, H; Laureys, G; Manoel, N; De Paepe, A; Speleman, F

    2001-10-01

    Cancer cell lines are essential gene discovery tools and have often served as models in genetic and functional studies of particular tumor types. One of the future challenges is comparison and interpretation of gene expression data with the available knowledge on the genomic abnormalities in these cell lines. In this context, accurate description of these genomic abnormalities is required. Here, we show that a combination of M-FISH with banding analysis, standard FISH, and CGH allowed a detailed description of the genetic alterations in 16 neuroblastoma cell lines. In total, 14 cryptic chromosome rearrangements were detected, including a balanced t(2;4)(p24.3;q34.3) translocation in cell line NBL-S, with the 2p24 breakpoint located at about 40 kb from MYCN. The chromosomal origin of 22 marker chromosomes and 41 cytogenetically undefined translocated segments was determined. Chromosome arm 2 short arm translocations were observed in six cell lines (38%) with and five (31%) without MYCN amplification, leading to partial chromosome arm 2p gain in all but one cell line and loss of material in the various partner chromosomes, including 1p and 11q. These 2p gains were often masked in the GGH profiles due to MYCN amplification. The commonly overrepresented region was chromosome segment 2pter-2p22, which contains the MYCN gene, and five out of eleven 2p breakpoints clustered to the interface of chromosome bands 2p16 and 2p21. In neuroblastoma cell line SJNB-12, with double minutes (dmins) but no MYCN amplification, the dmins were shown to be derived from 16q22-q23 sequences. The ATBF1 gene, an AT-binding transcription factor involved in normal neurogenesis and located at 16q22.2, was shown to be present in the amplicon. This is the first report describing the possible implication of ATBF1 in neuroblastoma cells. We conclude that a combined approach of M-FISH, cytogenetics, and CGH allowed a more complete and accurate description of the genetic alterations occurring in the

  9. Evaluation of Optimum Genetic Contribution Theory to Control Inbreeding While Maximizing Genetic Response

    Directory of Open Access Journals (Sweden)

    S.-H. Oh

    2012-03-01

    Full Text Available Inbreeding is the mating of relatives that produce progeny having more homozygous alleles than non-inbred animals. Inbreeding increases numbers of recessive alleles, which is often associated with decreased performance known as inbreeding depression. The magnitude of inbreeding depression depends on the level of inbreeding in the animal. Level of inbreeding is expressed by the inbreeding coefficient. One breeding goal in livestock is uniform productivity while maintaining acceptable inbreeding levels, especially keeping inbreeding less than 20%. However, in closed herds without the introduction of new genetic sources high levels of inbreeding over time are unavoidable. One method that increases selection response and minimizes inbreeding is selection of individuals by weighting estimated breeding values with average relationships among individuals. Optimum genetic contribution theory (OGC uses relationships among individuals as weighting factors. The algorithm is as follows: i Identify the individual having the best EBV; ii Calculate average relationships ( r j ¯ between selected and candidates; iii Select the individual having the best EBV adjusted for average relationships using the weighting factor k, E B V * = E B V j ( 1 - k r j ¯ . iv Repeat process until the number of individuals selected equals number required. The objective of this study was to compare simulated results based on OGC selection under different conditions over 30 generations. Individuals (n = 110 were generated for the base population with pseudo random numbers of N~ (0, 3, ten were assumed male, and the remainder female. Each male was mated to ten females, and every female was assumed to have 5 progeny resulting in 500 individuals in the following generation. Results showed the OGC algorithm effectively controlled inbreeding and maintained consistent increases in selection response. Difference in breeding values between selection with OGC algorithm and by EBV only was 8

  10. Dietary Modulation of Gut Microbiota Contributes to Alleviation of Both Genetic and Simple Obesity in Children☆

    Science.gov (United States)

    Zhang, Chenhong; Yin, Aihua; Li, Hongde; Wang, Ruirui; Wu, Guojun; Shen, Jian; Zhang, Menghui; Wang, Linghua; Hou, Yaping; Ouyang, Haimei; Zhang, Yan; Zheng, Yinan; Wang, Jicheng; Lv, Xiaofei; Wang, Yulan; Zhang, Feng; Zeng, Benhua; Li, Wenxia; Yan, Feiyan; Zhao, Yufeng; Pang, Xiaoyan; Zhang, Xiaojun; Fu, Huaqing; Chen, Feng; Zhao, Naisi; Hamaker, Bruce R.; Bridgewater, Laura C.; Weinkove, David; Clement, Karine; Dore, Joel; Holmes, Elaine; Xiao, Huasheng; Zhao, Guoping; Yang, Shengli; Bork, Peer; Nicholson, Jeremy K.; Wei, Hong; Tang, Huiru; Zhang, Xiaozhuang; Zhao, Liping

    2015-01-01

    Gut microbiota has been implicated as a pivotal contributing factor in diet-related obesity; however, its role in development of disease phenotypes in human genetic obesity such as Prader–Willi syndrome (PWS) remains elusive. In this hospitalized intervention trial with PWS (n = 17) and simple obesity (n = 21) children, a diet rich in non-digestible carbohydrates induced significant weight loss and concomitant structural changes of the gut microbiota together with reduction of serum antigen load and alleviation of inflammation. Co-abundance network analysis of 161 prevalent bacterial draft genomes assembled directly from metagenomic datasets showed relative increase of functional genome groups for acetate production from carbohydrates fermentation. NMR-based metabolomic profiling of urine showed diet-induced overall changes of host metabotypes and identified significantly reduced trimethylamine N-oxide and indoxyl sulfate, host-bacteria co-metabolites known to induce metabolic deteriorations. Specific bacterial genomes that were correlated with urine levels of these detrimental co-metabolites were found to encode enzyme genes for production of their precursors by fermentation of choline or tryptophan in the gut. When transplanted into germ-free mice, the pre-intervention gut microbiota induced higher inflammation and larger adipocytes compared with the post-intervention microbiota from the same volunteer. Our multi-omics-based systems analysis indicates a significant etiological contribution of dysbiotic gut microbiota to both genetic and simple obesity in children, implicating a potentially effective target for alleviation. Research in context Poorly managed diet and genetic mutations are the two primary driving forces behind the devastating epidemic of obesity-related diseases. Lack of understanding of the molecular chain of causation between the driving forces and the disease endpoints retards progress in prevention and treatment of the diseases. We found

  11. Basal cell carcinoma of the skin (part 1): epidemiology, pathology and genetic syndromes.

    Science.gov (United States)

    Correia de Sá, Tiago Ribeiro; Silva, Roberto; Lopes, José Manuel

    2015-11-01

    Basal cell carcinoma (BCC) is the most common skin cancer worldwide with increasing incidence, but difficult to assess due to the current under registration practice. Despite the low mortality rate, BCC is a cause of great morbidity and an economic burden to health services. There are several risk factors that increase the risk of BCC and partly explain its incidence. Low-penetrance susceptibility alleles, as well as genetic alterations in signaling pathways, namely SHH pathway, also contribute to the carcinogenesis. BCC associate with several genetic syndromes, of which basal cell nevus syndrome is the most common.

  12. Strong evidence for a genetic contribution to late-onset Alzheimer's disease mortality: a population-based study.

    Directory of Open Access Journals (Sweden)

    John S K Kauwe

    Full Text Available Alzheimer's disease (AD is an international health concern that has a devastating effect on patients and families. While several genetic risk factors for AD have been identified much of the genetic variance in AD remains unexplained. There are limited published assessments of the familiality of Alzheimer's disease. Here we present the largest genealogy-based analysis of AD to date.We assessed the familiality of AD in The Utah Population Database (UPDB, a population-based resource linking electronic health data repositories for the state with the computerized genealogy of the Utah settlers and their descendants. We searched UPDB for significant familial clustering of AD to evaluate the genetic contribution to disease. We compared the Genealogical Index of Familiality (GIF between AD individuals and randomly selected controls and estimated the Relative Risk (RR for a range of family relationships. Finally, we identified pedigrees with a significant excess of AD deaths.The GIF analysis showed that pairs of individuals dying from AD were significantly more related than expected. This excess of relatedness was observed for both close and distant relationships. RRs for death from AD among relatives of individuals dying from AD were significantly increased for both close and more distant relatives. Multiple pedigrees had a significant excess of AD deaths.These data strongly support a genetic contribution to the observed clustering of individuals dying from AD. This report is the first large population-based assessment of the familiality of AD mortality and provides the only reported estimates of relative risk of AD mortality in extended relatives to date. The high-risk pedigrees identified show a true excess of AD mortality (not just multiple cases and are greater in depth and width than published AD pedigrees. The presence of these high-risk pedigrees strongly supports the possibility of rare predisposition variants not yet identified.

  13. [Genetic and environmental contributions to body mass index in a Spanish adolescent twin sample].

    Science.gov (United States)

    Iranzo-Tatay, Carmen; Gimeno-Clemente, Natalia; Livianos-Aldana, Lorenzo; Rojo-Moreno, Luis

    2015-08-21

    Twin and family studies support large genetic influences on variability in body mass index (BMI), with heritability estimates ranging from 47% to over 90%. Our objective was to study the relative contributions of genetics and environment to BMI, evaluating sex differences, in an adolescent twin sample from Valencia, Spain. Five hundred eighty-four pairs of adolescent twins between 13 and 18 years of age completed the study (82 monozygotic [MZ] and 87 dizygotic [DZ] pairs of male twins, 118 MZ and 102 DZ pairs of female twins, and 195 opposite-sex pairs of DZ twins). To determine zygosity, teachers responded a questionnaire on physical similarity. They also measured the participant's height and weight. BMI was calculated and weight status was determined according to age. We used twin models to assess genetic and environmental (common and unique) factors affecting BMI. There was a 7.1% frequency of overweight and 2.8% of obesity. The estimated heritability of BMI was 88.0% in boys and 72.1% in girls, with the remaining variance attributable to non-shared environment in boys (12.0%) and 8.8% in girls. It was only in girls that common environment had an effect on BMI. Genetics appears to play an important role in explaining the variability in BMI in the adolescence, with slight variations between boys and girls. Common environmental factors exert their influence on BMI only in girls. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  14. MYC protein expression and genetic alterations have prognostic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy.

    Science.gov (United States)

    Valera, Alexandra; López-Guillermo, Armando; Cardesa-Salzmann, Teresa; Climent, Fina; González-Barca, Eva; Mercadal, Santiago; Espinosa, Iñigo; Novelli, Silvana; Briones, Javier; Mate, José L; Salamero, Olga; Sancho, Juan M; Arenillas, Leonor; Serrano, Sergi; Erill, Nadina; Martínez, Daniel; Castillo, Paola; Rovira, Jordina; Martínez, Antonio; Campo, Elias; Colomo, Luis

    2013-10-01

    MYC alterations influence the survival of patients with diffuse large B-cell lymphoma. Most studies have focused on MYC translocations but there is little information regarding the impact of numerical alterations and protein expression. We analyzed the genetic alterations and protein expression of MYC, BCL2, BCL6, and MALT1 in 219 cases of diffuse large B-cell lymphoma. MYC rearrangement occurred as the sole abnormality (MYC single-hit) in 3% of cases, MYC and concurrent BCL2 and/or BCL6 rearrangements (MYC double/triple-hit) in 4%, MYC amplifications in 2% and MYC gains in 19%. MYC single-hit, MYC double/triple-hit and MYC amplifications, but not MYC gains or other gene rearrangements, were associated with unfavorable progression-free survival and overall survival. MYC protein expression, evaluated using computerized image analysis, captured the unfavorable prognosis of MYC translocations/amplifications and identified an additional subset of patients without gene alterations but with similar poor prognosis. Patients with tumors expressing both MYC/BCL2 had the worst prognosis, whereas those with double-negative tumors had the best outcome. High MYC expression was associated with shorter overall survival irrespectively of the International Prognostic Index and BCL2 expression. In conclusion, MYC protein expression identifies a subset of diffuse large B-cell lymphoma with very poor prognosis independently of gene alterations and other prognostic parameters.

  15. Radiation protection philosophy alters

    International Nuclear Information System (INIS)

    Firmin, G.

    1977-01-01

    Two significant events that have taken place this year in the field of radiation protection are reported. New SI units have been proposed (and effectively adopted), and the ICRP has revised its recommendations. Changes of emphasis in the latest recommendations (ICRP Publication 26) imply an altered radiation protection philosophy, in particular the relation of dose limits to estimates of average risk, an altered view of the critical organ approach and a new attitude to genetic dose to the population. (author)

  16. Contribution of genetic diversity for improvement of some abiotic stresses in wheat (abstract)

    International Nuclear Information System (INIS)

    Kazi, M.; Swati, Z.A.

    2005-01-01

    Wheat improvement has predominantly been accomplished through conventional plant breeding methodologies. This approach shall continue to be the predominant procedure in the future. Genetic diversity is crucial for crop improvement and in the Triticeae family it resides in the primary, secondary and tertiary gene pools. These gene pools can be utilize for wheat improvement by producing genetic stocks where the alien gene pools can be combined with durum and bread wheat cultivars via interspecific and intergeneric hybridization. Adopting the interspecific route strategies has led to the production of several genetic stocks, which are elucidated here. The categories include the amphiploids of the A, B, and D genomes with durum cultivars (AAAABB, AABBBB, AABBDD) and new AADD tetraploids. Tertiary gene pool species (more complex to utilize) are a potent resource for gene pyramiding, which contribute towards stress durability and addresses sustainable agricultural aspects. The conventional classical protocols of introgressing alien genetic diversity into wheat are complex, and long-term in generating farmer usable products. The gene transfer procedures are further complicated when the stress trait has multigenic control associated with several alien chromosomes. Our current approach has incorporated a novel strategy for promoting alien chromosome introgression involving wheat/alien homeologous as well as non-homeologous chromosomes. The protocol comprises of hybridizing the Phph based amphiploid with the phph Chinese Spring wheat genetic stock to yield heterozygote Phph derivatives. From selfing of the heterozygotes or from their derived haploids via wheat/maize crosses the ph derivatives are identified by a PCR diagnostic. The ph seedlings form the reservoir of wheat/alien chromosome translocations which are identified by Giemsa C-banding / fluorescent in situ hybridization (FISH). Plants with translocations are step-wise advanced by backcrosses to elite wheat cultivars

  17. The genetic basis for altered blood vessel function in disease: large artery stiffening

    Directory of Open Access Journals (Sweden)

    Alex Agrotis

    2005-12-01

    Full Text Available Alex AgrotisThe Cell Biology Laboratory, Baker Heart Research Institute, Melbourne, Victoria, AustraliaAbstract: The progressive stiffening of the large arteries in humans that occurs during aging constitutes a potential risk factor for increased cardiovascular morbidity and mortality, and is accompanied by an elevation in systolic blood pressure and pulse pressure. While the underlying basis for these changes remains to be fully elucidated, factors that are able to influence the structure and composition of the extracellular matrix and the way it interacts with arterial smooth muscle cells could profoundly affect the properties of the large arteries. Thus, while age and sex represent important factors contributing to large artery stiffening, the variation in growth-stimulating factors and those that modulate extracellular production and homeostasis are also being increasingly recognized to play a key role in the process. Therefore, elucidating the contribution that genetic variation makes to large artery stiffening could ultimately provide the basis for clinical strategies designed to regulate the process for therapeutic benefit.Keywords: arterial stiffness, genes, polymorphism, extracellular matrix proteins

  18. Genes: Interactions with Language on Three Levels—Inter-Individual Variation, Historical Correlations and Genetic Biasing

    Science.gov (United States)

    Dediu, Dan

    The complex inter-relationships between genetics and linguistics encompass all four scales highlighted by the contributions to this book and, together with cultural transmission, the genetics of language holds the promise to offer a unitary understanding of this fascinating phenomenon. There are inter-individual differences in genetic makeup which contribute to the obvious fact that we are not identical in the way we understand and use language and, by studying them, we will be able to both better treat and enhance ourselves. There are correlations between the genetic configuration of human groups and their languages, reflecting the historical processes shaping them, and there also seem to exist genes which can influence some characteristics of language, biasing it towards or against certain states by altering the way language is transmitted across generations. Besides the joys of pure knowledge, the understanding of these three aspects of genetics relevant to language will potentially trigger advances in medicine, linguistics, psychology or the understanding of our own past and, last but not least, a profound change in the way we regard one of the emblems of being human: our capacity for language.

  19. Genetics of diabetic nephropathy

    DEFF Research Database (Denmark)

    Parving, H H; Tarnow, L; Rossing, P

    1996-01-01

    factor for cardiovascular disease in diabetic patients. However, a meta-analysis does not support the suggestion that this factor plays any role for the initiation of diabetic nephropathy. Similar negative results have been obtained in relation to polymorphisms of the genes encoding for angiotensinogen......Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria, a relentless decline in GFR, raised arterial blood pressure, and increased relative mortality for cardiovascular diseases. Diabetic nephropathy is a leading cause of end-stage renal failure. The pathogenesis...... of diabetic nephropathy is multifactorial, with contributions from metabolic abnormalities, hemodynamic alterations, and various growth factors and genetic factors. Epidemiologic and family studies have demonstrated that only a subset of the patients develop this complication that family clustering...

  20. Contribution of Genetic Background, Traditional Risk Factors, and HIV-Related Factors to Coronary Artery Disease Events in HIV-Positive Persons

    Science.gov (United States)

    Rotger, Margalida; Glass, Tracy R.; Junier, Thomas; Lundgren, Jens; Neaton, James D.; Poloni, Estella S.; van 't Wout, Angélique B.; Lubomirov, Rubin; Colombo, Sara; Martinez, Raquel; Rauch, Andri; Günthard, Huldrych F.; Neuhaus, Jacqueline; Wentworth, Deborah; van Manen, Danielle; Gras, Luuk A.; Schuitemaker, Hanneke; Albini, Laura; Torti, Carlo; Jacobson, Lisa P.; Li, Xiuhong; Kingsley, Lawrence A.; Carli, Federica; Guaraldi, Giovanni; Ford, Emily S.; Sereti, Irini; Hadigan, Colleen; Martinez, Esteban; Arnedo, Mireia; Egaña-Gorroño, Lander; Gatell, Jose M.; Law, Matthew; Bendall, Courtney; Petoumenos, Kathy; Rockstroh, Jürgen; Wasmuth, Jan-Christian; Kabamba, Kabeya; Delforge, Marc; De Wit, Stephane; Berger, Florian; Mauss, Stefan; de Paz Sierra, Mariana; Losso, Marcelo; Belloso, Waldo H.; Leyes, Maria; Campins, Antoni; Mondi, Annalisa; De Luca, Andrea; Bernardino, Ignacio; Barriuso-Iglesias, Mónica; Torrecilla-Rodriguez, Ana; Gonzalez-Garcia, Juan; Arribas, José R.; Fanti, Iuri; Gel, Silvia; Puig, Jordi; Negredo, Eugenia; Gutierrez, Mar; Domingo, Pere; Fischer, Julia; Fätkenheuer, Gerd; Alonso-Villaverde, Carlos; Macken, Alan; Woo, James; McGinty, Tara; Mallon, Patrick; Mangili, Alexandra; Skinner, Sally; Wanke, Christine A.; Reiss, Peter; Weber, Rainer; Bucher, Heiner C.; Fellay, Jacques; Telenti, Amalio; Tarr, Philip E.

    2013-01-01

    Background Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. Methods In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. Results A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9×10−4). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05–2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06–1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16–1.96), diabetes (OR = 1.66; 95% CI, 1.10–2.49), ≥1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06–1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17–2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. Conclusions In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD. PMID:23532479

  1. Genetic variability, correlation and path analysis of yield contributing characters in sweet potato (ipomoea batatas lam.)

    International Nuclear Information System (INIS)

    Hossain, M.D.; Rabbani, M.G.; Mollah, M.L.R.

    2000-01-01

    Evaluation of 30 sweet potato (Ipomoea batatas Lam.) genotypes for yield contributing characters and tuber yield per plant revealed high phenotypic and genotypic coefficient of variation (PCV and GCV, respectively) for number of tubers per plant, average tuber weight and tuber yield per plant. The heritability and genetic advance were higher for tuber yield per plant, average tuber weight and number of tubers per plant. These three characters also reflected high heritability as well as high genetic advance. As high positive significant correlation, as well as positive direct effect of average tuber weight and number of tubers per plant on tuber yield per plant were found, these characters should be given prime importance for selecting high yielding sweet potato genotypes. (author)

  2. Myc contribution to γ-ray induced thymic lymphomas in mice of different genetic predispositions

    International Nuclear Information System (INIS)

    Sato, Toshihiro

    2008-01-01

    Myc gene has been suggested to be one of radiation targets in early genesis of γ ray-induced thymic lymphoma where Myc trisomy often occurs, and Myc activation results in p53 activation and apoptosis. The purpose of this study is to see the effects of radiation and mutation on Myc activation in the mouse. The lymphoma was induced by a single exposure of 3 Gy γ ray in BALB/c Bcl11b/Rit+/- and MSM p53-/- mice at 4 weeks after birth and by 4 weekly exposures of 2.5 Gy in p53+/- mouse. Genetic allele analysis for trisomy identification in the lymphoma was done by quantitative PCR using brain DNA as a control. Myc trisomy was found in the lymphoma of p53+/- mouse in 62% (23/37 animals) and of p53+/+, 66% (23/25), a similar frequency, suggesting that the target of radiation was not only the Myc activation. In addition, Myc trisomy frequency was 15% (4/27) in the lymphoma of Bcl11b+/+p53+/- and 36% (9/25), in heterozygote Bcl11b+/-. This finding suggested that the functional failure of Bcl11b reduced the contribution of Myc trisomy to the genesis. It was concluded that contribution of Myc trisomy to genesis of the lymphoma was dependent on genetic predisposition, and Myc-activated-, Bcl11b/Rit1-signal pathways played a parallel role in the genesis. (R.T.)

  3. No Major Host Genetic Risk Factor Contributed to A(H1N12009 Influenza Severity.

    Directory of Open Access Journals (Sweden)

    Koldo Garcia-Etxebarria

    Full Text Available While most patients affected by the influenza A(H1N1 pandemic experienced mild symptoms, a small fraction required hospitalization, often without concomitant factors that could explain such a severe course. We hypothesize that host genetic factors could contribute to aggravate the disease. To test this hypothesis, we compared the allele frequencies of 547,296 genome-wide single nucleotide polymorphisms (SNPs between 49 severe and 107 mild confirmed influenza A cases, as well as against a general population sample of 549 individuals. When comparing severe vs. mild influenza A cases, only one SNP was close to the conventional p = 5×10-8. This SNP, rs28454025, sits in an intron of the GSK233 gene, which is involved in a neural development, but seems not to have any connections with immunological or inflammatory functions. Indirectly, a previous association reported with CD55 was replicated. Although sample sizes are low, we show that the statistical power in our design was sufficient to detect highly-penetrant, quasi-Mendelian genetic factors. Hence, and assuming that rs28454025 is likely to be a false positive, no major genetic factor was detected that could explain poor influenza A course.

  4. Understanding Child-Based Effects on Parenting: Temperament as a Moderator of Genetic and Environmental Contributions to Parenting

    Science.gov (United States)

    Ganiban, Jody M.; Ulbricht, Jennifer; Saudino, Kimberly J.; Reiss, David; Neiderhiser, Jenae M.

    2011-01-01

    The degree to which child temperament moderates genetic and environmental contributions to parenting was examined. Participants were drawn from the Nonshared Environment and Adolescent Development project and included 720 sibling pairs, ages 13.5 + 2.0 years (Sibling 1) to 12.1 + 1.3 years (Sibling 2). The sample consisted of 6 sibling types: 93…

  5. The genetic architecture of parallel armor plate reduction in threespine sticklebacks.

    Directory of Open Access Journals (Sweden)

    Pamela F Colosimo

    2004-05-01

    Full Text Available How many genetic changes control the evolution of new traits in natural populations? Are the same genetic changes seen in cases of parallel evolution? Despite long-standing interest in these questions, they have been difficult to address, particularly in vertebrates. We have analyzed the genetic basis of natural variation in three different aspects of the skeletal armor of threespine sticklebacks (Gasterosteus aculeatus: the pattern, number, and size of the bony lateral plates. A few chromosomal regions can account for variation in all three aspects of the lateral plates, with one major locus contributing to most of the variation in lateral plate pattern and number. Genetic mapping and allelic complementation experiments show that the same major locus is responsible for the parallel evolution of armor plate reduction in two widely separated populations. These results suggest that a small number of genetic changes can produce major skeletal alterations in natural populations and that the same major locus is used repeatedly when similar traits evolve in different locations.

  6. Genetic contributions to human brain morphology and intelligence

    DEFF Research Database (Denmark)

    Hulshoff Pol, HE; Schnack, HG; Posthuma, D

    2006-01-01

    the focal GM and WM densities of each twin are correlated with the psychometric intelligence quotient of his/her cotwin. Genes influenced individual differences in left and right superior occipitofrontal fascicle (heritability up to 0.79 and 0.77), corpus callosum (0.82, 0.80), optic radiation (0.69, 0.......79), corticospinal tract (0.78, 0.79), medial frontal cortex (0.78, 0.83), superior frontal cortex (0.76, 0.80), superior temporal cortex (0.80, 0.77), left occipital cortex (0.85), left postcentral cortex (0.83), left posterior cingulate cortex (0.83), right parahippocampal cortex (0.69), and amygdala (0.80, 0......Variation in gray matter (GM) and white matter (WM) volume of the adult human brain is primarily genetically determined. Moreover, total brain volume is positively correlated with general intelligence, and both share a common genetic origin. However, although genetic effects on morphology...

  7. Spatial and temporal dynamics of the genetic organization of small mammal populations

    International Nuclear Information System (INIS)

    Smith, M.H.; Manlove, M.N.; Joule, J.

    1978-01-01

    A functional population is a group of organisms and their offspring that contributes to a common gene pool within a certain area and time period. It is also the unit of evolution and should be viewed both in quantitative and qualitative terms. Selection, drift, dispersal, and mutation can alter the composition of populations. Spatial heterogeneity in allele frequencies argues for a conceptual model that has a series of relatively small populations semi-isolated from one another. Because of the relatively high levels of genetic variability characteristic of most mammalian species, significant amounts of gene flow between these spatially subdivided populations must occur when longer time periods are considered. Fluctuations in the genetic structure of populations seem to be important in altering the fitness of the individuals within the populations. The interaction of populations through gene flow is important in changing the levels of intrapopulational genetic variability. Populations can be characterized as existing on a continuum from relatively stable to unstable numbers and by other associated changes in their characteristics. Temporal changes in allele frequency occur in a variety of mammals. Conceptually, a species can be viewed as a series of dynamic populations that vary in numbers and quality in both a spatial and temporal context even over short distances and time periods. Short term changes in the quality of individuals in a population can be important in altering the short term dynamics of a population

  8. Hypergravity-induced altered behavior in Drosophila

    Science.gov (United States)

    Hosamani, Ravikumar; Wan, Judy; Marcu, Oana; Bhattacharya, Sharmila

    2012-07-01

    Microgravity and mechanical stress are important factors of the spaceflight environment, and affect astronaut health and behavior. Structural, functional, and behavioral mechanisms of all cells and organisms are adapted to Earth's gravitational force, 1G, while altered gravity can pose challenges to their adaptability to this new environment. On ground, hypergravity paradigms have been used to predict and complement studies on microgravity. Even small changes that take place at a molecular and genetic level during altered gravity may result in changes in phenotypic behavior. Drosophila provides a robust and simple, yet very reliable model system to understand the complexity of hypergravity-induced altered behavior, due to availability of a plethora of genetic tools. Locomotor behavior is a sensitive parameter that reflects the array of molecular adaptive mechanisms recruited during exposure to altered gravity. Thus, understanding the genetic basis of this behavior in a hypergravity environment could potentially extend our understanding of mechanisms of adaptation in microgravity. In our laboratory we are trying to dissect out the cellular and molecular mechanisms underlying hypergravity-induced oxidative stress, and its potential consequences on behavioral alterations by using Drosophila as a model system. In the present study, we employed pan-neuronal and mushroom body specific knock-down adult flies by using Gal4/UAS system to express inverted repeat transgenes (RNAi) to monitor and quantify the hypergravity-induced behavior in Drosophila. We established that acute hypergravity (3G for 60 min) causes a significant and robust decrease in the locomotor behavior in adult Drosophila, and that this change is dependent on genes related to Parkinson's disease, such as DJ-1α , DJ-1β , and parkin. In addition, we also showed that anatomically the control of this behavior is significantly processed in the mushroom body region of the fly brain. This work links a molecular

  9. Contribution of radiodiagnosis to genetically significant dose

    International Nuclear Information System (INIS)

    Pele, J.M.; Ouvrard, R.

    Surveys were carried out in France on 33,000 X-ray medical examinations. The genetically significant dose to the whole population from roentgenography and fluoroscopy, for typical examinations, should be about 65mrads [fr

  10. Genetics

    International Nuclear Information System (INIS)

    Hubitschek, H.E.

    1975-01-01

    Progress is reported on the following research projects: genetic effects of high LET radiations; genetic regulation, alteration, and repair; chromosome replication and the division cycle of Escherichia coli; effects of radioisotope decay in the DNA of microorganisms; initiation and termination of DNA replication in Bacillus subtilis; mutagenesis in mouse myeloma cells; lethal and mutagenic effects of near-uv radiation; effect of 8-methoxypsoralen on photodynamic lethality and mutagenicity in Escherichia coli; DNA repair of the lethal effects of far-uv; and near uv irradiation of bacterial cells

  11. Stem Cell Technology for (Epi)genetic Brain Disorders.

    Science.gov (United States)

    Riemens, Renzo J M; Soares, Edilene S; Esteller, Manel; Delgado-Morales, Raul

    2017-01-01

    Despite the enormous efforts of the scientific community over the years, effective therapeutics for many (epi)genetic brain disorders remain unidentified. The common and persistent failures to translate preclinical findings into clinical success are partially attributed to the limited efficiency of current disease models. Although animal and cellular models have substantially improved our knowledge of the pathological processes involved in these disorders, human brain research has generally been hampered by a lack of satisfactory humanized model systems. This, together with our incomplete knowledge of the multifactorial causes in the majority of these disorders, as well as a thorough understanding of associated (epi)genetic alterations, has been impeding progress in gaining more mechanistic insights from translational studies. Over the last years, however, stem cell technology has been offering an alternative approach to study and treat human brain disorders. Owing to this technology, we are now able to obtain a theoretically inexhaustible source of human neural cells and precursors in vitro that offer a platform for disease modeling and the establishment of therapeutic interventions. In addition to the potential to increase our general understanding of how (epi)genetic alterations contribute to the pathology of brain disorders, stem cells and derivatives allow for high-throughput drugs and toxicity testing, and provide a cell source for transplant therapies in regenerative medicine. In the current chapter, we will demonstrate the validity of human stem cell-based models and address the utility of other stem cell-based applications for several human brain disorders with multifactorial and (epi)genetic bases, including Parkinson's disease (PD), Alzheimer's disease (AD), fragile X syndrome (FXS), Angelman syndrome (AS), Prader-Willi syndrome (PWS), and Rett syndrome (RTT).

  12. Genetic KCa3.1-deficiency produces locomotor hyperactivity and alterations in cerebral monoamine levels.

    Directory of Open Access Journals (Sweden)

    Kate Lykke Lambertsen

    Full Text Available The calmodulin/calcium-activated K(+ channel KCa3.1 is expressed in red and white blood cells, epithelia and endothelia, and possibly central and peripheral neurons. However, our knowledge about its contribution to neurological functions and behavior is incomplete. Here, we investigated whether genetic deficiency or pharmacological activation of KCa3.1 change behavior and cerebral monoamine levels in mice.In the open field test, KCa3.1-deficiency increased horizontal activity, as KCa3.1(-/- mice travelled longer distances (≈145% of KCa3.1(+/+ and at higher speed (≈1.5-fold of KCa3.1(+/+. Working memory in the Y-maze was reduced by KCa3.1-deficiency. Motor coordination on the rotarod and neuromuscular functions were unchanged. In KCa3.1(-/- mice, HPLC analysis revealed that turn-over rates of serotonin were reduced in frontal cortex, striatum and brain stem, while noradrenalin turn-over rates were increased in the frontal cortex. Dopamine turn-over rates were unaltered. Plasma catecholamine and corticosterone levels were unaltered. Intraperitoneal injections of 10 mg/kg of the KCa3.1/KCa2-activator SKA-31 reduced rearing and turning behavior in KCa3.1(+/+ but not in KCa3.1(-/- mice, while 30 mg/kg SKA-31 caused strong sedation in 50% of the animals of either genotypes. KCa3.1(-/- mice were hyperactive (≈+60% in their home cage and SKA-31-administration reduced nocturnal physical activity in KCa3.1(+/+ but not in KCa3.1(-/- mice.KCa3.1-deficiency causes locomotor hyperactivity and altered monoamine levels in selected brain regions, suggesting a so far unknown functional link of KCa3.1 channels to behavior and monoaminergic neurotransmission in mice. The tranquilizing effects of low-dose SKA-31 raise the possibility to use KCa3.1/KCa2 channels as novel pharmacological targets for the treatment of neuropsychiatric hyperactivity disorders.

  13. Low Genetic Quality Alters Key Dimensions of the Mutational Spectrum.

    Directory of Open Access Journals (Sweden)

    Nathaniel P Sharp

    2016-03-01

    Full Text Available Mutations affect individual health, population persistence, adaptation, diversification, and genome evolution. There is evidence that the mutation rate varies among genotypes, but the causes of this variation are poorly understood. Here, we link differences in genetic quality with variation in spontaneous mutation in a Drosophila mutation accumulation experiment. We find that chromosomes maintained in low-quality genetic backgrounds experience a higher rate of indel mutation and a lower rate of gene conversion in a manner consistent with condition-based differences in the mechanisms used to repair DNA double strand breaks. These aspects of the mutational spectrum were also associated with body mass, suggesting that the effect of genetic quality on DNA repair was mediated by overall condition, and providing a mechanistic explanation for the differences in mutational fitness decline among these genotypes. The rate and spectrum of substitutions was unaffected by genetic quality, but we find variation in the probability of substitutions and indels with respect to several aspects of local sequence context, particularly GC content, with implications for models of molecular evolution and genome scans for signs of selection. Our finding that the chances of mutation depend on genetic context and overall condition has important implications for how sequences evolve, the risk of extinction, and human health.

  14. Association of genetic variants of the incretin-related genes with quantitative traits and occurrence of type 2 diabetes in Japanese

    Directory of Open Access Journals (Sweden)

    Mayumi Enya

    2014-01-01

    Conclusion: Rare variants of GIPR may contribute to the development of type 2 diabetes, possibly through insulin secretory defects. Furthermore, the genetic variant of PCSK1 might influence glucose homeostasis by altered insulin resistance independently of BMI, incretin level or proinsulin conversion, and may be associated with the occurrence of type 2 diabetes in Japanese.

  15. Genetic and environmental contributions to anxiety among Chinese children and adolescents--a multi-informant twin study.

    Science.gov (United States)

    Chen, Jie; Yu, Jing; Li, Xinying; Zhang, Jianxin

    2015-05-01

    Child and adolescent anxiety has become a major public health concern in China, but little was known about the etiology of anxiety in Chinese children and adolescents. The present study aimed to investigate genetic and environmental influences on trait anxiety among Chinese children and adolescents. Rater, sex, and age differences on these estimates were also examined. Self-reported and parent-reported child's trait anxiety was collected from 1,104 pairs of same-sex twins aged 9-18 years. Genetic models were fitted to data from each informant to determine the genetic (A), shared (C), and non-shared environmental (E) influences on trait anxiety. The parameter estimates and 95% confidence intervals (CI) of A, C, E on self-reported trait anxiety were 50% [30%, 60%], 5% [0%, 24%], 45% [40%, 49%]. For parent-reported data, the corresponding parameter estimates were 63% [47%, 78%], 13% [1%, 28%], and 24% [22%, 27%], respectively. The heritability of anxiety was higher in girls for self-reported data, but higher in boys for parent-reported data. There was no significant age difference in genetic and environmental contributions for self-reported data, but a significant increase of heritability with age for parent-reported data. The trait anxiety in Chinese children and adolescents was highly heritable. Non-shared environmental factors also played an important role. The estimates of genetic and environmental effects differed by rater, sex and age. Our findings largely suggest the cross-cultural generalizability of the etiological model of child and adolescent anxiety. © 2014 Association for Child and Adolescent Mental Health.

  16. Hereditary kidney cancer syndromes: Genetic disorders driven by alterations in metabolism and epigenome regulation.

    Science.gov (United States)

    Hasumi, Hisashi; Yao, Masahiro

    2018-03-01

    Although hereditary kidney cancer syndrome accounts for approximately five percent of all kidney cancers, the mechanistic insight into tumor development in these rare conditions has provided the foundation for the development of molecular targeting agents currently used for sporadic kidney cancer. In the late 1980s, the comprehensive study for hereditary kidney cancer syndrome was launched in the National Cancer Institute, USA and the first kidney cancer-associated gene, VHL, was identified through kindred analysis of von Hippel-Lindau (VHL) syndrome in 1993. Subsequent molecular studies on VHL function have elucidated that the VHL protein is a component of E3 ubiquitin ligase complex for hypoxia-inducible factor (HIF), which provided the basis for the development of tyrosine kinase inhibitors targeting the HIF-VEGF/PDGF pathway. Recent whole-exome sequencing analysis of sporadic kidney cancer exhibited the recurrent mutations in chromatin remodeling genes and the later study has revealed that several chromatin remodeling genes are altered in kidney cancer kindred at the germline level. To date, more than 10 hereditary kidney cancer syndromes together with each responsible gene have been characterized and most of the causative genes for these genetic disorders are associated with either metabolism or epigenome regulation. In this review article, we describe the molecular mechanisms of how an alteration of each kidney cancer-associated gene leads to renal tumorigenesis as well as denote therapeutic targets elicited by studies on hereditary kidney cancer. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  17. Ancient and recent Middle Eastern maternal genetic contribution to North Africa as viewed by mtDNA diversity in Tunisian Arab populations.

    Science.gov (United States)

    Elkamel, Sarra; Boussetta, Sami; Khodjet-El-Khil, Houssein; Benammar Elgaaied, Amel; Cherni, Lotfi

    2018-05-01

    Through previous mitochondrial DNA studies, the Middle Eastern maternal genetic contribution to Tunisian populations appears limited. In fact, most of the studied communities were cosmopolitan, or of Berber or Andalusian origin. To provide genetic evidence for the actual contribution of Middle Eastern mtDNA lineages to Tunisia, we focused on two Arab speaking populations from Kairouan and Wesletia known to belong to an Arab genealogical lineage. A total of 114 samples were sequenced for the mtDNA HVS-I and HVS-II regions. Using these data, we evaluated the distribution of Middle Eastern haplogroups in the study populations, constructed interpolation maps, and established phylogenetic networks allowing estimation of the coalescence time for three specific Middle Eastern subclades (R0a, J1b, and T1). Both studied populations displayed North African genetic structure and Middle Eastern lineages with a frequency of 12% and 28.12% in Kairouan and Wesletia, respectively. TMRCA estimates for haplogroups T1a, R0a, and J1b in Tunisian Arabian samples were around 15 000 YBP, 9000 to 5000 YBP, and 960 to 600 YBP, respectively. The Middle Eastern maternal genetic contribution to Tunisian populations, as to other North African populations, occurred mostly in deep prehistory. They were brought in different migration waves during the Upper Paleolithic, probably with the expansion of Iberomaurusian culture, and during Epipaleolithic and Early Neolithic periods, which are concomitant with the Capsian civilization. Middle Eastern lineages also came to Tunisia during the recent Islamic expansion of the 7th CE and the subsequent massive Bedouin migration during the 11th CE. © 2018 Wiley Periodicals, Inc.

  18. Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis.

    Science.gov (United States)

    Sieberts, Solveig K; Zhu, Fan; García-García, Javier; Stahl, Eli; Pratap, Abhishek; Pandey, Gaurav; Pappas, Dimitrios; Aguilar, Daniel; Anton, Bernat; Bonet, Jaume; Eksi, Ridvan; Fornés, Oriol; Guney, Emre; Li, Hongdong; Marín, Manuel Alejandro; Panwar, Bharat; Planas-Iglesias, Joan; Poglayen, Daniel; Cui, Jing; Falcao, Andre O; Suver, Christine; Hoff, Bruce; Balagurusamy, Venkat S K; Dillenberger, Donna; Neto, Elias Chaibub; Norman, Thea; Aittokallio, Tero; Ammad-Ud-Din, Muhammad; Azencott, Chloe-Agathe; Bellón, Víctor; Boeva, Valentina; Bunte, Kerstin; Chheda, Himanshu; Cheng, Lu; Corander, Jukka; Dumontier, Michel; Goldenberg, Anna; Gopalacharyulu, Peddinti; Hajiloo, Mohsen; Hidru, Daniel; Jaiswal, Alok; Kaski, Samuel; Khalfaoui, Beyrem; Khan, Suleiman Ali; Kramer, Eric R; Marttinen, Pekka; Mezlini, Aziz M; Molparia, Bhuvan; Pirinen, Matti; Saarela, Janna; Samwald, Matthias; Stoven, Véronique; Tang, Hao; Tang, Jing; Torkamani, Ali; Vert, Jean-Phillipe; Wang, Bo; Wang, Tao; Wennerberg, Krister; Wineinger, Nathan E; Xiao, Guanghua; Xie, Yang; Yeung, Rae; Zhan, Xiaowei; Zhao, Cheng; Greenberg, Jeff; Kremer, Joel; Michaud, Kaleb; Barton, Anne; Coenen, Marieke; Mariette, Xavier; Miceli, Corinne; Shadick, Nancy; Weinblatt, Michael; de Vries, Niek; Tak, Paul P; Gerlag, Danielle; Huizinga, Tom W J; Kurreeman, Fina; Allaart, Cornelia F; Louis Bridges, S; Criswell, Lindsey; Moreland, Larry; Klareskog, Lars; Saevarsdottir, Saedis; Padyukov, Leonid; Gregersen, Peter K; Friend, Stephen; Plenge, Robert; Stolovitzky, Gustavo; Oliva, Baldo; Guan, Yuanfang; Mangravite, Lara M; Bridges, S Louis; Criswell, Lindsey; Moreland, Larry; Klareskog, Lars; Saevarsdottir, Saedis; Padyukov, Leonid; Gregersen, Peter K; Friend, Stephen; Plenge, Robert; Stolovitzky, Gustavo; Oliva, Baldo; Guan, Yuanfang; Mangravite, Lara M

    2016-08-23

    Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in ∼one-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h(2)=0.18, P value=0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data.

  19. Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons

    NARCIS (Netherlands)

    Rotger, Margalida; Glass, Tracy R; Junier, Thomas; Lundgren, Jens; Neaton, James D; Poloni, Estella S; van 't Wout, Angélique B; Lubomirov, Rubin; Colombo, Sara; Martinez, Raquel; Rauch, Andri; Günthard, Huldrych F; Neuhaus, Jacqueline; Wentworth, Deborah; van Manen, Danielle; Gras, Luuk A; Schuitemaker, Hanneke; Albini, Laura; Torti, Carlo; Jacobson, Lisa P; Li, Xiuhong; Kingsley, Lawrence A; Carli, Federica; Guaraldi, Giovanni; Ford, Emily S; Sereti, Irini; Hadigan, Colleen; Martinez, Esteban; Arnedo, Mireia; Egaña-Gorroño, Lander; Gatell, Jose M; Law, Matthew; Bendall, Courtney; Petoumenos, Kathy; Rockstroh, Jürgen; Wasmuth, Jan-Christian; Kabamba, Kabeya; Delforge, Marc; De Wit, Stephane; Berger, Florian; Mauss, Stefan; de Paz Sierra, Mariana; Losso, Marcelo; Belloso, Waldo H; Leyes, Maria; Campins, Antoni; Mondi, Annalisa; De Luca, Andrea; Bernardino, Ignacio; Barriuso-Iglesias, Mónica; Torrecilla-Rodriguez, Ana; Gonzalez-Garcia, Juan; Arribas, José R; Fanti, Iuri; Gel, Silvia; Puig, Jordi; Negredo, Eugenia; Gutierrez, Mar; Domingo, Pere; Fischer, Julia; Fätkenheuer, Gerd; Alonso-Villaverde, Carlos; Macken, Alan; Woo, James; McGinty, Tara; Mallon, Patrick; Mangili, Alexandra; Skinner, Sally; Wanke, Christine A; Reiss, Peter; Weber, Rainer; Bucher, Heiner C; Fellay, Jacques; Telenti, Amalio; Tarr, Philip E; Schölvinck, Elisabeth H.

    BACKGROUND: Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the

  20. A genome-wide screen for genetic variants that modify the recruitment of REST to its target genes.

    Directory of Open Access Journals (Sweden)

    Rory Johnson

    Full Text Available Increasing numbers of human diseases are being linked to genetic variants, but our understanding of the mechanistic links leading from DNA sequence to disease phenotype is limited. The majority of disease-causing nucleotide variants fall within the non-protein-coding portion of the genome, making it likely that they act by altering gene regulatory sequences. We hypothesised that SNPs within the binding sites of the transcriptional repressor REST alter the degree of repression of target genes. Given that changes in the effective concentration of REST contribute to several pathologies-various cancers, Huntington's disease, cardiac hypertrophy, vascular smooth muscle proliferation-these SNPs should alter disease-susceptibility in carriers. We devised a strategy to identify SNPs that affect the recruitment of REST to target genes through the alteration of its DNA recognition element, the RE1. A multi-step screen combining genetic, genomic, and experimental filters yielded 56 polymorphic RE1 sequences with robust and statistically significant differences of affinity between alleles. These SNPs have a considerable effect on the the functional recruitment of REST to DNA in a range of in vitro, reporter gene, and in vivo analyses. Furthermore, we observe allele-specific biases in deeply sequenced chromatin immunoprecipitation data, consistent with predicted differenes in RE1 affinity. Amongst the targets of polymorphic RE1 elements are important disease genes including NPPA, PTPRT, and CDH4. Thus, considerable genetic variation exists in the DNA motifs that connect gene regulatory networks. Recently available ChIP-seq data allow the annotation of human genetic polymorphisms with regulatory information to generate prior hypotheses about their disease-causing mechanism.

  1. A Genome-Wide Screen for Genetic Variants That Modify the Recruitment of REST to Its Target Genes

    Science.gov (United States)

    Johnson, Rory; Richter, Nadine; Bogu, Gireesh K.; Bhinge, Akshay; Teng, Siaw Wei; Choo, Siew Hua; Andrieux, Lise O.; de Benedictis, Cinzia; Jauch, Ralf; Stanton, Lawrence W.

    2012-01-01

    Increasing numbers of human diseases are being linked to genetic variants, but our understanding of the mechanistic links leading from DNA sequence to disease phenotype is limited. The majority of disease-causing nucleotide variants fall within the non-protein-coding portion of the genome, making it likely that they act by altering gene regulatory sequences. We hypothesised that SNPs within the binding sites of the transcriptional repressor REST alter the degree of repression of target genes. Given that changes in the effective concentration of REST contribute to several pathologies—various cancers, Huntington's disease, cardiac hypertrophy, vascular smooth muscle proliferation—these SNPs should alter disease-susceptibility in carriers. We devised a strategy to identify SNPs that affect the recruitment of REST to target genes through the alteration of its DNA recognition element, the RE1. A multi-step screen combining genetic, genomic, and experimental filters yielded 56 polymorphic RE1 sequences with robust and statistically significant differences of affinity between alleles. These SNPs have a considerable effect on the the functional recruitment of REST to DNA in a range of in vitro, reporter gene, and in vivo analyses. Furthermore, we observe allele-specific biases in deeply sequenced chromatin immunoprecipitation data, consistent with predicted differenes in RE1 affinity. Amongst the targets of polymorphic RE1 elements are important disease genes including NPPA, PTPRT, and CDH4. Thus, considerable genetic variation exists in the DNA motifs that connect gene regulatory networks. Recently available ChIP–seq data allow the annotation of human genetic polymorphisms with regulatory information to generate prior hypotheses about their disease-causing mechanism. PMID:22496669

  2. How much do genetic covariances alter the rate of adaptation?

    Science.gov (United States)

    Agrawal, Aneil F; Stinchcombe, John R

    2009-03-22

    Genetically correlated traits do not evolve independently, and the covariances between traits affect the rate at which a population adapts to a specified selection regime. To measure the impact of genetic covariances on the rate of adaptation, we compare the rate fitness increases given the observed G matrix to the expected rate if all the covariances in the G matrix are set to zero. Using data from the literature, we estimate the effect of genetic covariances in real populations. We find no net tendency for covariances to constrain the rate of adaptation, though the quality and heterogeneity of the data limit the certainty of this result. There are some examples in which covariances strongly constrain the rate of adaptation but these are balanced by counter examples in which covariances facilitate the rate of adaptation; in many cases, covariances have little or no effect. We also discuss how our metric can be used to identify traits or suites of traits whose genetic covariances to other traits have a particularly large impact on the rate of adaptation.

  3. No Major Host Genetic Risk Factor Contributed to A(H1N1)2009 Influenza Severity.

    Science.gov (United States)

    Garcia-Etxebarria, Koldo; Bracho, María Alma; Galán, Juan Carlos; Pumarola, Tomàs; Castilla, Jesús; Ortiz de Lejarazu, Raúl; Rodríguez-Dominguez, Mario; Quintela, Inés; Bonet, Núria; Garcia-Garcerà, Marc; Domínguez, Angela; González-Candelas, Fernando; Calafell, Francesc

    2015-01-01

    While most patients affected by the influenza A(H1N1) pandemic experienced mild symptoms, a small fraction required hospitalization, often without concomitant factors that could explain such a severe course. We hypothesize that host genetic factors could contribute to aggravate the disease. To test this hypothesis, we compared the allele frequencies of 547,296 genome-wide single nucleotide polymorphisms (SNPs) between 49 severe and 107 mild confirmed influenza A cases, as well as against a general population sample of 549 individuals. When comparing severe vs. mild influenza A cases, only one SNP was close to the conventional p = 5×10-8. This SNP, rs28454025, sits in an intron of the GSK233 gene, which is involved in a neural development, but seems not to have any connections with immunological or inflammatory functions. Indirectly, a previous association reported with CD55 was replicated. Although sample sizes are low, we show that the statistical power in our design was sufficient to detect highly-penetrant, quasi-Mendelian genetic factors. Hence, and assuming that rs28454025 is likely to be a false positive, no major genetic factor was detected that could explain poor influenza A course.

  4. Inflammasome genetics contributes to the development and control of active pulmonary tuberculosis.

    Science.gov (United States)

    Souza de Lima, D; Ogusku, M M; Sadahiro, A; Pontillo, A

    2016-07-01

    Tuberculosis (TB) continues to be a major public health problem. An estimated one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb) but remains asymptomatic (latent TB) and only 5% to 10% of these latent individuals will develop active pulmonary TB. Factors affecting the balance between latent and active TB are mostly unknown, even if host genome has been shown to contribute to the outcome of Mtb response. Acute inflammation and Th1 response are important in the early clearance of the bacteria as it was emphasized by the association between immune genes (i.e.: HLA, IFNG, TNF, NRPAM1, IL10) variants and the development of active pulmonary TB. Recently, the role of the inflammasome in experimental TB has been demonstrated, however, to our knowledge, no data still exist about the contribution of inflammasome genetics to Mtb susceptibility and/or to the development of active TB. For this reason, selected polymorphisms in inflammasome genes were analysed in a case/control cohort of individuals with active pulmonary TB from an endemic area of Brazil Amazon. Our data evidence the novel association between polymorphisms in NLRP3-inflammasome encoding genes and active pulmonary TB, and replicated the association between P2X7 and TB observed in other populations. These results emphasize the role of NLRP3-inflammasome also in human TB, and contribute to our knowledge about pathways involved in the development of active TB, even if deeper investigation are needed to fully elucidate the role of the complex in Mtb infection. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Local Genetic Correlation Gives Insights into the Shared Genetic Architecture of Complex Traits.

    Science.gov (United States)

    Shi, Huwenbo; Mancuso, Nicholas; Spendlove, Sarah; Pasaniuc, Bogdan

    2017-11-02

    Although genetic correlations between complex traits provide valuable insights into epidemiological and etiological studies, a precise quantification of which genomic regions disproportionately contribute to the genome-wide correlation is currently lacking. Here, we introduce ρ-HESS, a technique to quantify the correlation between pairs of traits due to genetic variation at a small region in the genome. Our approach requires GWAS summary data only and makes no distributional assumption on the causal variant effect sizes while accounting for linkage disequilibrium (LD) and overlapping GWAS samples. We analyzed large-scale GWAS summary data across 36 quantitative traits, and identified 25 genomic regions that contribute significantly to the genetic correlation among these traits. Notably, we find 6 genomic regions that contribute to the genetic correlation of 10 pairs of traits that show negligible genome-wide correlation, further showcasing the power of local genetic correlation analyses. Finally, we report the distribution of local genetic correlations across the genome for 55 pairs of traits that show putative causal relationships. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  6. Prepubertal Ovariectomy Exaggerates Adult Affective Behaviors and Alters the Hippocampal Transcriptome in a Genetic Rat Model of Depression

    Directory of Open Access Journals (Sweden)

    Neha S. Raghavan

    2018-01-01

    Full Text Available Major depressive disorder (MDD is a debilitating illness that affects twice as many women than men postpuberty. This female bias is thought to be caused by greater heritability of MDD in women and increased vulnerability induced by female sex hormones. We tested this hypothesis by removing the ovaries from prepubertal Wistar Kyoto (WKY more immobile (WMI females, a genetic animal model of depression, and its genetically close control, the WKY less immobile (WLI. In adulthood, prepubertally ovariectomized (PrePubOVX animals and their Sham-operated controls were tested for depression- and anxiety-like behaviors, using the routinely employed forced swim and open field tests, respectively, and RNA-sequencing was performed on their hippocampal RNA. Our results confirmed that the behavioral and hippocampal expression changes that occur after prepubertal ovariectomy are the consequences of an interaction between genetic predisposition to depressive behavior and ovarian hormone-regulated processes. Lack of ovarian hormones during and after puberty in the WLIs led to increased depression-like behavior. In WMIs, both depression- and anxiety-like behaviors worsened by prepubertal ovariectomy. The unbiased exploration of the hippocampal transcriptome identified sets of differentially expressed genes (DEGs between the strains and treatment groups. The relatively small number of hippocampal DEGs resulting from the genetic differences between the strains confirmed the genetic relatedness of these strains. Nevertheless, the differences in DEGs between the strains in response to prepubertal ovariectomy identified different molecular processes, including the importance of glucocorticoid receptor-mediated mechanisms, that may be causative of the increased depression-like behavior in the presence or absence of genetic predisposition. This study contributes to the understanding of hormonal maturation-induced changes in affective behaviors and the hippocampal

  7. Potential Implications of Research on Genetic or Heritable Contributions to Pedophilia for the Objectives of Criminal Law

    Science.gov (United States)

    Berryessa, Colleen M.

    2015-01-01

    In recent years, there has been increasing scientific research on possible genetic or heritable influences to the etiology of pedophilia, driven by national and public concerns about better understanding the disorder in order to reduce children’s vulnerabilities to pedophilic and child sex offenders. This research has corresponded to growing academic dialogue on how advances in genetic research, especially concerning the causes and development of particular mental disorders or behaviors, may affect traditional practices of criminal law and how the justice system views, manages, and adjudicates different types of criminal behavior and offenders. This paper strives to supplement this dialogue by exploring several of the many possible effects and implications of research surrounding genetic or heritable contributions to pedophilia for the five widely accepted objectives that enforce and regulate the punishment of criminal law. These include retribution, incapacitation, deterrence, rehabilitation, and restoration. Although still currently in early stages, genetic and heritability research on the etiology of pedophilia may have the potential moving forward to influence the current and established punitive methods and strategies of how the justice system perceives, adjudicates, regulates, and punishes pedophilic and sex offenders, as well as how to best prevent sexual offending against children by pedophilic offenders in the future. PMID:25557668

  8. Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons

    NARCIS (Netherlands)

    Rotger, Margalida; Glass, Tracy R.; Junier, Thomas; Lundgren, Jens; Neaton, James D.; Poloni, Estella S.; van 't Wout, Angélique B.; Lubomirov, Rubin; Colombo, Sara; Martinez, Raquel; Rauch, Andri; Günthard, Huldrych F.; Neuhaus, Jacqueline; Wentworth, Deborah; van Manen, Danielle; Gras, Luuk A.; Schuitemaker, Hanneke; Albini, Laura; Torti, Carlo; Jacobson, Lisa P.; Li, Xiuhong; Kingsley, Lawrence A.; Carli, Federica; Guaraldi, Giovanni; Ford, Emily S.; Sereti, Irini; Hadigan, Colleen; Martinez, Esteban; Arnedo, Mireia; Egaña-Gorroño, Lander; Gatell, Jose M.; Law, Matthew; Bendall, Courtney; Petoumenos, Kathy; Rockstroh, Jürgen; Wasmuth, Jan-Christian; Kabamba, Kabeya; Delforge, Marc; de Wit, Stephane; Berger, Florian; Mauss, Stefan; de Paz Sierra, Mariana; Losso, Marcelo; Belloso, Waldo H.; Leyes, Maria; Campins, Antoni; Mondi, Annalisa; de Luca, Andrea; Bernardino, Ignacio; Barriuso-Iglesias, Mónica; Torrecilla-Rodriguez, Ana; Gonzalez-Garcia, Juan; Arribas, José R.; Fanti, Iuri; Gel, Silvia; Puig, Jordi; Negredo, Eugenia; Gutierrez, Mar; Domingo, Pere; Fischer, Julia; Fätkenheuer, Gerd; Alonso-Villaverde, Carlos; Macken, Alan; Woo, James; McGinty, Tara; Mallon, Patrick; Mangili, Alexandra; Skinner, Sally; Wanke, Christine A.; Reiss, Peter; Weber, Rainer; Bucher, Heiner C.; Fellay, Jacques; Telenti, Amalio; Tarr, Philip E.; Gras, A. Luuk; van Wout, Angelique B.; Arnedo-Valero, Mireia; Sierra, Mariana de Paz; Rodriguez, Ana Torrecilla; Garcia, Juan Gonzalez; Arribas, Jose R.; Aubert, V.; Barth, J.; Battegay, M.; Bernasconi, E.; Böni, J.; Bucher, H. C.; Burton-Jeangros, C.; Calmy, A.; Cavassini, M.; Egger, M.; Elzi, L.; Fehr, J.; Fellay, J.; Francioli, P.; Furrer, H.; Fux, C. A.; Gorgievski, M.; Günthard, H.; Haerry, D.; Hasse, B.; Hirsch, H. H.; Hirschel, B.; Hösli, I.; Kahlert, C.; Kaiser, L.; Keiser, O.; Kind, C.; Klimkait, T.; Kovari, H.; Ledergerber, B.; Martinetti, G.; Martinez de Tejada, B.; Metzner, K.; Müller, N.; Nadal, D.; Pantaleo, G.; Rauch, A.; Regenass, S.; Rickenbach, M.; Rudin, C.; Schmid, P.; Schultze, D.; Schöni-Affolter, F.; Schüpbach, J.; Speck, R.; Taffé, P.; Tarr, P.; Telenti, A.; Trkola, A.; Vernazza, P.; Weber, R.; Prins, Yerly S. J. M.; Kuijpers, T. W.; Scherpbier, H. J.; Boer, K.; van der Meer, J. T. M.; Wit, F. W. M. N.; Godfried, M. H.; van der Poll, T.; Nellen, F. J. B.; Lange, J. M. A.; Geerlings, S. E.; van Vugt, M.; Vrouenraets, S. M. E.; Pajkrt, D.; Bos, J. C.; van der Valk, M.; Schreij, G.; Lowe, S.; Oude Lashof, A.; Pronk, M. J. H.; Bravenboer, B.; van der Ende, M. E.; de Vries-Sluijs, T. E. M. S.; Schurink, C. A. M.; van der Feltz, M.; Nouwen, J. L.; Gelinck, L. B. S.; Verbon, A.; Rijnders, B. J. A.; van de Ven-de Ruiter, E. D.; Slobbe, L.; Haag, Den; Kauffmann, R. H.; Schippers, E. F.; Groeneveld, P. H. P.; Alleman, M. A.; Bouwhuis, J. W.; ten Kate, R. W.; Soetekouw, R.; Kroon, F. P.; van den Broek, P. J.; van Dissel, J. T.; Arend, S. M.; van Nieuwkoop, C.; de Boer, M. J. G.; Jolink, H.; den Hollander, J. G.; Pogany, K.; Bronsveld, W.; Kortmann, W.; van Twillert, G.; van Houte, D. P. F.; Polée, M. B.; van Vonderen, M. G. A.; ten Napel, C. H. H.; Kootstra, G. J.; Brinkman, K.; Blok, W. L.; Frissen, P. H. J.; Schouten, W. E. M.; van den Berk, G. E. L.; Juttmann, J. R.; van Kasteren, M. E. E.; Brouwer, A. E.; Mulder, J. W.; van Gorp, E. C. M.; Smit, P. M.; Weijer, S.; van Eeden, A.; Verhagen, D. W. M.; Sprenger, H. G.; Doedens, R.; Scholvinck, E. H.; van Assen, S.; Stek, C. J.; Hoepelman, I. M.; Mudrikova, T.; Schneider, M. M. E.; Jaspers, C. A. J. J.; Ellerbroek, P. M.; Peters, E. J. G.; Maarschalk-Ellerbroek, L. J.; Oosterheert, J. J.; Arends, J. E.; Wassenberg, M. W. M.; van der Hilst, J. C. H.; Richter, C.; van der Berg, J. P.; Gisolf, E. H.; Margolick, Joseph B.; Plankey, Michael; Crain, Barbara; Dobs, Adrian; Farzadegan, Homayoon; Gallant, Joel; Johnson-Hill, Lisette; Sacktor, Ned; Selnes, Ola; Shepard, James; Thio, Chloe; Phair, John P.; Wolinsky, Steven M.; Badri, Sheila; Conover, Craig; O'Gorman, Maurice; Ostrow, David; Palella, Frank; Ragin, Ann; Detels, Roger; Martínez-Maza, Otoniel; Aronow, Aaron; Bolan, Robert; Breen, Elizabeth; Butch, Anthony; Fahey, John; Jamieson, Beth; Miller, Eric N.; Oishi, John; Vinters, Harry; Visscher, Barbara R.; Wiley, Dorothy; Witt, Mallory; Yang, Otto; Young, Stephen; Zhang, Zuo Feng; Rinaldo, Charles R.; Becker, James T.; Cranston, Ross D.; Martinson, Jeremy J.; Mellors, John W.; Silvestre, Anthony J.; Stall, Ronald D.; Muñoz, Alvaro; Abraham, Alison; Althoff, Keri; Cox, Christopher; D'Souza, Gypsyamber; Gange, Stephen J.; Golub, Elizabeth; Schollenberger, Janet; Seaberg, Eric C.; Su, Sol; Huebner, Robin E.; Dominguez, Geraldina; Moroni, M.; Angarano, G.; Antinori, A.; Carosi, G.; Cauda, R.; Monforte, A. d'Arminio; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; Sagnelli, E.; Viale, P. L.; Von Schlosser, F.; d'Arminio Monforte, A.; Ammassari, A.; Andreoni, M.; Balotta, C.; Bonfanti, P.; Bonora, S.; Borderi, M.; Capobianchi, M. R.; Castagna, A.; Ceccherini-Silberstein, F.; Cozzi-Lepri, A.; de Luca, A.; Gargiulo, M.; Gervasoni, C.; Girardi, E.; Lichtner, M.; Lo Caputo, S.; Madeddu, G.; Maggiolo, F.; Marcotullio, S.; Monno, L.; Murri, R.; Mussini, C.; Puoti, M.; Torti, C.; Fanti, I.; Formenti, T.; Galli, Laura; Lorenzini, Patrizia; Montroni, M.; Giacometti, A.; Costantini, A.; Riva, A.; Tirelli, U.; Martellotta, F.; Ladisa, N.; Lazzari, G.; Verucchi, G.; Castelli, F.; Scalzini, A.; Minardi, C.; Bertelli, D.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Vecchiet, J.; Falasca, K.; Carnevale, G.; Lorenzotti, S.; Sighinolfi, L.; Segala, D.; Leoncini, F.; Mazzotta, F.; Pozzi, M.; Cassola, G.; Viscoli, G.; Viscoli, A.; Piscopo, R.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Caramma, I.; Chiodera, A.; Castelli, P.; Rizzardini, G.; Ridolfo, A. L.; Foschi, A.; Salpietro, S.; Galli, A.; Bigoloni, A.; Spagnuolo, V.; Merli, S.; Carenzi, L.; Moioli, M. C.; Cicconi, P.; Bisio, L.; Gori, A.; Lapadula, G.; Abrescia, N.; Chirianni, A.; de Marco, M.; Ferrari, C.; Borghi, R.; Baldelli, F.; Belfiori, B.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; Narciso, P.; Tozzi, V.; Vullo, V.; d'Avino, A.; Zaccarelli, M.; Gallo, L.; Acinapura, R.; Capozzi, M.; Libertone, R.; Trotta, M. P.; Tebano, G.; Cattelan, A. M.; Mura, M. S.; Caramello, P.; Orofino, G. C.; Sciandra, M.; Raise, N. N.; Ebo, F.; Pellizzer, G.; Manfrin, V.; Law, M.; Petoumenos, K.; McManus, H.; Wright, S.; Bendall, C.; Moore, R.; Edwards, S.

    2013-01-01

    Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV

  9. Contribution of conservation genetics in assessing neotropical freshwater fish biodiversity

    Directory of Open Access Journals (Sweden)

    NM. Piorski

    Full Text Available Human activities have a considerable impact on hydrographic systems and fish fauna. The present review on conservation genetics of neotropical freshwater fish reveals that DNA analyses have been promoting increased knowledge on the genetic structure of fish species and their response to environmental changes. This knowledge is fundamental to the management of wild fish populations and the establishment of Evolutionary Significant Units capable of conserving genetic integrity. While population structuring can occur even in long-distance migratory fish, isolated populations can show reduced genetic variation and be at greater risk of extinction. Phylogeography and phylogeny have been powerful tools in understanding the evolution of fish populations, species and communities in distinct neotropic environments. Captive fish can be used to introduce new individuals and genes into the wild and their benefits and disadvantages can be monitored through genetic analysis. Understanding how fish biodiversity in neotropical freshwaters is generated and maintained is highly important, as these habitats are transformed by human development and fish communities are increasingly exploited as food sources to sustain a growing human population.

  10. Contribution of altered signal transduction associated to glutamate receptors in brain to the neurological alterations of hepatic encephalopathy

    Institute of Scientific and Technical Information of China (English)

    Vicente Felipo

    2006-01-01

    Patients with liver disease may present hepatic encephalopathy (HE), a complex neuropsychiatric syndrome covering a wide range of neurological alterations,including cognitive and motor disturbances. HE reduces the quality of life of the patients and is associated with poor prognosis. In the worse cases HE may lead to coma or death.The mechanisms leading to HE which are not well known are being studied using animal models. The neurological alterations in HE are a consequence of impaired cerebral function mainly due to alterations in neurotransmission. We review here some studies indicating that alterations in neurotransmission associated to different types of glutamate receptors are responsible for some of the cognitive and motor alterations present in HE.These studies show that the function of the signal transduction pathway glutamate-nitric oxide-cGMP associated to the NMDA type of glutamate receptors is impaired in brain in vivo in HE animal models as well as in brain of patients died of HE. Activation of NMDA receptors in brain activates this pathway and increases cGMP. In animal models of HE this increase in cGMP induced by activation of NMDA receptors is reduced,which is responsible for the impairment in learning ability in these animal models. Increasing cGMP by pharmacological means restores learning ability in rats with HE and may be a new therapeutic approach to improve cognitive function in patients with HE.However, it is necessary to previously assess the possible secondary effects.Patients with HE may present psychomotor slowing,hypokinesia and bradykinesia. Animal models of HE also show hypolocomotion. It has been shown in rats with HE that hypolocomotion is due to excessive activation of metabotropic glutamate receptors (mGluRs) in substantia nigra pars reticulata. Blocking mGluR1 in this brain area normalizes motor activity in the rats, suggesting that a similar treatment for patients with HE could be useful to treat psychomotor slowing and

  11. The Contribution of Genetic Recombination to CRISPR Array Evolution.

    Science.gov (United States)

    Kupczok, Anne; Landan, Giddy; Dagan, Tal

    2015-06-16

    CRISPR (clustered regularly interspaced short palindromic repeats) is a microbial immune system against foreign DNA. Recognition sequences (spacers) encoded within the CRISPR array mediate the immune reaction in a sequence-specific manner. The known mechanisms for the evolution of CRISPR arrays include spacer acquisition from foreign DNA elements at the time of invasion and array erosion through spacer deletion. Here, we consider the contribution of genetic recombination between homologous CRISPR arrays to the evolution of spacer repertoire. Acquisition of spacers from exogenic arrays via recombination may confer the recipient with immunity against unencountered antagonists. For this purpose, we develop a novel method for the detection of recombination in CRISPR arrays by modeling the spacer order in arrays from multiple strains from the same species. Because the evolutionary signal of spacer recombination may be similar to that of pervasive spacer deletions or independent spacer acquisition, our method entails a robustness analysis of the recombination inference by a statistical comparison to resampled and perturbed data sets. We analyze CRISPR data sets from four bacterial species: two Gammaproteobacteria species harboring CRISPR type I and two Streptococcus species harboring CRISPR type II loci. We find that CRISPR array evolution in Escherichia coli and Streptococcus agalactiae can be explained solely by vertical inheritance and differential spacer deletion. In Pseudomonas aeruginosa, we find an excess of single spacers potentially incorporated into the CRISPR locus during independent acquisition events. In Streptococcus thermophilus, evidence for spacer acquisition by recombination is present in 5 out of 70 strains. Genetic recombination has been proposed to accelerate adaptation by combining beneficial mutations that arose in independent lineages. However, for most species under study, we find that CRISPR evolution is shaped mainly by spacer acquisition and

  12. Consideration of genetic contributions to the risk for spasmodic dysphonia.

    Science.gov (United States)

    Sharma, Nutan; Franco, Ramon A

    2011-09-01

    Spasmodic dysphonia, a form of the neurologic condition known as dystonia, results from involuntary spasms of the larynx, producing interruptions of speech and changes in voice quality. The pathogenesis of spasmodic dysphonia is not well understood. However, several genetic mutations have been identified that cause different forms of dystonia. In some individuals, these genetic mutations result in spasmodic dysphonia, either with no other signs of dystonia or as part of a broader dystonia phenotype. Thus, research in the growing field of dystonia genetics may help to inform our understanding of the pathogenesis of spasmodic dysphonia.

  13. Genetics of Oxidative Stress in Obesity

    Directory of Open Access Journals (Sweden)

    Azahara I. Rupérez

    2014-02-01

    Full Text Available Obesity is a multifactorial disease characterized by the excessive accumulation of fat in adipose tissue and peripheral organs. Its derived metabolic complications are mediated by the associated oxidative stress, inflammation and hypoxia. Oxidative stress is due to the excessive production of reactive oxygen species or diminished antioxidant defenses. Genetic variants, such as single nucleotide polymorphisms in antioxidant defense system genes, could alter the efficacy of these enzymes and, ultimately, the risk of obesity; thus, studies investigating the role of genetic variations in genes related to oxidative stress could be useful for better understanding the etiology of obesity and its metabolic complications. The lack of existing literature reviews in this field encouraged us to gather the findings from studies focusing on the impact of single nucleotide polymorphisms in antioxidant enzymes, oxidative stress-producing systems and transcription factor genes concerning their association with obesity risk and its phenotypes. In the future, the characterization of these single nucleotide polymorphisms (SNPs in obese patients could contribute to the development of controlled antioxidant therapies potentially beneficial for the treatment of obesity-derived metabolic complications.

  14. Genetics of oxidative stress in obesity.

    Science.gov (United States)

    Rupérez, Azahara I; Gil, Angel; Aguilera, Concepción M

    2014-02-20

    Obesity is a multifactorial disease characterized by the excessive accumulation of fat in adipose tissue and peripheral organs. Its derived metabolic complications are mediated by the associated oxidative stress, inflammation and hypoxia. Oxidative stress is due to the excessive production of reactive oxygen species or diminished antioxidant defenses. Genetic variants, such as single nucleotide polymorphisms in antioxidant defense system genes, could alter the efficacy of these enzymes and, ultimately, the risk of obesity; thus, studies investigating the role of genetic variations in genes related to oxidative stress could be useful for better understanding the etiology of obesity and its metabolic complications. The lack of existing literature reviews in this field encouraged us to gather the findings from studies focusing on the impact of single nucleotide polymorphisms in antioxidant enzymes, oxidative stress-producing systems and transcription factor genes concerning their association with obesity risk and its phenotypes. In the future, the characterization of these single nucleotide polymorphisms (SNPs) in obese patients could contribute to the development of controlled antioxidant therapies potentially beneficial for the treatment of obesity-derived metabolic complications.

  15. Genetic composition of captive panda population.

    Science.gov (United States)

    Yang, Jiandong; Shen, Fujun; Hou, Rong; Da, Yang

    2016-10-03

    A major function of the captive panda population is to preserve the genetic diversity of wild panda populations in their natural habitats. Understanding the genetic composition of the captive panda population in terms of genetic contributions from the wild panda populations provides necessary knowledge for breeding plans to preserve the genetic diversity of the wild panda populations. The genetic contributions from different wild populations to the captive panda population were highly unbalanced, with Qionglai accounting for 52.2 % of the captive panda gene pool, followed by Minshan with 21.5 %, Qinling with 10.6 %, Liangshan with 8.2 %, and Xiaoxiangling with 3.6 %, whereas Daxiangling, which had similar population size as Xiaoxiangling, had no genetic representation in the captive population. The current breeding recommendations may increase the contribution of some small wild populations at the expense of decreasing the contributions of other small wild populations, i.e., increasing the Xiaoxiangling contribution while decreasing the contribution of Liangshan, or sharply increasing the Qinling contribution while decreasing the contributions of Xiaoxiangling and Liangshan, which were two of the three smallest wild populations and were already severely under-represented in the captive population. We developed three habitat-controlled breeding plans that could increase the genetic contributions from the smallest wild populations to 6.7-11.2 % for Xiaoxiangling, 11.5-12.3 % for Liangshan and 12.9-20.0 % for Qinling among the offspring of one breeding season while reducing the risk of hidden inbreeding due to related founders from the same habitat undetectable by pedigree data. The three smallest wild panda populations of Daxiangling, Xiaoxiangling and Liangshan either had no representation or were severely unrepresented in the current captive panda population. By incorporating the breeding goal of increasing the genetic contributions from the smallest wild

  16. Population genetic diversity and fitness in multiple environments

    Directory of Open Access Journals (Sweden)

    McGreevy Thomas J

    2010-07-01

    Full Text Available Abstract Background When a large number of alleles are lost from a population, increases in individual homozygosity may reduce individual fitness through inbreeding depression. Modest losses of allelic diversity may also negatively impact long-term population viability by reducing the capacity of populations to adapt to altered environments. However, it is not clear how much genetic diversity within populations may be lost before populations are put at significant risk. Development of tools to evaluate this relationship would be a valuable contribution to conservation biology. To address these issues, we have created an experimental system that uses laboratory populations of an estuarine crustacean, Americamysis bahia with experimentally manipulated levels of genetic diversity. We created replicate cultures with five distinct levels of genetic diversity and monitored them for 16 weeks in both permissive (ambient seawater and stressful conditions (diluted seawater. The relationship between molecular genetic diversity at presumptive neutral loci and population vulnerability was assessed by AFLP analysis. Results Populations with very low genetic diversity demonstrated reduced fitness relative to high diversity populations even under permissive conditions. Population performance decreased in the stressful environment for all levels of genetic diversity relative to performance in the permissive environment. Twenty percent of the lowest diversity populations went extinct before the end of the study in permissive conditions, whereas 73% of the low diversity lines went extinct in the stressful environment. All high genetic diversity populations persisted for the duration of the study, although population sizes and reproduction were reduced under stressful environmental conditions. Levels of fitness varied more among replicate low diversity populations than among replicate populations with high genetic diversity. There was a significant correlation

  17. Contribution of genetics and genomics to seagrass biology and conservation

    NARCIS (Netherlands)

    Procaccini, Gabriele; Olsen, Jeanine L.; Reusch, Thorsten B. H.

    2007-01-01

    Genetic diversity is one of three forms of biodiversity recognized by the IUCN as deserving conservation along with species and ecosystems. Seagrasses provide all three levels in one. This review addresses the latest advances in our understanding of seagrass population genetics and genomics within

  18. Evolution with a seed bank: The population genetic consequences of microbial dormancy.

    Science.gov (United States)

    Shoemaker, William R; Lennon, Jay T

    2018-01-01

    Dormancy is a bet-hedging strategy that allows organisms to persist through conditions that are suboptimal for growth and reproduction by entering a reversible state of reduced metabolic activity. Dormancy allows a population to maintain a reservoir of genetic and phenotypic diversity (i.e., a seed bank) that can contribute to the long-term survival of a population. This strategy can be potentially adaptive and has long been of interest to ecologists and evolutionary biologists. However, comparatively little is known about how dormancy influences the fundamental evolutionary forces of genetic drift, mutation, selection, recombination, and gene flow. Here, we investigate how seed banks affect the processes underpinning evolution by reviewing existing theory, implementing novel simulations, and determining how and when dormancy can influence evolution as a population genetic process. We extend our analysis to examine how seed banks can alter macroevolutionary processes, including rates of speciation and extinction. Through the lens of population genetic theory, we can understand the extent that seed banks influence the evolutionary dynamics of microorganisms as well as other taxa.

  19. Genetic Romanticism

    DEFF Research Database (Denmark)

    Tupasela, Aaro

    2016-01-01

    inheritance as a way to unify populations within politically and geographically bounded areas. Thus, new genetics have contributed to the development of genetic romanticisms, whereby populations (human, plant, and animal) can be delineated and mobilized through scientific and medical practices to represent...

  20. A study of genetic and environmental contributions to structural brain changes over time in twins concordant and discordant for bipolar disorder

    NARCIS (Netherlands)

    Bootsman, F.; Brouwer, R. M.; Schnack, H. G.; Kemner, S. M.; Hillegers, M. H. J.; Sarkisyan, G.; van der Schot, A. C.; Vonk, R.; Pol, H. E. Hulshoff; Nolen, W. A.; Kahn, R. S.; van Haren, N. E. M.

    This is the first longitudinal twin study examining genetic and environmental contributions to the association between liability to bipolar disorder (BD) and changes over time in global brain volumes, and global and regional measures of cortical surface area, cortical thickness and cortical volume.

  1. Genetic Testing and Its Implications: Human Genetics Researchers Grapple with Ethical Issues.

    Science.gov (United States)

    Rabino, Isaac

    2003-01-01

    Contributes systematic data on the attitudes of scientific experts who engage in human genetics research about the pros, cons, and ethical implications of genetic testing. Finds that they are highly supportive of voluntary testing and the right to know one's genetic heritage. Calls for greater genetic literacy. (Contains 87 references.) (Author/NB)

  2. Evaluation of genetic divergence among clones of conilon coffee after scheduled cycle pruning.

    Science.gov (United States)

    Dalcomo, J M; Vieira, H D; Ferreira, A; Lima, W L; Ferrão, R G; Fonseca, A F A; Ferrão, M A G; Partelli, F L

    2015-11-30

    Coffea canephora genotypes from the breeding program of Instituto Capixaba de Pesquisa e Extensão Rural were evaluated, and genetic diversity was estimated with the aim of future improvement strategies. From an initial group of 55 genotypes, 18 from the region of Castelo, ES, were selected, and three clones of the cultivars "Vitória" and "robusta tropical." Upon completion of the scheduled cycle pruning, 17 morphoagronomic traits were measured in the 22 genotypes selected. The principal components method was used to evaluate the contributions relative to the traits. The genetic dissimilarity matrix was obtained through Mahalanobis generalized distance, and genotypes were grouped using the hierarchical method based on the mean of the distances. The most promising clones of Avaliação Castelo were AC02, AC03, AC12, AC13, AC22, AC24, AC26, AC27, AC28, AC29, AC30, AC35, AC36, AC37, AC39, AC40, AC43, and AC46. These methods detected high genetic variability, grouping, by similarity, the genotypes in five groups. The trait that contributed the least to genetic divergence was the number of leaves in plagiotropic branches; however, this was not eliminated, because discarding it altered the groups. There are superior genotypes with potential for use in the next stages of the breeding program, aimed at both the composition of clonal variety and hybridizations.

  3. Age and haplotype variations within FADS1 interact and associate with alterations in fatty acid composition in human male cortical brain tissue.

    Directory of Open Access Journals (Sweden)

    Erika Freemantle

    Full Text Available Fatty acids (FA play an integral role in brain function and alterations have been implicated in a variety of complex neurological disorders. Several recent genomic studies have highlighted genetic variability in the fatty acid desaturase (FADS1/2/3 gene cluster as an important contributor to FA alterations in serum lipids as well as measures of FA desaturase index estimated by ratios of relevant FAs. The contribution to alterations of FAs within the brain by local synthesis is still a matter of debate. Thus, the impact of genetic variants in FADS genes on gene expression and brain FA levels is an important avenue to investigate.Analyses were performed on brain tissue from prefrontal cortex Brodmann area 47 (BA47 of 61 male subjects of French Canadian ancestry ranging in age from young adulthood to middle age (18-58 years old, with the exception of one teenager (15 years old. Haplotype tagging SNPs were selected using the publicly available HapMap genotyping dataset in conjunction with Haploview. DNA sequencing was performed by the Sanger method and gene expression was measured by quantitative real-time PCR. FAs in brain tissue were analysed by gas chromatography. Variants in the FADS1 gene region were sequenced and analyzed for their influence on both FADS gene expression and FAs in brain tissue.Our results suggest an association of the minor haplotype with alteration in estimated fatty acid desaturase activity. Analysis of the impact of DNA variants on expression and alternative transcripts of FADS1 and FADS2, however, showed no differences. Furthermore, there was a significant interaction between haplotype and age on certain brain FA levels.This study suggests that genetic variability in the FADS genes cluster, previously shown to be implicated in alterations in peripheral FA levels, may also affect FA composition in brain tissue, but not likely by local synthesis.

  4. Immune dysregulation may contribute to disease pathogenesis in spinal muscular atrophy mice.

    Science.gov (United States)

    Deguise, Marc-Olivier; De Repentigny, Yves; McFall, Emily; Auclair, Nicole; Sad, Subash; Kothary, Rashmi

    2017-02-15

    Spinal muscular atrophy (SMA) has long been solely considered a neurodegenerative disorder. However, recent work has highlighted defects in many other cell types that could contribute to disease aetiology. Interestingly, the immune system has never been extensively studied in SMA. Defects in lymphoid organs could exacerbate disease progression by neuroinflammation or immunodeficiency. Smn depletion led to severe alterations in the thymus and spleen of two different mouse models of SMA. The spleen from Smn depleted mice was dramatically smaller at a very young age and its histological architecture was marked by mislocalization of immune cells in the Smn2B/- model mice. In comparison, the thymus was relatively spared in gross morphology but showed many histological alterations including cortex thinning in both mouse models at symptomatic ages. Thymocyte development was also impaired as evidenced by abnormal population frequencies in the Smn2B/- thymus. Cytokine profiling revealed major changes in different tissues of both mouse models. Consistent with our observations, we found that survival motor neuron (Smn) protein levels were relatively high in lymphoid organs compared to skeletal muscle and spinal cord during postnatal development in wild type mice. Genetic introduction of one copy of the human SMN2 transgene was enough to rescue splenic and thymic defects in Smn2B/- mice. Thus, Smn is required for the normal development of lymphoid organs, and altered immune function may contribute to SMA disease pathogenesis. © The Author 2017. Published by Oxford University Press.

  5. Alteration of medieval stained-glasses. Contribution to the long-term behaviour of vitrified wastes

    International Nuclear Information System (INIS)

    Sterpenich, J.

    1998-01-01

    In this work, the behaviour of glasses during alteration have been studied in two different ways: 1)study of the alteration of medieval stained-glasses 2)experimental leaching of modelled glasses. Medieval stained-glasses have a silico-calcic and alkaline composition. It appears three different alteration modes for these glasses: 1)by condensation waters 2)by atmospheric agents 3)by porosity waters and humic acids. A chemical study of the altered areas has allowed to understand the alteration behaviour of a lot of elements: in particular transition elements, heavy metals and some rare earths. On the other hand, two vitrified wastes and a glass having the same composition of the potassic medieval stained-glasses have been leached in a static mode (pH=1 to 10, T=20 to 80 degrees Celsius, T=12 hours to 6 months). These experiments have revealed that the alteration mechanisms depend on the pH of the solution and on the chemical composition of the glass. An increasing durability of glasses in terms of the global polymerization degree has been revealed too. At last, the behaviours of glasses during alteration, observed with natural and experimental conditions, show that it is necessary to study natural analogous for predicting the long-term behaviour of vitrified wastes. (O.M.)

  6. 4D Flow Analysis of BAV-Related Fluid-Dynamic Alterations: Evidences of Wall Shear Stress Alterations in Absence of Clinically-Relevant Aortic Anatomical Remodeling

    Directory of Open Access Journals (Sweden)

    Filippo Piatti

    2017-06-01

    Full Text Available Bicuspid aortic valve (BAV is the most common congenital cardiac disease and is a foremost risk factor for aortopathies. Despite the genetic basis of BAV and of the associated aortopathies, BAV-related alterations in aortic fluid-dynamics, and particularly in wall shear stresses (WSSs, likely play a role in the progression of aortopathy, and may contribute to its pathogenesis. To test whether WSS may trigger aortopathy, in this study we used 4D Flow sequences of phase-contrast cardiac magnetic resonance imaging (CMR to quantitatively compare the in vivo fluid dynamics in the thoracic aorta of two groups of subjects: (i five prospectively enrolled young patients with normo-functional BAV and with no aortic dilation and (ii ten age-matched healthy volunteers. Through the semi-automated processing of 4D Flow data, the aortic bulk flow at peak systole was quantified, and WSSs acting on the endothelium of the ascending aorta were characterized throughout the systolic phase in terms of magnitude and time-dependency through a method recently developed by our group. Variables computed for each BAV patient were compared vs. the corresponding distribution of values obtained for healthy controls. In BAV patients, ascending aorta diameter was measured on cine-CMR images at baseline and at 3-year follow-up. As compared to controls, normo-functional BAV patients were characterized by minor bulk flow disturbances at peak systole. However, they were characterized by evident alterations of WSS distribution and peak values in the ascending aorta. In particular, in four BAV patients, who were characterized by right-left leaflet fusion, WSS peak values exceeded by 27–46% the 90th percentile of the distribution obtained for healthy volunteers. Only in the BAV patient with right-non-coronary leaflet fusion the same threshold was exceeded by 132%. Also, evident alterations in the time-dependency of WSS magnitude and direction were observed. Despite, these fluid

  7. Development of a modular streamflow model to quantify runoff contributions from different land uses in tropical urban environments using Genetic Programming

    Science.gov (United States)

    Meshgi, Ali; Schmitter, Petra; Chui, Ting Fong May; Babovic, Vladan

    2015-06-01

    The decrease of pervious areas during urbanization has severely altered the hydrological cycle, diminishing infiltration and therefore sub-surface flows during rainfall events, and further increasing peak discharges in urban drainage infrastructure. Designing appropriate waster sensitive infrastructure that reduces peak discharges requires a better understanding of land use specific contributions towards surface and sub-surface processes. However, to date, such understanding in tropical urban environments is still limited. On the other hand, the rainfall-runoff process in tropical urban systems experiences a high degree of non-linearity and heterogeneity. Therefore, this study used Genetic Programming to establish a physically interpretable modular model consisting of two sub-models: (i) a baseflow module and (ii) a quick flow module to simulate the two hydrograph flow components. The relationship between the input variables in the model (i.e. meteorological data and catchment initial conditions) and its overall structure can be explained in terms of catchment hydrological processes. Therefore, the model is a partial greying of what is often a black-box approach in catchment modelling. The model was further generalized to the sub-catchments of the main catchment, extending the potential for more widespread applications. Subsequently, this study used the modular model to predict both flow components of events as well as time series, and applied optimization techniques to estimate the contributions of various land uses (i.e. impervious, steep grassland, grassland on mild slope, mixed grasses and trees and relatively natural vegetation) towards baseflow and quickflow in tropical urban systems. The sub-catchment containing the highest portion of impervious surfaces (40% of the area) contributed the least towards the baseflow (6.3%) while the sub-catchment covered with 87% of relatively natural vegetation contributed the most (34.9%). The results from the quickflow

  8. Genetic risk for attention-deficit/hyperactivity disorder contributes to neurodevelopmental traits in the general population.

    Science.gov (United States)

    Martin, Joanna; Hamshere, Marian L; Stergiakouli, Evangelia; O'Donovan, Michael C; Thapar, Anita

    2014-10-15

    Attention-deficit/hyperactivity disorder (ADHD) can be viewed as the extreme end of traits in the general population. Epidemiological and twin studies suggest that ADHD frequently co-occurs with and shares genetic susceptibility with autism spectrum disorder (ASD) and ASD-related traits. The aims of this study were to determine whether a composite of common molecular genetic variants, previously found to be associated with clinically diagnosed ADHD, predicts ADHD and ASD-related traits in the general population. Polygenic risk scores were calculated in the Avon Longitudinal Study of Parents and Children (ALSPAC) population sample (N = 8229) based on a discovery case-control genome-wide association study of childhood ADHD. Regression analyses were used to assess whether polygenic scores predicted ADHD traits and ASD-related measures (pragmatic language abilities and social cognition) in the ALSPAC sample. Polygenic scores were also compared in boys and girls endorsing any (rating ≥ 1) ADHD item (n = 3623). Polygenic risk for ADHD showed a positive association with ADHD traits (hyperactive-impulsive, p = .0039; inattentive, p = .037). Polygenic risk for ADHD was also negatively associated with pragmatic language abilities (p = .037) but not with social cognition (p = .43). In children with a rating ≥ 1 for ADHD traits, girls had a higher polygenic score than boys (p = .003). These findings provide molecular genetic evidence that risk alleles for the categorical disorder of ADHD influence hyperactive-impulsive and attentional traits in the general population. The results further suggest that common genetic variation that contributes to ADHD diagnosis may also influence ASD-related traits, which at their extreme are a characteristic feature of ASD. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  9. Genetic and environmental contributions to body mass index: comparative analysis of monozygotic twins, dizygotic twins and same-age unrelated siblings.

    Science.gov (United States)

    Segal, N L; Feng, R; McGuire, S A; Allison, D B; Miller, S

    2009-01-01

    Earlier studies have established that a substantial percentage of variance in obesity-related phenotypes is explained by genetic components. However, only one study has used both virtual twins (VTs) and biological twins and was able to simultaneously estimate additive genetic, non-additive genetic, shared environmental and unshared environmental components in body mass index (BMI). Our current goal was to re-estimate four components of variance in BMI, applying a more rigorous model to biological and virtual multiples with additional data. Virtual multiples share the same family environment, offering unique opportunities to estimate common environmental influence on phenotypes that cannot be separated from the non-additive genetic component using only biological multiples. Data included 929 individuals from 164 monozygotic twin pairs, 156 dizygotic twin pairs, five triplet sets, one quadruplet set, 128 VT pairs, two virtual triplet sets and two virtual quadruplet sets. Virtual multiples consist of one biological child (or twins or triplets) plus one same-aged adoptee who are all raised together since infancy. We estimated the additive genetic, non-additive genetic, shared environmental and unshared random components in BMI using a linear mixed model. The analysis was adjusted for age, age(2), age(3), height, height(2), height(3), gender and race. Both non-additive genetic and common environmental contributions were significant in our model (P-valuesrole in BMI and that common environmental factors such as diet or exercise also affect BMI. This conclusion is consistent with our earlier study using a smaller sample and shows the utility of virtual multiples for separating non-additive genetic variance from common environmental variance.

  10. Sir RA Fisher and the Evolution of Genetics

    Indian Academy of Sciences (India)

    quantitative genetics, a body of work that provides the conceptual underpinnings ... worked extensively with mutations that had large effects on structural ... altering the genetic composition of populations during adaptive ... exercise in ' writing.

  11. Genetic Mutations in Cancer

    Science.gov (United States)

    Many different types of genetic mutations are found in cancer cells. This infographic outlines certain types of alterations that are present in cancer, such as missense, nonsense, frameshift, and chromosome rearrangements.

  12. Peripheral myelin protein 22 alters membrane architecture

    Science.gov (United States)

    Mittendorf, Kathleen F.; Marinko, Justin T.; Hampton, Cheri M.; Ke, Zunlong; Hadziselimovic, Arina; Schlebach, Jonathan P.; Law, Cheryl L.; Li, Jun; Wright, Elizabeth R.; Sanders, Charles R.; Ohi, Melanie D.

    2017-01-01

    Peripheral myelin protein 22 (PMP22) is highly expressed in myelinating Schwann cells of the peripheral nervous system. PMP22 genetic alterations cause the most common forms of Charcot-Marie-Tooth disease (CMTD), which is characterized by severe dysmyelination in the peripheral nerves. However, the functions of PMP22 in Schwann cell membranes remain unclear. We demonstrate that reconstitution of purified PMP22 into lipid vesicles results in the formation of compressed and cylindrically wrapped protein-lipid vesicles that share common organizational traits with compact myelin of peripheral nerves in vivo. The formation of these myelin-like assemblies depends on the lipid-to-PMP22 ratio, as well as on the PMP22 extracellular loops. Formation of the myelin-like assemblies is disrupted by a CMTD-causing mutation. This study provides both a biochemical assay for PMP22 function and evidence that PMP22 directly contributes to membrane organization in compact myelin. PMID:28695207

  13. Phosphorylation states of cell cycle and DNA repair proteins can be altered by the nsSNPs

    International Nuclear Information System (INIS)

    Savas, Sevtap; Ozcelik, Hilmi

    2005-01-01

    Phosphorylation is a reversible post-translational modification that affects the intrinsic properties of proteins, such as structure and function. Non-synonymous single nucleotide polymorphisms (nsSNPs) result in the substitution of the encoded amino acids and thus are likely to alter the phosphorylation motifs in the proteins. In this study, we used the web-based NetPhos tool to predict candidate nsSNPs that either introduce or remove putative phosphorylation sites in proteins that act in DNA repair and cell cycle pathways. Our results demonstrated that a total of 15 nsSNPs (16.9%) were likely to alter the putative phosphorylation patterns of 14 proteins. Three of these SNPs (CDKN1A-S31R, OGG1-S326C, and XRCC3-T241M) have already found to be associated with altered cancer risk. We believe that this set of nsSNPs constitutes an excellent resource for further molecular and genetic analyses. The novel systematic approach used in this study will accelerate the understanding of how naturally occurring human SNPs may alter protein function through the modification of phosphorylation mechanisms and contribute to disease susceptibility

  14. Overexpression of AtLOV1 in Switchgrass alters plant architecture, lignin content, and flowering time.

    Directory of Open Access Journals (Sweden)

    Bin Xu

    Full Text Available BACKGROUND: Switchgrass (Panicum virgatum L. is a prime candidate crop for biofuel feedstock production in the United States. As it is a self-incompatible polyploid perennial species, breeding elite and stable switchgrass cultivars with traditional breeding methods is very challenging. Translational genomics may contribute significantly to the genetic improvement of switchgrass, especially for the incorporation of elite traits that are absent in natural switchgrass populations. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we constitutively expressed an Arabidopsis NAC transcriptional factor gene, LONG VEGETATIVE PHASE ONE (AtLOV1, in switchgrass. Overexpression of AtLOV1 in switchgrass caused the plants to have a smaller leaf angle by changing the morphology and organization of epidermal cells in the leaf collar region. Also, overexpression of AtLOV1 altered the lignin content and the monolignol composition of cell walls, and caused delayed flowering time. Global gene-expression analysis of the transgenic plants revealed an array of responding genes with predicted functions in plant development, cell wall biosynthesis, and flowering. CONCLUSIONS/SIGNIFICANCE: To our knowledge, this is the first report of a single ectopically expressed transcription factor altering the leaf angle, cell wall composition, and flowering time of switchgrass, therefore demonstrating the potential advantage of translational genomics for the genetic improvement of this crop.

  15. [Reverse genetics system of rotaviruses: development and application for analysis of VP4 spike protein].

    Science.gov (United States)

    Komoto, Satoshi

    2013-01-01

    The rotavirus genome is composed of 11 gene segments of double-stranded (ds)RNA. Reverse genetics is the powerful and ideal methodology for the molecular analysis of virus biology, which enables the virus genome to be artificially manipulated. Although reverse genetics systems exist for nearly all major groups of RNA viruses, development of such a system for rotaviruses is more challenging owing in part to the technical complexity of manipulation of their multi-segmented genome. A breakthrough in the field of rotavirus reverse genetics came in 2006, when we established the first reverse genetics system for rotaviruses, which is a partially plasmid-based system that permits replacement of a viral gene segment with the aid of a helper virus. Although this helper virus-driven system is technically limited and gives low levels of recombinant viruses, it allows alteration of the rotavirus genome, thus contributing to our understanding of these medically important viruses. In this review, I describe the development and application of our rotavirus reverse genetics system, and its future perspectives.

  16. Molecular alterations and biomarkers in colorectal cancer

    Science.gov (United States)

    Grady, William M.; Pritchard, Colin C.

    2013-01-01

    The promise of precision medicine is now a clinical reality. Advances in our understanding of the molecular genetics of colorectal cancer genetics is leading to the development of a variety of biomarkers that are being used as early detection markers, prognostic markers, and markers for predicting treatment responses. This is no more evident than in the recent advances in testing colorectal cancers for specific molecular alterations in order to guide treatment with the monoclonal antibody therapies cetuximab and panitumumab, which target the epidermal growth factor receptor (EGFR). In this review, we update a prior review published in 2010 and describe our current understanding of the molecular pathogenesis of colorectal cancer and how these alterations relate to emerging biomarkers for early detection and risk stratification (diagnostic markers), prognosis (prognostic markers), and the prediction of treatment responses (predictive markers). PMID:24178577

  17. Genetic Variants Contribute to Gene Expression Variability in Humans

    Science.gov (United States)

    Hulse, Amanda M.; Cai, James J.

    2013-01-01

    Expression quantitative trait loci (eQTL) studies have established convincing relationships between genetic variants and gene expression. Most of these studies focused on the mean of gene expression level, but not the variance of gene expression level (i.e., gene expression variability). In the present study, we systematically explore genome-wide association between genetic variants and gene expression variability in humans. We adapt the double generalized linear model (dglm) to simultaneously fit the means and the variances of gene expression among the three possible genotypes of a biallelic SNP. The genomic loci showing significant association between the variances of gene expression and the genotypes are termed expression variability QTL (evQTL). Using a data set of gene expression in lymphoblastoid cell lines (LCLs) derived from 210 HapMap individuals, we identify cis-acting evQTL involving 218 distinct genes, among which 8 genes, ADCY1, CTNNA2, DAAM2, FERMT2, IL6, PLOD2, SNX7, and TNFRSF11B, are cross-validated using an extra expression data set of the same LCLs. We also identify ∼300 trans-acting evQTL between >13,000 common SNPs and 500 randomly selected representative genes. We employ two distinct scenarios, emphasizing single-SNP and multiple-SNP effects on expression variability, to explain the formation of evQTL. We argue that detecting evQTL may represent a novel method for effectively screening for genetic interactions, especially when the multiple-SNP influence on expression variability is implied. The implication of our results for revealing genetic mechanisms of gene expression variability is discussed. PMID:23150607

  18. Wetlands explain most in the genetic divergence pattern of Oncomelania hupensis.

    Science.gov (United States)

    Liang, Lu; Liu, Yang; Liao, Jishan; Gong, Peng

    2014-10-01

    Understanding the divergence patterns of hosts could shed lights on the prediction of their parasite transmission. No effort has been devoted to understand the drivers of genetic divergence pattern of Oncomelania hupensis, the only intermediate host of Schistosoma japonicum. Based on a compilation of two O. hupensis gene datasets covering a wide geographic range in China and an array of geographical distance and environmental dissimilarity metrics built from earth observation data and ecological niche modeling, we conducted causal modeling analysis via simple, partial Mantel test and local polynomial fitting to understand the interactions among isolation-by-distance, isolation-by-environment, and genetic divergence. We found that geography contributes more to genetic divergence than environmental isolation, and among all variables involved, wetland showed the strongest correlation with the genetic pairwise distances. These results suggested that in China, O. hupensis dispersal is strongly linked to the distribution of wetlands, and the current divergence pattern of both O. hupensis and schistosomiasis might be altered due to the changed wetland pattern with the accomplishment of the Three Gorges Dam and the South-to-North water transfer project. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Immune and genetic gardening of the intestinal microbiome

    Science.gov (United States)

    Jacobs, Jonathan P.; Braun, Jonathan

    2014-01-01

    The mucosal immune system – consisting of adaptive and innate immune cells as well as the epithelium – is profoundly influenced by its microbial environment. There is now growing evidence that the converse is also true, that the immune system shapes the composition of the intestinal microbiome. During conditions of health, this bidirectional interaction achieves a homeostasis in which inappropriate immune responses to nonpathogenic microbes are averted and immune activity suppresses blooms of potentially pathogenic microbes (pathobionts). Genetic alteration in immune/epithelial function can affect host gardening of the intestinal microbiome, contributing to the diversity of intestinal microbiota within a population and in some cases allowing for unfavorable microbial ecologies (dysbiosis) that confer disease susceptibility. PMID:24613921

  20. Genetic alterations affecting cholesterol metabolism and human fertility.

    Science.gov (United States)

    DeAngelis, Anthony M; Roy-O'Reilly, Meaghan; Rodriguez, Annabelle

    2014-11-01

    Single nucleotide polymorphisms (SNPs) represent genetic variations among individuals in a population. In medicine, these small variations in the DNA sequence may significantly impact an individual's response to certain drugs or influence the risk of developing certain diseases. In the field of reproductive medicine, a significant amount of research has been devoted to identifying polymorphisms which may impact steroidogenesis and fertility. This review discusses current understanding of the effects of genetic variations in cholesterol metabolic pathways on human fertility that bridge novel linkages between cholesterol metabolism and reproductive health. For example, the role of the low-density lipoprotein receptor (LDLR) in cellular metabolism and human reproduction has been well studied, whereas there is now an emerging body of research on the role of the high-density lipoprotein (HDL) receptor scavenger receptor class B type I (SR-BI) in human lipid metabolism and female reproduction. Identifying and understanding how polymorphisms in the SCARB1 gene or other genes related to lipid metabolism impact human physiology is essential and will play a major role in the development of personalized medicine for improved diagnosis and treatment of infertility. © 2014 by the Society for the Study of Reproduction, Inc.

  1. What’s new in genetics of congenital heart defects

    Directory of Open Access Journals (Sweden)

    Maria Cristina Digilio

    2016-12-01

    Full Text Available Epidemiological studies, clinical observations and advances in molecular genetics are contributing to the understanding of the etiology of congenital heart defects (CHDs. Several phenotype-genotype correlation studies have suggested that specific morphogenetic mechanisms put in motion by genes can result in a specific cardiac phenotype. The use of new technologies has increased the possibility of identification of new genes and chromosomal loci in syndromic and non-syndromic CHDs. There are a number of methods available for genetic research studies of CHDs, including cytogenetic analysis, linkage and association studies, copy number variation (CNV and DNA micro-array analysis, and whole exome sequencing. The altered dosage of contigous genes included inside CNVs can produce new syndromic CHDs, so that several different new genomic conditions have been identified. These include duplication 22q11.2 syndrome, distal 22q11.2 deletion syndrome, deletion and duplication 1q21.1, deletion 1p36 syndrome. Molecular techniques as whole exome sequancing has lead to the identification of new genes for monogenic syndromes with CHD, as for example in Adams-Oliver, Noonan and Kabuki syndrome. The variable expressivity and reduced penetrance of CHDs in genetic syndromes is likely influenced by genetic factors, and several studies have been performed showing the involvement of modifier genes. It is not easy to define precisely the genetic defects underlying non-syndromic CHDs, due to the genetic and clinical heterogeneity of these malformations. Recent experimental studies have identified multiple CNVs contributing to non-syndromic CHD. The number of identified genes for non-syndromic CHDs is at this time limited and each of the identified gene has been shown to be implicated only in a small proportion of CHD. The application of new technologies to specific cases of CHD and pedigrees with familial recurrence and filtering genes mapping in CNV regions can probably

  2. Advancement of Phenotype Transformation of Cancer-associated Fibroblasts: 
from Genetic Alterations to Epigenetic Modification

    Directory of Open Access Journals (Sweden)

    Dali CHEN

    2015-02-01

    Full Text Available In the field of human cancer research, even though the vast majority attentions were paid to tumor cells as “the seeds”, the roles of tumor microenvironments as “the soil” are gradually explored in recent years. As a dominant compartment of tumor microenvironments, cancer-associated fibroblasts (CAFs were discovered to correlated with tumorigenesis, tumor progression and prognosis. And the exploration of the mechanisms of CAF phenotype transformation would conducive to the further understand of the CAFs function in human cancers. As we known that CAFs have four main origins, including epithelial cells, endothelial cells, mesenchymal stem cells (MSCs and local mesenchymal cells. However, researchers found that all these origins finally conduct similiar phenotypes from intrinsic to extrinsic ones. Thus, what and how a mechanism can conduct the phenotype transformation of CAFs with different origins? Two viewpoints are proposed to try to answer the quetsion, involving genetic alterations and epigenetic modifications. This review will systematically summarize the advancement of mechanisms of CAF phenotype transformations in the aspect of genentic and epigenetic modifications.

  3. Nasopharyngeal angiofibroma: review of the genetic and molecular aspects

    Directory of Open Access Journals (Sweden)

    Oliveira, Viviane Boaventura de

    2008-09-01

    Full Text Available Introduction: Juvenile nasopharyngeal angiofibroma (JNA is a rare fibrovascular tumor of unknown etiology, with few studies analyzing its pathogenesis. Objective: Reviewing JNA's pathogenesis, emphasizing genetic and molecular aspects. Method: All the relevant articles indexed in PUBMED and LILACS, besides reference book chapters, published between 1959 and 2007 were reviewed. Results: The sex selectivity seen in JNA may be explained by intranuclear accumulation of androgen receptor and beta-catenin, a co-activator which increases the tumor sensitivity to androgynous. The genetic alterations seen in JNA are most frequently located in sexual chromosomes. A number of growth factors seem to be related to the tumor pathogenesis. The insulin-like growth factor II is highly expressed while the vascular endothelial growth factor and the transforming growth factor beta are released by stromal cells and may influence the JNA's growth and vascularization. Conclusion: In spite of the scarce data describing the JNA etiology and pathogenesis, genetic and molecular factors seem to collaborate to the understanding of the disease's many clinical and morphological features. Knowledge regarding these specific issues could contribute for the establishment of potential therapeutic targets in the future.

  4. Fibromyalgia is Associated With Altered Skeletal Muscle Characteristics Which May Contribute to Post-Exertional Fatigue in Post-Menopausal Women

    Science.gov (United States)

    Srikuea, Ratchakrit; Symons, T. Brock; Long, Douglas E.; Lee, Jonah D.; Shang, Yu; Chomentowski, Peter J.; Yu, Guoqiang; Crofford, Leslie J.; Peterson, Charlotte A.

    2012-01-01

    Objective To identify muscle physiological properties that may contribute to post-exertional fatigue and malaise in women with fibromyalgia (FM). Methods Healthy postmenopausal women with (n=11) and without (n=11) fibromyalgia, age 51–70 years, participated in this study. Physical characteristics along with self-reported questionnaires were evaluated. Strength loss and tissue oxygenation in response to a fatiguing exercise protocol were used to quantify fatigability and the local muscle hemodynamic profile. Muscle biopsies were obtained to assess between-group differences in baseline muscle properties using histochemical, immunohistochemical and electron microscopic analyses. Results No significant difference in muscle fatigue in response to exercise was apparent between healthy controls and subjects with FM. However, self-reported fatigue and pain were correlated to prolonged loss of strength following 12-min of recovery in subjects with FM. Although there was no difference in percent SDH positive (type I) and SDH negative (type II) fibers or in mean fiber cross-sectional area between groups, subjects with FM showed greater size variability and altered fiber size distribution. Only in healthy controls, fatigue-resistance was strongly correlated with the size of SDH positive fibers and hemoglobin oxygenation. By contrast, subjects with FM with the highest percentage of SDH positive fibers recovered strength most effectively, which was correlated to capillary density. However, overall, capillary density was lower in subjects with FM. Conclusion Peripheral mechanisms i.e. altered muscle fiber size distribution and decreased capillary density may contribute to post-exertional fatigue in subjects with FM. Understanding these defects in fibromyalgic muscle may provide valuable insight for treatment. PMID:23124535

  5. Genetic and Environmental Contributions to Behavioral Stability and Change in Children 6-36 months of Age Using Louisville Twin Study Data.

    Science.gov (United States)

    Davis, Deborah Winders; Finkel, Deborah; Turkheimer, Eric; Dickens, William

    2015-11-01

    The Infant Behavior Record (IBR) from the Bayley Scales of Infant Development has been used to study behavioral development since the 1960s. Matheny (1983) examined behavioral development at 6, 12, 18, and 24 months from the Louisville Twin Study (LTS). The extracted temperament scales included Task Orientation, Affect-Extraversion, and Activity. He concluded that monozygotic twins were more similar than same-sex dizygotic twins on these dimensions. Since this seminal work was published, a larger LTS sample and more advanced analytical methods are available. In the current analyses, Choleksy decomposition was applied to behavioral data (n = 1231) from twins 6-36 months. Different patterns of genetic continuity vs genetic innovations were identified for each IBR scale. Single common genetic and shared environmental factors explained cross-age twin similarity in the Activity scale. Multiple shared environmental factors and a single genetic factor coming on line at age 18 months contributed to Affect-Extraversion. A single shared environmental factor and multiple genetic factors explained cross-age twin similarity in Task Orientation.

  6. Genetics of osteoarthritis.

    Science.gov (United States)

    Rodriguez-Fontenla, Cristina; Gonzalez, Antonio

    2015-01-01

    Osteoarthritis (OA) is a complex disease caused by the interaction of multiple genetic and environmental factors. This review focuses on the studies that have contributed to the discovery of genetic susceptibility factors in OA. The most relevant associations discovered until now are discussed in detail: GDF-5, 7q22 locus, MCF2L, DOT1L, NCOA3 and also some important findings from the arcOGEN study. Moreover, the different approaches that can be used to minimize the specific problems of the study of OA genetics are discussed. These include the study of microsatellites, phenotype standardization and other methods such as meta-analysis of GWAS and gene-based analysis. It is expected that these new approaches contribute to finding new susceptibility genetic factors for OA. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  7. Genetics of hereditary motor and sensory neuropathy and the Costa Rican contribution

    Directory of Open Access Journals (Sweden)

    Alejandro Leal

    2004-09-01

    Full Text Available Hereditary motor and sensory neuropathy (HMSN or Charcot-Marie-Tooth disease (CMT is the most common hereditary illness of the peripheral nervous system. The genetics and the physiopathological aspects of the disease clarified until know, are here summarized. More than twenty genes and ten additional loci have been related with HMSN. These findings contribute to understand the metabolism of peripheral nerves and give the basis for molecular diagnostics and future therapy. Several Costa Rican families with CMT have been identified, specially with axonal forms. Two families present mutations in the myelin protein zero gene (MPZ. In addition, linkage have been found between the disease and locus 19q13.3 in an extended family, and a mutation segregating with the disease is present in a candidate gene of the critical interval. Costa Rica has several advantages for genetical studies, that can contribute importantly in the generation of knowledge in the neurogenetical field. Rev. Biol. Trop. 52(3: 475-483. Epub 2004 Dic 15.El grupo de neuropatías motoras y sensoriales hereditarias (HMSN o enfermedad de Charcot-Marie-Tooth (CMT es el padecimiento hereditario más común del sistema nervioso periférico. El propósito de este trabajo es resumir los aspectos genéticos y fisiopatológicos más actuales de esta enfermedad. Más de veinte genes y diez loci adicionales han sido relacionados con HMSN. Estos hallazgos han contribuido con la comprensión del metabolismo de los nervios periféricos y sirven de base para el diagnóstico molecular y el diseño de terapias. Diversas familias costarricenses con CMT han sido identificadas: dos de ellas presentan mutaciones en el gen que codifica por la mielina proteína cero (MPZ. Además, un análisis de ligamiento localizó el gen que causa una forma axonal de la enfermedad en el cromosoma 19q13.3 en una extensa familia; también se detectó en esa región una mutación que co-segrega con la enfermedad y que

  8. Alteration of polymorphic systems of Centaurea scabiosa L. under chronic irradiation

    International Nuclear Information System (INIS)

    Lysenko, E.A.; Kal'chenko, V.A.; Shevchenko, V.A.; Lysenko, E.A.

    1999-01-01

    Isoenzyme and morphological polymorphism alteration in populations of perennial grass Centaurea scabiosa L. (scaly cornflower) has been studied. These populations exist on the territory of East Urals Radioactive Trace more than 40 years and are chronically exposed to β-radiation. Directional shift of allele frequencies on the loci Per 1 , Pgi 2 , Sod 1 , Lap has been detected. Fact of accumulating genetic load by chronically irradiated populations has been demonstrated. Possible reasons of discovered alterations are discussed. Analysis of the obtained data shows that the irradiation populations have greater similarity with one another than with a control, but relation between genetic distances and accumulated doses has not been revealed. Hypothesis is that an extra factor - gene flow from a clean territory influences the genetic structure of irradiated populations [ru

  9. Ancient DNA analysis of the oldest canid species from the Siberian Arctic and genetic contribution to the domestic dog.

    Directory of Open Access Journals (Sweden)

    Esther J Lee

    Full Text Available Modern Arctic Siberia provides a wealth of resources for archaeological, geological, and paleontological research to investigate the population dynamics of faunal communities from the Pleistocene, particularly as the faunal material coming from permafrost has proven suitable for genetic studies. In order to examine the history of the Canid species in the Siberian Arctic, we carried out genetic analysis of fourteen canid remains from various sites, including the well-documented Upper Paleolithic Yana RHS and Early Holocene Zhokhov Island sites. Estimated age of samples range from as recent as 1,700 years before present (YBP to at least 360,000 YBP for the remains of the extinct wolf, Canis cf. variabilis. In order to examine the genetic affinities of ancient Siberian canids species to the domestic dog and modern wolves, we obtained mitochondrial DNA control region sequences and compared them to published ancient and modern canid sequences. The older canid specimens illustrate affinities with pre-domestic dog/wolf lineages while others appear in the major phylogenetic clades of domestic dogs. Our results suggest a European origin of domestic dog may not be conclusive and illustrates an emerging complexity of genetic contribution of regional wolf breeds to the modern Canis gene pool.

  10. Optimal Genetic Contribution Selection in Danish Holstein Depends on Pedigree Qualtiy

    DEFF Research Database (Denmark)

    Sørensen, M K; Sørensen, A C; Baumung, R

    2008-01-01

    . In the analyses earlier breeding decisions were considered by including all AI waiting- and young bulls and contract matings. Twenty potential sires, 2169 potential dams, 1421 AI-bulls and 754 contract matings plus pedigree animals were included. Results showed that the outcome was very dependent on quality...... the increase in future inbreeding. The more weight put on the average additive genetic relationship in next generation relative to genetic merit, the lower the average merit of the matings, and the lower average additive genetic relationship among the chosen matings and the present breeding animals...

  11. Molecular genetics of glioblastomas: defining subtypes and understanding the biology.

    Science.gov (United States)

    Renault, Ilana Zalcberg; Golgher, Denise

    2015-02-01

    Despite comprehensive therapy, which includes surgery, radiotherapy, and chemotherapy, the prognosis of glioblastoma multiforme is very poor. Diagnosed individuals present an average of 12 to 18 months of life. This article provides an overview of the molecular genetics of these tumors. Despite the overwhelming amount of data available, so far little has been translated into real benefits for the patient. Because this is such a complex topic, the goal is to point out the main alterations in the biological pathways that lead to tumor formation, and how this can contribute to the development of better therapies and clinical care. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Mating animals by minimising the covariance between ancestral contributions generates less inbreeding without compromising genetic gain in breeding schemes with truncation selection

    DEFF Research Database (Denmark)

    Henryon, M; Berg, P; Sørensen, A C

    2009-01-01

    We reasoned that mating animals by minimising the covariance between ancestral contributions (MCAC mating) will generate less inbreeding and at least as much genetic gain as minimum-coancestry mating in breeding schemes where the animals are truncation-selected. We tested this hypothesis by stoch...

  13. Genetic and Environmental Risk for Chronic Pain and the Contribution of Risk Variants for Major Depressive Disorder: A Family-Based Mixed-Model Analysis.

    Science.gov (United States)

    McIntosh, Andrew M; Hall, Lynsey S; Zeng, Yanni; Adams, Mark J; Gibson, Jude; Wigmore, Eleanor; Hagenaars, Saskia P; Davies, Gail; Fernandez-Pujals, Ana Maria; Campbell, Archie I; Clarke, Toni-Kim; Hayward, Caroline; Haley, Chris S; Porteous, David J; Deary, Ian J; Smith, Daniel J; Nicholl, Barbara I; Hinds, David A; Jones, Amy V; Scollen, Serena; Meng, Weihua; Smith, Blair H; Hocking, Lynne J

    2016-08-01

    Chronic pain is highly prevalent and a significant source of disability, yet its genetic and environmental risk factors are poorly understood. Its relationship with major depressive disorder (MDD) is of particular importance. We sought to test the contribution of genetic factors and shared and unique environment to risk of chronic pain and its correlation with MDD in Generation Scotland: Scottish Family Health Study (GS:SFHS). We then sought to replicate any significant findings in the United Kingdom Biobank study. Using family-based mixed-model analyses, we examined the contribution of genetics and shared family environment to chronic pain by spouse, sibling, and household relationships. These analyses were conducted in GS:SFHS (n = 23,960), a family- and population-based study of individuals recruited from the Scottish population through their general practitioners. We then examined and partitioned the correlation between chronic pain and MDD and estimated the contribution of genetic factors and shared environment in GS:SFHS. Finally, we used data from two independent genome-wide association studies to test whether chronic pain has a polygenic architecture and examine whether genomic risk of psychiatric disorder predicted chronic pain and whether genomic risk of chronic pain predicted MDD. These analyses were conducted in GS:SFHS and repeated in UK Biobank, a study of 500,000 from the UK population, of whom 112,151 had genotyping and phenotypic data. Chronic pain is a moderately heritable trait (heritability = 38.4%, 95% CI 33.6% to 43.9%) that is significantly concordant in spouses (variance explained 18.7%, 95% CI 9.5% to 25.1%). Chronic pain is positively correlated with depression (ρ = 0.13, 95% CI 0.11 to 0.15, p = 2.72x10-68) and shows a tendency to cluster within families for genetic reasons (genetic correlation = 0.51, 95%CI 0.40 to 0.62, p = 8.24x10-19). Polygenic risk profiles for pain, generated using independent GWAS data, were associated with

  14. Genetic and Environmental Risk for Chronic Pain and the Contribution of Risk Variants for Major Depressive Disorder: A Family-Based Mixed-Model Analysis.

    Directory of Open Access Journals (Sweden)

    Andrew M McIntosh

    2016-08-01

    Full Text Available Chronic pain is highly prevalent and a significant source of disability, yet its genetic and environmental risk factors are poorly understood. Its relationship with major depressive disorder (MDD is of particular importance. We sought to test the contribution of genetic factors and shared and unique environment to risk of chronic pain and its correlation with MDD in Generation Scotland: Scottish Family Health Study (GS:SFHS. We then sought to replicate any significant findings in the United Kingdom Biobank study.Using family-based mixed-model analyses, we examined the contribution of genetics and shared family environment to chronic pain by spouse, sibling, and household relationships. These analyses were conducted in GS:SFHS (n = 23,960, a family- and population-based study of individuals recruited from the Scottish population through their general practitioners. We then examined and partitioned the correlation between chronic pain and MDD and estimated the contribution of genetic factors and shared environment in GS:SFHS. Finally, we used data from two independent genome-wide association studies to test whether chronic pain has a polygenic architecture and examine whether genomic risk of psychiatric disorder predicted chronic pain and whether genomic risk of chronic pain predicted MDD. These analyses were conducted in GS:SFHS and repeated in UK Biobank, a study of 500,000 from the UK population, of whom 112,151 had genotyping and phenotypic data. Chronic pain is a moderately heritable trait (heritability = 38.4%, 95% CI 33.6% to 43.9% that is significantly concordant in spouses (variance explained 18.7%, 95% CI 9.5% to 25.1%. Chronic pain is positively correlated with depression (ρ = 0.13, 95% CI 0.11 to 0.15, p = 2.72x10-68 and shows a tendency to cluster within families for genetic reasons (genetic correlation = 0.51, 95%CI 0.40 to 0.62, p = 8.24x10-19. Polygenic risk profiles for pain, generated using independent GWAS data, were associated

  15. Journal of Genetics | Indian Academy of Sciences

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics. MD. SAIMUL ISLAM. Articles written in Journal of Genetics. Volume 95 Issue 3 September 2016 pp 551-563 RESEARCH ARTICLE. Frequent alterations of SLIT2–ROBO1–CDC42 signalling pathway in breast cancer: clinicopathological correlation · RITTWIKA BHATTACHARYA NUPUR ...

  16. CD133+ cells contribute to radioresistance via altered regulation of DNA repair genes in human lung cancer cells

    International Nuclear Information System (INIS)

    Desai, Amar; Webb, Bryan; Gerson, Stanton L.

    2014-01-01

    Background: Radioresistance in human tumors has been linked in part to a subset of cells termed cancer stem cells (CSCs). The prominin 1 (CD133) cell surface protein is proposed to be a marker enriching for CSCs. We explore the importance of DNA repair in contributing to radioresistance in CD133+ lung cancer cells. Materials and methods: A549 and H1299 lung cancer cell lines were used. Sorted CD133+ cells were exposed to either single 4 Gy or 8 Gy doses and clonogenic survival measured. ϒ-H2AX immunofluorescence and quantitative real time PCR was performed on sorted CD133+ cells both in the absence of IR and after two single 4 Gy doses. Lentiviral shRNA was used to silence repair genes. Results: A549 but not H1299 cells expand their CD133+ population after single 4 Gy exposure, and isolated A549 CD133+ cells demonstrate IR resistance. This resistance corresponded with enhanced repair of DNA double strand breaks (DSBs) and upregulated expression of DSB repair genes in A549 cells. Prior IR exposure of two single 4 Gy doses resulted in acquired DNA repair upregulation and improved repair proficiency in both A549 and H1299. Finally Exo1 and Rad51 silencing in A549 cells abrogated the CD133+ IR expansion phenotype and induced IR sensitivity in sorted CD133+ cells. Conclusions: CD133 identifies a population of cells within specific tumor types containing altered expression of DNA repair genes that are inducible upon exposure to chemotherapy. This altered gene expression contributes to enhanced DSB resolution and the radioresistance phenotype of these cells. We also identify DNA repair genes which may serve as promising therapeutic targets to confer radiosensitivity to CSCs

  17. Feline genetics: clinical applications and genetic testing.

    Science.gov (United States)

    Lyons, Leslie A

    2010-11-01

    DNA testing for domestic cat diseases and appearance traits is a rapidly growing asset for veterinary medicine. Approximately 33 genes contain 50 mutations that cause feline health problems or alterations in the cat's appearance. A variety of commercial laboratories can now perform cat genetic diagnostics, allowing both the veterinary clinician and the private owner to obtain DNA test results. DNA is easily obtained from a cat via a buccal swab with a standard cotton bud or cytological brush, allowing DNA samples to be easily sent to any laboratory in the world. The DNA test results identify carriers of the traits, predict the incidence of traits from breeding programs, and influence medical prognoses and treatments. An overall goal of identifying these genetic mutations is the correction of the defect via gene therapies and designer drug therapies. Thus, genetic testing is an effective preventative medicine and a potential ultimate cure. However, genetic diagnostic tests may still be novel for many veterinary practitioners and their application in the clinical setting needs to have the same scrutiny as any other diagnostic procedure. This article will review the genetic tests for the domestic cat, potential sources of error for genetic testing, and the pros and cons of DNA results in veterinary medicine. Highlighted are genetic tests specific to the individual cat, which are a part of the cat's internal genome. Copyright © 2010 Elsevier Inc. All rights reserved.

  18. Circadian rhythms and metabolic syndrome: from experimental genetics to human disease.

    Science.gov (United States)

    Maury, Eleonore; Ramsey, Kathryn Moynihan; Bass, Joseph

    2010-02-19

    The incidence of the metabolic syndrome represents a spectrum of disorders that continue to increase across the industrialized world. Both genetic and environmental factors contribute to metabolic syndrome and recent evidence has emerged to suggest that alterations in circadian systems and sleep participate in the pathogenesis of the disease. In this review, we highlight studies at the intersection of clinical medicine and experimental genetics that pinpoint how perturbations of the internal clock system, and sleep, constitute risk factors for disorders including obesity, diabetes mellitus, cardiovascular disease, thrombosis and even inflammation. An exciting aspect of the field has been the integration of behavioral and physiological approaches, and the emerging insight into both neural and peripheral tissues in disease pathogenesis. Consideration of the cell and molecular links between disorders of circadian rhythms and sleep with metabolic syndrome has begun to open new opportunities for mechanism-based therapeutics.

  19. The genetic basis of addictive disorders.

    Science.gov (United States)

    Ducci, Francesca; Goldman, David

    2012-06-01

    Addictions are common, chronic, and relapsing diseases that develop through a multistep process. The impact of addictions on morbidity and mortality is high worldwide. Twin studies have shown that the heritability of addictions ranges from 0.39 (hallucinogens) to 0.72 (cocaine). Twin studies indicate that genes influence each stage from initiation to addiction, although the genetic determinants may differ. Addictions are by definition the result of gene × environment interaction. These disorders, which are in part volitional, in part inborn, and in part determined by environmental experience, pose the full range of medical, genetic, policy, and moral challenges. Gene discovery is being facilitated by a variety of powerful approaches, but is in its infancy. It is not surprising that the genes discovered so far act in a variety of ways: via altered metabolism of drug (the alcohol and nicotine metabolic gene variants), via altered function of a drug receptor (the nicotinic receptor, which may alter affinity for nicotine but as discussed may also alter circuitry of reward), and via general mechanisms of addiction (genes such as monoamine oxidase A and the serotonin transporter that modulate stress response, emotion, and behavioral control). Addiction medicine today benefits from genetic studies that buttress the case for a neurobiologic origin of addictive behavior, and some general information on familially transmitted propensity that can be used to guide prevention. A few well-validated, specific predictors such as OPRM1, ADH1B, ALDH2, CHRNA5, and CYP26 have been identified and can provide some specific guidance, for example, to understand alcohol-related flushing and upper GI cancer risk (ADH1B and AKLDH2), variation in nicotine metabolism (CYP26), and, potentially, naltrexone treatment response (OPRM1). However, the genetic predictors available are few in number and account for only a small portion of the genetic variance in liability, and have not been integrated

  20. Partial genetic deletion of neuregulin 1 and adolescent stress interact to alter NMDA receptor binding in the medial prefrontal cortex

    Directory of Open Access Journals (Sweden)

    Tariq Waseem Chohan

    2014-09-01

    Full Text Available Schizophrenia is thought to arise due to a complex interaction between genetic and environmental factors during early neurodevelopment. We have recently shown that partial genetic deletion of the schizophrenia susceptibility gene neuregulin 1 (Nrg1 and adolescent stress interact to disturb sensorimotor gating, neuroendocrine activity and dendritic morphology in mice. Both stress and Nrg1 may have converging effects upon N-methyl-D-aspartate receptors (NMDARs which are implicated in the pathogenesis of schizophrenia, sensorimotor gating and dendritic spine plasticity. Using an identical repeated restraint stress paradigm to our previous study, here we determined NMDAR binding across various brain regions in adolescent Nrg1 heterozygous (HET and wild-type (WT mice using [3H] MK-801 autoradiography. Repeated restraint stress increased NMDAR binding in the ventral part of the lateral septum (LSV and the dentate gyrus (DG of the hippocampus irrespective of genotype. Partial genetic deletion of Nrg1 interacted with adolescent stress to promote an altered pattern of NMDAR binding in the infralimbic (IL subregion of the medial prefrontal cortex. In the IL, whilst stress tended to increase NMDAR binding in WT mice, it decreased binding in Nrg1 HET mice. However in the DG, stress selectively increased the expression of NMDAR binding in Nrg1 HET mice but not WT mice. These results demonstrate a Nrg1-stress interaction during adolescence on NMDAR binding in the medial prefrontal cortex.

  1. Transgenerational Effects Alter Plant Defense and Resistance in Nature

    Science.gov (United States)

    Colicchio, Jack

    2017-01-01

    Trichomes, or leaf hairs, are epidermal extensions that take a variety of forms and perform many functions in plants, including herbivore defense. In this study, I document genetically determined variation, within-generation plasticity, and a direct role of trichomes in herbivore defense for Mimulus guttatus. After establishing the relationship between trichomes and herbivory, I test for transgenerational effects of wounding on trichome density and herbivore resistance. Patterns of inter-annual variation in herbivore density and the high cost of plant defense makes plant-herbivore interactions a system in which transgenerational phenotypic plasticity (TPP) is apt to evolve. Here, I demonstrate that parental damage alters offspring trichome density and herbivore resistance in nature. Moreover, this response varies between populations. This is among the first studies to demonstrate that TPP contributes to variation in nature, and also suggests that selection can modify TPP in response to local conditions. PMID:28102915

  2. Root exudate-induced alterations in Bacillus cereus cell wall contribute to root colonization and plant growth promotion.

    Directory of Open Access Journals (Sweden)

    Swarnalee Dutta

    Full Text Available The outcome of an interaction between plant growth promoting rhizobacteria and plants may depend on the chemical composition of root exudates (REs. We report the colonization of tobacco, and not groundnut, roots by a non-rhizospheric Bacillus cereus (MTCC 430. There was a differential alteration in the cell wall components of B. cereus in response to the REs from tobacco and groundnut. Attenuated total reflectance infrared spectroscopy revealed a split in amide I region of B. cereus cells exposed to tobacco-root exudates (TRE, compared to those exposed to groundnut-root exudates (GRE. In addition, changes in exopolysaccharides and lipid-packing were observed in B. cereus grown in TRE-amended minimal media that were not detectable in GRE-amended media. Cell-wall proteome analyses revealed upregulation of oxidative stress-related alkyl hydroperoxide reductase, and DNA-protecting protein chain (Dlp-2, in response to GRE and TRE, respectively. Metabolism-related enzymes like 2-amino-3-ketobutyrate coenzyme A ligase and 2-methylcitrate dehydratase and a 60 kDa chaperonin were up-regulated in response to TRE and GRE. In response to B. cereus, the plant roots altered their exudate-chemodiversity with respect to carbohydrates, organic acids, alkanes, and polyols. TRE-induced changes in surface components of B. cereus may contribute to successful root colonization and subsequent plant growth promotion.

  3. Association among genetic predisposition, gut microbiota, and host immune response in the etiopathogenesis of inflammatory bowel disease

    Directory of Open Access Journals (Sweden)

    P.J. Basso

    2014-09-01

    Full Text Available Inflammatory bowel disease (IBD, which includes Crohn's disease (CD and ulcerative colitis (UC, is a chronic disorder that affects thousands of people around the world. These diseases are characterized by exacerbated uncontrolled intestinal inflammation that leads to poor quality of life in affected patients. Although the exact cause of IBD still remains unknown, compelling evidence suggests that the interplay among immune deregulation, environmental factors, and genetic polymorphisms contributes to the multifactorial nature of the disease. Therefore, in this review we present classical and novel findings regarding IBD etiopathogenesis. Considering the genetic causes of the diseases, alterations in about 100 genes or allelic variants, most of them in components of the immune system, have been related to IBD susceptibility. Dysbiosis of the intestinal microbiota also plays a role in the initiation or perpetuation of gut inflammation, which develops under altered or impaired immune responses. In this context, unbalanced innate and especially adaptive immunity has been considered one of the major contributing factors to IBD development, with the involvement of the Th1, Th2, and Th17 effector population in addition to impaired regulatory responses in CD or UC. Finally, an understanding of the interplay among pathogenic triggers of IBD will improve knowledge about the immunological mechanisms of gut inflammation, thus providing novel tools for IBD control.

  4. Genetic contribution to 'theory of mind' in adolescence.

    Science.gov (United States)

    Warrier, Varun; Baron-Cohen, Simon

    2018-02-22

    Difficulties in 'theory of mind' (the ability to attribute mental states to oneself or others, and to make predictions about another's behaviour based on these attributions) have been observed in several psychiatric conditions. We investigate the genetic architecture of theory of mind in 4,577 13-year-olds who completed the Emotional Triangles Task (Triangles Task), a first-order test of theory of mind. We observe a small but significant female-advantage on the Triangles Task (Cohen's d = 0.19, P theory of mind. Genome-wide association analyses did not identify any significant loci, and SNP heritability was non-significant. Polygenic scores for six psychiatric conditions (ADHD, anorexia, autism, bipolar disorder, depression, and schizophrenia), and empathy were not associated with scores on the Triangles Task. However, polygenic scores of cognitive aptitude, and cognitive empathy, a term synonymous with theory of mind and measured using the "Reading the Mind in the Eyes" Test, were significantly associated with scores on the Triangles Task at multiple P-value thresholds, suggesting shared genetics between different measures of theory of mind and cognition.

  5. Patterns of somatic alterations between matched primary and metastatic colorectal tumors characterized by whole-genome sequencing.

    Science.gov (United States)

    Xie, Tao; Cho, Yong Beom; Wang, Kai; Huang, Donghui; Hong, Hye Kyung; Choi, Yoon-La; Ko, Young Hyeh; Nam, Do-Hyun; Jin, Juyoun; Yang, Heekyoung; Fernandez, Julio; Deng, Shibing; Rejto, Paul A; Lee, Woo Yong; Mao, Mao

    2014-10-01

    Colorectal cancer (CRC) patients have poor prognosis after formation of distant metastasis. Understanding the molecular mechanisms by which genetic changes facilitate metastasis is critical for the development of targeted therapeutic strategies aimed at controlling disease progression while minimizing toxic side effects. A comprehensive portrait of somatic alterations in CRC and the changes between primary and metastatic tumors has yet to be developed. We performed whole genome sequencing of two primary CRC tumors and their matched liver metastases. By comparing to matched germline DNA, we catalogued somatic alterations at multiple scales, including single nucleotide variations, small insertions and deletions, copy number aberrations and structural variations in both the primary and matched metastasis. We found that the majority of these somatic alterations are present in both sites. Despite the overall similarity, several de novo alterations in the metastases were predicted to be deleterious, in genes including FBXW7, DCLK1 and FAT2, which might contribute to the initiation and progression of distant metastasis. Through careful examination of the mutation prevalence among tumor cells at each site, we also proposed distinct clonal evolution patterns between primary and metastatic tumors in the two cases. These results suggest that somatic alterations may play an important role in driving the development of colorectal cancer metastasis and present challenges and opportunities when considering the choice of treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Obesity and diabetes: from genetics to epigenetics.

    Science.gov (United States)

    Burgio, Ernesto; Lopomo, Angela; Migliore, Lucia

    2015-04-01

    Obesity is becoming an epidemic health problem. During the last years not only genetic but also, and primarily, environmental factors have been supposed to contribute to the susceptibility to weight gain or to develop complications such as type 2 diabetes. In spite of the intense efforts to identify genetic predisposing variants, progress has been slow and success limited, and the common obesity susceptibility variants identified only explains a small part of the individual variation in risk. Moreover, there is evidence that the current epidemic of obesity and diabetes is environment-driven. Recent studies indicate that normal metabolic regulation during adulthood besides requiring a good balance between energy intake and energy expenditure, can be also affected by pre- and post-natal environments. In fact, maternal nutritional constraint during pregnancy can alter the metabolic phenotype of the offspring by means of epigenetic regulation of specific genes, and this can be passed to the next generations. Studies focused on epigenetic marks in obesity found altered methylation and/or histone acetylation levels in genes involved in specific but also in more general metabolic processes. Recent researches point out the continuous increase of "obesogens", in the environment and food chains, above all endocrine disruptors, chemicals that interfere with many homeostatic mechanisms. Taken into account the already existing data on the effects of obesogens, and the multiple potential targets with which they might interfere daily, it seems likely that the exposure to obesogens can have an important role in the obesity and diabesity pandemic.

  7. Genetic structure and genetic diversity of Swietenia macrophylla in areas subjected to selective logging in Quintana Roo, Mexico

    OpenAIRE

    Alcalá, Raúl Ernesto; Cruz, Silvia De la; Gutiérrez-Granados, Gabriel

    2015-01-01

    The hypothesis that selective logging has a negative effect by altering the genetic parameters of tropical tree species was evaluated. The genetic diversity and genetic structure between adult trees (N = 47) and saplings (N = 50) of Swietenia macrophylla were contrasted within an area subjected to selective logging in the Mayan zone. Although differences in the number of alleles and in their frequencies were detected between both groups, the observed and expected heterozygosity and the coeffi...

  8. 11β-hydroxysteroid dehydrogenase-1 deficiency alters the gut microbiome response to Western diet.

    Science.gov (United States)

    Johnson, Jethro S; Opiyo, Monica N; Thomson, Marian; Gharbi, Karim; Seckl, Jonathan R; Heger, Andreas; Chapman, Karen E

    2017-02-01

    The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) interconverts active glucocorticoids and their intrinsically inert 11-keto forms. The type 1 isozyme, 11β-HSD1, predominantly reactivates glucocorticoids in vivo and can also metabolise bile acids. 11β-HSD1-deficient mice show altered inflammatory responses and are protected against the adverse metabolic effects of a high-fat diet. However, the impact of 11β-HSD1 on the composition of the gut microbiome has not previously been investigated. We used high-throughput 16S rDNA amplicon sequencing to characterise the gut microbiome of 11β-HSD1-deficient and C57Bl/6 control mice, fed either a standard chow diet or a cholesterol- and fat-enriched 'Western' diet. 11β-HSD1 deficiency significantly altered the composition of the gut microbiome, and did so in a diet-specific manner. On a Western diet, 11β-HSD1 deficiency increased the relative abundance of the family Bacteroidaceae, and on a chow diet, it altered relative abundance of the family Prevotellaceae Our results demonstrate that (i) genetic effects on host-microbiome interactions can depend upon diet and (ii) that alterations in the composition of the gut microbiome may contribute to the aspects of the metabolic and/or inflammatory phenotype observed with 11β-HSD1 deficiency. © 2017 The authors.

  9. Clinical impact of genetic variants of drug transporters in different ethnic groups within and across regions.

    Science.gov (United States)

    Ono, Chiho; Kikkawa, Hironori; Suzuki, Akiyuki; Suzuki, Misaki; Yamamoto, Yuichi; Ichikawa, Katsuomi; Fukae, Masato; Ieiri, Ichiro

    2013-11-01

    Drug transporters, together with drug metabolic enzymes, are major determinants of drug disposition and are known to alter the response to many commonly used drugs. Substantial frequency differences for known variants exist across geographic regions for certain drug transporters. To deliver efficacious medicine with the right dose for each patient, it is important to understand the contribution of genetic variants for drug transporters. Recently, mutual pharmacokinetic data usage among Asian regions, which are thought to be relatively similar in their own genetic background, is expected to accelerate new drug applications and reduce developmental costs. Polymorphisms of drug transporters could be key factors to be considered in implementing multiethnic global clinical trials. This review addresses the current knowledge on genetic variations of major drug transporters affecting drug disposition, efficacy and toxicity, focusing on the east Asian populations, and provides insights into future directions for precision medicine and drug development in east Asia.

  10. Previous climatic alterations are caused by the sun

    International Nuclear Information System (INIS)

    Groenaas, Sigbjoern

    2003-01-01

    The article surveys the scientific results of previous research into the contribution of the sun to climatic alterations. The author concludes that there is evidence of eight cold periods after the last ice age and that the alterations largely were due to climate effects from the sun. However, these effects are only causing a fraction of the registered global warming. It is assumed that the human activities are contributing to the rest of the greenhouse effect

  11. Journal of Genetics | Indian Academy of Sciences

    Indian Academy of Sciences (India)

    pp 223-226 Commentary on J. Genet. Classic. Towards a genetic architecture of cryptic genetic variation and genetic assimilation: the contribution of K. G. Bateman · Ian Dworkin · More Details Fulltext PDF. pp 227-257 J. Genet. Classic. The Genetic Assimilation of Four Venation Phenocopies (Published on 1959 J. Genet.

  12. Genetic contributions to variation in general cognitive function: A meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

    NARCIS (Netherlands)

    G. Davies (Gail); N.J. Armstrong (Nicola J.); J.C. Bis (Joshua); J. Bressler (Jan); V. Chouraki (Vincent); S. Giddaluru (Sudheer); E. Hofer; C.A. Ibrahim-Verbaas (Carla); M. Kirin (Mirna); J. Lahti; S.J. van der Lee (Sven); S. Le Hellard (Stephanie); T. Liu; R.E. Marioni (Riccardo); C. Oldmeadow (Christopher); D. Postmus (Douwe); G.D. Smith; J.A. Smith (Jennifer A); A. Thalamuthu (Anbupalam); R. Thomson (Russell); V. Vitart (Veronique); J. Wang; L. Yu; L. Zgaga (Lina); W. Zhao (Wei); R. Boxall (Ruth); S.E. Harris (Sarah); W.D. Hill (W. David); D.C. Liewald (David C.); M. Luciano (Michelle); H.H.H. Adams (Hieab); D. Ames (David); N. Amin (Najaf); P. Amouyel (Philippe); A.A. Assareh; R. Au; J.T. Becker (James); A. Beiser; C. Berr (Claudine); L. Bertram (Lars); E.A. Boerwinkle (Eric); B.M. Buckley (Brendan M.); H. Campbell (Harry); J. Corley; P.L. De Jager; C. Dufouil (Carole); J.G. Eriksson (Johan G.); T. Espeseth (Thomas); J.D. Faul; I. Ford; G. Scotland (Generation); R.F. Gottesman (Rebecca); M.D. Griswold (Michael); V. Gudnason (Vilmundur); T.B. Harris; G. Heiss (Gerardo); A. Hofman (Albert); E.G. Holliday (Elizabeth); J.E. Huffman (Jennifer); S.L.R. Kardia (Sharon); N.A. Kochan (Nicole A.); D.S. Knopman (David); J.B. Kwok; J.-C. Lambert; T. Lee; G. Li; S.-C. Li; M. Loitfelder (Marisa); O.L. Lopez (Oscar); A.J. Lundervold; A. Lundqvist; R. Mather; S.S. Mirza (Saira); L. Nyberg; B.A. Oostra (Ben); A. Palotie (Aarno); G. Papenberg; A. Pattie (Alison); K. Petrovic (Katja); O. Polasek (Ozren); B.M. Psaty (Bruce); P. Redmond (Paul); S. Reppermund; J.I. Rotter; R. Schmidt (Reinhold); M. Schuur (Maaike); P.W. Schofield; R.J. Scott; V.M. Steen (Vidar); D.J. Stott (David J.); J.C. van Swieten (John); K.D. Taylor (Kent); J. Trollor; S. Trompet (Stella); A.G. Uitterlinden (André); G. Weinstein; E. Widen (Elisabeth); B.G. Windham (B Gwen); J.W. Jukema (Jan Wouter); A. Wright (Alan); M.J. Wright (Margaret); Q. Yang (Qiong Fang); H. Amieva (Hélène); J. Attia (John); D.A. Bennett (David); H. Brodaty (Henry); A.J. de Craen (Anton); C. Hayward; M.A. Ikram (Arfan); U. Lindenberger; L.-G. Nilsson; D.J. Porteous (David J.); K. Räikkönen (Katri); I. Reinvang (Ivar); I. Rudan (Igor); P.S. Sachdev (Perminder); R. Schmidt; P. Schofield (Peter); V. Srikanth; J.M. Starr (John); S.T. Turner (Stephen); D.R. Weir (David R.); J.F. Wilson (James F); C.M. van Duijn (Cornelia); L.J. Launer (Lenore); A.L. Fitzpatrick (Annette); S. Seshadri (Sudha); T.H. Mosley (Thomas H.); I.J. Deary (Ian J.)

    2015-01-01

    textabstractGeneral cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of

  13. Male and female contributions to behavioral isolation in darters as a function of genetic distance and color distance

    Science.gov (United States)

    Moran, Rachel L.; Zhou, Muchu; Catchen, Julian M.; Fuller, Rebecca C.

    2017-01-01

    Abstract Determining which reproductive isolating barriers arise first between geographically isolated lineages is critical to understanding allopatric speciation. We examined behavioral isolation among four recently diverged allopatric species in the orangethroat darter clade (Etheostoma: Ceasia). We also examined behavioral isolation between each Ceasia species and the sympatric rainbow darter Etheostoma caeruleum. We asked (1) is behavioral isolation present between allopatric Ceasia species, and how does this compare to behavioral isolation with E. caeruleum, (2) does male color distance and/or genetic distance predict behavioral isolation between species, and (3) what are the relative contributions of female choice, male choice, and male competition to behavioral isolation? We found that behavioral isolation, genetic differentiation, and male color pattern differentiation were present between allopatric Ceasia species. Males, but not females, discerned between conspecific and heterospecific mates. Males also directed more aggression toward conspecific rival males. The high levels of behavioral isolation among Ceasia species showed no obvious pattern with genetic distance or male color distance. However, when the E. caeruleum was included in the analysis, an association between male aggression and male color distance was apparent. We discuss the possibility that reinforcement between Ceasia and E. caeruleum is driving behavioral isolation among allopatric Ceasia species. PMID:28776645

  14. Genetic conservation and paddlefish propagation

    Science.gov (United States)

    Sloss, Brian L.; Klumb, Robert A.; Heist, Edward J.

    2009-01-01

    The conservation of genetic diversity of our natural resources is overwhelmingly one of the central foci of 21st century management practices. Three recommendations related to the conservation of paddlefish Polyodon spathula genetic diversity are to (1) identify genetic diversity at both nuclear and mitochondrial DNA loci using a suggested list of 20 sampling locations, (2) use genetic diversity estimates to develop genetic management units, and (3) identify broodstock sources to minimize effects of supplemental stocking on the genetic integrity of native paddlefish populations. We review previous genetic work on paddlefish and described key principles and concepts associated with maintaining genetic diversity within and among paddlefish populations and also present a genetic case study of current paddlefish propagation at the U.S. Fish and Wildlife Service Gavins Point National Fish Hatchery. This study confirmed that three potential sources of broodfish were genetically indistinguishable at the loci examined, allowing the management agencies cooperating on this program flexibility in sampling gametes. This study also showed significant bias in the hatchery occurred in terms of male reproductive contribution, which resulted in a shift in the genetic diversity of progeny compared to the broodfish. This shift was shown to result from differential male contributions, partially attributed to the mode of egg fertilization. Genetic insights enable implementation of a paddlefish propagation program within an adaptive management strategy that conserves inherent genetic diversity while achieving demographic goals.

  15. Shedding subspecies: The influence of genetics on reptile subspecies taxonomy.

    Science.gov (United States)

    Torstrom, Shannon M; Pangle, Kevin L; Swanson, Bradley J

    2014-07-01

    The subspecies concept influences multiple aspects of biology and management. The 'molecular revolution' altered traditional methods (morphological traits) of subspecies classification by applying genetic analyses resulting in alternative or contradictory classifications. We evaluated recent reptile literature for bias in the recommendations regarding subspecies status when genetic data were included. Reviewing characteristics of the study, genetic variables, genetic distance values and noting the species concepts, we found that subspecies were more likely elevated to species when using genetic analysis. However, there was no predictive relationship between variables used and taxonomic recommendation. There was a significant difference between the median genetic distance values when researchers elevated or collapsed a subspecies. Our review found nine different concepts of species used when recommending taxonomic change, and studies incorporating multiple species concepts were more likely to recommend a taxonomic change. Since using genetic techniques significantly alter reptile taxonomy there is a need to establish a standard method to determine the species-subspecies boundary in order to effectively use the subspecies classification for research and conservation purposes. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Gut Microbiota: a contributing factor to obesity

    Directory of Open Access Journals (Sweden)

    Steve M Harakeh

    2016-08-01

    Full Text Available Obesity, a global epidemic of the modern era, is a risk factor for cardiovascular diseases (CVD and diabetes. The pervasiveness of obesity and overweight in both developed as well as developing populations is on the rise and placing a huge burden on health and economic resources. Consequently, research to control this emerging epidemic is of utmost importance. Recently, host interactions with their resident gut microbiota (GM have been reported to be involved in the pathogenesis of many metabolic diseases, including obesity, diabetes, and CVD. Around 1014 microorganisms reside within the lower human intestine and many of these 1014microorganisms have developed mutualistic or commensal associations with the host and actively involved in many physiological processes of the host. However, dysbiosis (altered gut microbial composition with other predisposing genetic and environmental factors, may contribute to host metabolic disorders resulting in many ailments. Therefore, delineating the role of GM as a contributing factor to obesity is the main objective of this review.Obesity research, as a field is expanding rapidly due to major advances in nutrigenomics, metabolomics, RNA silencing, epigenetics and other disciplines that may result in the emergence of new technologies and methods to better interpret causal relationships between microbiota and obesity.

  17. Gut Microbiota: A Contributing Factor to Obesity

    Science.gov (United States)

    Harakeh, Steve M.; Khan, Imran; Kumosani, Taha; Barbour, Elie; Almasaudi, Saad B.; Bahijri, Suhad M.; Alfadul, Sulaiman M.; Ajabnoor, Ghada M. A.; Azhar, Esam I.

    2016-01-01

    Obesity, a global epidemic of the modern era, is a risk factor for cardiovascular diseases (CVD) and diabetes. The pervasiveness of obesity and overweight in both developed as well as developing populations is on the rise and placing a huge burden on health and economic resources. Consequently, research to control this emerging epidemic is of utmost importance. Recently, host interactions with their resident gut microbiota (GM) have been reported to be involved in the pathogenesis of many metabolic diseases, including obesity, diabetes, and CVD. Around 1014 microorganisms reside within the lower human intestine and many of these 1014 microorganisms have developed mutualistic or commensal associations with the host and actively involved in many physiological processes of the host. However, dysbiosis (altered gut microbial composition) with other predisposing genetic and environmental factors, may contribute to host metabolic disorders resulting in many ailments. Therefore, delineating the role of GM as a contributing factor to obesity is the main objective of this review. Obesity research, as a field is expanding rapidly due to major advances in nutrigenomics, metabolomics, RNA silencing, epigenetics, and other disciplines that may result in the emergence of new technologies and methods to better interpret causal relationships between microbiota and obesity. PMID:27625997

  18. Genetic Pathways to Insomnia

    OpenAIRE

    Mackenzie J. Lind; Philip R. Gehrman

    2016-01-01

    This review summarizes current research on the genetics of insomnia, as genetic contributions are thought to be important for insomnia etiology. We begin by providing an overview of genetic methods (both quantitative and measured gene), followed by a discussion of the insomnia genetics literature with regard to each of the following common methodologies: twin and family studies, candidate gene studies, and genome-wide association studies (GWAS). Next, we summarize the most recent gene identif...

  19. Defining population structure and genetic signatures of decline in the giant garter snake (Thamnophis gigas): implications for conserving threatened species within highly altered landscapes

    Science.gov (United States)

    Wood, Dustin A.; Halstead, Brian J.; Casazza, Michael L.; Hansen, Eric C.; Wylie, Glenn D.; Vandergast, Amy

    2015-01-01

    Anthropogenic habitat fragmentation can disrupt the ability of species to disperse across landscapes, which can alter the levels and distribution of genetic diversity within populations and negatively impact long-term viability. The giant gartersnake (Thamnophis gigas) is a state and federally threatened species that historically occurred in the wetland habitats of California’s Great Central Valley. Despite the loss of 93 % of historic wetlands throughout the Central Valley, giant gartersnakes continue to persist in relatively small, isolated patches of highly modified agricultural wetlands. Gathering information regarding genetic diversity and effective population size represents an essential component for conservation management programs aimed at this species. Previous mitochondrial sequence studies have revealed historical patterns of differentiation, yet little is known about contemporary population structure and diversity. On the basis of 15 microsatellite loci, we estimate population structure and compare indices of genetic diversity among populations spanning seven drainage basins within the Central Valley. We sought to understand how habitat loss may have affected genetic differentiation, genetic diversity and effective population size, and what these patterns suggest in terms of management and restoration actions. We recovered five genetic clusters that were consistent with regional drainage basins, although three northern basins within the Sacramento Valley formed a single genetic cluster. Our results show that northern drainage basin populations have higher connectivity than among central and southern basins populations, and that greater differentiation exists among the more geographically isolated populations in the central and southern portion of the species’ range. Genetic diversity measures among basins were significantly different, and were generally lower in southern basin populations. Levels of inbreeding and evidence of population

  20. Identification of the genetic and clinical characteristics of neuroblastomas using genome-wide analysis.

    Science.gov (United States)

    Uryu, Kumiko; Nishimura, Riki; Kataoka, Keisuke; Sato, Yusuke; Nakazawa, Atsuko; Suzuki, Hiromichi; Yoshida, Kenichi; Seki, Masafumi; Hiwatari, Mitsuteru; Isobe, Tomoya; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Koh, Katsuyoshi; Hanada, Ryoji; Oka, Akira; Hayashi, Yasuhide; Ohira, Miki; Kamijo, Takehiko; Nagase, Hiroki; Takimoto, Tetsuya; Tajiri, Tatsuro; Nakagawara, Akira; Ogawa, Seishi; Takita, Junko

    2017-12-08

    To provide better insight into the genetic signatures of neuroblastomas, we analyzed 500 neuroblastomas (included specimens from JNBSG) using targeted-deep sequencing for 10 neuroblastoma-related genes and SNP arrays analysis. ALK expression was evaluated using immunohistochemical analysis in 259 samples. Based on genetic alterations, the following 6 subgroups were identified: groups A ( ALK abnormalities), B (other gene mutations), C ( MYCN amplification), D (11q loss of heterozygosity [LOH]), E (at least 1 copy number variants), and F (no genetic changes). Groups A to D showed advanced disease and poor prognosis, whereas groups E and F showed excellent prognosis. Intriguingly, in group A, MYCN amplification was not a significant prognostic marker, while high ALK expression was a relevant indicator for prognosis ( P = 0.033). Notably, the co-existence of MYCN amplification and 1p LOH, and the co-deletion of 3p and 11q were significant predictors of relapse ( P = 0.043 and P = 0.040). Additionally, 6q/8p LOH and 17q gain were promising indicators of survival in patients older than 5 years, and 1p, 4p, and 11q LOH potentially contributed to outcome prediction in the intermediate-risk group. Our genetic overview clarifies the clinical impact of genetic signatures and aids in the better understanding of genetic basis of neuroblastoma.

  1. Methyl vitamins contribute to obesogenic effects of a high multivitamin gestational diet and epigenetic alterations in hypothalamic feeding pathways in Wistar rat offspring.

    Science.gov (United States)

    Cho, Clara E; Pannia, Emanuela; Huot, Pedro S P; Sánchez-Hernández, Diana; Kubant, Ruslan; Dodington, David W; Ward, Wendy E; Bazinet, Richard P; Anderson, G Harvey

    2015-03-01

    High multivitamin (HV, tenfold AIN-93G) gestational diets fed to Wistar rats increase food intake, obesity, and characteristics of metabolic syndrome in the offspring. We hypothesized that methyl vitamins, and specifically folate, in the HV gestational diet contribute to the obesogenic phenotypes consistent with their epigenetic effects on hypothalamic food intake regulatory mechanisms. Male offspring of dams fed the AIN-93G diet with high methyl vitamins (HMethyl; tenfold folate, vitamins B12, and B6) (Study 1) and HV with recommended folate (HVRF) (Study 2) were compared with those from HV and recommended vitamin (RV) fed dams. All offspring were weaned to a high fat diet for 8 wks. HMethyl diet, similar to HV, and compared to RV, resulted in higher food intake, body weight, and metabolic disturbances. Removing folate additions to the HV diet in HVRF offspring normalized the obesogenic phenotype. Methyl vitamins, and folate in HV diets, altered hypothalamic gene expression toward increased food intake concurrent with DNA methylation and leptin and insulin receptor signaling dysfunction. Methyl vitamins in HV gestational diets contribute to obesogenic phenotypes and epigenetic alterations in the hypothalamic feeding pathways in the offspring. Folate alone accounts for many of these effects. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Genetic variants in long non-coding RNA MIAT contribute to risk of paranoid schizophrenia in a Chinese Han population.

    Science.gov (United States)

    Rao, Shu-Quan; Hu, Hui-Ling; Ye, Ning; Shen, Yan; Xu, Qi

    2015-08-01

    The heritability of schizophrenia has been reported to be as high as ~80%, but the contribution of genetic variants identified to this heritability remains to be estimated. Long non-coding RNAs (LncRNAs) are involved in multiple processes critical to normal cellular function and dysfunction of lncRNA MIAT may contribute to the pathophysiology of schizophrenia. However, the genetic evidence of lncRNAs involved in schizophrenia has not been documented. Here, we conducted a two-stage association analysis on 8 tag SNPs that cover the whole MIAT locus in two independent Han Chinese schizophrenia case-control cohorts (discovery sample from Shanxi Province: 1093 patients with paranoid schizophrenia and 1180 control subjects; replication cohort from Jilin Province: 1255 cases and 1209 healthy controls). In discovery stage, significant genetic association with paranoid schizophrenia was observed for rs1894720 (χ(2)=74.20, P=7.1E-18), of which minor allele (T) had an OR of 1.70 (95% CI=1.50-1.91). This association was confirmed in the replication cohort (χ(2)=22.66, P=1.9E-06, OR=1.32, 95%CI 1.18-1.49). Besides, a weak genotypic association was detected for rs4274 (χ(2)=4.96, df=2, P=0.03); the AA carriers showed increased disease risk (OR=1.30, 95%CI=1.03-1.64). No significant association was found between any haplotype and paranoid schizophrenia. The present studies showed that lncRNA MIAT was a novel susceptibility gene for paranoid schizophrenia in the Chinese Han population. Considering that most lncRNAs locate in non-coding regions, our result may explain why most susceptibility loci for schizophrenia identified by genome wide association studies were out of coding regions. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. The ecological imperative and its application to ethical issues in human genetic technology

    OpenAIRE

    W. Malcolm Byrnes

    2003-01-01

    As a species, we are on the cusp of being able to alter that which makes us uniquely human, our genome. Two new genetic technologies, embryo selection and germline engineering, are either in use today or may be developed in the future. Embryo selection acts to alter the human gene pool, reducing genetic diversity, while germline engineering will have the ability to alter directly the genomes of engineered individuals. Our genome has come to be what it is through an evolutionary process extend...

  4. Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons

    OpenAIRE

    Rotger, Margalida; Glass, Tracy R; Junier, Thomas; Lundgren, Jens; Neaton, James D; Poloni, Estella S; van 't Wout, Angélique B; Lubomirov, Rubin; Colombo, Sara; Martinez, Raquel; Rauch, Andri; Günthard, Huldrych F; Neuhaus, Jacqueline; Wentworth, Deborah; van Manen, Danielle

    2013-01-01

    BACKGROUND: Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. METHODS: In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the ...

  5. DNA methylation mediates genetic variation for adaptive transgenerational plasticity.

    Science.gov (United States)

    Herman, Jacob J; Sultan, Sonia E

    2016-09-14

    Environmental stresses experienced by individual parents can influence offspring phenotypes in ways that enhance survival under similar conditions. Although such adaptive transgenerational plasticity is well documented, its transmission mechanisms are generally unknown. One possible mechanism is environmentally induced DNA methylation changes. We tested this hypothesis in the annual plant Polygonum persicaria, a species known to express adaptive transgenerational plasticity in response to parental drought stress. Replicate plants of 12 genetic lines (sampled from natural populations) were grown in dry versus moist soil. Their offspring were exposed to the demethylating agent zebularine or to control conditions during germination and then grown in dry soil. Under control germination conditions, the offspring of drought-stressed parents grew longer root systems and attained greater biomass compared with offspring of well-watered parents of the same genetic lines. Demethylation removed these adaptive developmental effects of parental drought, but did not significantly alter phenotypic expression in offspring of well-watered parents. The effect of demethylation on the expression of the parental drought effect varied among genetic lines. Differential seed provisioning did not contribute to the effect of parental drought on offspring phenotypes. These results demonstrate that DNA methylation can mediate adaptive, genotype-specific effects of parental stress on offspring phenotypes. © 2016 The Author(s).

  6. [Copy number alterations in adult patients with mature B acute lymphoblastic leukemia treated with specific immunochemotherapy].

    Science.gov (United States)

    Ribera, Jordi; Zamora, Lurdes; García, Olga; Hernández-Rivas, Jesús-María; Genescà, Eulàlia; Ribera, Josep-Maria

    2016-12-02

    Unlike Burkitt lymphoma, molecular abnormalities other than C-MYC rearrangements have scarcely been studied in patients with mature B acute lymphoblastic leukemia (B-ALL). The aim of this study was to analyze the frequency and prognostic significance of copy number alterations (CNA) in genes involved in lymphoid differentiation, cell cycle and tumor suppression in adult patients with B-ALL. We have analyzed by multiplex ligation-dependent probe amplification the genetic material from bone marrow at diagnosis from 25 adult B-ALL patients treated with rituximab and specific chemotherapy. The most frequent CNA were alterations in the 14q32.33 region (11 cases, 44%) followed by alterations in the cell cycle regulator genes CDKN2A/B and RB1 (16%). No correlation between the presence of specific CNA and the clinical-biologic features or the response to therapy was found. The high frequency of CNA in the 14q32.33 region, CDKN2A/B and RB1 found in our study could contribute to the aggressiveness and invasiveness of mature B-ALL. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  7. Genetics of Alcoholism.

    Science.gov (United States)

    Zhu, Ena C; Soundy, Timothy J; Hu, Yueshan

    2017-05-01

    Consuming excessive amounts of alcohol has the potential to modify an individual's brain and lead to alcohol dependence. Alcohol use leads to 88,000 deaths every year in the U.S. alone and can lead to other health issues including cancers, such as colorectal cancer, and mental health problems. While drinking behavior varies due to environmental factors, genetic factors also contribute to the risk of alcoholism. Certain genes affecting alcohol metabolism and neurotransmitters have been found to contribute to or inhibit the risk. Geneenvironment interactions may also play a role in the susceptibility of alcoholism. With a better understanding of the different components that can contribute to alcoholism, more personalized treatment could cater to the individual. This review discusses the major genetic factors and some small variants in other genes that contribute to alcoholism, as well as considers the gene-environmental interactions. Copyright© South Dakota State Medical Association.

  8. Relationships among walleye population characteristics and genetic diversity in northern Wisconsin Lakes

    Science.gov (United States)

    Waterhouse, Matthew D.; Sloss, Brian L.; Isermann, Daniel A.

    2014-01-01

    The maintenance of genetic integrity is an important goal of fisheries management, yet little is known regarding the effects of management actions (e.g., stocking, harvest regulations) on the genetic diversity of many important fish species. Furthermore, relationships between population characteristics and genetic diversity remain poorly understood. We examined relationships among population demographics (abundance, recruitment, sex ratio, and mean age of the breeding population), stocking intensity, and genetic characteristics (heterozygosity, effective number of alleles, allelic richness, Wright's inbreeding coefficient, effective population size [Ne], mean d2 [a measure of inbreeding], mean relatedness, and pairwise population ΦST estimates) for 15 populations of Walleye Sander vitreus in northern Wisconsin. We also tested for potential demographic and genetic influences on Walleye body condition and early growth. Combinations of demographic variables explained 47.1–79.8% of the variation in genetic diversity. Skewed sex ratios contributed to a reduction in Ne and subsequent increases in genetic drift and relatedness among individuals within populations; these factors were correlated to reductions in allelic richness and early growth rate. Levels of inbreeding were negatively related to both age-0 abundance and mean age, suggesting Ne was influenced by recruitment and generational overlap. A negative relationship between the effective number of alleles and body condition suggests stocking affected underlying genetic diversity of recipient populations and the overall productivity of the population. These relationships may result from poor performance of stocked fish, outbreeding depression, or density-dependent factors. An isolation-by-distance pattern of genetic diversity was apparent in nonstocked populations, but was disrupted in stocked populations, suggesting that stocking affected genetic structure. Overall, demographic factors were related to genetic

  9. The landscape of genomic alterations across childhood cancers

    DEFF Research Database (Denmark)

    Gröbner, Susanne N; Worst, Barbara C; Weischenfeldt, Joachim

    2018-01-01

    Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adoles...

  10. Genetic variation in food choice behaviour of amino acid-deprived Drosophila.

    Science.gov (United States)

    Toshima, Naoko; Hara, Chieko; Scholz, Claus-Jürgen; Tanimura, Teiichi

    2014-10-01

    To understand homeostatic regulation in insects, we need to understand the mechanisms by which they respond to external stimuli to maintain the internal milieu. Our previous study showed that Drosophila melanogaster exhibit specific amino acid preferences. Here, we used the D.melanogaster Genetic Reference Panel (DGRP), which is comprised of multiple inbred lines derived from a natural population, to examine how amino acid preference changes depending on the internal nutritional state in different lines. We performed a two-choice preference test and observed genetic variations in the response to amino acid deprivation. For example, a high-responding line showed an enhanced preference for amino acids even after only 1day of deprivation and responded to a fairly low concentration of amino acids. Conversely, a low-responding line showed no increased preference for amino acids after deprivation. We compared the gene expression profiles between selected high- and the low-responding lines and performed SNP analyses. We found several groups of genes putatively involved in altering amino acid preference. These results will contribute to future studies designed to explore how the genetic architecture of an organism evolves to adapt to different nutritional environments. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Transgenerational effects alter plant defence and resistance in nature.

    Science.gov (United States)

    Colicchio, J

    2017-04-01

    Trichomes, or leaf hairs, are epidermal extensions that take a variety of forms and perform many functions in plants, including herbivore defence. In this study, I document genetically determined variation, within-generation plasticity, and a direct role of trichomes in herbivore defence for Mimulus guttatus. After establishing the relationship between trichomes and herbivory, I test for transgenerational effects of wounding on trichome density and herbivore resistance. Patterns of interannual variation in herbivore density and the high cost of plant defence makes plant-herbivore interactions a system in which transgenerational phenotypic plasticity (TPP) is apt to evolve. Here, I demonstrate that parental damage alters offspring trichome density and herbivore resistance in nature. Moreover, this response varies between populations. This is among the first studies to demonstrate that TPP contributes to variation in nature, and also suggests that selection can modify TPP in response to local conditions. © 2017 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2017 European Society For Evolutionary Biology.

  12. [Hereditary colorectal cancer : An update on genetics and entities in terms of differential diagnosis].

    Science.gov (United States)

    Rau, T T; Dawson, H; Hartmann, A; Rüschoff, J

    2017-05-01

    The pathologist can contribute to recognizing hereditary causes of colorectal cancer via morphology. By identifying so-called index patients, it is possible to take preventive measures in affected families. The precise definition of the clinical presentation and the histopathological phenotype help to narrow the spectrum of expected genetic alterations. Novelties within Lynch syndrome include the recognition of EPCAM as a fifth gene locus, as well as the newly defined Lynch-like syndrome with evidence of somatic mismatch repair (MMR) mutations. With regard to polyposis-associated syndromes, the spectrum of polyps, whether serrated, hamartomatous or classic adenoma, is of crucial importance. The resulting differential diagnosis includes (attenuated) familial adenomatous polyposis ([a]FAP), MUTYH-associated polyposis (MAP), polymerase proofreading-associated polyposis (PPAP), phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS), Peutz-Jeghers syndrome and juvenile polyposis, each with a specific genetic background.

  13. Consecutive five-year analysis of paternal and maternal gene flow and contributions of gametic heterogeneities to overall genetic composition of dispersed seeds of Pinus densiflora (Pinaceae).

    Science.gov (United States)

    Iwaizumi, Masakazu G; Takahashi, Makoto; Isoda, Keiya; Austerlitz, Frédéric

    2013-09-01

    Genetic variability in monoecious woody plant populations results from the assemblage of individuals issued from asymmetrical male and female reproductive functions, produced during spatially and temporarily heterogeneous reproductive and dispersal events. Here we investigated the dispersal patterns and levels of genetic diversity and differentiation of both paternal and maternal gametes in a natural population of Pinus densiflora at the multiple-year scale as long as five consecutive years. • We analyzed the paternity and maternity for 1576 seeds and 454 candidate adult trees using nuclear DNA polymorphisms of diploid biparental embryos and haploid maternal megagametophytes at eight microsatellite loci. • Despite the low levels of genetic differentiation among gamete groups, a two-way AMOVA analysis showed that the parental origin (paternal vs. maternal gametes), the year of gamete production and their interaction had significant effects on the genetic composition of the seeds. While maternal gamete groups showed a significant FST value across the 5 years, this was not true for their paternal counterparts. Within the population, we found that the relative reproductive contributions of the paternal vs. the maternal parent differed among adult trees, the maternal contributions showing a larger year-to-year fluctuation. • The overall genetic variability of dispersed seeds appeared to result from two sources of heterogeneity: the difference between paternal and maternal patterns of reproduction and gamete dispersal and year-to-year heterogeneity of reproduction of adult trees, especially in their maternal reproduction.

  14. Empathy in early childhood: genetic, environmental, and affective contributions.

    Science.gov (United States)

    Knafo, Ariel; Zahn-Waxler, Carolyn; Davidov, Maayan; Van Hulle, Carol; Robinson, JoAnn L; Rhee, Soo Hyun

    2009-06-01

    We investigated the genetic and environmental origins of children's empathy toward a distress victim and its correlates with emotional symptoms and affective knowledge. The cognitive (hypothesis testing) and affective (empathic concern) empathy of 122 twin pairs in response to simulated pain by an adult examiner was observed at 3.5 years of age. Moderate (0.19 to 0.44) heritabilities were estimated for individual differences in empathy, and the nonshared environment and error accounted for the rest of the variance. Hypothesis testing and empathic concern were moderately correlated, mainly through overlapping genetic effects. Although children's affective knowledge did not correlate with their empathy, affective knowledge interacted with mother-rated emotional symptoms in predicting empathy; knowledge about emotions was associated with greater empathy in children low in emotional symptoms. In contrast, among children with high degrees of emotional symptoms, those with better affective knowledge tended to show lower empathy.

  15. Clerics urge ban on altering germline cells.

    Science.gov (United States)

    Norman, C

    1983-06-24

    A resolution calling for a ban on genetic engineering of human reproductive cells has been signed by leaders of almost every major church group in the United States. Some of the religious leaders, while not certain that a total moratorium should be placed on altering germline cells, signed the statement in order to stimulate public debate on the issue. Legislation has recently been introduced in Congress to set up a committee to monitor genetic engineering and its human applications, but author Jeremy Rifkin, the impetus behind the church leaders' resolution, argues that such tampering threatens the gene pool and should be banned altogether.

  16. The Tourette International Collaborative Genetics (TIC Genetics) study, finding the genes causing Tourette syndrome

    DEFF Research Database (Denmark)

    Dietrich, Andrea; Fernandez, Thomas V; King, Robert A

    2015-01-01

    Tourette syndrome (TS) is a neuropsychiatric disorder characterized by recurrent motor and vocal tics, often accompanied by obsessive-compulsive disorder and/or attention-deficit/hyperactivity disorder. While the evidence for a genetic contribution is strong, its exact nature has yet to be clarif......Tourette syndrome (TS) is a neuropsychiatric disorder characterized by recurrent motor and vocal tics, often accompanied by obsessive-compulsive disorder and/or attention-deficit/hyperactivity disorder. While the evidence for a genetic contribution is strong, its exact nature has yet......, it is clear that large patient cohorts and open-access repositories will be essential to further advance the field. To that end, the large multicenter Tourette International Collaborative Genetics (TIC Genetics) study was established. The goal of the TIC Genetics study is to undertake a comprehensive gene...... discovery effort, focusing both on familial genetic variants with large effects within multiply affected pedigrees and on de novo mutations ascertained through the analysis of apparently simplex parent-child trios with non-familial tics. The clinical data and biomaterials (DNA, transformed cell lines, RNA...

  17. Utilization of farm animal genetic resources in a changing agro-ecological environment in the Nordic countries

    DEFF Research Database (Denmark)

    Kantanen, Juha; Løvendahl, Peter; Strandberg, Erling

    2015-01-01

    Livestock production is the most important component of northern European agriculture and contributes to and will be affected by climate change. Nevertheless, the role of farm animal genetic resources in the adaptation to new agro-ecological conditions and mitigation of animal production’s effects...... to a future with altered production systems. Some animals with useful phenotypes and genotypes may be more useful than others in the changing environment. Robust animal breeds with the potential to adapt to new agro-ecological conditions and tolerate new diseases will be needed. The key issue in mitigation...

  18. Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers.

    Science.gov (United States)

    Nath, Aritro; Chan, Christina

    2016-01-04

    Reprogramming of cellular metabolism is a hallmark feature of cancer cells. While a distinct set of processes drive metastasis when compared to tumorigenesis, it is yet unclear if genetic alterations in metabolic pathways are associated with metastatic progression of human cancers. Here, we analyzed the mutation, copy number variation and gene expression patterns of a literature-derived model of metabolic genes associated with glycolysis (Warburg effect), fatty acid metabolism (lipogenesis, oxidation, lipolysis, esterification) and fatty acid uptake in >9000 primary or metastatic tumor samples from the multi-cancer TCGA datasets. Our association analysis revealed a uniform pattern of Warburg effect mutations influencing prognosis across all tumor types, while copy number alterations in the electron transport chain gene SCO2, fatty acid uptake (CAV1, CD36) and lipogenesis (PPARA, PPARD, MLXIPL) genes were enriched in metastatic tumors. Using gene expression profiles, we established a gene-signature (CAV1, CD36, MLXIPL, CPT1C, CYP2E1) that strongly associated with epithelial-mesenchymal program across multiple cancers. Moreover, stratification of samples based on the copy number or expression profiles of the genes identified in our analysis revealed a significant effect on patient survival rates, thus confirming prominent roles of fatty acid uptake and metabolism in metastatic progression and poor prognosis of human cancers.

  19. 76 FR 80869 - Monsanto Co.; Determination of Nonregulated Status of Corn Genetically Engineered for Drought...

    Science.gov (United States)

    2011-12-27

    ... and products altered or produced through genetic engineering that are plant pests or that there is... in 7 CFR part 340, ``Introduction of Organisms and Products Altered or Produced Through Genetic Engineering Which Are Plant Pests or Which There Is Reason to Believe Are Plant Pests,'' regulate, among other...

  20. Alterations of the TP53 Gene in Gastric and Esophageal Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Marilanda Ferreira Bellini

    2012-01-01

    Full Text Available TP53 genes is one of more important tumor suppressor gene, which acts as a potent transcription factor with fundamental role in the maintenance of genetic stability. The development of esophageal and gastric cancers is a multistep process resulting in successive accumulation of genetic alterations that culminates in the malignant transformation. Thus, this study highlights the participation of the main genetic alterations of the TP53 gene in esophageal and gastric carcinogenesis. Among these changes, high frequency of TP53 mutations, loss of heterozygosity (LOH, overexpression of the p53 protein, and consequently loss of p53 function, which would be early events in esophageal and gastric cancers, as well as an important biomarker of the prognosis and treatment response. Furthermore, Single Nucleotide Polymorphisms (SNPs of TP53 have been implicated in the development and prognosis of several cancers, mainly TP53 codon 72 polymorphism whose role has been extensively studied in relation to susceptibility for esophageal and gastric cancer development.

  1. The molecular genetic makeup of acute lymphoblastic leukemia.

    Science.gov (United States)

    Mullighan, Charles G

    2012-01-01

    Genomic profiling has transformed our understanding of the genetic basis of acute lymphoblastic leukemia (ALL). Recent years have seen a shift from microarray analysis and candidate gene sequencing to next-generation sequencing. Together, these approaches have shown that many ALL subtypes are characterized by constellations of structural rearrangements, submicroscopic DNA copy number alterations, and sequence mutations, several of which have clear implications for risk stratification and targeted therapeutic intervention. Mutations in genes regulating lymphoid development are a hallmark of ALL, and alterations of the lymphoid transcription factor gene IKZF1 (IKAROS) are associated with a high risk of treatment failure in B-ALL. Approximately 20% of B-ALL cases harbor genetic alterations that activate kinase signaling that may be amenable to treatment with tyrosine kinase inhibitors, including rearrangements of the cytokine receptor gene CRLF2; rearrangements of ABL1, JAK2, and PDGFRB; and mutations of JAK1 and JAK2. Whole-genome sequencing has also identified novel targets of mutation in aggressive T-lineage ALL, including hematopoietic regulators (ETV6 and RUNX1), tyrosine kinases, and epigenetic regulators. Challenges for the future are to comprehensively identify and experimentally validate all genetic alterations driving leukemogenesis and treatment failure in childhood and adult ALL and to implement genomic profiling into the clinical setting to guide risk stratification and targeted therapy.

  2. Molecular and pro-inflammatory genetic profile in gastric carcinomas

    NARCIS (Netherlands)

    Sitarz, R.

    2009-01-01

    Gastric cancer is a result from the combination of environmental factors and an accumulation of specific genetic alterations, and affects mainly the older population. It is known that genetic factors play a more important role in early onset gastric cancers than in conventional gastric cancer

  3. The Effects of Predator Evolution and Genetic Variation on Predator-Prey Population-Level Dynamics.

    Science.gov (United States)

    Cortez, Michael H; Patel, Swati

    2017-07-01

    This paper explores how predator evolution and the magnitude of predator genetic variation alter the population-level dynamics of predator-prey systems. We do this by analyzing a general eco-evolutionary predator-prey model using four methods: Method 1 identifies how eco-evolutionary feedbacks alter system stability in the fast and slow evolution limits; Method 2 identifies how the amount of standing predator genetic variation alters system stability; Method 3 identifies how the phase lags in predator-prey cycles depend on the amount of genetic variation; and Method 4 determines conditions for different cycle shapes in the fast and slow evolution limits using geometric singular perturbation theory. With these four methods, we identify the conditions under which predator evolution alters system stability and shapes of predator-prey cycles, and how those effect depend on the amount of genetic variation in the predator population. We discuss the advantages and disadvantages of each method and the relations between the four methods. This work shows how the four methods can be used in tandem to make general predictions about eco-evolutionary dynamics and feedbacks.

  4. Hydrothermal alteration at Roosevelt Hot Springs KGRA: DDH 1976-1

    Energy Technology Data Exchange (ETDEWEB)

    Bryant, N.L.; Parry, W.T.

    1977-09-01

    Hot waters of the Roosevelt Thermal Area, Utah, have altered granitic rocks and detritus of the Mineral Range pluton, Utah. Alteration and mineral deposition recognized in a 200' drill core from DDH 1-76 is most intense in the upper 100 feet which consists of altered alluvium and opal deposits; the lower 100 feet is weakly altered quartz monzonite. Petrographic, x-ray, and chemical methods were used to characterize systematic changes in chemistry and mineralogy. Comparison of the alteration mineral assemblages with known water chemistry and equilibrium activity diagrams suggests that a simple solution equilibrium model cannot account for the alteration. A model is proposed in which upward moving thermal water supersaturated with respect to quartz and a downward moving cool water undersaturated with respect to quartz produces the observed alteration. An estimate of the heat flow contributions from hydrothermal alteration was made by calculating reaction enthalpies for alteration reactions at each depth. The estimated heat flow varied from .02 HFU (for 200' depth, 400,000 yr duration, and no sulfur oxidation) to 67 HFU (for 5,000' depth, 1,000 yr duration, and all sulfur oxidized from sulfide). Heat flow contributions from hydrothermal alteration are comparable with those from a cooling granitic magma.

  5. Genetic associations with valvular calcification and aortic stenosis

    DEFF Research Database (Denmark)

    Thanassoulis, George; Campbell, Catherine Y; Owens, David S

    2013-01-01

    Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease.......Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease....

  6. Semi-automatic classification of skeletal morphology in genetically altered mice using flat-panel volume computed tomography.

    Directory of Open Access Journals (Sweden)

    Christian Dullin

    2007-07-01

    Full Text Available Rapid progress in exploring the human and mouse genome has resulted in the generation of a multitude of mouse models to study gene functions in their biological context. However, effective screening methods that allow rapid noninvasive phenotyping of transgenic and knockout mice are still lacking. To identify murine models with bone alterations in vivo, we used flat-panel volume computed tomography (fpVCT for high-resolution 3-D imaging and developed an algorithm with a computational intelligence system. First, we tested the accuracy and reliability of this approach by imaging discoidin domain receptor 2- (DDR2- deficient mice, which display distinct skull abnormalities as shown by comparative landmark-based analysis. High-contrast fpVCT data of the skull with 200 microm isotropic resolution and 8-s scan time allowed segmentation and computation of significant shape features as well as visualization of morphological differences. The application of a trained artificial neuronal network to these datasets permitted a semi-automatic and highly accurate phenotype classification of DDR2-deficient compared to C57BL/6 wild-type mice. Even heterozygous DDR2 mice with only subtle phenotypic alterations were correctly determined by fpVCT imaging and identified as a new class. In addition, we successfully applied the algorithm to classify knockout mice lacking the DDR1 gene with no apparent skull deformities. Thus, this new method seems to be a potential tool to identify novel mouse phenotypes with skull changes from transgenic and knockout mice on the basis of random mutagenesis as well as from genetic models. However for this purpose, new neuronal networks have to be created and trained. In summary, the combination of fpVCT images with artificial neuronal networks provides a reliable, novel method for rapid, cost-effective, and noninvasive primary screening tool to detect skeletal phenotypes in mice.

  7. Integrated analysis of HPV-mediated immune alterations in cervical cancer.

    Science.gov (United States)

    Chen, Long; Luan, Shaohong; Xia, Baoguo; Liu, Yansheng; Gao, Yuan; Yu, Hongyan; Mu, Qingling; Zhang, Ping; Zhang, Weina; Zhang, Shengmiao; Wei, Guopeng; Yang, Min; Li, Ke

    2018-05-01

    Human papillomavirus (HPV) infection is the primary cause of cervical cancer. HPV-mediated immune alterations are known to play crucial roles in determining viral persistence and host cell transformation. We sought to thoroughly understand HPV-directed immune alterations in cervical cancer by exploring publically available datasets. 130 HPV positive and 7 HPV negative cervical cancer cases from The Cancer Genome Atlas were compared for differences in gene expression levels and functional enrichment. Analyses for copy number variation (CNV) and genetic mutation were conducted for differentially expressed immune genes. Kaplan-Meier analysis was performed to assess survival and relapse differences across cases with or without alterations of the identified immune signature genes. Genes up-regulated in HPV positive cervical cancer were enriched for various gene ontology terms of immune processes (P=1.05E-14~1.00E-05). Integrated analysis of the differentially expressed immune genes identified 9 genes that displayed either CNV, genetic mutation and/or gene expression changes in at least 10% of the cases of HPV positive cervical cancer. Genomic amplification may cause elevated levels of these genes in some HPV positive cases. Finally, patients with alterations in at least one of the nine signature genes overall had earlier relapse compared to those without any alterations. The altered expression of either TFRC or MMP13 may indicate poor survival for a subset of cervical cancer patients (P=1.07E-07). We identified a novel immune gene signature for HPV positive cervical cancer that is potentially associated with early relapse of cervical cancer. Copyright © 2018. Published by Elsevier Inc.

  8. Genetic and Environmental Contributions to Cranial Capacity in Black and White Adolescents.

    Science.gov (United States)

    Rushton, J. Philippe; Osborne, R. Travis

    1995-01-01

    Data from 236 pairs of black twins and white twins aged 13-17 years were used to examine genetic and environmental factors influencing cranial size, an indirect estimate of brain volume. Genetic factors are required to account for the phenotypic variance in cranial capacity. (SLD)

  9. 76 FR 63279 - Monsanto Co.; Determination of Nonregulated Status for Soybean Genetically Engineered for Insect...

    Science.gov (United States)

    2011-10-12

    ... and products altered or produced through genetic engineering that are plant pests or that there is... regulations in 7 CFR part 340, ``Introduction of Organisms and Products Altered or Produced Through Genetic Engineering Which Are Plant Pests or Which There Is Reason to Believe Are Plant Pests,'' regulate, among other...

  10. Modelling the loss of genetic diversity in vole populations in a spatially and temporally varying environment

    DEFF Research Database (Denmark)

    Topping, Christopher John; Østergaard, Siri; Pertoldi, Cino

    2003-01-01

    conditions, but exclude factors such as animal behaviour, environmental structure, and breeding biology, all of which influence genetic diversity. Most populations are unique in some of these characteristics, and therefore may be unsuitable for the classical approach. Here, an alternative approach using...... to habitat availability and their influence on vole behaviour. Interaction between spatial and temporal dynamics altered the ratio of effective population size to census size. This indicates an altered reproductive potential, crucial in conservation biology applications. However, when the loss......Altering environmental conditions affects the genetic composition of populations via demographic and selective responses by creating of variety of population substructuring types. Classical genetic approaches can predict the genetic composition of populations under long-term or structurally stable...

  11. Phylogeography of Pinus armandii and its relatives: heterogeneous contributions of geography and climate changes to the genetic differentiation and diversification of Chinese white pines.

    Directory of Open Access Journals (Sweden)

    Liu Liu

    Full Text Available Geographic barriers and Quaternary climate changes are two major forces driving the evolution, speciation, and genetic structuring of extant organisms. In this study, we used Pinus armandii and eleven other Asian white pines (subsection Strobus, subgenus Pinus to explore the influences of geographic factors and Pleistocene climatic oscillations on species in South China, a region known to be centers of plant endemism and biodiversity hotspots. Range-wide patterns of genetic variation were investigated using chloroplast and mitochondrial DNA markers, with extensive sampling throughout the entire range of P. armandii. Both cpDNA and mtDNA revealed that P. armandii exhibits high levels of genetic diversity and significant population differentiation. Three geographically distinct subdivisions corresponding to the Qinling-Daba Mountains (QDM, Himalaya-Hengduan Mountains (HHM and Yungui Plateau (YGP were revealed in mainland China by cpDNA. Their break zone was located in the southeastern margin of the Qinghai-Tibetan Plateau (QTP. A series of massive mountains, induced by the QTP uplift, imposed significant geographic barriers to genetic exchange. The disjunct distribution patterns of ancestral haplotypes suggest that a large continuous population of the white pines may have existed from southwest to subtropical China. Repeated range shifts in response to the Pleistocene glaciations led to the isolation and diversification of the subtropical species. The two Taiwanese white pines share a common ancestor with the species in mainland China and obtain their chloroplasts via long-distance pollen dispersal from North Asian pines. Distinct genetic patterns were detected in populations from the Qinling-Daba Mountains, Yungui Plateau, Himalaya-Hengduan Mountains, and subtropical China, indicating significant contributions of geographic factors to the genetic differentiation in white pines. Our study depicts a clear picture of the evolutionary history of

  12. Genetics and epigenetics of obesity

    OpenAIRE

    Herrera, Blanca M.; Keildson, Sarah; Lindgren, Cecilia M.

    2011-01-01

    Obesity results from interactions between environmental and genetic factors. Despite a relatively high heritability of common, non-syndromic obesity (40?70%), the search for genetic variants contributing to susceptibility has been a challenging task. Genome wide association (GWA) studies have dramatically changed the pace of detection of common genetic susceptibility variants. To date, more than 40 genetic variants have been associated with obesity and fat distribution. However, since these v...

  13. Genetics of Vitiligo

    Science.gov (United States)

    Spritz, Richard; Andersen, Genevieve

    2016-01-01

    Synopsis Vitiligo is “complex disorder” (also termed polygenic and multifactorial), reflecting simultaneous contributions of multiple genetic risk factors and environmental triggers. Large-scale genome-wide association studies, principally in European-derived whites and in Chinese, have discovered approximately 50 different genetic loci that contribute to vitiligo risk, some of which also contribute to other autoimmune diseases that are epidemiologically associated with vitiligo. At many of these vitiligo susceptibility loci the corresponding relevant genes have now been identified, and for some of these genes the specific DNA sequence variants that contribute to vitiligo risk are also now known. A large fraction of these genes encode proteins involved in immune regulation, a number of others play roles in cellular apoptosis, and still others are involved in regulating functions of melanocytes. For this last group, there appears to be an opposite relationship between susceptibility to vitiligo and susceptibility to melanoma, suggesting that vitiligo may engage a normal mechanism of immune surveillance for melanoma. While many of the specific biologic mechanisms through which these genetic factors operate to cause vitiligo remain to be elucidated, it is now clear that vitiligo is an autoimmune disease involving a complex relationship between programming and function of the immune system, aspects of the melanocyte autoimmune target, and dysregulation of the immune response. PMID:28317533

  14. An altered redox balance and increased genetic instability characterize primary fibroblasts derived from xeroderma pigmentosum group A patients

    International Nuclear Information System (INIS)

    Parlanti, Eleonora; Pietraforte, Donatella; Iorio, Egidio; Visentin, Sergio; De Nuccio, Chiara; Zijno, Andrea; D’Errico, Mariarosaria; Simonelli, Valeria; Sanchez, Massimo; Fattibene, Paola; Falchi, Mario; Dogliotti, Eugenia

    2015-01-01

    Highlights: • Increased levels and different types of intracellular radical species as well as an altered glutathione redox state characterize XP-A human cells when compared to normal. • A more glycolytic metabolism and higher ATP levels are associated with alteration of mitochondrial morphology and response to mitochondrial toxicants when XPA is defective. • XP-A human cells show increased spontaneous micronuclei frequency, a hallmark of cancer risk. - Abstract: Xeroderma pigmentosum (XP)-A patients are characterized by increased solar skin carcinogenesis and present also neurodegeneration. XPA deficiency is associated with defective nucleotide excision repair (NER) and increased basal levels of oxidatively induced DNA damage. In this study we search for the origin of increased levels of oxidatively generated DNA lesions in XP-A cell genome and then address the question of whether increased oxidative stress might drive genetic instability. We show that XP-A human primary fibroblasts present increased levels and different types of intracellular reactive oxygen species (ROS) as compared to normal fibroblasts, with O_2_−· and H_2O_2 being the major reactive species. Moreover, XP-A cells are characterized by decreased reduced glutathione (GSH)/oxidized glutathione (GSSG) ratios as compared to normal fibroblasts. The significant increase of ROS levels and the alteration of the glutathione redox state following silencing of XPA confirmed the causal relationship between a functional XPA and the control of redox balance. Proton nuclear magnetic resonance ("1H NMR) analysis of the metabolic profile revealed a more glycolytic metabolism and higher ATP levels in XP-A than in normal primary fibroblasts. This perturbation of bioenergetics is associated with different morphology and response of mitochondria to targeted toxicants. In line with cancer susceptibility, XP-A primary fibroblasts showed increased spontaneous micronuclei (MN) frequency, a hallmark of cancer

  15. An altered redox balance and increased genetic instability characterize primary fibroblasts derived from xeroderma pigmentosum group A patients

    Energy Technology Data Exchange (ETDEWEB)

    Parlanti, Eleonora [Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome (Italy); Pietraforte, Donatella; Iorio, Egidio; Visentin, Sergio; De Nuccio, Chiara [Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome (Italy); Zijno, Andrea; D’Errico, Mariarosaria; Simonelli, Valeria [Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome (Italy); Sanchez, Massimo [Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome (Italy); Fattibene, Paola [Department of Technology and Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome (Italy); Falchi, Mario [National AIDS Center, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome (Italy); Dogliotti, Eugenia, E-mail: dogliotti@iss.it [Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome (Italy)

    2015-12-15

    Highlights: • Increased levels and different types of intracellular radical species as well as an altered glutathione redox state characterize XP-A human cells when compared to normal. • A more glycolytic metabolism and higher ATP levels are associated with alteration of mitochondrial morphology and response to mitochondrial toxicants when XPA is defective. • XP-A human cells show increased spontaneous micronuclei frequency, a hallmark of cancer risk. - Abstract: Xeroderma pigmentosum (XP)-A patients are characterized by increased solar skin carcinogenesis and present also neurodegeneration. XPA deficiency is associated with defective nucleotide excision repair (NER) and increased basal levels of oxidatively induced DNA damage. In this study we search for the origin of increased levels of oxidatively generated DNA lesions in XP-A cell genome and then address the question of whether increased oxidative stress might drive genetic instability. We show that XP-A human primary fibroblasts present increased levels and different types of intracellular reactive oxygen species (ROS) as compared to normal fibroblasts, with O{sub 2−}· and H{sub 2}O{sub 2} being the major reactive species. Moreover, XP-A cells are characterized by decreased reduced glutathione (GSH)/oxidized glutathione (GSSG) ratios as compared to normal fibroblasts. The significant increase of ROS levels and the alteration of the glutathione redox state following silencing of XPA confirmed the causal relationship between a functional XPA and the control of redox balance. Proton nuclear magnetic resonance ({sup 1}H NMR) analysis of the metabolic profile revealed a more glycolytic metabolism and higher ATP levels in XP-A than in normal primary fibroblasts. This perturbation of bioenergetics is associated with different morphology and response of mitochondria to targeted toxicants. In line with cancer susceptibility, XP-A primary fibroblasts showed increased spontaneous micronuclei (MN) frequency, a

  16. Medulloblastoma: Molecular Genetics and Animal Models

    Directory of Open Access Journals (Sweden)

    Corey Raffel

    2004-07-01

    Full Text Available Medulloblastoma is a primary brain tumor found in the cerebellum of children. The tumor occurs in association with two inherited cancer syndromes: Turcot syndrome and Gorlin syndrome. Insights into the molecular biology of the tumor have come from looking at alterations in the genes altered in these syndromes, PTC and APC, respectively. Murine models of medulloblastoma have been constructed based on these alterations. Additional murine models that, while mimicking the appearance of the human tumor, seem unrelated to the human tumor's molecular alterations have been made. In this review, the clinical picture, origin, molecular biology, murine models of medulloblastoma are discussed. Although a great deal has been discovered about this tumor, the genetic alterations responsible for tumor development in a majority of patients have yet to be described.

  17. Somatic retrotransposition alters the genetic landscape of the human brain

    NARCIS (Netherlands)

    Baillie, J.K.; Barnett, M.W.; Upton, K.R.; Gerhardt, D.J.; Richmond, T.A.; De Sapio, F.; Brennan, P.; Rizzu, P.; Smith, S.; Fell, M.; Talbot, R.T.; Gustincich, S.; Freeman, T.C.; Mattick, J.S.; Hume, D.A.; Heutink, P.; Carninci, P.; Jeddeloh, J.A.; Faulkner, G.J.

    2011-01-01

    Retrotransposons are mobile genetic elements that use a germline 'copy-and-paste' mechanism to spread throughout metazoan genomes1. At least 50 per cent of the human genome is derived from retrotransposons, with three active families (L1, Alu and SVA) associated with insertional mutagenesis and

  18. Microbiome, inflammation, epigenetic alterations, and mental diseases.

    Science.gov (United States)

    Alam, Reza; Abdolmaleky, Hamid M; Zhou, Jin-Rong

    2017-09-01

    Major mental diseases such as autism, bipolar disorder, schizophrenia, and major depressive disorder are debilitating illnesses with complex etiologies. Recent findings show that the onset and development of these illnesses cannot be well described by the one-gene; one-disease approach. Instead, their clinical presentation is thought to result from the regulative interplay of a large number of genes. Even though the involvement of many genes are likely, up regulating and activation or down regulation and silencing of these genes by the environmental factors play a crucial role in contributing to their pathogenesis. Much of this interplay may be moderated by epigenetic changes. Similar to genetic mutations, epigenetic modifications such as DNA methylation, histone modifications, and RNA interference can influence gene expression and therefore may cause behavioral and neuronal changes observed in mental disorders. Environmental factors such as diet, gut microbiota, and infections have significant role in these epigenetic modifications. Studies show that bioactive nutrients and gut microbiota can alter either DNA methylation and histone signatures through a variety of mechanisms. Indeed, microbes within the human gut may play a significant role in the regulation of various elements of "gut-brain axis," via their influence on inflammatory cytokines and production of antimicrobial peptides that affect the epigenome through their involvement in generating short chain fatty acids, vitamin synthesis, and nutrient absorption. In addition, they may participate in-gut production of many common neurotransmitters. In this review we will consider the potential interactions of diet, gastrointestinal microbiome, inflammation, and epigenetic alterations in psychiatric disorders. © 2017 Wiley Periodicals, Inc.

  19. Genetic Variation in Schizophrenia Liability is Shared With Intellectual Ability and Brain Structure.

    Science.gov (United States)

    Bohlken, Marc M; Brouwer, Rachel M; Mandl, René C W; Kahn, René S; Hulshoff Pol, Hilleke E

    2016-09-01

    Alterations in intellectual ability and brain structure are important genetic markers for schizophrenia liability. How variations in these phenotypes interact with variance in schizophrenia liability due to genetic or environmental factors is an area of active investigation. Studying these genetic markers using a multivariate twin modeling approach can provide novel leads for (genetic) pathways of schizophrenia development. In a sample of 70 twins discordant for schizophrenia and 130 healthy control twins, structural equation modeling was applied to quantify unique contributions of genetic and environmental factors on human brain structure (cortical thickness, cortical surface and global white matter fractional anisotropy [FA]), intellectual ability and schizophrenia liability. In total, up to 28.1% of the genetic variance (22.8% of total variance) in schizophrenia liability was shared with intelligence quotient (IQ), global-FA, cortical thickness, and cortical surface. The strongest contributor was IQ, sharing on average 16.4% of the genetic variance in schizophrenia liability, followed by cortical thickness (6.3%), global-FA (4.7%) and cortical surface (0.5%). Furthermore, we found that up to 57.4% of the variation due to environmental factors (4.6% of total variance) in schizophrenia was shared with IQ (34.2%) and cortical surface (13.4%). Intellectual ability, FA and cortical thickness show significant and independent shared genetic variance with schizophrenia liability. This suggests that measuring brain-imaging phenotypes helps explain genetic variance in schizophrenia liability that is not captured by variation in IQ. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  20. Diagnostic and therapeutic implications of genetic heterogeneity in myeloid neoplasms uncovered by comprehensive mutational analysis

    Directory of Open Access Journals (Sweden)

    Sarah M. Choi

    2017-01-01

    Full Text Available While growing use of comprehensive mutational analysis has led to the discovery of innumerable genetic alterations associated with various myeloid neoplasms, the under-recognized phenomenon of genetic heterogeneity within such neoplasms creates a potential for diagnostic confusion. Here, we describe two cases where expanded mutational testing led to amendment of an initial diagnosis of chronic myelogenous leukemia with subsequent altered treatment of each patient. We demonstrate the power of comprehensive testing in ensuring appropriate classification of genetically heterogeneous neoplasms, and emphasize thoughtful analysis of molecular and genetic data as an essential component of diagnosis and management.

  1. Alteration of plant meristem function by manipulation of the Retinoblastoma-like plant RRB gene

    Science.gov (United States)

    Durfee, Tim [Madison, WI; Feiler, Heidi [Albany, CA; Gruissem, Wilhelm [Forch, CH; Jenkins, Susan [Martinez, CA; Roe, Judith [Manhattan, KS; Zambryski, Patricia [Berkeley, CA

    2007-01-16

    This invention provides methods and compositions for altering the growth, organization, and differentiation of plant tissues. The invention is based on the discovery that, in plants, genetically altering the levels of Retinoblastoma-related gene (RRB) activity produces dramatic effects on the growth, proliferation, organization, and differentiation of plant meristem.

  2. Lower expression of glutamic acid decarboxylase 67 in the prefrontal cortex in schizophrenia: contribution of altered regulation by Zif268.

    Science.gov (United States)

    Kimoto, Sohei; Bazmi, H Holly; Lewis, David A

    2014-09-01

    Cognitive deficits of schizophrenia may be due at least in part to lower expression of the 67-kDa isoform of glutamic acid decarboxylase (GAD67), a key enzyme for GABA synthesis, in the dorsolateral prefrontal cortex of individuals with schizophrenia. However, little is known about the molecular regulation of lower cortical GAD67 levels in schizophrenia. The GAD67 promoter region contains a conserved Zif268 binding site, and Zif268 activation is accompanied by increased GAD67 expression. Thus, altered expression of the immediate early gene Zif268 may contribute to lower levels of GAD67 mRNA in the dorsolateral prefrontal cortex in schizophrenia. The authors used polymerase chain reaction to quantify GAD67 and Zif268 mRNA levels in dorsolateral prefrontal cortex area 9 from 62 matched pairs of schizophrenia and healthy comparison subjects, and in situ hybridization to assess Zif268 expression at laminar and cellular levels of resolution. The effects of potentially confounding variables were assessed in human subjects, and the effects of antipsychotic treatments were tested in antipsychotic-exposed monkeys. The specificity of the Zif268 findings was assessed by quantifying mRNA levels for other immediate early genes. GAD67 and Zif268 mRNA levels were significantly lower and were positively correlated in the schizophrenia subjects. Both Zif268 mRNA-positive neuron density and Zif268 mRNA levels per neuron were significantly lower in the schizophrenia subjects. These findings were robust to the effects of the confounding variables examined and differed from other immediate early genes. Deficient Zif268 mRNA expression may contribute to lower cortical GAD67 levels in schizophrenia, suggesting a potential mechanistic basis for altered cortical GABA synthesis and impaired cognition in schizophrenia.

  3. Genetic parameters of reproductive traits in pigs: a contribution

    Directory of Open Access Journals (Sweden)

    G. Pagnacco

    2011-03-01

    Full Text Available Generally pig breeding efficiency is defined as the number of piglets weaned per sow per year, so in every pig breeding programmes, great emphasis is placed on improving reproductive traits in sow lines and generally, the evaluation of litter size is carried out in most selection planes. Usually, the reproduction breeding goal is to increase the number of piglets born, but this trait, as reported by Hanenberg et al. (2001 gives an undesirable correlation with the number of stillborn piglets. Litter size is the result of a large number of traits as number of total piglets born, number of born alive, stillbirth, weaned survival; as reported by Tummaruk et al. (2000 the variation in these parameters is influenced by genetic value of the sow and by environmental factors, such as management and season. Regarding the genetic influence on the litter size, we know that the breed can influence the number of born, but its interaction with stillbirth is not significant, although Leenhouwers et al. (1999 found an higher stillbirth incidence in purebred than in crossbred litters........

  4. Relative contribution of different altered motor unit control to muscle weakness in stroke: a simulation study

    Science.gov (United States)

    Shin, Henry; Suresh, Nina L.; Zev Rymer, William; Hu, Xiaogang

    2018-02-01

    Objective. Chronic muscle weakness impacts the majority of individuals after a stroke. The origins of this hemiparesis is multifaceted, and an altered spinal control of the motor unit (MU) pool can lead to muscle weakness. However, the relative contribution of different MU recruitment and discharge organization is not well understood. In this study, we sought to examine these different effects by utilizing a MU simulation with variations set to mimic the changes of MU control in stroke. Approach. Using a well-established model of the MU pool, this study quantified the changes in force output caused by changes in MU recruitment range and recruitment order, as well as MU firing rate organization at the population level. We additionally expanded the original model to include a fatigue component, which variably decreased the output force with increasing length of contraction. Differences in the force output at both the peak and fatigued time points across different excitation levels were quantified and compared across different sets of MU parameters. Main results. Across the different simulation parameters, we found that the main driving factor of the reduced force output was due to the compressed range of MU recruitment. Recruitment compression caused a decrease in total force across all excitation levels. Additionally, a compression of the range of MU firing rates also demonstrated a decrease in the force output mainly at the higher excitation levels. Lastly, changes to the recruitment order of MUs appeared to minimally impact the force output. Significance. We found that altered control of MUs alone, as simulated in this study, can lead to a substantial reduction in muscle force generation in stroke survivors. These findings may provide valuable insight for both clinicians and researchers in prescribing and developing different types of therapies for the rehabilitation and restoration of lost strength after stroke.

  5. Parental and offspring contribution of genetic markers of adult blood pressure in early life: The FAMILY study.

    Directory of Open Access Journals (Sweden)

    Sébastien Robiou-du-Pont

    Full Text Available Previous genome wide association studies (GWAS identified associations of multiple common variants with diastolic and systolic blood pressure traits in adults. However, the contribution of these loci to variations of blood pressure in early life is unclear. We assessed the child and parental contributions of 33 GWAS single-nucleotide polymorphisms (SNPs for blood pressure in 1,525 participants (515 children, 406 mothers and 237 fathers of the Family Atherosclerosis Monitoring In early life (FAMILY study followed-up for 5 years. Two genotype scores for systolic (29 SNPs and diastolic (24 SNPs blood pressure were built. Linear mixed-effect regressions showed significant association between rs1378942 in CSK and systolic blood pressure (β = 0.98±0.46, P = 3.4×10-2. The child genotype scores for diastolic and systolic blood pressure were not associated in children. Nominally significant parental genetic effects were found between the SNPs rs11191548 (CYP17A1 (paternal, β = 2.78±1.49, P = 6.1×10-2 for SBP and β = 3.60±1.24, P = 3.7×10-3 for DBP, rs17367504 (MTHFR (paternal, β = 2.42±0.93, P = 9.3×10-3 for SBP and β = 1.89±0.80, P = 1.8×10-2 for DBP and maternal, β = -1.32±0.60, P = 2.9×10-2 and β = -1.97±0.77, P = 1.0×10-2, for SBP and DBP respectively and child blood pressure. Our study supports the view that adult GWAS loci have a limited impact on blood pressure during the five first years of life. The parental genetic effects observed on blood pressure in children may suggest epigenetic mechanisms in the transmission of the risk of hypertension. Further replication is needed to confirm our results.

  6. Contribution of transposable elements in the plant's genome.

    Science.gov (United States)

    Sahebi, Mahbod; Hanafi, Mohamed M; van Wijnen, Andre J; Rice, David; Rafii, M Y; Azizi, Parisa; Osman, Mohamad; Taheri, Sima; Bakar, Mohd Faizal Abu; Isa, Mohd Noor Mat; Noor, Yusuf Muhammad

    2018-07-30

    Plants maintain extensive growth flexibility under different environmental conditions, allowing them to continuously and rapidly adapt to alterations in their environment. A large portion of many plant genomes consists of transposable elements (TEs) that create new genetic variations within plant species. Different types of mutations may be created by TEs in plants. Many TEs can avoid the host's defense mechanisms and survive alterations in transposition activity, internal sequence and target site. Thus, plant genomes are expected to utilize a variety of mechanisms to tolerate TEs that are near or within genes. TEs affect the expression of not only nearby genes but also unlinked inserted genes. TEs can create new promoters, leading to novel expression patterns or alternative coding regions to generate alternate transcripts in plant species. TEs can also provide novel cis-acting regulatory elements that act as enhancers or inserts within original enhancers that are required for transcription. Thus, the regulation of plant gene expression is strongly managed by the insertion of TEs into nearby genes. TEs can also lead to chromatin modifications and thereby affect gene expression in plants. TEs are able to generate new genes and modify existing gene structures by duplicating, mobilizing and recombining gene fragments. They can also facilitate cellular functions by sharing their transposase-coding regions. Hence, TE insertions can not only act as simple mutagens but can also alter the elementary functions of the plant genome. Here, we review recent discoveries concerning the contribution of TEs to gene expression in plant genomes and discuss the different mechanisms by which TEs can affect plant gene expression and reduce host defense mechanisms. Copyright © 2018 Elsevier B.V. All rights reserved.

  7. Imaging and cognitive genetics: the Norwegian Cognitive NeuroGenetics sample.

    Science.gov (United States)

    Espeseth, Thomas; Christoforou, Andrea; Lundervold, Astri J; Steen, Vidar M; Le Hellard, Stephanie; Reinvang, Ivar

    2012-06-01

    Data collection for the Norwegian Cognitive NeuroGenetics sample (NCNG) was initiated in 2003 with a research grant (to Ivar Reinvang) to study cognitive aging, brain function, and genetic risk factors. The original focus was on the effects of aging (from middle age and up) and candidate genes (e.g., APOE, CHRNA4) in cross-sectional and longitudinal designs, with the cognitive and MRI-based data primarily being used for this purpose. However, as the main topic of the project broadened from cognitive aging to imaging and cognitive genetics more generally, the sample size, age range of the participants, and scope of available phenotypes and genotypes, have developed beyond the initial project. In 2009, a genome-wide association (GWA) study was undertaken, and the NCNG proper was established to study the genetics of cognitive and brain function more comprehensively. The NCNG is now controlled by the NCNG Study Group, which consists of the present authors. Prominent features of the NCNG are the adult life-span coverage of healthy participants with high-dimensional imaging, and cognitive data from a genetically homogenous sample. Another unique property is the large-scale (sample size 300-700) use of experimental cognitive tasks focusing on attention and working memory. The NCNG data is now used in numerous ongoing GWA-based studies and has contributed to several international consortia on imaging and cognitive genetics. The objective of the following presentation is to give other researchers the information necessary to evaluate possible contributions from the NCNG to various multi-sample data analyses.

  8. In vitro short-term exposure to air pollution PM{sub 2.5-0.3} induced cell cycle alterations and genetic instability in a human lung cell coculture model

    Energy Technology Data Exchange (ETDEWEB)

    Abbas, Imane [Université de Lille, Lille (France); EA4492-UCEIV, Université du Littoral-Côte d’Opale, Dunkerque (France); Lebanese Atomic Energy Commission – CNRS, Beirut (Lebanon); Verdin, Anthony [Université de Lille, Lille (France); EA4492-UCEIV, Université du Littoral-Côte d’Opale, Dunkerque (France); Escande, Fabienne [Centre de Biologie Pathologie, Centre Hospitalier Régional et Universitaire, Lille (France); Saint-Georges, Françoise [Université de Lille, Lille (France); Groupement Hospitalier de l’Institut Catholique de Lille, Lille (France); Cazier, Fabrice [Université de Lille, Lille (France); Centre Commun de Mesures, Université du Littoral-Côte d’Opale, Dunkerque (France); Mulliez, Philippe [Université de Lille, Lille (France); Groupement Hospitalier de l’Institut Catholique de Lille, Lille (France); Courcot, Dominique; Shirali, Pirouz [Université de Lille, Lille (France); EA4492-UCEIV, Université du Littoral-Côte d’Opale, Dunkerque (France); Gosset, Pierre [Université de Lille, Lille (France); Groupement Hospitalier de l’Institut Catholique de Lille, Lille (France); and others

    2016-05-15

    Although its adverse health effects of air pollution particulate matter (PM2.5) are well-documented and often related to oxidative stress and pro-inflammatory response, recent evidence support the role of the remodeling of the airway epithelium involving the regulation of cell death processes. Hence, the overarching goals of the present study were to use an in vitro coculture model, based on human AM and L132 cells to study the possible alteration of TP53-RB gene signaling pathways (i.e. cell cycle phases, gene expression of TP53, BCL2, BAX, P21, CCND1, and RB, and protein concentrations of their active forms), and genetic instability (i.e. LOH and/or MSI) in the PM{sub 2.5-0.3}-exposed coculture model. PM{sub 2.5-0.3} exposure of human AM from the coculture model induced marked cell cycle alterations after 24 h, as shown by increased numbers of L132 cells in subG1 and S+G2 cell cycle phases, indicating apoptosis and proliferation. Accordingly, activation of the TP53-RB gene signaling pathways after the coculture model exposure to PM{sub 2.5-0.3} was reported in the L132 cells. Exposure of human AM from the coculture model to PM{sub 2.5-0.3} resulted in MS alterations in 3p chromosome multiple critical regions in L132 cell population. Hence, in vitro short-term exposure of the coculture model to PM{sub 2.5-0.3} induced cell cycle alterations relying on the sequential occurrence of molecular abnormalities from TP53-RB gene signaling pathway activation and genetic instability. - Highlights: • Better knowledge on health adverse effects of air pollution PM{sub 2.5}. • Human alveolar macrophage and normal human epithelial lung cell coculture. • Molecular abnormalities from TP53-RB gene signaling pathway. • Loss of heterozygosity and microsatellite instability. • Pathologic changes in morphology and number of cells in relation to airway remodeling.

  9. Genetic manipulation of carotenoid biosynthesis and photoprotection.

    Science.gov (United States)

    Pogson, B J; Rissler, H M

    2000-10-29

    There are multiple complementary and redundant mechanisms to provide protection against photo-oxidative damage, including non-photochemical quenching (NPQ). NPQ dissipates excess excitation energy as heat by using xanthophylls in combination with changes to the light-harvesting complex (LHC) antenna. The xanthophylls are oxygenated carotenoids that in addition to contributing to NPQ can quench singlet or triplet chlorophyll and are necessary for the assembly and stability of the antenna. We have genetically manipulated the expression of the epsilon-cyclase and beta-carotene hydroxylase carotenoid biosynthetic enzymes in Arabidopsis thaliana. The epsilon-cyclase overexpression confirmed that lut2 (lutein deficient) is a mutation in the epsilon-cyclase gene and demonstrated that lutein content can be altered at the level of mRNA abundance with levels ranging from 0 to 180% of wild-type. Also, it is clear that lutein affects the induction and extent of NPQ. The deleterious effects of lutein deficiency on NPQ in Arabidopsis and Chlamydomonas are additive, no matter what the genetic background, whether npq1 (zeaxanthin deficient), aba1 or antisense beta-hydroxylase (xanthophyll cycle pool decreased). Additionally, increasing lutein content causes a marginal, but significant, increase in the rate of induction of NPQ despite a reduction in the xanthophyll cycle pool size.

  10. [Genetic diagnostics of cancer diseases].

    Science.gov (United States)

    Cobilanschi, Joana

    2013-11-27

    Cancer is caused by genetic alterations, but only 10% of the cancer diseases are inherited. The probability for an individual or a family of having inherited cancer, individual consequences of the respective results of genetic testing, as well as its costs and reimbursement by the health insurance must be addressed by expert genetic counseling which at-risk requires special expertise. Identification of a germline mutation which may predispose to a variety of different cancer types allows determination of an individual's specific life time risk in symptomatic as well as in a-symptomatic family members. Identification of the underlying defective gene in heritable cancer disorders also enables optimized preventive and novel therapeutic approaches specifically targeting the underlying molecular pathomechanisms.

  11. Genetic and environmental interactions

    International Nuclear Information System (INIS)

    Strong, L.C.

    1977-01-01

    Cancer may result from a multistage process occurring over a long period of time. Presumably, initial and progressive stages of carcinogenesis may be modified by both genetic and environmental factors. Theoretically, genetic factors may alter susceptibility to the carcinogenic effects of an environmental agent at the initial exposure due to variation in metabolism of the carcinogen or variation in specific target cell response to the active carcinogen, or during the latent phase due to numerous factors that might increase the probability of tumor expression, including growth-promoting factors or immunodeficiency states. Observed genetic and environmental interactions in carcinogenesis include an association between genetically determined inducibility of aryl hydrocarbon hydroxylase and smoking-related cancers, familial susceptibility to certain environmental carcinogens, an association between hereditary disorders of mutagenesis and carcinogenesis, and enhancement of tissue-specific, dominantly inherited tumor predisposition by radiation. Multiple primary tumors occur frequently in genetically predisposed individuals. Specific markers for susceptibility must be sought in order that high-risk individuals be identified and appropriate measures taken for early cancer detection or prevention. Study of the nature of the genetically determined susceptibility and interactions with environmental agents may be revealing in the understanding of carcinogenesis in general

  12. Genetics of uveal melanoma and cutaneous melanoma: two of a kind?

    NARCIS (Netherlands)

    T. van den Bosch (Thomas); E. Kiliç (Emine); A.D.A. Paridaens (Dion); J.E.M.M. de Klein (Annelies)

    2010-01-01

    textabstractCutaneous melanoma and uveal melanoma both derive from melanocytes but show remarkable differences in tumorigenesis, mode of metastatic spread, genetic alterations, and therapeutic response. In this review we discuss the differences and similarities along with the genetic research

  13. Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity

    Science.gov (United States)

    Xu, Ning; Cui, Jinrui; Mengesha, Emebet; Chen, Yii-Der I.; Taylor, Kent D.; Azziz, Ricardo; Goodarzi, Mark O.

    2015-01-01

    Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS. PMID:26305227

  14. Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity.

    Science.gov (United States)

    Jones, Michelle R; Brower, Meredith A; Xu, Ning; Cui, Jinrui; Mengesha, Emebet; Chen, Yii-Der I; Taylor, Kent D; Azziz, Ricardo; Goodarzi, Mark O

    2015-08-01

    Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.

  15. Differential alterations in gene expression profiles contribute to time-dependent effects of nandrolone to prevent denervation atrophy

    Directory of Open Access Journals (Sweden)

    Bauman William A

    2010-10-01

    Full Text Available Abstract Background Anabolic steroids, such as nandrolone, slow muscle atrophy, but the mechanisms responsible for this effect are largely unknown. Their effects on muscle size and gene expression depend upon time, and the cause of muscle atrophy. Administration of nandrolone for 7 days beginning either concomitantly with sciatic nerve transection (7 days or 29 days later (35 days attenuated denervation atrophy at 35 but not 7 days. We reasoned that this model could be used to identify genes that are regulated by nandrolone and slow denervation atrophy, as well as genes that might explain the time-dependence of nandrolone effects on such atrophy. Affymetrix microarrays were used to profile gene expression changes due to nandrolone at 7 and 35 days and to identify major gene expression changes in denervated muscle between 7 and 35 days. Results Nandrolone selectively altered expression of 124 genes at 7 days and 122 genes at 35 days, with only 20 genes being regulated at both time points. Marked differences in biological function of genes regulated by nandrolone at 7 and 35 days were observed. At 35, but not 7 days, nandrolone reduced mRNA and protein levels for FOXO1, the mTOR inhibitor REDD2, and the calcineurin inhibitor RCAN2 and increased those for ApoD. At 35 days, correlations between mRNA levels and the size of denervated muscle were negative for RCAN2, and positive for ApoD. Nandrolone also regulated genes for Wnt signaling molecules. Comparison of gene expression at 7 and 35 days after denervation revealed marked alterations in the expression of 9 transcriptional coregulators, including Ankrd1 and 2, and many transcription factors and kinases. Conclusions Genes regulated in denervated muscle after 7 days administration of nandrolone are almost entirely different at 7 versus 35 days. Alterations in levels of FOXO1, and of genes involved in signaling through calcineurin, mTOR and Wnt may be linked to the favorable action of nandrolone on

  16. Y chromosome microdeletions and alterations of spermatogenesis, patient approach and genetic counseling.

    Science.gov (United States)

    Rives, Nathalie

    2014-05-01

    Infertility affects 15% of couples at reproductive age and human male infertility appears frequently idiopathic. The main genetic causes of spermatogenesis defect responsible for non-obstructive azoospermia and severe oligozoospermia are constitutional chromosomal abnormalities and microdeletions in the azoospermia factor region of the Y chromosome. The improvement of the Yq microdeletion screening method gave new insights in the mechanism responsible for the genesis of Yq microdeletions and for the consequences of the management of male infertility and genetic counselling in case of assisted reproductive technology. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  17. Genetic Alterations in Gastric Cancer Associated with Helicobacter pylori Infection

    Directory of Open Access Journals (Sweden)

    Gonzalo Castillo-Rojas

    2017-05-01

    Full Text Available Gastric cancer is a world health problem and depicts the fourth leading mortality cause from malignancy in Mexico. Causation of gastric cancer is not only due to the combined effects of environmental factors and genetic variants. Recent molecular studies have transgressed a number of genes involved in gastric carcinogenesis. The aim of this review is to understand the recent basics of gene expression in the development of the process of gastric carcinogenesis. Genetic variants, polymorphisms, desoxyribonucleic acid methylation, and genes involved in mediating inflammation have been associated with the development of gastric carcinogenesis. Recently, these genes (interleukin 10, Il-17, mucin 1, β-catenin, CDX1, SMAD4, SERPINE1, hypoxia-inducible factor 1 subunit alpha, GSK3β, CDH17, matrix metalloproteinase 7, RUNX3, RASSF1A, TFF1, HAI-2, and COX-2 have been studied in association with oncogenic activation or inactivation of tumor suppressor genes. All these mechanisms have been investigated to elucidate the process of gastric carcinogenesis, as well as their potential use as biomarkers and/or molecular targets to treatment of disease.

  18. How Darwinian reductionism refutes genetic determinism.

    Science.gov (United States)

    Rosoff, Philip M; Rosenberg, Alex

    2006-03-01

    Genetic determinism labels the morally problematical claim that some socially significant traits, traits we care about, such as sexual orientation, gender roles, violence, alcoholism, mental illness, intelligence, are largely the results of the operation of genes and not much alterable by environment, learning or other human intervention. Genetic determinism does not require that genes literally fix these socially significant traits, but rather that they constrain them within narrow channels beyond human intervention. In this essay we analyze genetic determinism in light of what is now known about the inborn error of metabolism phenylketonuria (PKU), which has for so long been the poster child 'simple' argument in favor of some form of genetic determinism. We demonstrate that this case proves the exact opposite of what it has been proposed to support and provides a strong refutation of genetic determinism in all its guises.

  19. Compensatory mechanisms in genetic models of neurodegeneration: are the mice better than humans?

    Directory of Open Access Journals (Sweden)

    Grzegorz eKreiner

    2015-03-01

    Full Text Available Neurodegenerative diseases are one of the main causes of mental and physical disabilities. Neurodegeneration has been estimated to begin many years before the first clinical symptoms manifest, and even a prompt diagnosis at this stage provides very little advantage for a more effective treatment as the currently available pharmacotherapies are based on disease symptomatology. The etiology of the majority of neurodegenerative diseases remains unknown, and even for those diseases caused by identified genetic mutations, the direct pathways from gene alteration to final cell death have not yet been fully elucidated. Advancements in genetic engineering have provided many transgenic mice that are used as an alternative to pharmacological models of neurodegenerative diseases. Surprisingly, even the models reiterating the same causative mutations do not fully recapitulate the inevitable neuronal loss, and some fail to even show phenotypic alterations, which suggests the possible existence of compensatory mechanisms. A better evaluation of these mechanisms may not only help us to explain why neurodegenerative diseases are mostly late-onset disorders in humans but may also provide new markers and targets for novel strategies designed to extend neuronal function and survival. The aim of this mini-review is to draw attention to this under-explored field in which investigations may reasonably contribute to unveiling hidden reserves in the organism.

  20. Genetic Influences on Adolescent Eating Habits

    Science.gov (United States)

    Beaver, Kevin M.; Flores, Tori; Boutwell, Brian B.; Gibson, Chris L.

    2012-01-01

    Behavioral genetic research shows that variation in eating habits and food consumption is due to genetic and environmental factors. The current study extends this line of research by examining the genetic contribution to adolescent eating habits. Analysis of sibling pairs drawn from the National Longitudinal Study of Adolescent Health (Add Health)…

  1. A Genetic Epidemiological Study of Behavioral Traits

    NARCIS (Netherlands)

    N. Amin (Najaf)

    2011-01-01

    textabstractHuman behavioural genetics aims to unravel the genetic and environmental contributions to variations in human behaviour. Behaviour is a complex trait, involving multiple genes that are affected by a variety of other factors. Genetic epidemiological research of behaviour goes back to

  2. Genetic variation within the TRPM5 locus associates with prediabetic phenotypes in subjects at increased risk for type 2 diabetes

    DEFF Research Database (Denmark)

    Ketterer, Caroline; Müssig, Karsten; Heni, Martin

    2011-01-01

    The functional knockout of the calcium-sensitive, nonselective cation channel TRPM5 alters glucose-induced insulin secretion and glucose tolerance. We hypothesized that genetic variation in the TRPM5 gene may contribute to prediabetic phenotypes, including pancreatic ß-cell dysfunction. We...... glucagon-like peptide-1 levels at 30 minutes during the OGTT compared with major allele homozygotes (P = .0124), whereas in male subjects, no significant differences were found (P = .3). In our German population, the common TRPM5 variants are likely to be associated with prediabetic phenotypes...

  3. A new definition of Genetic Counseling: National Society of Genetic Counselors' Task Force report.

    Science.gov (United States)

    Resta, Robert; Biesecker, Barbara Bowles; Bennett, Robin L; Blum, Sandra; Hahn, Susan Estabrooks; Strecker, Michelle N; Williams, Janet L

    2006-04-01

    The Genetic Counseling Definition Task Force of the National Society of Genetic Counselors (NSGC) developed the following definition of genetic counseling that was approved by the NSGC Board of Directors: Genetic counseling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. This process integrates the following: Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence. Education about inheritance, testing, management, prevention, resources and research. Counseling to promote informed choices and adaptation to the risk or condition. The definition was approved after a peer review process with input from the NSGC membership, genetic professional organizations, the NSGC legal counsel, and leaders of several national genetic advocacy groups.

  4. Population genetics of non-genetic traits: Evolutionary roles of stochasticity in gene expression

    KAUST Repository

    Mineta, Katsuhiko

    2015-05-01

    The role of stochasticity in evolutionary genetics has long been debated. To date, however, the potential roles of non-genetic traits in evolutionary processes have been largely neglected. In molecular biology, growing evidence suggests that stochasticity in gene expression (SGE) is common and that SGE has major impacts on phenotypes and fitness. Here, we provide a general overview of the potential effects of SGE on population genetic parameters, arguing that SGE can indeed have a profound effect on evolutionary processes. Our analyses suggest that SGE potentially alters the fate of mutations by influencing effective population size and fixation probability. In addition, a genetic control of SGE magnitude could evolve under certain conditions, if the fitness of the less-fit individual increases due to SGE and environmental fluctuation. Although empirical evidence for our arguments is yet to come, methodological developments for precisely measuring SGE in living organisms will further advance our understanding of SGE-driven evolution.

  5. Population genetics of non-genetic traits: Evolutionary roles of stochasticity in gene expression

    KAUST Repository

    Mineta, Katsuhiko; Matsumoto, Tomotaka; Osada, Naoki; Araki, Hitoshi

    2015-01-01

    The role of stochasticity in evolutionary genetics has long been debated. To date, however, the potential roles of non-genetic traits in evolutionary processes have been largely neglected. In molecular biology, growing evidence suggests that stochasticity in gene expression (SGE) is common and that SGE has major impacts on phenotypes and fitness. Here, we provide a general overview of the potential effects of SGE on population genetic parameters, arguing that SGE can indeed have a profound effect on evolutionary processes. Our analyses suggest that SGE potentially alters the fate of mutations by influencing effective population size and fixation probability. In addition, a genetic control of SGE magnitude could evolve under certain conditions, if the fitness of the less-fit individual increases due to SGE and environmental fluctuation. Although empirical evidence for our arguments is yet to come, methodological developments for precisely measuring SGE in living organisms will further advance our understanding of SGE-driven evolution.

  6. Evaluation of genetic alteration induced by radon gas using the micronucleus test (Tradescantia sp. clone KU-20)

    International Nuclear Information System (INIS)

    Bruschi, Armando L.; Azevedo, Heliana de; Macacini, Jose F.; Roque, Claudio V.

    2011-01-01

    The first observations over the existence of radon gas (Rn), initially known as 'thorium emanation', were carried out between the end of 19 th and beginning of 20 th centuries. A result of uranium-238 (U 238 ) radioactive decay, radon is a tasteless, odorless and colorless gas under room temperature, with a 3.825-day half life and particle α emission in its decay, and as final product of its disintegration, the stable lead-206 isotope (Pb 206 ). Being it is the gas with the highest density known, closed and poor ventilated environments are favorable to its accumulation, with its inhalation being the highest health risk. The use of vegetal bioindicators has shown to be excellent on the monitoring of air quality and on mutagenic potential of various pollutants contained in the atmosphere. Within this context, the objective of this study was to evaluate the micronucleus test application potential utilizing the Tradescantia sp. clone KU-20, in order to evaluate genetic alterations induced by radon gas. Stems of Tradescantia sp. clone KU-20, previously immerse in Hoagland solution, were introduced in a radon detection equipment's calibration chamber (Alphaguard), containing radium salt. Afterwards, the accommodated stems were exposed to radon gas (the average radon concentration was 7.639 KBq/m3) for 24 hours. The results demonstrated an increase on micronucleus formation (39.23 + 2.143 MCN/100 tetrads) in stems exposed in relation to the negative control (18.00 + 1.396 MCN/100 tetrads). The difference between the values indicated a significant increase on micronucleus frequency in the inflorescences subjected to radon gas. The presented results demonstrated the micronucleus test application potential using Tradescantia clone KU-20 to evaluate genetic effects induced by radon gas. (author)

  7. Periodontal disease associated to systemic genetic disorders.

    Science.gov (United States)

    Nualart Grollmus, Zacy Carola; Morales Chávez, Mariana Carolina; Silvestre Donat, Francisco Javier

    2007-05-01

    A number of systemic disorders increase patient susceptibility to periodontal disease, which moreover evolves more rapidly and more aggressively. The underlying factors are mainly related to alterations in immune, endocrine and connective tissue status. These alterations are associated with different pathologies and syndromes that generate periodontal disease either as a primary manifestation or by aggravating a pre-existing condition attributable to local factors. This is where the role of bacterial plaque is subject to debate. In the presence of qualitative or quantitative cellular immune alterations, periodontal disease may manifest early on a severe localized or generalized basis--in some cases related to the presence of plaque and/or specific bacteria (severe congenital neutropenia or infantile genetic agranulocytosis, Chediak-Higiashi syndrome, Down syndrome and Papillon-Lefévre syndrome). In the presence of humoral immune alterations, periodontal damage may result indirectly as a consequence of alterations in other systems. In connective tissue disorders, bacterial plaque and alterations of the periodontal tissues increase patient susceptibility to gingival inflammation and alveolar resorption (Marfan syndrome and Ehler-Danlos syndrome). The management of periodontal disease focuses on the control of infection and bacterial plaque by means of mechanical and chemical methods. Periodontal surgery and even extraction of the most seriously affected teeth have also been suggested. There are variable degrees of consensus regarding the background systemic disorder, as in the case of Chediak-Higiashi syndrome, where antibiotic treatment proves ineffective; in severe congenital neutropenia or infantile genetic agranulocytosis, where antibiotic prophylaxis is suggested; and in Papillon-Lefévre syndrome, where an established treatment protocol is available.

  8. Producing genetic knowledge and citizenship through the Internet: mothers, pediatric genetics, and cybermedicine.

    Science.gov (United States)

    Schaffer, Rebecca; Kuczynski, Kristine; Skinner, Debra

    2008-01-01

    This article analyses data from a longitudinal, ethnographic study conducted in the United States to examine how 100 mothers of children with genetic disorders used the Internet to interpret, produce, and circulate genetic knowledge pertaining to their child's condition. We describe how they came to value their own experiential knowledge, helped shift the boundaries of what counts as authoritative knowledge, and assumed the role of genetic citizen, fighting for specific rights while shouldering and contesting concomitant duties and obligations. This exploration of e-health use contributes to our understanding of the social practices and power relations that cut across online and off-line worlds to co-produce genetic knowledge and genetic citizenship in multiple contexts.

  9. Molecular-genetic analysis of two cases with retinoblastoma ...

    Indian Academy of Sciences (India)

    Unknown

    Effective counselling and management of retinoblastoma families using genetic information is presently practised in many parts of ... to chromosomal deletion, single-nucleotide alteration, microdeletion, loss ... informed consent of the parent.

  10. Genetic Alterations in Essential Thrombocythemia Progression to Acute Myeloid Leukemia: A Case Series and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Jackline P. Ayres-Silva

    2018-02-01

    Full Text Available The genetic events associated with transformation of myeloproliferative neoplasms (MPNs to secondary acute myeloid leukemia (sAML, particularly in the subgroup of essential thrombocythemia (ET patients, remain incompletely understood. Deep studies using high-throughput methods might lead to a better understanding of genetic landscape of ET patients who transformed to sAML. We performed array-based comparative genomic hybridization (aCGH and whole exome sequencing (WES to analyze paired samples from ET and sAML phases. We investigated five patients with previous history of MPN, which four had initial diagnosis of ET (one case harboring JAK2 p.Val617Phe and the remaining three CALR type II p.Lys385fs*47, and one was diagnosed with MPN/myelodysplastic syndrome with thrombocytosis (SF3B1 p.Lys700Glu. All were homogeneously treated with hydroxyurea, but subsequently transformed to sAML (mean time of 6 years/median of 4 years to transformation. Two of them have chromosomal abnormalities, and both acquire 2p gain and 5q deletion at sAML stage. The molecular mechanisms associated with leukemic progression in MPN patients are not clear. Our WES data showed TP53 alterations recurrently observed as mutations (missense and frameshift and monoallelic loss. On the other hand, aCGH showed novel chromosome abnormalities (+2p and del5q potentially associated with disease progression. The results reported here add valuable information to the still fragmented molecular basis of ET to sAML evolution. Further studies are necessary to identify minimal deleted/amplified region and genes relevant to sAML transformation.

  11. Review: Biological imprinting: Some genetic considerations | Saad ...

    African Journals Online (AJOL)

    ... as for interpretation of possible mechanisms implicated in its occurrence. Keywords: Genetic imprinting; Mutations; Re-sense mutation; Epigenetic alterations; DNA methylation/demethylation; Parthenogenesis; Position-effect variegation; Post-fertilization genomic imprinting; microRNA; Chromatin modifications; Pyknons ...

  12. Genetic and environmental factors affecting birth size variation

    DEFF Research Database (Denmark)

    Yokoyama, Yoshie; Jelenkovic, Aline; Hur, Yoon-Mi

    2018-01-01

    Background: The genetic architecture of birth size may differ geographically and over time. We examined differences in the genetic and environmental contributions to birthweight, length and ponderal index (PI) across geographical-cultural regions (Europe, North America and Australia, and East Asia......) and across birth cohorts, and how gestational age modifies these effects. Methods: Data from 26 twin cohorts in 16 countries including 57 613 monozygotic and dizygotic twin pairs were pooled. Genetic and environmental variations of birth size were estimated using genetic structural equation modelling....... Results: The variance of birthweight and length was predominantly explained by shared environmental factors, whereas the variance of PI was explained both by shared and unique environmental factors. Genetic variance contributing to birth size was small. Adjusting for gestational age decreased...

  13. High salt diet induces metabolic alterations in multiple biological processes of Dahl salt-sensitive rats.

    Science.gov (United States)

    Wang, Yanjun; Liu, Xiangyang; Zhang, Chen; Wang, Zhengjun

    2018-06-01

    High salt induced renal disease is a condition resulting from the interactions of genetic and dietary factors causing multiple complications. To understand the metabolic alterations associated with renal disease, we comprehensively analyzed the metabonomic changes induced by high salt intake in Dahl salt-sensitive (SS) rats using GC-MS technology and biochemical analyses. Physiological features, serum chemistry, and histopathological data were obtained as complementary information. Our results showed that high salt (HS) intake for 16 weeks caused significant metabolic alterations in both the renal medulla and cortex involving a variety pathways involved in the metabolism of organic acids, amino acids, fatty acids, and purines. In addition, HS enhanced glycolysis (hexokinase, phosphofructokinase and pyruvate kinase) and amino acid metabolism and suppressed the TCA (citrate synthase and aconitase) cycle. Finally, HS intake caused up-regulation of the pentose phosphate pathway (glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase), the ratio of NADPH/NADP + , NADPH oxidase activity and ROS production, suggesting that increased oxidative stress was associated with an altered PPP pathway. The metabolic pathways identified may serve as potential targets for the treatment of renal damage. Our findings provide comprehensive biochemical details about the metabolic responses to a high salt diet, which may contribute to the understanding of renal disease and salt-induced hypertension in SS rats. Copyright © 2018. Published by Elsevier Inc.

  14. Genetic and molecular analysis of radon-induced rat lung tumours

    International Nuclear Information System (INIS)

    Guilly, M.N.; Joubert, Ch.; Levalois, C.; Dano, L.; Chevillard, S.

    2002-01-01

    We have a model of radon-induced rat lung tumours, which allow us to analyse the cytogenetic and molecular alterations of the tumours. The aim is to better understand the mechanisms of radio-induced carcinogenesis and to define if it exists a specificity of radio-induced genetic alterations as compared to the genetic alterations found in the sporadic tumours. We have started our analysis by developing global cytogenetic and molecular approaches. We have shown that some alterations are recurrent. The genes that are potentially involved are the oncogene MET and the tumour suppressor Bene p16, which are also frequently altered in human lung tumours. Simultaneously, we have focussed our analysis by targeting the search of mutation in the tumour suppressor gene TP3. We have found that 8 of 39 tumours were mutated by deletion in the coding sequence of TP53. This high frequency of deletion, which is not observed in the human p53 mutation database could constitute a signature of radio-induced alterations. On this assumption, this type of alteration should not be only found on TP53 Bene but also in other suppressor genes which are inactivated by a mutation such as p16 for example. The work we are carrying out on radio-induced tumours among humans and animals is directed to this end. (author)

  15. How spatio-temporal habitat connectivity affects amphibian genetic structure.

    Science.gov (United States)

    Watts, Alexander G; Schlichting, Peter E; Billerman, Shawn M; Jesmer, Brett R; Micheletti, Steven; Fortin, Marie-Josée; Funk, W Chris; Hapeman, Paul; Muths, Erin; Murphy, Melanie A

    2015-01-01

    Heterogeneous landscapes and fluctuating environmental conditions can affect species dispersal, population genetics, and genetic structure, yet understanding how biotic and abiotic factors affect population dynamics in a fluctuating environment is critical for species management. We evaluated how spatio-temporal habitat connectivity influences dispersal and genetic structure in a population of boreal chorus frogs (Pseudacris maculata) using a landscape genetics approach. We developed gravity models to assess the contribution of various factors to the observed genetic distance as a measure of functional connectivity. We selected (a) wetland (within-site) and (b) landscape matrix (between-site) characteristics; and (c) wetland connectivity metrics using a unique methodology. Specifically, we developed three networks that quantify wetland connectivity based on: (i) P. maculata dispersal ability, (ii) temporal variation in wetland quality, and (iii) contribution of wetland stepping-stones to frog dispersal. We examined 18 wetlands in Colorado, and quantified 12 microsatellite loci from 322 individual frogs. We found that genetic connectivity was related to topographic complexity, within- and between-wetland differences in moisture, and wetland functional connectivity as contributed by stepping-stone wetlands. Our results highlight the role that dynamic environmental factors have on dispersal-limited species and illustrate how complex asynchronous interactions contribute to the structure of spatially-explicit metapopulations.

  16. How spatio-temporal habitat connectivity affects amphibian genetic structure

    Science.gov (United States)

    Watts, Alexander G.; Schlichting, P; Billerman, S; Jesmer, B; Micheletti, S; Fortin, M.-J.; Funk, W.C.; Hapeman, P; Muths, Erin L.; Murphy, M.A.

    2015-01-01

    Heterogeneous landscapes and fluctuating environmental conditions can affect species dispersal, population genetics, and genetic structure, yet understanding how biotic and abiotic factors affect population dynamics in a fluctuating environment is critical for species management. We evaluated how spatio-temporal habitat connectivity influences dispersal and genetic structure in a population of boreal chorus frogs (Pseudacris maculata) using a landscape genetics approach. We developed gravity models to assess the contribution of various factors to the observed genetic distance as a measure of functional connectivity. We selected (a) wetland (within-site) and (b) landscape matrix (between-site) characteristics; and (c) wetland connectivity metrics using a unique methodology. Specifically, we developed three networks that quantify wetland connectivity based on: (i) P. maculata dispersal ability, (ii) temporal variation in wetland quality, and (iii) contribution of wetland stepping-stones to frog dispersal. We examined 18 wetlands in Colorado, and quantified 12 microsatellite loci from 322 individual frogs. We found that genetic connectivity was related to topographic complexity, within- and between-wetland differences in moisture, and wetland functional connectivity as contributed by stepping-stone wetlands. Our results highlight the role that dynamic environmental factors have on dispersal-limited species and illustrate how complex asynchronous interactions contribute to the structure of spatially-explicit metapopulations.

  17. Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity.

    Directory of Open Access Journals (Sweden)

    Michelle R Jones

    2015-08-01

    Full Text Available Genome wide association studies (GWAS have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS, a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.

  18. Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons

    DEFF Research Database (Denmark)

    Rotger, Margalida; Glass, Tracy R; Junier, Thomas

    2013-01-01

    in the setting of HIV infection. METHODS: In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies......, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. RESULTS: A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9 × 10(-4)). In the final multivariable model, participants...

  19. Alterations in the α2 δ ligand, thrombospondin-1, in a rat model of spontaneous absence epilepsy and in patients with idiopathic/genetic generalized epilepsies.

    Science.gov (United States)

    Santolini, Ines; Celli, Roberta; Cannella, Milena; Imbriglio, Tiziana; Guiducci, Michela; Parisi, Pasquale; Schubert, Julian; Iacomino, Michele; Zara, Federico; Lerche, Holger; Moyanova, Slavianka; Ngomba, Richard Teke; van Luijtelaar, Gilles; Battaglia, Giuseppe; Bruno, Valeria; Striano, Pasquale; Nicoletti, Ferdinando

    2017-11-01

    Thrombospondins, which are known to interact with the α 2 δ subunit of voltage-sensitive calcium channels to stimulate the formation of excitatory synapses, have recently been implicated in the process of epileptogenesis. No studies have been so far performed on thrombospondins in models of absence epilepsy. We examined whether expression of the gene encoding for thrombospondin-1 was altered in the brain of WAG/Rij rats, which model absence epilepsy in humans. In addition, we examined the frequency of genetic variants of THBS1 in a large cohort of children affected by idiopathic/genetic generalized epilepsies (IGE/GGEs). We measured the transcripts of thrombospondin-1 and α 2 δ subunit, and protein levels of α 2 δ, Rab3A, and the vesicular glutamate transporter, VGLUT1, in the somatosensory cortex and ventrobasal thalamus of presymptomatic and symptomatic WAG/Rij rats and in two control strains by real-time polymerase chain reaction (PCR) and immunoblotting. We examined the genetic variants of THBS1 and CACNA2D1 in two independent cohorts of patients affected by IGE/GGE recruited through the Genetic Commission of the Italian League Against Epilepsy (LICE) and the EuroEPINOMICS-CoGIE Consortium. Thrombospondin-1 messenger RNA (mRNA) levels were largely reduced in the ventrobasal thalamus of both presymptomatic and symptomatic WAG/Rij rats, whereas levels in the somatosensory cortex were unchanged. VGLUT1 protein levels were also reduced in the ventrobasal thalamus of WAG/Rij rats. Genetic variants of THBS1 were significantly more frequent in patients affected by IGE/GGE than in nonepileptic controls, whereas the frequency of CACNA2D1 was unchanged. These findings suggest that thrombospondin-1 may have a role in the pathogenesis of IGE/GGEs. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

  20. Chapter VIII. Contributions of propagation techniques and genetic modification to breeding - genetic engineering for disease resistance

    Science.gov (United States)

    Genetic engineering offers an opportunity to develop flower bulb crops with resistance to fungal, viral, and bacterial pathogens. Several of the flower bulb crops, Lilium spp., Gladiolus, Zantedeschia, Muscari, Hyacinthus, Narcissus, Ornithogalum, Iris, and Alstroemeria, have been transformed with t...

  1. Genetic and Environmental Contributions to Self-Reported Thoughts of Self-Harm and Suicide

    NARCIS (Netherlands)

    Althoff, R.R.; Hudziak, J.J.; Willemsen, G.; Hudziak, V.; Bartels, M.; Boomsma, D.I.

    2012-01-01

    Thoughts of self-harm and suicidal behavior are thought to be influenced by both genetics and environment. Molecular genetic studies are beginning to address the question of which genes may be involved and whether different genes may be expressed in men and women. We examined thoughts of self-harm

  2. Genetic influences on chronic obstructive pulmonary disease - a twin study

    DEFF Research Database (Denmark)

    Sylvan Ingebrigtsen, Truls; Thomsen, Simon Francis; Vestbo, Jørgen

    2010-01-01

    Genes that contribute to the risk of developing Chronic Obstructive Pulmonary Disease (COPD) have been identified, but an attempt to accurately quantify the total genetic contribution to COPD has to our knowledge never been conducted.......Genes that contribute to the risk of developing Chronic Obstructive Pulmonary Disease (COPD) have been identified, but an attempt to accurately quantify the total genetic contribution to COPD has to our knowledge never been conducted....

  3. Metabolic development of the porcine placenta in response to alterations in maternal or fetal homeostasis

    International Nuclear Information System (INIS)

    Namsey, T.G.; kasser, T.R.; Hausman, G.J.; Martin, R.J.

    1986-01-01

    Porcine placenta has been utilized as a model for elucidating contributions of both fetal and maternal tissues to metabolic activity of the placenta in response to a variety of stresses. Alloxan diabetes, food restriction and genetic obesity all produced alterations in placental metablolism with differences in responses of fetal and maternal placentas. Further analysis of nutrient untilization by the placenta produced dramatic differences in the partitioning of substrates by fetal and maternal tissues during placental development. Metabolic activity of maternal tissue contributed to overall placental metabolic activity to a greater degree than fetal tissue. However, experiments with in utero fetal decapitation indicated that some of differences between fetal and maternal placental metabolic activity may be due to the influence of fetal regulatory mechanisms. Maternal endometrium plays a critical role in metabolic response of uteroplacenta and thus availability of nutrients to the fetus and fetal placenta. Differences in metabolic development of fetal and maternal tissues suggested that regulation of placental metabolism may originate from fetal as well as maternal sources

  4. Experiencing the genetic body: parents' encounters with pediatric clinical genetics.

    Science.gov (United States)

    Raspberry, Kelly; Skinner, Debra

    2007-01-01

    Because of advancements in genetic research and technologies, the clinical practice of genetics is becoming a prevalent component of biomedicine. As the genetic basis for more and more diseases are found, it is possible that ways of experiencing health, illness, identity, kin relations, and the body are becoming geneticized, or understood within a genetic model of disease. Yet, other models and relations that go beyond genetic explanations also shape interpretations of health and disease. This article explores how one group of individuals for whom genetic disorder is highly relevant formulates their views of the body in light of genetic knowledge. Using data from an ethnographic study of 106 parents or potential parents of children with known or suspected genetic disorders who were referred to a pediatric genetic counseling and evaluation clinic in the southeastern United States, we find that these parents do, to some degree, perceive of their children's disorders in terms of a genetic body that encompasses two principal qualities: a sense of predetermined health and illness and an awareness of a profound historicity that reaches into the past and extends into the present and future. They experience this genetic body as both fixed and historical, but they also express ideas of a genetic body made less deterministic by their own efforts and future possibilities. This account of parents' experiences with genetics and clinical practice contributes to a growing body of work on the ways in which genetic information and technologies are transforming popular and medical notions of the body, and with it, health, illness, kinship relations, and personal and social identities.

  5. Genetic variation in ABC transporter A1 contributes to HDL cholesterol in the general population

    DEFF Research Database (Denmark)

    Frikke-Schmidt, Ruth; Nordestgaard, Børge G; Jensen, Gorm B

    2004-01-01

    Homozygosity for mutations in ABC transporter A1 (ABCA1) causes Tangier disease, a rare HDL-deficiency syndrome. Whether heterozygosity for genetic variation in ABCA1 also contributes to HDL cholesterol (HDL-C) levels in the general population is presently unclear. We determined whether mutations...... or single-nucleotide polymorphisms (SNPs) in ABCA1 were overrepresented in individuals with the lowest 1% (n=95) or highest 1% (n=95) HDL-C levels in the general population by screening the core promoter and coding region of ABCA1. For all nonsynonymous SNPs identified, we determined the effect of genotype...... on lipid traits in 9,259 individuals from the general population. Heterozygosity for ABCA1 mutations was identified in 10% of individuals with low HDL-C only. Three of 6 nonsynonymous SNPs (V771M, V825I, and R1587K) were associated with increases or decreases in HDL-C in women in the general population...

  6. Highly sensitivity adhesion molecules detection in hereditary haemochromatosis patients reveals altered expression.

    LENUS (Irish Health Repository)

    Norris, S

    2012-02-01

    Several abnormalities in the immune status of patients with hereditary haemochromatosis (HH) have been reported, suggesting an imbalance in their immune function. This may include persistent production of, or exposure to, altered immune signalling contributing to the pathogenesis of this disorder. Adhesion molecules L-, E- and P-Selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) are some of the major regulators of the immune processes and altered levels of these proteins have been found in pathological states including cardiovascular diseases, arthritis and liver cancer. The aim of this study was to assess L-, E- and P-Selectin, ICAM-1 and VCAM-1 expression in patients with HH and correlate these results with HFE mutation status and iron indexes. A total of 139 subjects were diagnosed with HH (C282Y homozygotes = 87, C282Y\\/H63D = 26 heterozygotes, H63D homozygotes = 26), 27 healthy control subjects with no HFE mutation (N\\/N), 18 normal subjects heterozygous for the H63D mutation served as age-sex-matched controls. We observed a significant decrease in L-selectin (P = 0.0002) and increased E-selectin and ICAM-1 (P = 0.0006 and P = 0.0059) expression in HH patients compared with healthy controls. This study observes for the first time that an altered adhesion molecules profile occurs in patients with HH that is associated with specific HFE genetic component for iron overload, suggesting that differential expression of adhesion molecules may play a role in the pathogenesis of HH.

  7. Short communication: Genetic lag represents commercial herd genetic merit more accurately than the 4-path selection model.

    Science.gov (United States)

    Dechow, C D; Rogers, G W

    2018-05-01

    Expectation of genetic merit in commercial dairy herds is routinely estimated using a 4-path genetic selection model that was derived for a closed population, but commercial herds using artificial insemination sires are not closed. The 4-path model also predicts a higher rate of genetic progress in elite herds that provide artificial insemination sires than in commercial herds that use such sires, which counters other theoretical assumptions and observations of realized genetic responses. The aim of this work is to clarify whether genetic merit in commercial herds is more accurately reflected under the assumptions of the 4-path genetic response formula or by a genetic lag formula. We demonstrate by tracing the transmission of genetic merit from parents to offspring that the rate of genetic progress in commercial dairy farms is expected to be the same as that in the genetic nucleus. The lag in genetic merit between the nucleus and commercial farms is a function of sire and dam generation interval, the rate of genetic progress in elite artificial insemination herds, and genetic merit of sires and dams. To predict how strategies such as the use of young versus daughter-proven sires, culling heifers following genomic testing, or selective use of sexed semen will alter genetic merit in commercial herds, genetic merit expectations for commercial herds should be modeled using genetic lag expectations. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  8. ARID1B alterations identify aggressive tumors in neuroblastoma.

    Science.gov (United States)

    Lee, Soo Hyun; Kim, Jung-Sun; Zheng, Siyuan; Huse, Jason T; Bae, Joon Seol; Lee, Ji Won; Yoo, Keon Hee; Koo, Hong Hoe; Kyung, Sungkyu; Park, Woong-Yang; Sung, Ki W

    2017-07-11

    Targeted panel sequencing was performed to determine molecular targets and biomarkers in 72 children with neuroblastoma. Frequent genetic alterations were detected in ALK (16.7%), BRCA1 (13.9%), ATM (12.5%), and PTCH1 (11.1%) in an 83-gene panel. Molecular targets for targeted therapy were identified in 16 of 72 patients (22.2%). Two-thirds of ALK mutations were known to increase sensitivity to ALK inhibitors. Sequence alterations in ARID1B were identified in 5 of 72 patients (6.9%). Four of five ARID1B alterations were detected in tumors of high-risk patients. Two of five patients with ARID1B alterations died of disease progression. Relapse-free survival was lower in patients with ARID1B alterations than in those without (p = 0.01). In analysis confined to high-risk patients, 3-year overall survival was lower in patients with an ARID1B alteration (33.3 ± 27.2%) or MYCN amplification (30.0 ± 23.9%) than in those with neither ARID1B alteration nor MYCN amplification (90.5 ± 6.4%, p = 0.05). These results provide possibilities for targeted therapy and a new biomarker identifying a subgroup of neuroblastoma patients with poor prognosis.

  9. Genetic variability of six French meat sheep breeds in relation to their genetic management.

    Science.gov (United States)

    Huby, Marie; Griffon, Laurent; Moureaux, Sophie; De Rochambeau, Hubert; Danchin-Burge, Coralie; Verrier, Etienne

    2003-01-01

    Some demographic parameters, the genetic structure and the evolution of the genetic variability of six French meat sheep breeds were analysed in relation with their management. Four of these breeds are submitted to more or less intense selection: the Berrichon du Cher (BCH), Blanc du Massif Central (BMC), Charollais (CHA) and Limousin (LIM); the other two breeds are under conservation: the Roussin de La Hague (RLH) and Solognot (SOL). Genealogical data of the recorded animals born from 1970 to 2000 and of their known ancestors were used. The most balanced contributions of the different flocks to the sire-daughter path was found in the SOL. In the BCH, a single flock provided 43% of the sire-AI sire path, whereas the contributions of the flocks were more balanced in the BMC and LIM (the only other breeds where AI is used to a substantial amount). The distribution of the expected genetic contribution of the founder animals was found to be unbalanced, especially in the BCH and LIM. The effective numbers of ancestors (founders or not) for the ewes born from 1996 to 2000 were equal to 35 (BCH), 144 (BMC), 112 (CHA), 69 (LIM), 40 (RLH) and 49 (SOL). Inbreeding was not analysed in the BMC, due to incomplete pedigree information. From 1980 on, the rates of inbreeding, in percentage points per year, were +0.112 (BCH), +0.045 (CHA), +0.036 (LIM), +0.098 (RLH) and +0.062 (SOL). The implications of the observed trends on genetic variability are discussed in relation to the genetic management of each breed. The need for a larger selection basis in the BCH, the efficiency of the rules applied in the SOL to preserve the genetic variability and the need for a more collective organisation in the CHA and RLH are outlined.

  10. Genetic variability of six French meat sheep breeds in relation to their genetic management

    Directory of Open Access Journals (Sweden)

    Coralie Danchin-Burge

    2003-11-01

    Full Text Available Abstract Some demographic parameters, the genetic structure and the evolution of the genetic variability of six French meat sheep breeds were analysed in relation with their management. Four of these breeds are submitted to more or less intense selection: the Berrichon du Cher (BCH, Blanc du Massif Central (BMC, Charollais (CHA and Limousin (LIM; the other two breeds are under conservation: the Roussin de La Hague (RLH and Solognot (SOL. Genealogical data of the recorded animals born from 1970 to 2000 and of their known ancestors were used. The most balanced contributions of the different flocks to the sire-daughter path was found in the SOL. In the BCH, a single flock provided 43% of the sire-AI sire path, whereas the contributions of the flocks were more balanced in the BMC and LIM (the only other breeds where AI is used to a substantial amount. The distribution of the expected genetic contribution of the founder animals was found to be unbalanced, especially in the BCH and LIM. The effective numbers of ancestors (founders or not for the ewes born from 1996 to 2000 were equal to 35 (BCH, 144 (BMC, 112 (CHA, 69 (LIM, 40 (RLH and 49 (SOL. Inbreeding was not analysed in the BMC, due to incomplete pedigree information. From 1980 on, the rates of inbreeding, in percentage points per year, were +0.112 (BCH, +0.045 (CHA, +0.036 (LIM, +0.098 (RLH and +0.062 (SOL. The implications of the observed trends on genetic variability are discussed in relation to the genetic management of each breed. The need for a larger selection basis in the BCH, the efficiency of the rules applied in the SOL to preserve the genetic variability and the need for a more collective organisation in the CHA and RLH are outlined.

  11. Genetic testing and its implications: human genetics researchers grapple with ethical issues.

    Science.gov (United States)

    Rabino, Isaac

    2003-01-01

    To better understand ethical issues involved in the field of human genetics and promote debate within the scientific community, the author surveyed scientists who engage in human genetics research about the pros, cons, and ethical implications of genetic testing. This study contributes systematic data on attitudes of scientific experts. The survey finds respondents are highly supportive of voluntary testing and the right to know one's genetic heritage. The majority consider in utero testing and consequent pregnancy termination acceptable for cases involving likelihood of serious disease but disapprove for genetic reasons they consider arbitrary, leaving a gray area of distinguishing between treatment of disorders and enhancement still to be resolved. While safeguarding patient confidentiality versus protecting at-risk third parties (kin, reproductive partners) presents a dilemma, preserving privacy from misuse by institutional third parties (employers, insurers) garners strong consensus for legislation against discrimination. Finally, a call is made for greater genetic literacy.

  12. Coping with genetic diversity: the contribution of pathogen and human genomics to modern vaccinology

    International Nuclear Information System (INIS)

    Lemaire, D.; Barbosa, T.; Rihet, P.

    2011-01-01

    Vaccine development faces major difficulties partly because of genetic variation in both infectious organisms and humans. This causes antigenic variation in infectious agents and a high interindividual variability in the human response to the vaccine. The exponential growth of genome sequence information has induced a shift from conventional culture-based to genome-based vaccinology, and allows the tackling of challenges in vaccine development due to pathogen genetic variability. Additionally, recent advances in immunogenetics and genomics should help in the understanding of the influence of genetic factors on the interindividual and interpopulation variations in immune responses to vaccines, and could be useful for developing new vaccine strategies. Accumulating results provide evidence for the existence of a number of genes involved in protective immune responses that are induced either by natural infections or vaccines. Variation in immune responses could be viewed as the result of a perturbation of gene networks; this should help in understanding how a particular polymorphism or a combination thereof could affect protective immune responses. Here we will present: i) the first genome-based vaccines that served as proof of concept, and that provided new critical insights into vaccine development strategies; ii) an overview of genetic predisposition in infectious diseases and genetic control in responses to vaccines; iii) population genetic differences that are a rationale behind group-targeted vaccines; iv) an outlook for genetic control in infectious diseases, with special emphasis on the concept of molecular networks that will provide a structure to the huge amount of genomic data

  13. Multispecies genetic objectives in spatial conservation planning.

    Science.gov (United States)

    Nielsen, Erica S; Beger, Maria; Henriques, Romina; Selkoe, Kimberly A; von der Heyden, Sophie

    2017-08-01

    Growing threats to biodiversity and global alteration of habitats and species distributions make it increasingly necessary to consider evolutionary patterns in conservation decision making. Yet, there is no clear-cut guidance on how genetic features can be incorporated into conservation-planning processes, despite multiple molecular markers and several genetic metrics for each marker type to choose from. Genetic patterns differ between species, but the potential tradeoffs among genetic objectives for multiple species in conservation planning are currently understudied. We compared spatial conservation prioritizations derived from 2 metrics of genetic diversity (nucleotide and haplotype diversity) and 2 metrics of genetic isolation (private haplotypes and local genetic differentiation) in mitochondrial DNA of 5 marine species. We compared outcomes of conservation plans based only on habitat representation with plans based on genetic data and habitat representation. Fewer priority areas were selected for conservation plans based solely on habitat representation than on plans that included habitat and genetic data. All 4 genetic metrics selected approximately similar conservation-priority areas, which is likely a result of prioritizing genetic patterns across a genetically diverse array of species. Largely, our results suggest that multispecies genetic conservation objectives are vital to creating protected-area networks that appropriately preserve community-level evolutionary patterns. © 2016 Society for Conservation Biology.

  14. Genetic and epigenetic variations induced by wheat-rye 2R and 5R monosomic addition lines.

    Science.gov (United States)

    Fu, Shulan; Sun, Chuanfei; Yang, Manyu; Fei, Yunyan; Tan, Feiqun; Yan, Benju; Ren, Zhenglong; Tang, Zongxiang

    2013-01-01

    Monosomic alien addition lines (MAALs) can easily induce structural variation of chromosomes and have been used in crop breeding; however, it is unclear whether MAALs will induce drastic genetic and epigenetic alterations. In the present study, wheat-rye 2R and 5R MAALs together with their selfed progeny and parental common wheat were investigated through amplified fragment length polymorphism (AFLP) and methylation-sensitive amplification polymorphism (MSAP) analyses. The MAALs in different generations displayed different genetic variations. Some progeny that only contained 42 wheat chromosomes showed great genetic/epigenetic alterations. Cryptic rye chromatin has introgressed into the wheat genome. However, one of the progeny that contained cryptic rye chromatin did not display outstanding genetic/epigenetic variation. 78 and 49 sequences were cloned from changed AFLP and MSAP bands, respectively. Blastn search indicated that almost half of them showed no significant similarity to known sequences. Retrotransposons were mainly involved in genetic and epigenetic variations. Genetic variations basically affected Gypsy-like retrotransposons, whereas epigenetic alterations affected Copia-like and Gypsy-like retrotransposons equally. Genetic and epigenetic variations seldom affected low-copy coding DNA sequences. The results in the present study provided direct evidence to illustrate that monosomic wheat-rye addition lines could induce different and drastic genetic/epigenetic variations and these variations might not be caused by introgression of rye chromatins into wheat. Therefore, MAALs may be directly used as an effective means to broaden the genetic diversity of common wheat.

  15. [Genetics of congenital heart diseases].

    Science.gov (United States)

    Bonnet, Damien

    2017-06-01

    Developmental genetics of congenital heart diseases has evolved from analysis of serial slices in embryos towards molecular genetics of cardiac morphogenesis with a dynamic view of cardiac development. Genetics of congenital heart diseases has also changed from formal genetic analysis of familial recurrences or population-based analysis to screening for mutations in candidates genes identified in animal models. Close cooperation between molecular embryologists, pathologists involved in heart development and pediatric cardiologists is crucial for further increase of knowledge in the field of cardiac morphogenesis and genetics of cardiac defects. The genetic model for congenital heart disease has to be revised to favor a polygenic origin rather than a monogenic one. The main mechanism is altered genic dosage that can account for heart diseases in chromosomal anomalies as well as in point mutations in syndromic and isolated congenital heart diseases. The use of big data grouping information from cardiac development, interactions between genes and proteins, epigenetic factors such as chromatin remodeling or DNA methylation is the current source for improving our knowledge in the field and to give clues for future therapies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  16. [Genetic and environmental contribution to rheumatoid arthritis: a family study].

    Science.gov (United States)

    Iebba, Filippo; Di Sora, Fiorella; Leti, Wilma; Montella, Tatiana; Montella, Francesco

    2012-01-01

    We report on the HLA typing of three brothers (A, B, C) with rheumatoid arthritis (RA) and their six sons. This family is interesting for the full concordance for RA between parents. The aim of this study was the discovery of genetic and/or enviromental cofactors determining this absolute concordance.

  17. The ecological imperative and its application to ethical issues in human genetic technology

    Directory of Open Access Journals (Sweden)

    W. Malcolm Byrnes

    2003-08-01

    Full Text Available As a species, we are on the cusp of being able to alter that which makes us uniquely human, our genome. Two new genetic technologies, embryo selection and germline engineering, are either in use today or may be developed in the future. Embryo selection acts to alter the human gene pool, reducing genetic diversity, while germline engineering will have the ability to alter directly the genomes of engineered individuals. Our genome has come to be what it is through an evolutionary process extending over millions of years, a process that has involved exceedingly complex and unpredictable interactions between ourselves or our ancestors and myriad other life forms within Earth's biosphere. In this paper, the ecological imperativ e, which states that we must not alter the human genome or the collective human genetic inheritance, will be introduced. It will be argued based on ecological principles that embryo selection and germline engineering are unethical and unwise because they will diminish our survivability as a species, will disrupt our relationship with the natural world, and will destroy the very basis of that which makes us human.

  18. Familial aggregation of gout and relative genetic and environmental contributions: a nationwide population study in Taiwan.

    Science.gov (United States)

    Kuo, Chang-Fu; Grainge, Matthew J; See, Lai-Chu; Yu, Kuang-Hui; Luo, Shue-Fen; Valdes, Ana M; Zhang, Weiya; Doherty, Michael

    2015-02-01

    To examine familial aggregation of gout and to estimate the heritability and environmental contributions to gout susceptibility in the general population. Using data from the National Health Insurance (NHI) Research Database in Taiwan, we conducted a nationwide cross-sectional study of data collected from 22 643 748 beneficiaries of the NHI in 2004; among them 1 045 059 individuals had physician-diagnosed gout. We estimated relative risks (RR) of gout in individuals with affected first-degree and second-degree relatives and relative contributions of genes (heritability), common environment shared by family members and non-shared environment to gout susceptibility. RRs for gout were significantly higher in individuals with affected first-degree relatives (men, 1.91 (95% CI 1.90 to 1.93); women, 1.97 (95% CI 1.94 to 1.99)) and also in those with affected second-degree relatives (men, 1.27 (95% CI 1.23 to 1.31); women, 1.40 (95% CI 1.35 to 1.46)). RRs (95% CIs) for individuals with an affected twin, sibling, offspring, parent, grandchild, nephew/niece, uncle/aunt and grandparent were 8.02 (6.95 to 9.26), 2.59 (2.54 to 2.63), 1.96 (1.95 to 1.97), 1.93 (1.91 to 1.94), 1.48 (1.43 to 1.53), 1.40 (1.32 to 1.47), 1.31 (1.24 to 1.39), and 1.26 (1.21 to 1.30), respectively. The relative contributions of heritability, common and non-shared environmental factors to phenotypic variance of gout were 35.1, 28.1 and 36.8% in men and 17.0, 18.5 and 64.5% in women, respectively. This population-based study confirms that gout aggregates within families. The risk of gout is higher in people with a family history. Genetic and environmental factors contribute to gout aetiology, and the relative contributions are sexually dimorphic. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  19. Genetic and Epigenetic Tumor Suppressor Gene Silencing Are Distinct Molecular Phenotypes Driven by Growth Promoting Mutations in Nonsmall Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Carmen J. Marsit

    2008-01-01

    Full Text Available Both genetic and epigenetic alterations characterize human nonsmall cell lung cancer (NSCLC, but the biological processes that create or select these alterations remain incompletely investigated. Our hypothesis posits that a roughly reciprocal relationship between the propensity for promoter hypermethylation and a propensity for genetic deletion leads to distinct molecular phenotypes of lung cancer. To test this hypothesis, we examined promoter hypermethylation of 17 tumor suppressor genes, as a marker of epigenetic alteration propensity, and deletion events at the 3p21 region, as a marker of genetic alteration. To model the complex biology between these somatic alterations, we utilized an item response theory model. We demonstrated that tumors exhibiting LOH at greater than 30% of informative alleles in the 3p21 region have a significantly reduced propensity for hypermethylation. At the same time, tumors with activating KRAS mutations showed a significantly increased propensity for hypermethylation of the loci examined, a result similar to what has been observed in colon cancer. These data suggest that NSCLCs have distinct epigenetic or genetic alteration phenotypes acting upon tumor suppressor genes and that mutation of oncogenic growth promoting genes, such as KRAS, is associated with the epigenetic phenotype.

  20. What Use Is Population Genetics?

    Science.gov (United States)

    Charlesworth, Brian

    2015-07-01

    The Genetic Society of America's Thomas Hunt Morgan Medal is awarded to an individual GSA member for lifetime achievement in the field of genetics. For over 40 years, 2015 recipient Brian Charlesworth has been a leader in both theoretical and empirical evolutionary genetics, making substantial contributions to our understanding of how evolution acts on genetic variation. Some of the areas in which Charlesworth's research has been most influential are the evolution of sex chromosomes, transposable elements, deleterious mutations, sexual reproduction, and life history. He also developed the influential theory of background selection, whereby the recurrent elimination of deleterious mutations reduces variation at linked sites, providing a general explanation for the correlation between recombination rate and genetic variation. Copyright © 2015 by the Genetics Society of America.

  1. The Contribution of Epigenetics to Understanding Genetic Factors in Autism

    Science.gov (United States)

    Hall, Layla; Kelley, Elizabeth

    2014-01-01

    Autism spectrum disorder is a grouping of neurodevelopmental disorders characterized by deficits in social communication and language, as well as by repetitive and stereotyped behaviors. While the environment is believed to play a role in the development of autism spectrum disorder, there is now strong evidence for a genetic link to autism.…

  2. Effects of trawl selectivity and genetic parameters on fish body length under long-term trawling

    Science.gov (United States)

    Yu, Yang; Sun, Peng; Cui, He; Sheng, Huaxiang; Zhao, Fenfang; Tang, Yanli; Chen, Zelin

    2015-10-01

    Long-term fishing pressure affects the biological characteristics of exploited fish stocks. The biological characteristics of hairtail ( Trichiurus lepturus) in the East China Sea are unable to recover because of long-term trawling. Fishing induces evolutionary effects on the fish's biological characteristics. Evidence of these changes includes small size at age, a shift to earlier age structure, and early maturation. Natural and artificial selection usually affect the fish's life history. Selection can induce different chances of reproduction, and individual fish can give a different genetic contribution to the next generation. In this study, analysis of time-dependent probability of significance and test of sensitivity were used to explore the effects of fish exploitation rate, mesh size, and heritability with long-term trawling. Results showed that fishing parameters were important drivers to exploited fish population. However, genetic traits altered by fishing were slow, and the changes in biological characteristics were weaker than those caused by fishing selection. Exploitation rate and mesh size exhibited similar evolutionary trend tendency under long-term fishing. The time-dependent probability of significance trend showed a gradual growth and tended to be stable. Therefore, the direction of fishing-induced evolution and successful management of fish species require considerable attention to contribute to sustainable fisheries in China.

  3. Genetic Variation in Schizophrenia Liability is Shared With Intellectual Ability and Brain Structure

    NARCIS (Netherlands)

    Bohlken, Marc M; Brouwer, Rachel M; Mandl, René C W; Kahn, René S; Hulshoff Pol, Hilleke E

    2016-01-01

    BACKGROUND: Alterations in intellectual ability and brain structure are important genetic markers for schizophrenia liability. How variations in these phenotypes interact with variance in schizophrenia liability due to genetic or environmental factors is an area of active investigation. Studying

  4. Tumor suppressor WWOX and p53 alterations and drug resistance in glioblastomas

    Directory of Open Access Journals (Sweden)

    Ming-Fu eChiang

    2013-03-01

    Full Text Available Tumor suppressor p53 are frequently mutated in glioblastomas (GBMs and appears to contribute, in part, to resistance to temozolomide and therapeutic drugs. WW domain-containing oxidoreductase WWOX (FOR or WOX1 is a proapoptotic protein and is considered as a tumor suppressor. Loss of WWOX gene expression is frequently seen in malignant cancer cells due to promoter hypermethylation, genetic alterations, and translational blockade. Intriguingly, ectopic expression of wild type WWOX preferentially induces apoptosis in human glioblastoma cells harboring mutant p53. WWOX is known to physically bind and stabilize wild type p53. Here, we provide an overview for the updated knowledge in p53 and WWOX, and postulate a potential scenarios that wild type and mutant p53, or isoforms, modulate the apoptotic function of WWOX. We propose that triggering WWOX activation by therapeutic drugs under p53 functional deficiency is needed to overcome TMZ resistance and induce GBM cell death.

  5. Converging models of schizophrenia - Network alterations of prefrontal cortex underlying cognitive impairments

    Science.gov (United States)

    Sakurai, Takeshi; Gamo, Nao J; Hikida, Takatoshi; Kim, Sun-Hong; Murai, Toshiya; Tomoda, Toshifumi; Sawa, Akira

    2015-01-01

    The prefrontal cortex (PFC) and its connections with other brain areas are crucial for cognitive function. Cognitive impairments are one of the core symptoms associated with schizophrenia, and manifest even before the onset of the disorder. Altered neural networks involving PFC contribute to cognitive impairments in schizophrenia. Both genetic and environmental risk factors affect the development of the local circuitry within PFC as well as development of broader brain networks, and make the system vulnerable to further insults during adolescence, leading to the onset of the disorder in young adulthood. Since spared cognitive functions correlate with functional outcome and prognosis, a better understanding of the mechanisms underlying cognitive impairments will have important implications for novel therapeutics for schizophrenia focusing on cognitive functions. Multidisciplinary approaches, from basic neuroscience to clinical studies, are required to link molecules, circuitry, networks, and behavioral phenotypes. Close interactions among such fields by sharing a common language on connectomes, behavioral readouts, and other concepts are crucial for this goal. PMID:26408506

  6. Human genetics of diabetic vascular complications

    Indian Academy of Sciences (India)

    Diabetic vascular complications (DVC) affecting several important organ systems of human body such as the cardiovascular system constitute a major public health problem. There is evidence demonstrating that genetic factors contribute to the risk of DVC genetic variants, structural variants, and epigenetic changes play ...

  7. Functional and genetic deconstruction of the cellular origin in liver cancer

    DEFF Research Database (Denmark)

    Marquardt, Jens U; Andersen, Jesper B; Thorgeirsson, Snorri S

    2015-01-01

    During the past decade, research on primary liver cancers has particularly highlighted the uncommon plasticity of differentiated parenchymal liver cells (that is, hepatocytes and cholangiocytes (also known as biliary epithelial cells)), the role of liver progenitor cells in malignant transformation......, the importance of the tumour microenvironment and the molecular complexity of liver tumours. Whereas other reviews have focused on the landscape of genetic alterations that promote development and progression of primary liver cancers and the role of the tumour microenvironment, the crucial importance...... of the cellular origin of liver cancer has been much less explored. Therefore, in this Review, we emphasize the importance and complexity of the cellular origin in tumour initiation and progression, and attempt to integrate this aspect with recent discoveries in tumour genomics and the contribution...

  8. Monitoring adaptive genetic responses to environmental change

    DEFF Research Database (Denmark)

    Hansen, M.M.; Olivieri, I.; Waller, D.M.

    2012-01-01

    Widespread environmental changes including climate change, selective harvesting and landscape alterations now greatly affect selection regimes for most organisms. How animals and plants can adapt to these altered environments via contemporary evolution is thus of strong interest. We discuss how...... for selection and establishing clear links between genetic and environmental change. We then review a few exemplary studies that explore adaptive responses to climate change in Drosophila, selective responses to hunting and fishing, and contemporary evolution in Daphnia using resurrected resting eggs. We...

  9. Genetics of aggression.

    Science.gov (United States)

    Anholt, Robert R H; Mackay, Trudy F C

    2012-01-01

    Aggression mediates competition for food, mating partners, and habitats and, among social animals, establishes stable dominance hierarchies. In humans, abnormal aggression is a hallmark of neuropsychiatric disorders and can be elicited by environmental factors acting on an underlying genetic susceptibility. Identifying the genetic architecture that predisposes to aggressive behavior in people is challenging because of difficulties in quantifying the phenotype, genetic heterogeneity, and uncontrolled environmental conditions. Studies on mice have identified single-gene mutations that result in hyperaggression, contingent on genetic background. These studies can be complemented by systems genetics approaches in Drosophila melanogaster, in which mutational analyses together with genome-wide transcript analyses, artificial selection studies, and genome-wide analysis of epistasis have revealed that a large segment of the genome contributes to the manifestation of aggressive behavior with widespread epistatic interactions. Comparative genomic analyses based on the principle of evolutionary conservation are needed to enable a complete dissection of the neurogenetic underpinnings of this universal fitness trait.

  10. Co-inheritance of the rare β hemoglobin variants Hb Yaounde, Hb Görwihl and Hb City of Hope with other alterations in globin genes: impact in genetic counseling.

    Science.gov (United States)

    Vinciguerra, Margherita; Passarello, Cristina; Leto, Filippo; Cassarà, Filippo; Cannata, Monica; Maggio, Aurelio; Giambona, Antonino

    2015-04-01

    Nearly 1183 different molecular defects of the globin genes leading to hemoglobin variants have been identified (http://globin.bx.psu.edu) over the past decades. The purpose of this study was to report three cases, never described in the literature, of co-inheritance of three β hemoglobin variants with other alterations in globin genes and to evaluate the clinical significance to conduct an appropriate genetic counseling. We report the molecular study performed in three probands and their families, sampling during the screening program conducted at the Laboratory for Molecular Prenatal Diagnosis of Hemoglobinopathies at Villa Sofia-Cervello Hospital in Palermo, Italy. This work allowed us to describe the co-inheritance of three rare β hemoglobin variants with other alterations in globin genes: the β hemoglobin variant Hb Yaounde [β134(H12)Val>Ala], found for the first time in combination with ααα(anti3.7) arrangement, and the β hemoglobin variants Hb Görwihl [β5(A2)Pro>Ala] and Hb City of Hope [β69(E13)Gly>Ser], found both in association with β(0) -thalassemia. The present work emphasizes the importance of a careful evaluation of the hematological data, especially in cases of atypical hematological parameters, to carry out an adequate and complete molecular study and to formulate an appropriate genetic counseling for couples at risk. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Genetic divergence of tomato subsamples

    Directory of Open Access Journals (Sweden)

    André Pugnal Mattedi

    2014-02-01

    Full Text Available Understanding the genetic variability of a species is crucial for the progress of a genetic breeding program and requires characterization and evaluation of germplasm. This study aimed to characterize and evaluate 101 tomato subsamples of the Salad group (fresh market and two commercial controls, one of the Salad group (cv. Fanny and another of the Santa Cruz group (cv. Santa Clara. Four experiments were conducted in a randomized block design with three replications and five plants per plot. The joint analysis of variance was performed and characteristics with significant complex interaction between control and experiment were excluded. Subsequently, the multicollinearity diagnostic test was carried out and characteristics that contributed to severe multicollinearity were excluded. The relative importance of each characteristics for genetic divergence was calculated by the Singh's method (Singh, 1981, and the less important ones were excluded according to Garcia (1998. Results showed large genetic divergence among the subsamples for morphological, agronomic and organoleptic characteristics, indicating potential for genetic improvement. The characteristics total soluble solids, mean number of good fruits per plant, endocarp thickness, mean mass of marketable fruit per plant, total acidity, mean number of unmarketable fruit per plant, internode diameter, internode length, main stem thickness and leaf width contributed little to the genetic divergence between the subsamples and may be excluded in future studies.

  12. Genetics Home Reference: esophageal atresia/tracheoesophageal fistula

    Science.gov (United States)

    ... are some genetic conditions more common in particular ethnic groups? Genetic Changes Isolated EA/TEF is considered to be a multifactorial condition, which means that multiple gene variations and environmental factors likely contribute to its occurrence. ...

  13. Cellular, Molecular, and Genetic Substrates Underlying the Impact of Nicotine on Learning

    Science.gov (United States)

    Gould, Thomas J.; Leach, Prescott T.

    2013-01-01

    Addiction is a chronic disorder marked by long-lasting maladaptive changes in behavior and in reward system function. However, the factors that contribute to the behavioral and biological changes that occur with addiction are complex and go beyond reward. Addiction involves changes in cognitive control and the development of disruptive drug-stimuli associations that can drive behavior. A reason for the strong influence drugs of abuse can exert on cognition may be the striking overlap between the neurobiological substrates of addiction and of learning and memory, especially areas involved in declarative memory. Declarative memories are critically involved in the formation of autobiographical memories, and the ability of drugs of abuse to alter these memories could be particularly detrimental. A key structure in this memory system is the hippocampus, which is critically involved in binding multimodal stimuli together to form complex long-term memories. While all drugs of abuse can alter hippocampal function, this review focuses on nicotine. Addiction to tobacco products is insidious, with the majority of smokers wanting to quit; yet the majority of those that attempt to quit fail. Nicotine addiction is associated with the presence of drug-context and drug-cue associations that trigger drug seeking behavior and altered cognition during periods of abstinence, which contributes to relapse. This suggests that understanding the effects of nicotine on learning and memory will advance understanding and potentially facilitate treating nicotine addiction. The following sections examine: 1) how the effects of nicotine on hippocampus-dependent learning change as nicotine administration transitions from acute to chronic and then to withdrawal from chronic treatment and the potential impact of these changes on addiction, 2) how nicotine usurps the cellular mechanisms of synaptic plasticity, 3) the physiological changes in the hippocampus that may contribute to nicotine withdrawal

  14. Human diseases with genetically altered DNA repair processes

    International Nuclear Information System (INIS)

    Cleaver, J.E.; Bootsma, D.; Friedberg, E.

    1975-01-01

    DNA repair of single-strand breaks (produced by ionizing radiation) and of base damage (produced by ultraviolet (uv) light) are two repair mechanisms that most mammalian cells possess. Genetic defects in these repair mechanisms are exemplified by cells from the human premature-aging disease, progeria, which fail to rejoin single-strand breaks, and the skin disease, xeroderma pigmentosum (XP), which exhibits high actinic carcinogenesis and involves failure to repair base damage. In terms of the response of XP cells, many chemical carcinogens can be classified as either x-ray-like (i.e., they cause damage that XP cells can repair) or uv-like (i.e., they cause damage that XP cells cannot repair). The first group contains some of the more strongly carcinogenic chemicals (e.g., alkylating agents). XP occurs in at least two clinical forms, and somatic cell hybridization indicates at least three complementation groups. In order to identify cell lines from various different laboratories unambiguously, a modified nomenclature of XP lines is proposed. (U.S.)

  15. Human diseases with genetically altered DNA repair processes

    International Nuclear Information System (INIS)

    Cleaver, J.E.; Bootsma, D.; Friedberg, E.

    1975-01-01

    DNA repair of single-strand breaks (produced by ionizing radiation) and of base damage (produced by ultraviolet (UV) light) are two repair mechanisms that most mammalian cells possess. Genetic defects in these repair mechanisms are exemplified by cells from the human premature-aging disease, progeria, which fail to rejoin single-strand breaks, and the skin disease, xeroderma pigmentosum (XP), which exhibits high actinic carcinogenesis and involves failure to repair base damage. In terms of the response of XP cells, many chemical carcinogens can be classified as either X-ray-like (i.e., they cause damage that XP cells can repair) or UV-like (i.e., they cause damage that XP cells cannot repair). The first group contains some of the more strongly carcinogenic chemicals (e.g., alkylating agents). XP occurs in at least two clinical forms, and somatic cell hybridization indicates at least three complementation groups. In order to identify cell lines from various different laboratories unambiguously, a modified nomenclature of XP lines is proposed

  16. Deletion of Rictor in catecholaminergic neurons alters locomotor activity and ingestive behavior.

    Science.gov (United States)

    Kaska, Sophia; Brunk, Rebecca; Bali, Vedrana; Kechner, Megan; Mazei-Robison, Michelle S

    2017-05-01

    While the etiology of depression is not fully understood, increasing evidence from animal models suggests a role for the ventral tegmental area (VTA) in pathogenesis. In this paper, we investigate the potential role of VTA mechanistic target of rapamycin 2 (TORC2) signaling in mediating susceptibility to chronic social defeat stress (CSDS), a well-established mouse model of depression. Utilizing genetic and viral knockout of Rictor (rapamycin-insensitive companion of target of rapamycin), a requisite component of TORC2, we demonstrate that decreasing Rictor-dependent TORC2 signaling in catecholaminergic neurons, or within the VTA specifically, does not alter susceptibility to CSDS. Opiate abuse and mood disorders are often comorbid, and previous data demonstrate a role for VTA TORC2 in mediating opiate reward. Thus, we also investigated its potential role in mediating changes in opiate reward following CSDS. Catecholaminergic deletion of Rictor increases water, sucrose, and morphine intake but not preference in a two-bottle choice assay in stress-naïve mice, and these effects are maintained after stress. VTA-specific knockout of Rictor increases water and sucrose intake after physical CSDS, but does not alter consummatory behavior in the absence of stress. These findings suggest a novel role for TORC2 in mediating stress-induced changes in consummatory behaviors that may contribute to some aspects of mood disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Genetic and epigenetic variations induced by wheat-rye 2R and 5R monosomic addition lines.

    Directory of Open Access Journals (Sweden)

    Shulan Fu

    Full Text Available BACKGROUND: Monosomic alien addition lines (MAALs can easily induce structural variation of chromosomes and have been used in crop breeding; however, it is unclear whether MAALs will induce drastic genetic and epigenetic alterations. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, wheat-rye 2R and 5R MAALs together with their selfed progeny and parental common wheat were investigated through amplified fragment length polymorphism (AFLP and methylation-sensitive amplification polymorphism (MSAP analyses. The MAALs in different generations displayed different genetic variations. Some progeny that only contained 42 wheat chromosomes showed great genetic/epigenetic alterations. Cryptic rye chromatin has introgressed into the wheat genome. However, one of the progeny that contained cryptic rye chromatin did not display outstanding genetic/epigenetic variation. 78 and 49 sequences were cloned from changed AFLP and MSAP bands, respectively. Blastn search indicated that almost half of them showed no significant similarity to known sequences. Retrotransposons were mainly involved in genetic and epigenetic variations. Genetic variations basically affected Gypsy-like retrotransposons, whereas epigenetic alterations affected Copia-like and Gypsy-like retrotransposons equally. Genetic and epigenetic variations seldom affected low-copy coding DNA sequences. CONCLUSIONS/SIGNIFICANCE: The results in the present study provided direct evidence to illustrate that monosomic wheat-rye addition lines could induce different and drastic genetic/epigenetic variations and these variations might not be caused by introgression of rye chromatins into wheat. Therefore, MAALs may be directly used as an effective means to broaden the genetic diversity of common wheat.

  18. Genetics of nonsyndromic obesity.

    Science.gov (United States)

    Lee, Yung Seng

    2013-12-01

    Common obesity is widely regarded as a complex, multifactorial trait influenced by the 'obesogenic' environment, sedentary behavior, and genetic susceptibility contributed by common and rare genetic variants. This review describes the recent advances in understanding the role of genetics in obesity. New susceptibility loci and genetic variants are being uncovered, but the collective effect is relatively small and could not explain most of the BMI heritability. Yet-to-be identified common and rare variants, epistasis, and heritable epigenetic changes may account for part of the 'missing heritability'. Evidence is emerging about the role of epigenetics in determining obesity susceptibility, mediating developmental plasticity, which confers obesity risk from early life experiences. Genetic prediction scores derived from selected genetic variants, and also differential DNA methylation levels and methylation scores, have been shown to correlate with measures of obesity and response to weight loss intervention. Genetic variants, which confer susceptibility to obesity-related morbidities like nonalcoholic fatty liver disease, were also discovered recently. We can expect discovery of more rare genetic variants with the advent of whole exome and genome sequencing, and also greater understanding of epigenetic mechanisms by which environment influences genetic expression and which mediate the gene-environment interaction.

  19. Imaging genetics and the neurobiological basis of individual differences in vulnerability to addiction.

    Science.gov (United States)

    Sweitzer, Maggie M; Donny, Eric C; Hariri, Ahmad R

    2012-06-01

    Addictive disorders are heritable, but the search for candidate functional polymorphisms playing an etiological role in addiction is hindered by complexity of the phenotype and the variety of factors interacting to impact behavior. Advances in human genome sequencing and neuroimaging technology provide an unprecedented opportunity to explore the impact of functional genetic variants on variability in behaviorally relevant neural circuitry. Here, we present a model for merging these technologies to trace the links between genes, brain, and addictive behavior. We describe imaging genetics and discuss the utility of its application to addiction. We then review data pertaining to impulsivity and reward circuitry as an example of how genetic variation may lead to variation in behavioral phenotype. Finally, we present preliminary data relating the neural basis of reward processing to individual differences in nicotine dependence. Complex human behaviors such as addiction can be traced to their basic genetic building blocks by identifying intermediate behavioral phenotypes, associated neural circuitry, and underlying molecular signaling pathways. Impulsivity has been linked with variation in reward-related activation in the ventral striatum (VS), altered dopamine signaling, and functional polymorphisms of DRD2 and DAT1 genes. In smokers, changes in reward-related VS activation induced by smoking abstinence may be associated with severity of nicotine dependence. Variation in genes related to dopamine signaling may contribute to heterogeneity in VS sensitivity to reward and, ultimately, to addiction. These findings illustrate the utility of the imaging genetics approach for investigating the neurobiological basis for vulnerability to addiction. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  20. 76 FR 8707 - Syngenta Seeds, Inc.; Determination of Nonregulated Status for Corn Genetically Engineered To...

    Science.gov (United States)

    2011-02-15

    ... Organisms and Products Altered or Produced Through Genetic Engineering Which Are Plant Pests or Which There... genetic engineering that are plant pests or that there is reason to believe are plant pests. Such...

  1. [Genetics factors in pathogenesis and clinical genetics of binge eating disorder].

    Science.gov (United States)

    Kibitov, А О; Мazo, G E

    2016-01-01

    Genetic studies have shown that binge eating disorder (ВЕD) aggregates in families, heritability was estimated as about 60% and additive genetic influences on BED up to 50%. Using a genetic approach has proved useful for verifying the diagnostic categories of BED using DSM-IV criteria and supporting the validity of considering this pathology as a separate nosological category. The results confirmed the genetic and pathogenic originality of BED as a separate psychopathological phenomenon, but not a subtype of obesity. It seems fruitful to considerate BED as a disease with hereditary predisposition with significant genetic influence and a complex psychopathological syndrome, including not only eating disorders, but also depressive and addictive component. A possible mechanism of pathogenesis of BED may be the interaction of the neuroendocrine and neurotransmitters systems including the active involvement of the reward system in response to a variety of chronic stress influences with the important modulatory role of specific personality traits. The high level of genetic influence on the certain clinical manifestations of BED confirms the ability to identify the subphenotypes of BED on genetic basis involving clinical criteria. It can not only contribute to further genetic studies, taking into account more homogeneous samples, but also help in finding differentiated therapeutic approaches.

  2. Estimation of genetic structure of a Mycosphaerella musicola population using inter-simple sequence repeat markers.

    Science.gov (United States)

    Peixouto, Y S; Dórea Bragança, C A; Andrade, W B; Ferreira, C F; Haddad, F; Oliveira, S A S; Darosci Brito, F S; Miller, R N G; Amorim, E P

    2015-07-17

    Among the diseases affecting banana (Musa sp), yellow Sigatoka, caused by the fungal pathogen Mycosphaerella musicola Leach, is considered one of the most important in Brazil, causing losses throughout the year. Understanding the genetic structure of pathogen populations will provide insight into the life history of pathogens, including the evolutionary processes occurring in agrosystems. Tools for estimating the possible emergence of pathogen variants with altered pathogenicity, virulence, or aggressiveness, as well as resistance to systemic fungicides, can also be developed from such data. The objective of this study was to analyze the genetic diversity and population genetics of M. musicola in the main banana-producing regions in Brazil. A total of 83 isolates collected from different banana cultivars in the Brazilian states of Bahia, Rio Grande do Norte, and Minas Gerais were evaluated using inter-simple sequence repeat markers. High variability was detected between the isolates, and 85.5% of the haplotypes were singletons in the populations. The highest source of genetic diversity (97.22%) was attributed to variations within populations. Bayesian cluster analysis revealed the presence of 2 probable ancestral groups, however, showed no relationship to population structure in terms of collection site, state of origin, or cultivar. Similarly, we detected noevidence of genetic recombination between individuals within different states, indicating that asexual cycles play a major role in M. musicola reproduction and that long-distance dispersal of the pathogen is the main factor contributing to the lack of population structure in the fungus.

  3. Genetic deletion of the P2Y2 receptor offers significant resistance to development of lithium-induced polyuria accompanied by alterations in PGE2 signaling.

    Science.gov (United States)

    Zhang, Yue; Pop, Ioana L; Carlson, Noel G; Kishore, Bellamkonda K

    2012-01-01

    Lithium (Li)-induced polyuria is due to resistance of the medullary collecting duct (mCD) to the action of arginine vasopressin (AVP), apparently mediated by increased production of PGE(2). We previously reported that the P2Y(2) receptor (P2Y(2)-R) antagonizes the action of AVP on the mCD and may play a role in Li-induced polyuria by enhancing the production of PGE(2) in mCD. Hence, we hypothesized that genetic deletion of P2Y(2)-R should ameliorate Li-induced polyuria. Wild-type (WT) or P2Y(2)-R knockout (KO) mice were fed normal or Li-added diets for 14 days and euthanized. Li-induced polyuria, and decreases in urine osmolality and AQP2 protein abundance in the renal medulla, were significantly less compared with WT mice despite the lack of differences in Li intake or terminal serum or inner medullary tissue Li levels. Li-induced increased urinary excretion of PGE(2) was not affected in KO mice. However, prostanoid EP(3) receptor (EP3-R) protein abundance in the renal medulla of KO mice was markedly lower vs. WT mice, irrespective of the dietary regimen. The protein abundances of other EP-Rs were not altered across the groups irrespective of the dietary regimen. Ex vivo stimulation of mCD with PGE(2) generated significantly more cAMP in Li-fed KO mice (130%) vs. Li-fed WT mice (100%). Taken together, these data suggest 1) genetic deletion of P2Y(2)-R offers significant resistance to the development of Li-induced polyuria; and 2) this resistance is apparently due to altered PGE(2) signaling mediated by a marked decrease in EP3-R protein abundance in the medulla, thus attenuating the EP3-mediated decrease in cAMP levels in mCD.

  4. Journal of Genetics | Indian Academy of Sciences

    Indian Academy of Sciences (India)

    The genetic polymorphisms areassociated with varying levels of risk within the population, as gene products of varied genotype alter the biotransformation of exogenous/endogenous substrates. This paper is aimed to review the impact of endogenous and exogenous factors on a mechanistic pathway of organophosphate ...

  5. Maternal genetic mutations as gestational and early life influences in producing psychiatric disease-like phenotypes in mice

    Directory of Open Access Journals (Sweden)

    Georgia eGleason

    2011-05-01

    Full Text Available Risk factors for psychiatric disorders have traditionally been classified as genetic or environmental. Risk (candidate genes, although typically possessing small effects, represent a clear starting point to elucidate downstream cellular/molecular pathways of disease. Environmental effects, especially during development, can also lead to altered behavior and increased risk for disease. An important environmental factor is the mother, demonstrated by the negative effects elicited by maternal gestational stress and altered maternal care. These maternal effects can also have a genetic basis (e.g. maternal genetic variability and mutations. The focus of this review is maternal genotype effects that influence the emotional development of the offspring resulting in life-long psychiatric disease-like phenotypes. We have recently found that genetic inactivation of the serotonin1A receptor (5-HT1AR and the fmr-1 gene (encoding the fragile X mental retardation protein in mouse dams results in psychiatric disease-like phenotypes in their genetically unaffected offspring. 5-HT1AR deficiency in dams results in anxiety and increased stress responsiveness in their offspring. Mice with 5-HT1AR deficient dams display altered development of the hippocampus, which could be linked to their anxiety-like phenotype. Maternal inactivation of fmr-1, like its inactivation in the offspring, results in a hyperactivity-like condition and is associated with receptor alterations in the striatum. These data indicate a high sensitivity of the offspring to maternal mutations and suggest that maternal genotype effects can increase the impact of genetic risk factors in a population by increasing the risk of the genetically normal offspring as well as by enhancing the effects of offspring mutations.

  6. Genetic Variability Under the Seedbank Coalescent.

    Science.gov (United States)

    Blath, Jochen; González Casanova, Adrián; Eldon, Bjarki; Kurt, Noemi; Wilke-Berenguer, Maite

    2015-07-01

    We analyze patterns of genetic variability of populations in the presence of a large seedbank with the help of a new coalescent structure called the seedbank coalescent. This ancestral process appears naturally as a scaling limit of the genealogy of large populations that sustain seedbanks, if the seedbank size and individual dormancy times are of the same order as those of the active population. Mutations appear as Poisson processes on the active lineages and potentially at reduced rate also on the dormant lineages. The presence of "dormant" lineages leads to qualitatively altered times to the most recent common ancestor and nonclassical patterns of genetic diversity. To illustrate this we provide a Wright-Fisher model with a seedbank component and mutation, motivated from recent models of microbial dormancy, whose genealogy can be described by the seedbank coalescent. Based on our coalescent model, we derive recursions for the expectation and variance of the time to most recent common ancestor, number of segregating sites, pairwise differences, and singletons. Estimates (obtained by simulations) of the distributions of commonly employed distance statistics, in the presence and absence of a seedbank, are compared. The effect of a seedbank on the expected site-frequency spectrum is also investigated using simulations. Our results indicate that the presence of a large seedbank considerably alters the distribution of some distance statistics, as well as the site-frequency spectrum. Thus, one should be able to detect from genetic data the presence of a large seedbank in natural populations. Copyright © 2015 by the Genetics Society of America.

  7. Evolution of Genetic Variance during Adaptive Radiation.

    Science.gov (United States)

    Walter, Greg M; Aguirre, J David; Blows, Mark W; Ortiz-Barrientos, Daniel

    2018-04-01

    Genetic correlations between traits can concentrate genetic variance into fewer phenotypic dimensions that can bias evolutionary trajectories along the axis of greatest genetic variance and away from optimal phenotypes, constraining the rate of evolution. If genetic correlations limit adaptation, rapid adaptive divergence between multiple contrasting environments may be difficult. However, if natural selection increases the frequency of rare alleles after colonization of new environments, an increase in genetic variance in the direction of selection can accelerate adaptive divergence. Here, we explored adaptive divergence of an Australian native wildflower by examining the alignment between divergence in phenotype mean and divergence in genetic variance among four contrasting ecotypes. We found divergence in mean multivariate phenotype along two major axes represented by different combinations of plant architecture and leaf traits. Ecotypes also showed divergence in the level of genetic variance in individual traits and the multivariate distribution of genetic variance among traits. Divergence in multivariate phenotypic mean aligned with divergence in genetic variance, with much of the divergence in phenotype among ecotypes associated with changes in trait combinations containing substantial levels of genetic variance. Overall, our results suggest that natural selection can alter the distribution of genetic variance underlying phenotypic traits, increasing the amount of genetic variance in the direction of natural selection and potentially facilitating rapid adaptive divergence during an adaptive radiation.

  8. Causal Genetic Variation Underlying Metabolome Differences.

    Science.gov (United States)

    Swain-Lenz, Devjanee; Nikolskiy, Igor; Cheng, Jiye; Sudarsanam, Priya; Nayler, Darcy; Staller, Max V; Cohen, Barak A

    2017-08-01

    An ongoing challenge in biology is to predict the phenotypes of individuals from their genotypes. Genetic variants that cause disease often change an individual's total metabolite profile, or metabolome. In light of our extensive knowledge of metabolic pathways, genetic variants that alter the metabolome may help predict novel phenotypes. To link genetic variants to changes in the metabolome, we studied natural variation in the yeast Saccharomyces cerevisiae We used an untargeted mass spectrometry method to identify dozens of metabolite Quantitative Trait Loci (mQTL), genomic regions containing genetic variation that control differences in metabolite levels between individuals. We mapped differences in urea cycle metabolites to genetic variation in specific genes known to regulate amino acid biosynthesis. Our functional assays reveal that genetic variation in two genes, AUA1 and ARG81 , cause the differences in the abundance of several urea cycle metabolites. Based on knowledge of the urea cycle, we predicted and then validated a new phenotype: sensitivity to a particular class of amino acid isomers. Our results are a proof-of-concept that untargeted mass spectrometry can reveal links between natural genetic variants and metabolome diversity. The interpretability of our results demonstrates the promise of using genetic variants underlying natural differences in the metabolome to predict novel phenotypes from genotype. Copyright © 2017 by the Genetics Society of America.

  9. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine and quinine in Guinea-Bissau between 2003 and 2012

    DEFF Research Database (Denmark)

    Jovel, Irina Tatiana; Kofoed, Poul-Erik; Rombo, Lars

    2015-01-01

    BACKGROUND: Guinea-Bissau, West-Africa introduced artemether-lumefantrine in 2008 but quinine has also been commonly prescribed for treatment of uncomplicated Plasmodium falciparum malaria. An efficacious high-dose chloroquine treatment regimen was used previously. Temporal and seasonal changes...... of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine and quinine are described. METHODS: Pfcrt K76T, pfmdr1 gene copy numbers, N86Y, Y184F and 1034-1246 sequences were determined using PCR-based methods. Blood samples came from virtually all (n=1806) children aged.......001). CONCLUSIONS: Following the discontinuation of an effective chloroquine regimen highly artemether-lumefantrine susceptible P. falciparum (with pfcrt 76T) accumulated possibly due to suboptimal use of quinine and despite a fitness cost linked to 76T....

  10. The contribution of the mitochondrial genome to sex-specific fitness variance.

    Science.gov (United States)

    Smith, Shane R T; Connallon, Tim

    2017-05-01

    Maternal inheritance of mitochondrial DNA (mtDNA) facilitates the evolutionary accumulation of mutations with sex-biased fitness effects. Whereas maternal inheritance closely aligns mtDNA evolution with natural selection in females, it makes it indifferent to evolutionary changes that exclusively benefit males. The constrained response of mtDNA to selection in males can lead to asymmetries in the relative contributions of mitochondrial genes to female versus male fitness variation. Here, we examine the impact of genetic drift and the distribution of fitness effects (DFE) among mutations-including the correlation of mutant fitness effects between the sexes-on mitochondrial genetic variation for fitness. We show how drift, genetic correlations, and skewness of the DFE determine the relative contributions of mitochondrial genes to male versus female fitness variance. When mutant fitness effects are weakly correlated between the sexes, and the effective population size is large, mitochondrial genes should contribute much more to male than to female fitness variance. In contrast, high fitness correlations and small population sizes tend to equalize the contributions of mitochondrial genes to female versus male variance. We discuss implications of these results for the evolution of mitochondrial genome diversity and the genetic architecture of female and male fitness. © 2017 The Author(s). Evolution © 2017 The Society for the Study of Evolution.

  11. Similarities between the Epstein-Barr Virus (EBV) Nuclear Protein EBNA1 and the Pioneer Transcription Factor FoxA: Is EBNA1 a “Bookmarking” Oncoprotein that Alters the Host Cell Epigenotype?

    Science.gov (United States)

    Niller, Hans Helmut; Minarovits, Janos

    2012-01-01

    EBNA1, a nuclear protein expressed in all EBV-associated neoplasms is indispensable for the maintenance of the viral episomes in latently infected cells. EBNA1 may induce genetic alterations by upregulating cellular recombinases, production of reactive oxygen species (ROS) and affecting p53 levels and function. All these changes may contribute to tumorigenesis. In this overview we focus, however, on the epigenetic alterations elicited by EBNA1 by drawing a parallel between EBNA1 and the FoxA family of pioneer transcription factors. Both EBNA1 and FoxA induce local DNA demethylation, nucleosome destabilization and bind to mitotic chromosomes. Local DNA demethylation and nucleosome rearrangement mark active promoters and enhancers. In addition, EBNA1 and FoxA, when associated with mitotic chromatin may “bookmark” active genes and ensure their reactivation in postmitotic cells (epigenetic memory). We speculate that DNA looping induced by EBNA1-EBNA1 interactions may reorganize the cellular genome. Such chromatin loops, sustained in mitotic chromatin similarly to the long-distance interactions mediated by the insulator protein CTCF, may also mediate the epigenetic inheritance of gene expression patterns. We suggest that EBNA1 has the potential to induce patho-epigenetic alterations contributing to tumorigenesis. PMID:25436603

  12. Progress in cancer genetics: lessons from pancreatic cancer

    NARCIS (Netherlands)

    Goggins, M.; Kern, S. E.; Offerhaus, J. A.; Hruban, R. H.

    1999-01-01

    In the near future advances in the molecular basis of cancer are expected to facilitate cancer diagnosis, to rationalize treatment, to facilitate screening, and to identify individuals requiring cancer prevention strategies. The literature was reviewed concerning the genetic alterations that

  13. G protein-coupled receptor mutations and human genetic disease.

    Science.gov (United States)

    Thompson, Miles D; Hendy, Geoffrey N; Percy, Maire E; Bichet, Daniel G; Cole, David E C

    2014-01-01

    Genetic variations in G protein-coupled receptor genes (GPCRs) disrupt GPCR function in a wide variety of human genetic diseases. In vitro strategies and animal models have been used to identify the molecular pathologies underlying naturally occurring GPCR mutations. Inactive, overactive, or constitutively active receptors have been identified that result in pathology. These receptor variants may alter ligand binding, G protein coupling, receptor desensitization and receptor recycling. Receptor systems discussed include rhodopsin, thyrotropin, parathyroid hormone, melanocortin, follicle-stimulating hormone (FSH), luteinizing hormone, gonadotropin-releasing hormone (GNRHR), adrenocorticotropic hormone, vasopressin, endothelin-β, purinergic, and the G protein associated with asthma (GPRA or neuropeptide S receptor 1 (NPSR1)). The role of activating and inactivating calcium-sensing receptor (CaSR) mutations is discussed in detail with respect to familial hypocalciuric hypercalcemia (FHH) and autosomal dominant hypocalemia (ADH). The CASR mutations have been associated with epilepsy. Diseases caused by the genetic disruption of GPCR functions are discussed in the context of their potential to be selectively targeted by drugs that rescue altered receptors. Examples of drugs developed as a result of targeting GPCRs mutated in disease include: calcimimetics and calcilytics, therapeutics targeting melanocortin receptors in obesity, interventions that alter GNRHR loss from the cell surface in idiopathic hypogonadotropic hypogonadism and novel drugs that might rescue the P2RY12 receptor congenital bleeding phenotype. De-orphanization projects have identified novel disease-associated receptors, such as NPSR1 and GPR35. The identification of variants in these receptors provides genetic reagents useful in drug screens. Discussion of the variety of GPCRs that are disrupted in monogenic Mendelian disorders provides the basis for examining the significance of common

  14. Altered dopamine ontogeny in the developmentally vitamin D deficient rat and its relevance to schizophrenia.

    Science.gov (United States)

    Kesby, James P; Cui, Xiaoying; Burne, Thomas H J; Eyles, Darryl W

    2013-01-01

    Schizophrenia is a heterogeneous group of disorders with unknown etiology. Although abnormalities in multiple neurotransmitter systems have been linked to schizophrenia, alterations in dopamine (DA) neurotransmission remain central to the treatment of this disorder. Given that schizophrenia is considered a neurodevelopmental disorder we have hypothesized that abnormal DA signaling in the adult patient may result from altered DA signaling during fetal brain development. Environmental and genetic risk factors can be modeled in rodents to allow for the investigation of early neurodevelopmental pathogenesis that may lead to clues into the etiology of schizophrenia. To address this we created an animal model of one such risk factor, developmental vitamin D (DVD) deficiency. DVD-deficient adult rats display an altered behavioral profile in response to DA releasing and blocking agents that are reminiscent of that seen in schizophrenia patients. Furthermore, developmental studies revealed that DVD deficiency also altered cell proliferation, apoptosis, and neurotransmission across the embryonic brain. In particular, DVD deficiency reduces the expression of crucial dopaminergic specification factors and alters DA metabolism in the developing brain. We speculate such alterations in fetal brain development may change the trajectory of DA neuron ontogeny to induce the behavioral abnormalities observed in adult offspring. The widespread evidence that both dopaminergic and structural changes are present in people who develop schizophrenia prior to onset also suggest that early alterations in development are central to the disease. Taken together, early alterations in DA ontogeny may represent a core feature in the pathology of schizophrenia. Such a mechanism could bring together evidence from multiple risk factors and genetic vulnerabilities to form a convergent pathway in disease pathophysiology.

  15. Altered dopamine ontogeny in the developmentally vitamin D deficient rat and its relevance to schizophrenia

    Directory of Open Access Journals (Sweden)

    James P. Kesby

    2013-07-01

    Full Text Available Schizophrenia is a heterogeneous group of disorders with unknown aetiology. Although abnormalities in multiple neurotransmitter systems have been linked to schizophrenia, alterations in dopamine neurotransmission remain central to the treatment of this disorder. Given that schizophrenia is considered a neurodevelopmental disorder we have hypothesised that abnormal dopamine signalling in the adult patient may result from altered dopamine signalling during foetal brain development. Environmental and genetic risk factors can be modelled in rodents to allow for the investigation of early neurodevelopmental pathogenesis that may lead to clues into the aetiology of schizophrenia. To address this we created an animal model of one such risk factor, developmental vitamin D (DVD deficiency. DVD-deficient adult rats display an altered behavioural profile in response to dopamine releasing and blocking agents that are reminiscent of that seen in schizophrenia patients. Furthermore, developmental studies revealed that DVD deficiency also altered cell proliferation, apoptosis and neurotransmission across the embryonic brain. In particular, DVD deficiency reduces the expression of crucial dopaminergic specification factors and alters dopamine metabolism in the developing brain. We speculate such alterations in foetal brain development may change the trajectory of dopamine neuron ontogeny to induce the behavioural abnormalities observed in adult offspring. The widespread evidence that both dopaminergic and structural changes are present in people who develop schizophrenia prior to onset also suggest that early alterations in development are central to the disease. Taken together, early alterations in dopamine ontogeny may represent a core feature in the pathology of schizophrenia. Such a mechanism could bring together evidence from multiple risk factors and genetic vulnerabilities to form a convergent pathway in disease pathophysiology.

  16. Convergent synaptic and circuit substrates underlying autism genetic risks.

    Science.gov (United States)

    McGee, Aaron; Li, Guohui; Lu, Zhongming; Qiu, Shenfeng

    2014-02-01

    There has been a surge of diagnosis of autism spectrum disorders (ASD) over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, research efforts to understanding how each of these risk factors contributes to the development autism has met with limited success. Revealing the mechanisms by which these genetic risk factors affect brain development and predispose a child to autism requires mechanistic understanding of the neurobiological changes underlying this devastating group of developmental disorders at multifaceted molecular, cellular and system levels. It has been increasingly clear that the normal trajectory of neurodevelopment is compromised in autism, in multiple domains as much as aberrant neuronal production, growth, functional maturation, patterned connectivity, and balanced excitation and inhibition of brain networks. Many autism risk factors identified in humans have been now reconstituted in experimental mouse models to allow mechanistic interrogation of the biological role of the risk gene. Studies utilizing these mouse models have revealed that underlying the enormous heterogeneity of perturbed cellular events, mechanisms directing synaptic and circuit assembly may provide a unifying explanation for the pathophysiological changes and behavioral endophenotypes seen in autism, although synaptic perturbations are far from being the only alterations relevant for ASD. In this review, we discuss synaptic and circuit abnormalities obtained from several prevalent mouse models, particularly those reflecting syndromic forms of ASD that are caused by single gene perturbations. These compiled results reveal that ASD risk genes contribute to proper signaling of the developing gene networks that maintain synaptic and circuit homeostasis, which is fundamental to normal brain development.

  17. Genetic variations altering FSH action affect circulating hormone levels as well as follicle growth in healthy peripubertal girls.

    Science.gov (United States)

    Busch, Alexander S; Hagen, Casper P; Almstrup, Kristian; Main, Katharina M; Juul, Anders

    2016-04-01

    Do variants of the genes encoding follicle stimulating hormone (FSH) beta subunit (B) and FSH receptor (R) impact circulating reproductive hormone levels and ovarian follicle maturation in healthy peripubertal girls? FSHB and FSHR genetic variants exert, alone or their combination, distinct effects on reproductive hormone levels as well as ovarian follicle maturation in healthy peripubertal girls. FSHB and FSHR genetic variants impact reproductive hormone levels as well as associated pathologies in women. While FSHR c. 2039A>G is known to alter gonadotrophin levels in women, FSHR c.-29G>A has not yet been shown to exert effect and there are conflicting results concerning FSHB c.-211G>T. This population-based study included 633 girls recruited as part of two cohorts, the COPENHAGEN Puberty Study (2006-2014, a cross-sectional and ongoing longitudinal study) and the Copenhagen Mother-Child Cohort (1997-2002, including transabdominal ultrasound (TAUS) of the ovaries in a subset of 91 peripubertal girls). Clinical examinations, including pubertal breast stage (Tanner's classification B1-B5) were performed. Circulating levels of FSH, luteinizing hormone (LH), estradiol, anti-Mullerian hormone (AMH) and inhibin-B were assessed by immunoassays. In a subset of the girls (n = 91), ovarian volume and the number/size of antral follicles were assessed by TAUS. Genotypes were determined by competitive PCR. FSHR c.2039A>G minor alleles were positively associated with serum FSH (β = 0.08, P = 0.004), LH (β = 0.06, P = 0.012) and estradiol (β = 0.06, P = 0.017) (adjusted for Tanner stages). In a combined model, FSHR c.-29G>A and FSHR c.2039A>G alleles were positively associated with FSH levels in early-pubertal girls (B2 + B3, n = 327, r = 0.1, P = 0.02) and in young adolescents (B4 + B5, n = 149, r = 0.2, P = 0.01). Serum AMH and inhibin B levels were not significantly influenced by the single nucleotide polymorphisms (SNPs). Single SNPs were not associated with follicles

  18. [Assessment of allergenicity of genetically modified food crops].

    Science.gov (United States)

    Schauzu, M; Pöting, A; Rubin, D; Lampen, A

    2012-03-01

    The placing on the European Union's market of genetically modified crops requires authorization by the European Commission which is based on the proof that the derived foods are as safe as their conventional counterparts. The assessment of potential allergenicity is part of the necessary investigations recommended in the updated Guidance Document of the Scientific Panel on Genetically Modified Organisms (GMO) of the European Food Safety Authority (EFSA), which is based on internationally agreed recommendations. All genetically modified crops which so far have been authorized in the European Union were evaluated by the EFSA GMO Panel which considered it unlikely that their overall allergenicity has been altered.

  19. Common genetic variants influence human subcortical brain structures

    Science.gov (United States)

    Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Olde Loohuis, Loes M.; Luciano, Michelle; Macare, Christine; Mather, Karen A.; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Roiz-Santiañez, Roberto; Rose, Emma J.; Salami, Alireza; Sämann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn K.; Heister, Angelien J. G. A. M.; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, D. Reese; Needham, Margaret; Nugent, Allison C.; Pütz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; van Hulzen, Kimm J. E.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Cichon, Sven; Corvin, Aiden; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, J. Raphael; Göring, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Mühleisen, Thomas W.; Nalls, Michael A.; Nichols, Thomas E.; Nilsson, Lars G.; Nöthen, Markus M.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Rujescu, Dan; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Turner, Jessica A.; Valdés Hernández, Maria C.; van ’t Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan B.; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; McMahon, Francis J.; Morris, Derek W.; Williams, Robert W.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Cahn, Wiepke; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Crespo-Facorro, Benedicto; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S.; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Roffman, Joshua L.; Sisodiya, Sanjay M.; Smoller, Jordan W.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Völzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A.; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E.; Jönsson, Erik G.; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S.; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M.; Ophoff, Roel A.; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S.; Saykin, Andrew J.; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M.; Weale, Michael E.; Weinberger, Daniel R.; Adams, Hieab H. H.; Launer, Lenore J.; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L.; Becker, James T.; Yanek, Lisa; van der Lee, Sven J.; Ebling, Maritza; Fischl, Bruce; Longstreth, W. T.; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N.; van Duijn, Cornelia M.; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C.; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M. Arfan; Martin, Nicholas G.; Wright, Margaret J.; Schumann, Gunter; Franke, Barbara; Thompson, Paul M.; Medland, Sarah E.

    2015-01-01

    The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability inhuman brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. PMID:25607358

  20. Common genetic variants influence human subcortical brain structures.

    Science.gov (United States)

    Hibar, Derrek P; Stein, Jason L; Renteria, Miguel E; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S; Armstrong, Nicola J; Bernard, Manon; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brown, Andrew A; Chakravarty, M Mallar; Chen, Qiang; Ching, Christopher R K; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Olde Loohuis, Loes M; Luciano, Michelle; Macare, Christine; Mather, Karen A; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rose, Emma J; Salami, Alireza; Sämann, Philipp G; Schmaal, Lianne; Schork, Andrew J; Shin, Jean; Strike, Lachlan T; Teumer, Alexander; van Donkelaar, Marjolein M J; van Eijk, Kristel R; Walters, Raymond K; Westlye, Lars T; Whelan, Christopher D; Winkler, Anderson M; Zwiers, Marcel P; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M H; Hartberg, Cecilie B; Haukvik, Unn K; Heister, Angelien J G A M; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C M; Lopez, Lorna M; Makkinje, Remco R R; Matarin, Mar; Naber, Marlies A M; McKay, D Reese; Needham, Margaret; Nugent, Allison C; Pütz, Benno; Royle, Natalie A; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S L; van Hulzen, Kimm J E; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A; Bastin, Mark E; Brodaty, Henry; Bulayeva, Kazima B; Carless, Melanie A; Cichon, Sven; Corvin, Aiden; Curran, Joanne E; Czisch, Michael; de Zubicaray, Greig I; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Fedko, Iryna O; Ferrucci, Luigi; Foroud, Tatiana M; Fox, Peter T; Fukunaga, Masaki; Gibbs, J Raphael; Göring, Harald H H; Green, Robert C; Guelfi, Sebastian; Hansell, Narelle K; Hartman, Catharina A; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G; Heslenfeld, Dirk J; Hoekstra, Pieter J; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Liu, Xinmin; Longo, Dan L; McMahon, Katie L; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W; Mostert, Jeanette C; Mühleisen, Thomas W; Nalls, Michael A; Nichols, Thomas E; Nilsson, Lars G; Nöthen, Markus M; Ohi, Kazutaka; Olvera, Rene L; Perez-Iglesias, Rocio; Pike, G Bruce; Potkin, Steven G; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D; Rujescu, Dan; Schnell, Knut; Schofield, Peter R; Smith, Colin; Steen, Vidar M; Sussmann, Jessika E; Thalamuthu, Anbupalam; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Valdés Hernández, Maria C; van 't Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J A; van Tol, Marie-Jose; Veltman, Dick J; Wassink, Thomas H; Westman, Eric; Zielke, Ronald H; Zonderman, Alan B; Ashbrook, David G; Hager, Reinmar; Lu, Lu; McMahon, Francis J; Morris, Derek W; Williams, Robert W; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Cahn, Wiepke; Calhoun, Vince D; Cavalleri, Gianpiero L; Crespo-Facorro, Benedicto; Dale, Anders M; Davies, Gareth E; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C; Espeseth, Thomas; Gollub, Randy L; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W J H; Roffman, Joshua L; Sisodiya, Sanjay M; Smoller, Jordan W; van Bokhoven, Hans; van Haren, Neeltje E M; Völzke, Henry; Walter, Henrik; Weiner, Michael W; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A; Blangero, John; Boomsma, Dorret I; Brouwer, Rachel M; Cannon, Dara M; Cookson, Mark R; de Geus, Eco J C; Deary, Ian J; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E; Francks, Clyde; Glahn, David C; Grabe, Hans J; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E; Jönsson, Erik G; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M; Ophoff, Roel A; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S; Saykin, Andrew J; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M; Weale, Michael E; Weinberger, Daniel R; Adams, Hieab H H; Launer, Lenore J; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L; Becker, James T; Yanek, Lisa; van der Lee, Sven J; Ebling, Maritza; Fischl, Bruce; Longstreth, W T; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N; van Duijn, Cornelia M; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M Arfan; Martin, Nicholas G; Wright, Margaret J; Schumann, Gunter; Franke, Barbara; Thompson, Paul M; Medland, Sarah E

    2015-04-09

    The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

  1. Genetic and Epigenetic Tumor Suppressor Gene Silencing are Distinct Molecular Phenotypes Driven by Growth Promoting Mutations in Non small Cell Lung Cancer

    International Nuclear Information System (INIS)

    Marsit, C. J.; Kelsey, K. T.; Houseman, E. A.; Kelsey, K. T.; Houseman, E. A.; Nelson, H. H.

    2008-01-01

    Both genetic and epigenetic alterations characterize human non small cell lung cancer (NSCLC), but the biological processes that create or select these alterations remain incompletely investigated. Our hypothesis posits that a roughly reciprocal relationship between the propensity for promoter hyper methylation and a propensity for genetic deletion leads to distinct molecular phenotypes of lung cancer. To test this hypothesis, we examined promoter hyper methylation of 17 tumor suppressor genes, as a marker of epigenetic alteration propensity, and deletion events at the 3p21 region, as a marker of genetic alteration. To model the complex biology between these somatic alterations, we utilized an item response theory model. We demonstrated that tumors exhibiting LOH at greater than 30% of informative alleles in the 3p21 region have a significantly reduced propensity for hyper methylation. At the same time, tumors with activating KRAS mutations showed a significantly increased propensity for hyper methylation of the loci examined, a result similar to what has been observed in colon cancer. These data suggest that NSCLCs have distinct epigenetic or genetic alteration phenotypes acting upon tumor suppressor genes and that mutation of oncogenic growth promoting genes, such as KRAS, is associated with the epigenetic phenotype.

  2. Theory and Practice in Quantitative Genetics

    DEFF Research Database (Denmark)

    Posthuma, Daniëlle; Beem, A Leo; de Geus, Eco J C

    2003-01-01

    With the rapid advances in molecular biology, the near completion of the human genome, the development of appropriate statistical genetic methods and the availability of the necessary computing power, the identification of quantitative trait loci has now become a realistic prospect for quantitative...... geneticists. We briefly describe the theoretical biometrical foundations underlying quantitative genetics. These theoretical underpinnings are translated into mathematical equations that allow the assessment of the contribution of observed (using DNA samples) and unobserved (using known genetic relationships......) genetic variation to population variance in quantitative traits. Several statistical models for quantitative genetic analyses are described, such as models for the classical twin design, multivariate and longitudinal genetic analyses, extended twin analyses, and linkage and association analyses. For each...

  3. Genetic programming theory and practice XII

    CERN Document Server

    Riolo, Rick; Kotanchek, Mark

    2015-01-01

    These contributions, written by the foremost international researchers and practitioners of Genetic Programming (GP), explore the synergy between theoretical and empirical results on real-world problems, producing a comprehensive view of the state of the art in GP. Topics in this volume include: gene expression regulation, novel genetic models for glaucoma, inheritable epigenetics, combinators in genetic programming, sequential symbolic regression, system dynamics, sliding window symbolic regression, large feature problems, alignment in the error space, HUMIE winners, Boolean multiplexer funct

  4. Development of gypsum alteration on marble and limestone

    Science.gov (United States)

    McGee, E.S.

    1996-01-01

    Blackened alteration crusts of gypsum plus particulates that form on sheltered areas on marble and limestone buildings pose a challenge for rehabilitation and cleaning. Fresh marble and limestone samples exposed at monitored exposure sites present conditions of simple geometry and well-documented exposures but have short exposure histories (one to five years). The gypsum alteration crusts that develop on these samples provide insight into the early stages and rate of alteration crust formation. Alteration crusts from buildings give a longer, but less well known exposure history and present much more complex surfaces for gypsum accumulation. Integrated observations and measurements of alteration crusts from exposure samples and from buildings identify four factors that are important in the formation and development of alteration crusts on marble and limestone: (1) pollution levels, (2) exposure to rain or washing, (3) geometry of exposure of the stone surface, and (4) permeability of the stone. The combination of these factors contributes to both the distribution and the physical characteristics of the gypsum crusts which may affect cleaning decisions.

  5. Effects of genetic distance on heterosis in a Drosophila melanogaster model system

    DEFF Research Database (Denmark)

    Jensen, Charlotte; Ørsted, Michael; Kristensen, Torsten Nygaard

    2018-01-01

    Habitat fragmentation and small population sizes can lead to inbreeding and loss of genetic variation, which can potentially cause inbreeding depression and decrease the ability of populations to adapt to altered environmental conditions. One solution to these genetic problems is the implementati...

  6. Sudden infant death syndrome and the genetics of inflammation

    Directory of Open Access Journals (Sweden)

    Linda eFerrante

    2015-02-01

    Full Text Available Several studies report signs of slight infection prior to death in cases of sudden infant death syndrome (SIDS. Based on this, a hypothesis of an altered immunological homeostasis has been postulated. The cytokines are important cellular mediators that are crucial for infant health by regulating cell activity during the inflammatory process. The pro-inflammatory cytokines favor inflammation; the most important of these are IL-1α, IL-1β, IL-6, IL-8, IL-12, IL-18, TNF-α and IFN-γ. These cytokines are controlled by the anti-inflammatory cytokines. This is accomplished by reducing the pro-inflammatory cytokine production, and thus counteracts their biological effect. The major anti-inflammatory cytokines are interleukin 1 receptor antagonist (IL-1ra, IL-4, IL-10, IL-11, and IL-13. The last decade there has been focus on genetic studies within genes that are important for the immune system, for SIDS with a special interest of the genes encoding the cytokines. This is because the cytokine genes are considered to be the genes most likely to explain the vulnerability to infection, and several studies have investigated these genes in an attempt to uncover associations between SIDS and different genetic variants. So far the genes encoding IL-1, IL-6, IL-10 and TNF-α are the most investigated within SIDS research, and several studies indicates associations between specific variants of these genes and SIDS. Taken together this may indicate that in at least a subset of SIDS predisposing genetic variants of the immune genes are involved. However, the immune system and the cytokine network are complex, and more studies are needed in order to better understand the interplay between different genetic variations and how this may contribute to an unfavorable immunological response.

  7. Genetic manipulation of structural color in bacterial colonies

    DEFF Research Database (Denmark)

    Johansen, Villads Egede; Catón, Laura; Hamidjaja, Raditijo

    2018-01-01

    analysis, we obtained a detailed correlation of how genetic modifications alter structural color in bacterial colonies. Understanding of genotype and phenotype relations in this system opens the way to genetic engineering of on-demand living optical materials, for use as paints and living sensors.......Naturally occurring photonic structures are responsible for the bright and vivid coloration in a large variety of living organisms. Despite efforts to understand their biological functions, development, and complex optical response, little is known of the underlying genes involved...

  8. Amygdala functional connectivity, HPA axis genetic variation, and life stress in children and relations to anxiety and emotion regulation

    Science.gov (United States)

    Pagliaccio, David; Luby, Joan L.; Bogdan, Ryan; Agrawal, Arpana; Gaffrey, Michael S.; Belden, Andrew C.; Botteron, Kelly N.; Harms, Michael P.; Barch, Deanna M.

    2015-01-01

    Internalizing pathology is related to alterations in amygdala resting state functional connectivity, potentially implicating altered emotional reactivity and/or emotion regulation in the etiological pathway. Importantly, there is accumulating evidence that stress exposure and genetic vulnerability impact amygdala structure/function and risk for internalizing pathology. The present study examined whether early life stress and genetic profile scores (10 single nucleotide polymorphisms within four hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predicted individual differences in amygdala functional connectivity in school-age children (9–14 year olds; N=120). Whole-brain regression analyses indicated that increasing genetic ‘risk’ predicted alterations in amygdala connectivity to the caudate and postcentral gyrus. Experience of more stressful and traumatic life events predicted weakened amygdala-anterior cingulate cortex connectivity. Genetic ‘risk’ and stress exposure interacted to predict weakened connectivity between the amygdala and the inferior and middle frontal gyri, caudate, and parahippocampal gyrus in those children with the greatest genetic and environmental risk load. Furthermore, amygdala connectivity longitudinally predicted anxiety symptoms and emotion regulation skills at a later follow-up. Amygdala connectivity mediated effects of life stress on anxiety and of genetic variants on emotion regulation. The current results suggest that considering the unique and interacting effects of biological vulnerability and environmental risk factors may be key to understanding the development of altered amygdala functional connectivity, a potential factor in the risk trajectory for internalizing pathology. PMID:26595470

  9. Amygdala functional connectivity, HPA axis genetic variation, and life stress in children and relations to anxiety and emotion regulation.

    Science.gov (United States)

    Pagliaccio, David; Luby, Joan L; Bogdan, Ryan; Agrawal, Arpana; Gaffrey, Michael S; Belden, Andrew C; Botteron, Kelly N; Harms, Michael P; Barch, Deanna M

    2015-11-01

    Internalizing pathology is related to alterations in amygdala resting state functional connectivity, potentially implicating altered emotional reactivity and/or emotion regulation in the etiological pathway. Importantly, there is accumulating evidence that stress exposure and genetic vulnerability impact amygdala structure/function and risk for internalizing pathology. The present study examined whether early life stress and genetic profile scores (10 single nucleotide polymorphisms within 4 hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predicted individual differences in amygdala functional connectivity in school-age children (9- to 14-year-olds; N = 120). Whole-brain regression analyses indicated that increasing genetic "risk" predicted alterations in amygdala connectivity to the caudate and postcentral gyrus. Experience of more stressful and traumatic life events predicted weakened amygdala-anterior cingulate cortex connectivity. Genetic "risk" and stress exposure interacted to predict weakened connectivity between the amygdala and the inferior and middle frontal gyri, caudate, and parahippocampal gyrus in those children with the greatest genetic and environmental risk load. Furthermore, amygdala connectivity longitudinally predicted anxiety symptoms and emotion regulation skills at a later follow-up. Amygdala connectivity mediated effects of life stress on anxiety and of genetic variants on emotion regulation. The current results suggest that considering the unique and interacting effects of biological vulnerability and environmental risk factors may be key to understanding the development of altered amygdala functional connectivity, a potential factor in the risk trajectory for internalizing pathology. (c) 2015 APA, all rights reserved).

  10. Somatic and genetic effects

    International Nuclear Information System (INIS)

    Broerse, J.J.; Barendsen, G.W.; Kal, H.B.; Kogel, A.J. van der

    1983-01-01

    This book contains the extended abstracts of the contributions of the poster workshop sessions on somatic and genetic effects of the 7th international congress of radiation research. They cover the following main topics: haematopoietic and immune systems, mechanisms of late effects in various tissues, endogenous and exogenous factors in radiation carcinogenesis, teratogenic effects, genetic effects, in vitro transformation, tumour induction in different tissues, carcinogenesis in incorporated tissues, cancer epidemology and risk assessment. refs.; figs.; tabs

  11. Environmental carcinogenesis and genetic variability

    International Nuclear Information System (INIS)

    Knudsen, A.G. Jr

    1977-01-01

    It was found that carcinogenesis in man may involve the interaction of genetic and environmental forces, and that mutation, whether germinal or somatic, seems to be involved in the origin of many, perhaps all cancers. The cancers of man may be visualized as occurring in four groups of individuals according to whether (1) neither genetic nor environmental factors are dominant, i.e. 'background' or 'spontaneous' cancer, (2) heredity alone is dominant, (3) environment alone is important, or (4) both are operating (Knudsen, 1977). The last two groups together are widely thought to contribute 70-80% of cancer cases in the United States; the relative contribution of each group is a major question to be answered

  12. Research on structure-alteration zone related to uranium mineralization and its exploration significance

    International Nuclear Information System (INIS)

    Huang Xianfang; Liu Dechang; Ye Fawang; Dong Xiuzhen; Yang Xu Zhang Hongguang

    2008-01-01

    The paper is focused on recommending geological characteristics of structure-alteration zone which is found from image interpretation in Bashibulake District, north of Tarim Basin, expounding remote sensing information enhancement and extraction technique, analyzing image feature, genetic mechanism and discussing the relationship between uranium mineralization and structure-alteration zone. A new discovery is raised through applying remote sensing information analysis and geologic analysis, that is, the uranium deposits in Bashibulake District are controlled by structure-alteration zone. The new understanding provides a new view point for reconsidering main controlling factors and uranium mineralization distribution in the area. It is helpful for further reconnaissance and exploration in the area. (authors)

  13. Genetic and Environmental Continuity in Personality Development: A Meta-Analysis

    Science.gov (United States)

    Briley, Daniel A.; Tucker-Drob, Elliot M.

    2014-01-01

    The longitudinal stability of personality is low in childhood, but increases substantially into adulthood. Theoretical explanations for this trend differ in the emphasis placed on intrinsic maturation and socializing influences. To what extent does the increasing stability of personality result from the continuity and crystallization of genetically influenced individual differences, and to what extent does the increasing stability of life experiences explain increases in personality trait stability? Behavioral genetic studies, which decompose longitudinal stability into sources associated with genetic and environmental variation, can help to address this question. We aggregated effect sizes from 24 longitudinal behavioral genetic studies containing information on a total of 21,057 sibling pairs from six types that varied in terms of genetic relatedness and ranged in age from infancy to old age. A combination of linear and nonlinear meta-analytic regression models were used to evaluate age-trends in levels of heritability and environmentality, stabilities of genetic and environmental effects, and the contributions of genetic and environmental effects to overall phenotypic stability. Both the genetic and environmental influences on personality increase in stability with age. The contribution of genetic effects to phenotypic stability is moderate in magnitude and relatively constant with age, in part because of small-to-moderate decreases in the heritability of personality over child development that offset increases in genetic stability. In contrast, the contribution of environmental effects to phenotypic stability increases from near-zero in early childhood to moderate in adulthood. The lifespan trend of increasing phenotypic stability, therefore, predominantly results from environmental mechanisms. PMID:24956122

  14. Common genetic variants influence human subcortical brain structures

    NARCIS (Netherlands)

    Hibar, D.P.; Stein, J.L.; Renteria, M.E.; Arias-Vasquez, A.; Desrivières, S.; Jahanshad, N.; Toro, R.; Wittfeld, K.; Abramovic, L.; Andersson, M.; Aribisala, B.S.; Armstrong, N.J.; Bernard, M.; Bohlken, M.M.; Biks, M.P.; Bralten, J.; Brown, A.A.; Chakravarty, M.M.; Chen, Q.; Ching, C.R.K.; Cuellar-Partida, G.; den Braber, A.; Giddaluru, S.; Goldman, A.L.; Grimm, O.; Guadalupe, T.; Hass, J.; Woldehawariat, G.; Holmes, A.J.; Hoogman, M.; Janowitz, D.; Jia, T.; Kim, S.; Klein, M.; Kraemer, B.; Lee, P.H.; Olde Loohuis, L.M.; Luciano, M.; Macare, C.; Mather, K.A.; Mattheisen, M.; Milaneschi, Y.; Nho, K.; Papmeyer, M.; Ramasamy, A.; Risacher, S.L.; Roiz-Santiañez, R.; Rose, E.J.; Salami, A.; Sämann, P.G.; Schmaal, L.; Schork, A.J.; Shin, J.; Strike, L.T.; Teumer, A.; Donkelaar, M.M.J.; van Eijk, K.R.; Walters, R.K.; Westlye, L.T.; Welan, C.D.; Winkler, A.M.; Zwiers, M.P.; Alhusaini, S.; Athanasiu, L.; Ehrlich, S.; Hakobjan, M.M.H.; Hartberg, C.B.; Haukvik, U.K.; Heister, A.J.G.A.M.; Hoehn, D.; Kasperaviciute, D.; Liewald, D.C.M.; Lopez, L.M.; Makkinje, R.R.; Matarin, M.; Naber, M.A.M.; Reese McKay, D.; Needham, M.; Nugent, A.C.; Pütz, B.; Royle, N.A.; Shen, L.; Sprooten, E.; Trabzuni, D.; van der Marel, S.S.L.; van Hulzen, K.J.E.; Walton, E.; Wolf, C.; Almasy, L.; Ames, D.; Arepalli, S.; Assareh, A.A.; Bastin, M.E.; Brodaty, H.; Bulayeva, K.B.; Carless, M.A.; Cichon, S.; Corvin, A.; Curran, J.E.; Czisch, M.; de Zubicaray, G.I.; Dillman, A.; Duggirala, R.; Dyer, T.D.; Erk, S.; Fedko, I.O.; Ferrucci, L.; Foroud, T.M.; Fox, P.T.; Fukunaga, M.; Gibbs, J.R.; Göring, H.H.H.; Green, R.C.; Guelfi, S.; Hansell, N.K.; Hartman, C.A.; Hegenscheid, K.; Heinz, A.; Hernandez, D.G.; Heslenfeld, D.J.; Hoekstra, P.J.; Holsboer, F.; Homuth, G.; Hottenga, J.J.; Ikeda, M.; Jack, C.R., Jr.; Jenkinson, M.; Johnson, R.; Kanai, R.; Keil, M.; Kent, J.W. Jr.; Kochunov, P.; Kwok, J.B.; Lawrie, S.M.; Liu, X.; Longo, D.L.; McMahon, K.L.; Meisenzahl, E.; Melle, I.; Mohnke, S.; Montgomery, G.W.; Mostert, J.C.; Mühleisen, T.W.; Nalls, M.A.; Nichols, T.E.; Nilsson, L.G.; Nöthen, M.M.; Ohi, K.; Olvera, R.L.; Perez-Iglesias, R.; Pike, G.B.; Potkin, S.G.; Reinvang, I.; Reppermund, S.; Rietschel, M.; Romanczuk-Seiferth, N.; Rosen, G.D.; Rujescu, D.; Schnell, K.; Schofield, P.R.; Smith, C.; Steen, V.M.; Sussmann, J.E.; Thalamuthu, A.; Toga, A.W.; Traynor, B.J.; Troncoso, J.; Turner, J.A.; Valdés Hernández, M.C.; van t Ent, D.; van der Brug, M.; van der Wee, N.J.A.; van Tol, M.J.; Veltman, D.J.; Wassink, T.H.; Westmann, E.; Zielke, R.H.; Zonderman, A.B.; Ashbrook, D.G.; Hager, R.; Lu, L.; McMahon, F.J.; Morris, D.W.; Williams, R.W.; Brunner, H.G.; Buckner, R.L.; Buitelaar, J.K.; Cahn, W.; Calhoun, V.D.; Cavalleri, G.L.; Crespo-Facorro, B.; Dale, A.M.; Davies, G.E.; Delanty, N.; Depondt, C.; Djurovic, S.; Drevets, W.C.; Espeseth, T.; Gollub, R.L.; Ho, B.C.; Hoffmann, W.; Hosten, N.; Kahn, R.S.; Le Hellard, S.; Meyer-Lindenberg, A.; Müller-Myhsok, B.; Nauck, M.; Nyberg, L.; Pandolfo, M.; Penninx, B.W.J.H.; Roffman, J.L.; Sisodiya, SM; Smoller, J.W.; van Bokhoven, H.; van Haren, N.E.M.; Völzke, H.; Walter, H.; Weiner, M.W.; Wen, W.; White, T.; Agartz, I.; Andreassen, O.A.; Blangero, J.; Boomsma, D.I.; Brouwer, R.M.; Cannon, D.M.; Cookson, M.R.; de Geus, E.J.C.; Deary, I.J.; Donohoe, G.; Fernandez, G.; Fisher, S.E.; Francks, C.; Glahn, D.C.; Grabe, H.J.; Gruber, O.; Hardy, J.; Hashimoto, R.; Hulshoff Pol, H.E.; Jönsson, E.G.; Kloszewska, I.; Lovestone, S.; Mattay, V.S.; Mecocci, P.; McDonald, C.; McIntosh, A.M.; Ophoff, R.A.; Paus, T.; Pausova, Z.; Ryten, M.; Sachdev, P.S.; Saykin, A.J.; Simmons, A.; Singleton, A.; Soininen, H.; Wardlaw, J.M.; Weale, M.E.; Weinberger, D.R.; Adams, H.H.H.; Launer, L.J.; Seiler, S.; Schmidt, R.; Chauhan, G.; Satizabal, C.L.; Becker, J.T.; Yanek, L.; van der Lee, S.J.; Ebling, M.; Fischl, B.; Longstreth, Jr. W.T.; Greve, D.; Schmidt, H.; Nyquist, P.; Vinke, L.N.; van Duijn, C.M.; Xue, L.; Mazoyer, B.; Bis, J.C.; Gudnason, V.; Seshadri, S.; Arfan Ikram, M.; Martin, N.G.; Wright, M.J.; Schumann, G.; Franke, B.; Thompson, P.M.; Medland, S.E.

    2015-01-01

    The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common

  15. Common genetic variants influence human subcortical brain structures

    NARCIS (Netherlands)

    D.P. Hibar (Derrek); J.L. Stein; M.E. Rentería (Miguel); A. Arias-Vásquez (Alejandro); S. Desrivières (Sylvane); N. Jahanshad (Neda); R. Toro (Roberto); K. Wittfeld (Katharina); L. Abramovic (Lucija); M. Andersson (Micael); B. Aribisala (Benjamin); N.J. Armstrong (Nicola J.); M. Bernard (Manon); M.M. Bohlken (Marc M.); M.P.M. Boks (Marco); L.B.C. Bralten (Linda); A.A. Brown (Andrew); M.M. Chakravarty (M. Mallar); Q. Chen (Qiang); C.R.K. Ching (Christopher); G. Cuellar-Partida (Gabriel); A. den Braber (Anouk); S. Giddaluru (Sudheer); A.L. Goldman (Aaron L.); O. Grimm (Oliver); T. Guadalupe (Tulio); J. Hass (Johanna); G. Woldehawariat (Girma); A.J. Holmes (Avram); M. Hoogman (Martine); D. Janowitz (Deborah); T. Jia (Tianye); S. Kim (Shinseog); M. Klein (Marieke); B. Kraemer (Bernd); P.H. Lee (Phil H.); L.M. Olde Loohuis (Loes M.); M. Luciano (Michelle); C. MacAre (Christine); R. Mather; M. Mattheisen (Manuel); Y. Milaneschi (Yuri); K. Nho (Kwangsik); M. Papmeyer (Martina); A. Ramasamy (Adaikalavan); S.L. Risacher (Shannon); R. Roiz-Santiañez (Roberto); E.J. Rose (Emma); A. Salami (Alireza); P.G. Sämann (Philipp); L. Schmaal (Lianne); N.J. Schork (Nicholas); J. Shin (Jean); L.T. Strike (Lachlan); A. Teumer (Alexander); M.M.J. Van Donkelaar (Marjolein M. J.); K.R. van Eijk (Kristel); R.K. Walters (Raymond); L.T. Westlye (Lars); C.D. Whelan (Christopher); A.M. Winkler (Anderson); M.P. Zwiers (Marcel); S. Alhusaini (Saud); L. Athanasiu (Lavinia); S.M. Ehrlich (Stefan); M. Hakobjan (Marina); C.B. Hartberg (Cecilie B.); U.K. Haukvik (Unn); A.J.G.A.M. Heister (Angelien J. G. A. M.); D. Hoehn (David); D. Kasperaviciute (Dalia); D.C. Liewald (David C.); L.M. Lopez (Lorna); R.R.R. Makkinje (Remco R. R.); M. Matarin (Mar); M.A.M. Naber (Marlies A. M.); D. Reese McKay; M. Needham (Margaret); A.C. Nugent (Allison); B. Pütz (Benno); N.A. Royle (Natalie); L. Shen (Li); R. Sprooten (Roy); D. Trabzuni (Danyah); S.S.L. Van Der Marel (Saskia S. L.); K.J.E. Van Hulzen (Kimm J. E.); E. Walton (Esther); A. Björnsson (Asgeir); L. Almasy (Laura); D.J. Ames (David); S. Arepalli (Sampath); A.A. Assareh; M.E. Bastin (Mark); H. Brodaty (Henry); K. Bulayeva (Kazima); M.A. Carless (Melanie); S. Cichon (Sven); A. Corvin (Aiden); J.E. Curran (Joanne); M. Czisch (Michael); G.I. de Zubicaray (Greig); A. Dillman (Allissa); A. Duggirala (Aparna); M.D. Dyer (Matthew); S. Erk; I. Fedko (Iryna); L. Ferrucci (Luigi); T. Foroud (Tatiana); P.T. Fox (Peter); M. Fukunaga (Masaki); J. Raphael Gibbs; H.H.H. Göring (Harald H.); R.C. Green (Robert C.); S. Guelfi (Sebastian); N.K. Hansell (Narelle); C.A. Hartman (Catharina); K. Hegenscheid (Katrin); J. Heinz (Judith); D.G. Hernandez (Dena); D.J. Heslenfeld (Dirk); P.J. Hoekstra (Pieter); F. Holsboer; G. Homuth (Georg); J.J. Hottenga (Jouke Jan); M. Ikeda (Masashi); C.R. Jack Jr. (Clifford); S. Jenkinson (Sarah); R. Johnson (Robert); R. Kanai (Ryota); M. Keil (Maria); J.W. Kent (Jack W.); P. Kochunov (Peter); J.B. Kwok (John B.); S. Lawrie (Stephen); X. Liu (Xinmin); D.L. Longo (Dan L.); K.L. Mcmahon (Katie); E. Meisenzahl (Eva); I. Melle (Ingrid); S. Mohnke (Sebastian); G.W. Montgomery (Grant); J.C. Mostert (Jeanette C.); T.W. Mühleisen (Thomas); M.A. Nalls (Michael); T.E. Nichols (Thomas); L.G. Nilsson; M.M. Nöthen (Markus); K. Ohi (Kazutaka); R.L. Olvera (Rene); R. Perez-Iglesias (Rocio); G. Bruce Pike; S.G. Potkin (Steven); I. Reinvang (Ivar); S. Reppermund; M. Rietschel (Marcella); N. Seiferth (Nina); G.D. Rosen (Glenn D.); D. Rujescu (Dan); K. Schnell (Kerry); C.J. Schofield (Christopher); C. Smith (Colin); V.M. Steen (Vidar); J. Sussmann (Jessika); A. Thalamuthu (Anbupalam); A.W. Toga (Arthur W.); B. Traynor (Bryan); J.C. Troncoso (Juan); J. Turner (Jessica); M.C. Valdés Hernández (Maria); D. van 't Ent (Dennis); M.P. van der Brug (Marcel); N.J. van der Wee (Nic); M.J.D. van Tol (Marie-José); D.J. Veltman (Dick); A.M.J. Wassink (Annemarie); E. Westman (Eric); R.H. Zielke (Ronald H.); A.B. Zonderman (Alan B.); D.G. Ashbrook (David G.); R. Hager (Reinmar); L. Lu (Lu); F.J. Mcmahon (Francis J); D.W. Morris (Derek W); R.W. Williams (Robert W.); H.G. Brunner; M. Buckner; J.K. Buitelaar (Jan K.); W. Cahn (Wiepke); V.D. Calhoun Vince D. (V.); G. Cavalleri (Gianpiero); B. Crespo-Facorro (Benedicto); A.M. Dale (Anders); G.E. Davies (Gareth); N. Delanty; C. Depondt (Chantal); S. Djurovic (Srdjan); D.A. Drevets (Douglas); T. Espeseth (Thomas); R.L. Gollub (Randy); B.C. Ho (Beng ); W. Hoffmann (Wolfgang); N. Hosten (Norbert); R. Kahn (René); S. Le Hellard (Stephanie); A. Meyer-Lindenberg; B. Müller-Myhsok (B.); M. Nauck (Matthias); L. Nyberg (Lars); M. Pandolfo (Massimo); B.W.J.H. Penninx (Brenda); J.L. Roffman (Joshua); S.M. Sisodiya (Sanjay); J.W. Smoller; H. van Bokhoven (Hans); N.E.M. van Haren (Neeltje E.); H. Völzke (Henry); H.J. Walter (Henrik); M.W. Weiner (Michael); W. Wen (Wei); T.J.H. White (Tonya); I. Agartz (Ingrid); O.A. Andreassen (Ole); J. Blangero (John); D.I. Boomsma (Dorret); R.M. Brouwer (Rachel); D.M. Cannon (Dara); M.R. Cookson (Mark); E.J.C. de Geus (Eco); I.J. Deary (Ian J.); D.J. Donohoe (Dennis); G. Fernandez (Guillén); S.E. Fisher (Simon); C. Francks (Clyde); D.C. Glahn (David); H.J. Grabe (Hans Jörgen); O. Gruber (Oliver); J. Hardy (John); R. Hashimoto (Ryota); H.E. Hulshoff Pol (Hilleke); E.G. Jönsson (Erik); I. Kloszewska (Iwona); S. Lovestone (Simon); V.S. Mattay (Venkata S.); P. Mecocci (Patrizia); C. McDonald (Colm); A.M. McIntosh (Andrew); R.A. Ophoff (Roel); T. Paus (Tomas); Z. Pausova (Zdenka); M. Ryten (Mina); P.S. Sachdev (Perminder); A.J. Saykin (Andrew); A. Simmons (Andrew); A. Singleton (Andrew); H. Soininen (H.); J.M. Wardlaw (J.); M.E. Weale (Michael); D.R. Weinberger (Daniel); H.H.H. Adams (Hieab); L.J. Launer (Lenore); S. Seiler (Stephan); R. Schmidt (Reinhold); G. Chauhan (Ganesh); C.L. Satizabal (Claudia L.); J.T. Becker (James); L.R. Yanek (Lisa); S.J. van der Lee (Sven); M. Ebling (Maritza); B. Fischl (Bruce); W.T. Longstreth Jr; D. Greve (Douglas); R. Schmidt (Reinhold); P. Nyquist (Paul); L.N. Vinke (Louis N.); C.M. van Duijn (Cornelia); L. Xue (Luting); B. Mazoyer (Bernard); J.C. Bis (Joshua); V. Gudnason (Vilmundur); S. Seshadri (Sudha); M.A. Ikram (Arfan); N.G. Martin (Nicholas); M.J. Wright (Margaret); G. Schumann (Gunter); B. Franke (Barbara); P.M. Thompson (Paul); S.E. Medland (Sarah Elizabeth)

    2015-01-01

    textabstractThe highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate

  16. Dominance genetic variance for traits under directional selection in Drosophila serrata.

    Science.gov (United States)

    Sztepanacz, Jacqueline L; Blows, Mark W

    2015-05-01

    In contrast to our growing understanding of patterns of additive genetic variance in single- and multi-trait combinations, the relative contribution of nonadditive genetic variance, particularly dominance variance, to multivariate phenotypes is largely unknown. While mechanisms for the evolution of dominance genetic variance have been, and to some degree remain, subject to debate, the pervasiveness of dominance is widely recognized and may play a key role in several evolutionary processes. Theoretical and empirical evidence suggests that the contribution of dominance variance to phenotypic variance may increase with the correlation between a trait and fitness; however, direct tests of this hypothesis are few. Using a multigenerational breeding design in an unmanipulated population of Drosophila serrata, we estimated additive and dominance genetic covariance matrices for multivariate wing-shape phenotypes, together with a comprehensive measure of fitness, to determine whether there is an association between directional selection and dominance variance. Fitness, a trait unequivocally under directional selection, had no detectable additive genetic variance, but significant dominance genetic variance contributing 32% of the phenotypic variance. For single and multivariate morphological traits, however, no relationship was observed between trait-fitness correlations and dominance variance. A similar proportion of additive and dominance variance was found to contribute to phenotypic variance for single traits, and double the amount of additive compared to dominance variance was found for the multivariate trait combination under directional selection. These data suggest that for many fitness components a positive association between directional selection and dominance genetic variance may not be expected. Copyright © 2015 by the Genetics Society of America.

  17. Predicting cell types and genetic variations contributing to disease by combining GWAS and epigenetic data.

    Directory of Open Access Journals (Sweden)

    Anna Gerasimova

    Full Text Available Genome-wide association studies (GWASs identify single nucleotide polymorphisms (SNPs that are enriched in individuals suffering from a given disease. Most disease-associated SNPs fall into non-coding regions, so that it is not straightforward to infer phenotype or function; moreover, many SNPs are in tight genetic linkage, so that a SNP identified as associated with a particular disease may not itself be causal, but rather signify the presence of a linked SNP that is functionally relevant to disease pathogenesis. Here, we present an analysis method that takes advantage of the recent rapid accumulation of epigenomics data to address these problems for some SNPs. Using asthma as a prototypic example; we show that non-coding disease-associated SNPs are enriched in genomic regions that function as regulators of transcription, such as enhancers and promoters. Identifying enhancers based on the presence of the histone modification marks such as H3K4me1 in different cell types, we show that the location of enhancers is highly cell-type specific. We use these findings to predict which SNPs are likely to be directly contributing to disease based on their presence in regulatory regions, and in which cell types their effect is expected to be detectable. Moreover, we can also predict which cell types contribute to a disease based on overlap of the disease-associated SNPs with the locations of enhancers present in a given cell type. Finally, we suggest that it will be possible to re-analyze GWAS studies with much higher power by limiting the SNPs considered to those in coding or regulatory regions of cell types relevant to a given disease.

  18. Genetic counselling in the beta-thalassaemias

    Directory of Open Access Journals (Sweden)

    Adonis S. Ioannides

    2013-03-01

    Full Text Available The beta-thalassaemias are very important genetic disorders of haemoglobin synthesis and are amongst the commonest monogenic disorders. In view of the severity of beta-thalassaemia major, a number of screening programmes have been developed aimed at reducing the number of individuals born with the condition. Genetic counsellingplays a vital role in this process supporting the successful implementation of screening and delineating available options to at risk individuals. This review assesses the contribution of genetic counsellingat each stage of this process in the context of new diagnostic techniques and therapeutic options and discusses some of the more challenging aspects such as genotype/ phenotype correlation and coinheritance of other genetic conditions or genetic modifiers.

  19. Anthropogenic fragmentation may not alter pre-existing patterns of genetic diversity and differentiation in perennial shrubs.

    Science.gov (United States)

    Llorens, Tanya M; Ayre, David J; Whelan, Robert J

    2018-04-01

    Many plant species have pollination and seed dispersal systems and evolutionary histories that have produced strong genetic structuring. These genetic patterns may be consistent with expectations following recent anthropogenic fragmentation, making it difficult to detect fragmentation effects if no prefragmentation genetic data are available. We used microsatellite markers to investigate whether severe habitat fragmentation may have affected the structure and diversity of populations of the endangered Australian bird-pollinated shrub Grevillea caleyi R.Br., by comparing current patterns of genetic structure and diversity with those of the closely related G. longifolia R.Br. that has a similar life history but has not experienced anthropogenic fragmentation. Grevillea caleyi and G. longifolia showed similar and substantial population subdivision at all spatial levels (global F' ST  = 0.615 and 0.454; S p  = 0.039 and 0.066), marked isolation by distance and large heterozygous deficiencies. These characteristics suggest long-term effects of inbreeding in self-compatible species that have poor seed dispersal, limited connectivity via pollen flow and undergo population bottlenecks because of periodic fires. Highly structured allele size distributions, most notably in G. caleyi, imply historical processes of drift and mutation were important in isolated subpopulations. Genetic diversity did not vary with population size but was lower in more isolated populations for both species. Through this comparison, we reject the hypothesis that anthropogenic fragmentation has impacted substantially on the genetic composition or structure of G. caleyi populations. Our results suggest that highly self-compatible species with limited dispersal may be relatively resilient to the genetic changes predicted to follow habitat fragmentation. © 2018 John Wiley & Sons Ltd.

  20. Domain altering SNPs in the human proteome and their impact on signaling pathways.

    Directory of Open Access Journals (Sweden)

    Yichuan Liu

    Full Text Available Single nucleotide polymorphisms (SNPs constitute an important mode of genetic variations observed in the human genome. A small fraction of SNPs, about four thousand out of the ten million, has been associated with genetic disorders and complex diseases. The present study focuses on SNPs that fall on protein domains, 3D structures that facilitate connectivity of proteins in cell signaling and metabolic pathways. We scanned the human proteome using the PROSITE web tool and identified proteins with SNP containing domains. We showed that SNPs that fall on protein domains are highly statistically enriched among SNPs linked to hereditary disorders and complex diseases. Proteins whose domains are dramatically altered by the presence of an SNP are even more likely to be present among proteins linked to hereditary disorders. Proteins with domain-altering SNPs comprise highly connected nodes in cellular pathways such as the focal adhesion, the axon guidance pathway and the autoimmune disease pathways. Statistical enrichment of domain/motif signatures in interacting protein pairs indicates extensive loss of connectivity of cell signaling pathways due to domain-altering SNPs, potentially leading to hereditary disorders.

  1. Genetic background contributes to the co-morbidity of anxiety and depression with audiogenic seizure propensity and responses to fluoxetine treatment.

    Science.gov (United States)

    Sarkisova, Karine Yu; Fedotova, Irina B; Surina, Natalia M; Nikolaev, Georgy M; Perepelkina, Olga V; Kostina, Zoya A; Poletaeva, Inga I

    2017-03-01

    Anxiety and depression are the most frequent comorbidities of different types of convulsive and non-convulsive epilepsies. Increased anxiety and depression-like phenotype have been described in the genetic absence epilepsy models as well as in models of limbic epilepsy and acquired seizure models, suggesting a neurobiological connection. However, whether anxiety and/or depression are comorbid to audiogenic epilepsy remains unclear. The aim of this study was to investigate whether anxiety or depression-like behavior can be found in rat strains with different susceptibility to audiogenic seizures (AS) and whether chronic fluoxetine treatment affects this co-morbidity. Behavior in the elevated plus-maze and the forced swimming test was studied in four strains: Wistar rats non-susceptible to AS; Krushinsky-Molodkina (KM) strain, selectively bred for AS propensity from outbred Wistar rats; and a selection lines bred for maximal AS expression (strain "4") and for a lack of AS (strain "0") from KM×Wistar F2 hybrids. Effects of chronic antidepressant treatment on AS and behavior were also evaluated. Anxiety and depression levels were higher in KM rats (with AS) compared with Wistar rats (without AS), indicating the comorbidity with AS. However, in strains "4" and "0" with contrasting AS expression, but with a genetic background close to KM rats, anxiety and depression were not as divergent as in KMs versus Wistars. Fluoxetine treatment exerted an antidepressant effect in all rat strains irrespective of its effect on AS. Genetic background contributes substantively to the co-morbidity of anxiety and depression with AS propensity. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Characterization of unknown genetic modifications using high throughput sequencing and computational subtraction

    Directory of Open Access Journals (Sweden)

    Butenko Melinka A

    2009-10-01

    Full Text Available Abstract Background When generating a genetically modified organism (GMO, the primary goal is to give a target organism one or several novel traits by using biotechnology techniques. A GMO will differ from its parental strain in that its pool of transcripts will be altered. Currently, there are no methods that are reliably able to determine if an organism has been genetically altered if the nature of the modification is unknown. Results We show that the concept of computational subtraction can be used to identify transgenic cDNA sequences from genetically modified plants. Our datasets include 454-type sequences from a transgenic line of Arabidopsis thaliana and published EST datasets from commercially relevant species (rice and papaya. Conclusion We believe that computational subtraction represents a powerful new strategy for determining if an organism has been genetically modified as well as to define the nature of the modification. Fewer assumptions have to be made compared to methods currently in use and this is an advantage particularly when working with unknown GMOs.

  3. Applying genetics in inflammatory disease drug discovery

    DEFF Research Database (Denmark)

    Folkersen, Lasse; Biswas, Shameek; Frederiksen, Klaus Stensgaard

    2015-01-01

    , with several notable exceptions, the journey from a small-effect genetic variant to a functional drug has proven arduous, and few examples of actual contributions to drug discovery exist. Here, we discuss novel approaches of overcoming this hurdle by using instead public genetics resources as a pragmatic guide...... alongside existing drug discovery methods. Our aim is to evaluate human genetic confidence as a rationale for drug target selection....

  4. Molecular genetic alterations in egfr CA-SSR-1 microsatellite and egfr copy number changes are associated with aggressiveness in thymoma.

    Science.gov (United States)

    Conti, Salvatore; Gallo, Enzo; Sioletic, Stefano; Facciolo, Francesco; Palmieri, Giovannella; Lauriola, Libero; Evoli, Amelia; Martucci, Robert; Di Benedetto, Anna; Novelli, Flavia; Giannarelli, Diana; Deriu, Gloria; Granone, Pierluigi; Ottaviano, Margaret; Muti, Paola; Pescarmona, Edoardo; Marino, Mirella

    2016-03-01

    The key role of egfr in thymoma pathogenesis has been questioned following the failure in identifying recurrent genetic alterations of egfr coding sequences and relevant egfr amplification rate. We investigated the role of the non-coding egfr CA simple sequence repeat 1 (CA-SSR-1) in a thymoma case series. We used sequencing and egfr-fluorescence in situ hybridization (FISH) to genotype 43 thymomas; (I) for polymorphisms and somatic loss of heterozygosity of the non-coding egfr CA-SSR-1 microsatellite and (II) for egfr gene copy number changes. We found two prevalent CA-SSR-1 genotypes: a homozygous 16 CA repeat and a heterozygous genotype, bearing alleles with 16 and 20 CA repeats. The average combined allele length was correlated with tumor subtype: shorter sequences were significantly associated with the more aggressive WHO thymoma subtype group including B2/B3, B3 and B3/C histotypes. Four out of 29 informative cases analysed for somatic CA-SSR-1 loss of heterozygosity showed allelic imbalance (AI), 3/4 with loss of the longer allele. By egfr-FISH analysis, 9 out of 33 cases were FISH positive. Moreover, the two integrated techniques demonstrated that 3 out of 4 CA-SSR-1-AI positive cases with short allele relative prevalence showed significantly low or high chromosome 7 "polysomy"/increased gene copy number by egfr-FISH. Our molecular and genetic and follow up data indicated that CA-SSR-1-allelic imbalance with short allele relative prevalence significantly correlated with EGFR 3+ immunohistochemical score, increased egfr Gene Copy Number, advanced stage and with relapsing/metastatic behaviour in thymomas.

  5. Mission Planning for Unmanned Aircraft with Genetic Algorithms

    DEFF Research Database (Denmark)

    Hansen, Karl Damkjær

    unmanned aircraft are used for aerial surveying of the crops. The farmer takes the role of the analyst above, who does not necessarily have any specific interest in remote controlled aircraft but needs the outcome of the survey. The recurring method in the study is the genetic algorithm; a flexible...... contributions are made in the area of the genetic algorithms. One is a method to decide on the right time to stop the computation of the plan, when the right balance is stricken between using the time planning and using the time flying. The other contribution is a characterization of the evolutionary operators...... used in the genetic algorithm. The result is a measure based on entropy to evaluate and control the diversity of the population of the genetic algorithm, which is an important factor its effectiveness....

  6. Contribution of electron microscopy to the study of alteration layers formed on the surface of glasses

    International Nuclear Information System (INIS)

    Crovisier, J.L.; Eberhart, J.P.

    1985-01-01

    In order to understand the whole process of glass corrosion in aqueous solutions, the analysis of the reagent must be completed by a study of the actual alteration layers on the glass surface. Transmission electron microscopy on ultramicrotomic thin sections turns out to be a most suitable tool to achieve this. It enables to supplement the conventional methods of surface investigation, such as A.E.S., ESCA, IRRS, SIMS. Two examples are given. The first deals with a (SiO 2 -CaO-Na 2 O-P 2 O 5 )- glass leached in a buffer solution of tris-hydromethyl-aminomethane at 40 0 C. The major feature is ion exchange within a residual porous glass, followed by the precipitation of hydroxyapatite. In the second example, a basaltic glass is altered in sea-water at 50 0 C. The glass constituents are dissolved simultaneously and the alteration layer is a precipitate of crystalline and amorphous phases which have reached their saturation level [fr

  7. The genetics of radiation-induced and sporadic osteosarcoma: a unifying theory?

    International Nuclear Information System (INIS)

    Rosemann, Michael; Kuosaite, Virginija; Nathrath, Michaela; Atkinson, Michael J.

    2002-01-01

    Cancer is a disease of the genome, with the neoplastic phenotype being passed from one cell generation to the other. Radiation-induced cancer has often been considered to represent a unique entity amongst neoplasia, with the energy deposition being held responsible for both direct (gene mutations) and indirect (bystander effects, induced instability etc) alterations to the cellular genome. However, radiogenic tumours in man and experimental animals appear to be physiologically and genetically indistinguishable from their sporadic counterparts, suggesting that the aetiologies of these two tumour types are in fact closely related. We have conducted a general screen of the genetic alterations in radiation-induced mouse osteosarcoma, a tumour that is histopathologically indistinguishable from human sporadic osteosarcoma. Comparison of the two tumour types indicates the existence of a common set of genetic changes, providing additional evidence to support the concept that the molecular pathology of radiation-induced malignancy is no different to that of sporadic cancers. (author)

  8. Genetically altering the expression of neutral trehalase gene affects conidiospore thermotolerance of the entomopathogenic fungus Metarhizium acridum

    Directory of Open Access Journals (Sweden)

    Peng Guoxiong

    2011-02-01

    Full Text Available Abstract Background The entomopathogenic fungus Metarhizium acridum has been used as an important biocontrol agent instead of insecticides for controlling crop pests throughout the world. However, its virulence varies with environmental factors, especially temperature. Neutral trehalase (Ntl hydrolyzes trehalose, which plays a role in environmental stress response in many organisms, including M. acridum. Demonstration of a relationship between Ntl and thermotolerance or virulence may offer a new strategy for enhancing conidiospore thermotolerance of entomopathogenic fungi through genetic engineering. Results We selected four Ntl over-expression and four Ntl RNA interference (RNAi transformations in which Ntl expression is different. Compared to the wild-type, Ntl mRNA expression was reduced to 35-66% in the RNAi mutants and increased by 2.5-3.5-fold in the over-expression mutants. The RNAi conidiospores exhibited less trehalase activity, accumulated more trehalose, and were much more tolerant of heat stress than the wild-type. The opposite effects were found in conidiospores of over-expression mutants compared to RNAi mutants. Furthermore, virulence was not altered in the two types of mutants compared to the wild type. Conclusions Ntl controlled trehalose accumulation in M. acridum by degrading trehalose, and thus affected conidiospore thermotolerance. These results offer a new strategy for enhancing conidiospore thermotolerance of entomopathogenic fungi without affecting virulence.

  9. Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels

    Science.gov (United States)

    Emdin, Connor A.; Khera, Amit V.; Natarajan, Pradeep; Klarin, Derek; Won, Hong-Hee; Peloso, Gina M.; Stitziel, Nathan O.; Nomura, Akihiro; Zekavat, Seyedeh M.; Bick, Alexander G.; Gupta, Namrata; Asselta, Rosanna; Duga, Stefano; Merlini, Piera Angelica; Correa, Adolfo; Kessler, Thorsten; Wilson, James G.; Bown, Matthew J.; Hall, Alistair S.; Braund, Peter S.; Samani, Nilesh J.; Schunkert, Heribert; Marrugat, Jaume; Elosua, Roberto; McPherson, Ruth; Farrall, Martin; Watkins, Hugh; Willer, Cristen; Abecasis, Gonçalo R.; Felix, Janine F.; Vasan, Ramachandran S.; Lander, Eric; Rader, Daniel J.; Danesh, John; Ardissino, Diego; Gabriel, Stacey; Saleheen, Danish; Kathiresan, Sekar

    2017-01-01

    BACKGROUND Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose-response curve of target perturbation. OBJECTIVES We attempted to establish the full phenotypic impact of LPA gene variation and to estimate a dose-response curve between genetically altered plasma Lp(a) and risk for CHD. METHODS We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the UK Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from cases with and controls free of CHD. RESULTS One standard deviation genetically lowered Lp(a) level was associated with 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased risk for CHD whereas those that led to loss of gene function reduced CHD risk. CONCLUSIONS Beyond CHD, genetically lowered Lp(a) is associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may impact a range of atherosclerosis-related diseases. PMID:28007139

  10. Novel Gentic Variations Contributing to Asthma Susceptability in Saudi Arabia

    Science.gov (United States)

    2014-04-13

    Collection of Clinical Data That Will be Used in This Study and Will Form a Data Bank for Asthma in Saudi Arabia; Identify Known and NOVEL Genetic Risk Factors Contributing to Asthma Susceptibility; Study the Mechanistic Roles of the Genetic Variants Within Major Asthma Susceptibility Genes

  11. Genetic Deletion of Rheb1 in the Brain Reduces Food Intake and Causes Hypoglycemia with Altered Peripheral Metabolism

    Directory of Open Access Journals (Sweden)

    Wanchun Yang

    2014-01-01

    Full Text Available Excessive food/energy intake is linked to obesity and metabolic disorders, such as diabetes. The hypothalamus in the brain plays a critical role in the control of food intake and peripheral metabolism. The signaling pathways in hypothalamic neurons that regulate food intake and peripheral metabolism need to be better understood for developing pharmacological interventions to manage eating behavior and obesity. Mammalian target of rapamycin (mTOR, a serine/threonine kinase, is a master regulator of cellular metabolism in different cell types. Pharmacological manipulations of mTOR complex 1 (mTORC1 activity in hypothalamic neurons alter food intake and body weight. Our previous study identified Rheb1 (Ras homolog enriched in brain 1 as an essential activator of mTORC1 activity in the brain. Here we examine whether central Rheb1 regulates food intake and peripheral metabolism through mTORC1 signaling. We find that genetic deletion of Rheb1 in the brain causes a reduction in mTORC1 activity and impairs normal food intake. As a result, Rheb1 knockout mice exhibit hypoglycemia and increased lipid mobilization in adipose tissue and ketogenesis in the liver. Our work highlights the importance of central Rheb1 signaling in euglycemia and energy homeostasis in animals.

  12. Common genetic variants influence human subcortical brain structures

    NARCIS (Netherlands)

    Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro; Desrivieres, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Loohuis, Loes M. Olde; Luciano, Michelle; Macare, Christine; Mather, Karen A.; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Roiz-Santianez, Roberto; Rose, Emma J.; Salami, Alireza; Saemann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn K.; Heister, Angelien J. G. A. M.; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C. M.; L