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Sample records for genetic phenotypic information

  1. Systematic analysis, comparison, and integration of disease based human genetic association data and mouse genetic phenotypic information

    Directory of Open Access Journals (Sweden)

    Wang S Alex

    2010-01-01

    Full Text Available Abstract Background The genetic contributions to human common disorders and mouse genetic models of disease are complex and often overlapping. In common human diseases, unlike classical Mendelian disorders, genetic factors generally have small effect sizes, are multifactorial, and are highly pleiotropic. Likewise, mouse genetic models of disease often have pleiotropic and overlapping phenotypes. Moreover, phenotypic descriptions in the literature in both human and mouse are often poorly characterized and difficult to compare directly. Methods In this report, human genetic association results from the literature are summarized with regard to replication, disease phenotype, and gene specific results; and organized in the context of a systematic disease ontology. Similarly summarized mouse genetic disease models are organized within the Mammalian Phenotype ontology. Human and mouse disease and phenotype based gene sets are identified. These disease gene sets are then compared individually and in large groups through dendrogram analysis and hierarchical clustering analysis. Results Human disease and mouse phenotype gene sets are shown to group into disease and phenotypically relevant groups at both a coarse and fine level based on gene sharing. Conclusion This analysis provides a systematic and global perspective on the genetics of common human disease as compared to itself and in the context of mouse genetic models of disease.

  2. Quantifying Phenotypic Plasticity Using Genetic Information for Simulating Plant Height in Winter Wheat

    Science.gov (United States)

    A challenge for crop simulation modeling is to incorporate existing and rapidly emerging genomic information into models to develop new and improved algorithms. The objective of this effort was to simulate plant height in winter wheat (Triticum aestivum L.) across a range of environments in Nebraska...

  3. Genetic background of phenotypic variation

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    A noteworthy feature of the living world is its bewildering variability. A key issue in several biological disciplines is the achievement of an understanding of the hereditary basis of this variability. Two opposing, but not necessarily irreconcilable conceptions attempt to explain the underlying mechanism. The gene function paradigm postulates that phenotypic variance is generated by the polymorphism in the coding sequences of genes. However, comparisons of a great number of homologous gene and protein sequences have revealed that they predominantly remained functionally conserved even across distantly related phylogenic taxa. Alternatively, the gene regulation paradigm assumes that differences in the cis-regulatory region of genes do account for phenotype variation within species. An extension of this latter concept is that phenotypic variability is generated by the polyrnorphism in the overall gene expression profiles of gene networks.In other words, the activity of a particular gene is a system property determined both by the cis-regulatory sequences of the given genes and by the other genes of a gene network, whose expressions vary among individuals, too. Novel proponents of gene function paradigm claim that functional genetic variance within the coding sequences of regulatory genes is critical for the generation of morphological polymorphism. Note, however, that these developmental genes play direct regulatory roles in the control of gene expression.

  4. Genetic and phenotypic variation of some reproductive traits in ...

    African Journals Online (AJOL)

    Unknown

    Genetic and phenotypic variation of some reproductive traits in Egyptian buffalo ... genetic and phenotypic parameters for these traits using a multi-trait animal model. Season ..... Genetic improvement of buffalo productivity under farm and field.

  5. Elucidation of the full genetic information of Japanese rubella vaccines and the genetic changes associated with in vitro and in vivo vaccine virus phenotypes.

    Science.gov (United States)

    Otsuki, Noriyuki; Abo, Hitoshi; Kubota, Toru; Mori, Yoshio; Umino, Yukiko; Okamoto, Kiyoko; Takeda, Makoto; Komase, Katsuhiro

    2011-02-24

    Rubella is a mild disease characterized by low-grade fever, and a morbilliform rash, but causes congenital defects in neonates born from mothers who suffered from rubella during the pregnancy. After many passages of wild-type rubella virus strains in various types of cultured cells, five live attenuated rubella vaccines were developed in Japan. An inability to elicit anti-rubella virus antibodies in experimentally infected animals was used as an in vivo marker phenotype of Japanese rubella vaccines. All Japanese rubella vaccine viruses exhibit a temperature-sensitive (ts) phenotype, and replicate very poorly at a high temperature. We determined the entire genome sequences of three Japanese rubella vaccines (Matsuba, TCRB19, and Matsuura), thereby completing the sequencing of all five Japanese rubella vaccines. In addition, the entire genome sequences of three vaccine progenitors were determined. Comparative nucleotide sequence analyses revealed mutations that were introduced into the genomes of the TO-336 and Matsuura vaccines during their production by laboratory passaging. Analyses involving cellular expression of viral P150 nonstructural protein-derived peptides revealed that the N1159S mutation conferred the ts phenotype on the TO-336 vaccine, and that reduced thermal stability of the P150 protease domain was a cause of the ts phenotype of some rubella vaccine viruses. The ts phenotype of vaccine viruses was not necessarily correlated with their inability to elicit humoral immune responses in animals. Therefore, the molecular mechanisms underlying the inability of these vaccines to elicit humoral responses in animals are more complicated than the previously considered mechanism involving the ts phenotype as the major cause.

  6. The quantitative genetics of phenotypic robustness.

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    Hunter B Fraser

    Full Text Available Phenotypic robustness, or canalization, has been extensively investigated both experimentally and theoretically. However, it remains unknown to what extent robustness varies between individuals, and whether factors buffering environmental variation also buffer genetic variation. Here we introduce a quantitative genetic approach to these issues, and apply this approach to data from three species. In mice, we find suggestive evidence that for hundreds of gene expression traits, robustness is polymorphic and can be genetically mapped to discrete genomic loci. Moreover, we find that the polymorphisms buffering genetic variation are distinct from those buffering environmental variation. In fact, these two classes have quite distinct mechanistic bases: environmental buffers of gene expression are predominantly sex-specific and trans-acting, whereas genetic buffers are not sex-specific and often cis-acting. Data from studies of morphological and life-history traits in plants and yeast support the distinction between polymorphisms buffering genetic and environmental variation, and further suggest that loci buffering different types of environmental variation do overlap with one another. These preliminary results suggest that naturally occurring polymorphisms affecting phenotypic robustness could be abundant, and that these polymorphisms may generally buffer either genetic or environmental variation, but not both.

  7. Phenotypic evolution from genetic polymorphisms in a radial network architecture

    Directory of Open Access Journals (Sweden)

    Siegel Paul B

    2007-11-01

    Full Text Available Abstract Background The genetic architecture of a quantitative trait influences the phenotypic response to natural or artificial selection. One of the main objectives of genetic mapping studies is to identify the genetic factors underlying complex traits and understand how they contribute to phenotypic expression. Presently, we are good at identifying and locating individual loci with large effects, but there is a void in describing more complex genetic architectures. Although large networks of connected genes have been reported, there is an almost complete lack of information on how polymorphisms in these networks contribute to phenotypic variation and change. To date, most of our understanding comes from theoretical, model-based studies, and it remains difficult to assess how realistic their conclusions are as they lack empirical support. Results A previous study provided evidence that nearly half of the difference in eight-week body weight between two divergently selected lines of chickens was a result of four loci organized in a 'radial' network (one central locus interacting with three 'radial' loci that, in turn, only interacted with the central locus. Here, we study the relationship between phenotypic change and genetic polymorphism in this empirically detected network. We use a model-free approach to study, through individual-based simulations, the dynamic properties of this polymorphic and epistatic genetic architecture. The study provides new insights to how epistasis can modify the selection response, buffer and reveal effects of major loci leading to a progressive release of genetic variation. We also illustrate the difficulty of predicting genetic architecture from observed selection response, and discuss mechanisms that might lead to misleading conclusions on underlying genetic architectures from quantitative trait locus (QTL experiments in selected populations. Conclusion Considering both molecular (QTL and phenotypic (selection

  8. Recovery of native genetic background in admixed populations using haplotypes, phenotypes, and pedigree information--using Cika cattle as a case breed.

    Science.gov (United States)

    Simčič, Mojca; Smetko, Anamarija; Sölkner, Johann; Seichter, Doris; Gorjanc, Gregor; Kompan, Dragomir; Medugorac, Ivica

    2015-01-01

    The aim of this study was to obtain unbiased estimates of the diversity parameters, the population history, and the degree of admixture in Cika cattle which represents the local admixed breeds at risk of extinction undergoing challenging conservation programs. Genetic analyses were performed on the genome-wide Single Nucleotide Polymorphism (SNP) Illumina Bovine SNP50 array data of 76 Cika animals and 531 animals from 14 reference populations. To obtain unbiased estimates we used short haplotypes spanning four markers instead of single SNPs to avoid an ascertainment bias of the BovineSNP50 array. Genome-wide haplotypes combined with partial pedigree and type trait classification show the potential to improve identification of purebred animals with a low degree of admixture. Phylogenetic analyses demonstrated unique genetic identity of Cika animals. Genetic distance matrix presented by rooted Neighbour-Net suggested long and broad phylogenetic connection between Cika and Pinzgauer. Unsupervised clustering performed by the admixture analysis and two-dimensional presentation of the genetic distances between individuals also suggest Cika is a distinct breed despite being similar in appearance to Pinzgauer. Animals identified as the most purebred could be used as a nucleus for a recovery of the native genetic background in the current admixed population. The results show that local well-adapted strains, which have never been intensively managed and differentiated into specific breeds, exhibit large haplotype diversity. They suggest a conservation and recovery approach that does not rely exclusively on the search for the original native genetic background but rather on the identification and removal of common introgressed haplotypes would be more powerful. Successful implementation of such an approach should be based on combining phenotype, pedigree, and genome-wide haplotype data of the breed of interest and a spectrum of reference breeds which potentially have had

  9. Nunukan Chicken: Genetic Characteristics, Phenotype and Utilization

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    Tike Sartika

    2006-12-01

    Full Text Available Nunukan chicken is a local chicken from East Kalimantan which spreads out in Tarakan and Nunukan Islands . The chicken has a specific buff color and Columbian type feather and also has very late feathering (VLF trait . The Nunukan cocks and hens have no wing and tail primary feather; the tail feathers are short and fragile . The VLF trait is known to have association with a K gene on the Z chromosome. The chicken is efficient in protein metabolism . Sulfur amino acids (cystine and methionine that needed for feather growth, could be utilized for meat and egg production . The egg production of Nunukan chicken was better than the Kampung chicken . The average of hen day, hen house and peak production of Nunukan chicken was 45 . 39.1 and 62%, respectively, while the Kampung chicken was 35 .9, 30 .9 and 48%, respectively . Based on genetic analysis, the external genotype characteristic of the Nunukan chicken is ii ce ss Idld pp. It means that the phenotype appearance of the Nunukan chicken was columbian and gold feathering type, yellow and white shank color and single comb type. This phenotype is similar to Merawang Chicken . The genetic introgression of the Nunukan chicken is affected by the Rhode Island Red with the genetic introgression value of 0.964 .

  10. Phenotypic and genetic consequences of protein damage.

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    Anita Krisko

    Full Text Available Although the genome contains all the information necessary for maintenance and perpetuation of life, it is the proteome that repairs, duplicates and expresses the genome and actually performs most cellular functions. Here we reveal strong phenotypes of physiological oxidative proteome damage at the functional and genomic levels. Genome-wide mutations rates and biosynthetic capacity were monitored in real time, in single Escherichia coli cells with identical levels of reactive oxygen species and oxidative DNA damage, but with different levels of irreversible oxidative proteome damage (carbonylation. Increased protein carbonylation correlates with a mutator phenotype, whereas reducing it below wild type level produces an anti-mutator phenotype identifying proteome damage as the leading cause of spontaneous mutations. Proteome oxidation elevates also UV-light induced mutagenesis and impairs cellular biosynthesis. In conclusion, protein damage reduces the efficacy and precision of vital cellular processes resulting in high mutation rates and functional degeneracy akin to cellular aging.

  11. Genetic Regulation of Phenotypic Plasticity and Canalisation in Yeast Growth

    OpenAIRE

    Yadav, Anupama; Dhole, Kaustubh; Sinha, Himanshu

    2016-01-01

    The ability of a genotype to show diverse phenotypes in different environments is called phenotypic plasticity. Phenotypic plasticity helps populations to evade extinctions in novel environments, facilitates adaptation and fuels evolution. However, most studies focus on understanding the genetic basis of phenotypic regulation in specific environments. As a result, while it’s evolutionary relevance is well established, genetic mechanisms regulating phenotypic plasticity and their overlap with ...

  12. Information, Genetics and Entropy

    Directory of Open Access Journals (Sweden)

    Julio Ernesto Rubio Barrios

    2015-04-01

    Full Text Available The consolidation of the informational paradigm in molecular biology research concluded on a system to convert the epistemic object into an operational technological object and a stable epistemic product. However, the acceptance of the informational properties of genetic acids failed to clarify the meaning of the concept of information. The “information”’ as a property of the genetic molecules remained as an informal notion that allows the description of the mechanism of inheritance, but it was not specified in a logic–semantic structure. The metaphorical implications associated with the idea of genes as molecules with meaning, questioned the linguistics that seemed too foreign to molecular biology. A reformulation of the concept of information in molecular biology was developed upon the theory of Claude Shannon. The node for the structural coupling between biology, physics and information theory was the identification of an analog structure between the coded messages of Shannon’s theory.

  13. Methods for Analyzing Multivariate Phenotypes in Genetic Association Studies

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    Qiong Yang

    2012-01-01

    Full Text Available Multivariate phenotypes are frequently encountered in genetic association studies. The purpose of analyzing multivariate phenotypes usually includes discovery of novel genetic variants of pleiotropy effects, that is, affecting multiple phenotypes, and the ultimate goal of uncovering the underlying genetic mechanism. In recent years, there have been new method development and application of existing statistical methods to such phenotypes. In this paper, we provide a review of the available methods for analyzing association between a single marker and a multivariate phenotype consisting of the same type of components (e.g., all continuous or all categorical or different types of components (e.g., some are continuous and others are categorical. We also reviewed causal inference methods designed to test whether the detected association with the multivariate phenotype is truly pleiotropy or the genetic marker exerts its effects on some phenotypes through affecting the others.

  14. Original Paper Patterns of genetic structure and phenotypic diversity ...

    African Journals Online (AJOL)

    Patterns of genetic structure and phenotypic diversity in sorghum landraces in relation to farmers' management in Burkina Faso ... the role of farmer practices in phenotypic and genetic evolution of sorghum. ... varieties to marginal environments such as ...... Supporting the Convention on Biological ... A new method to.

  15. A New Method to Infer Causal Phenotype Networks Using QTL and Phenotypic Information

    NARCIS (Netherlands)

    Wang, H.; Eeuwijk, van F.

    2014-01-01

    In the context of genetics and breeding research on multiple phenotypic traits, reconstructing the directional or causal structure between phenotypic traits is a prerequisite for quantifying the effects of genetic interventions on the traits. Current approaches mainly exploit the genetic effects at

  16. Autistic phenotypes and genetic testing: state-of-the-art for the clinical geneticist.

    Science.gov (United States)

    Lintas, C; Persico, A M

    2009-01-01

    Autism spectrum disorders represent a group of developmental disorders with strong genetic underpinnings. Several cytogenetic abnormalities or de novo mutations able to cause autism have recently been uncovered. In this study, the literature was reviewed to highlight genotype-phenotype correlations between causal gene mutations or cytogenetic abnormalities and behavioural or morphological phenotypes. Based on this information, a set of practical guidelines is proposed to help clinical geneticists pursue targeted genetic testing for patients with autism whose clinical phenotype is suggestive of a specific genetic or genomic aetiology.

  17. Genetic architecture and phenotypic plasticity of thermally-regulated traits in an eruptive species, Dendroctonus ponderosae

    Science.gov (United States)

    Barbara J. Bentz; Ryan B. Bracewell; Karen E. Mock; Michael E. Pfrender

    2011-01-01

    Phenotypic plasticity in thermally-regulated traits enables close tracking of changing environmental conditions, and can thereby enhance the potential for rapid population increase, a hallmark of outbreak insect species. In a changing climate, exposure to conditions that exceed the capacity of existing phenotypic plasticity may occur. Combining information on genetic...

  18. Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism.

    Science.gov (United States)

    Bonomi, M; Rochira, V; Pasquali, D; Balercia, G; Jannini, E A; Ferlin, A

    2017-02-01

    Klinefelter Syndrome (KS) is characterized by an extreme heterogeneity in its clinical and genetic presentation. The relationship between clinical phenotype and genetic background has been partially disclosed; nevertheless, physicians are aware that several aspects concerning this issue are far to be fully understood. By improving our knowledge on the role of some genetic aspects as well as on the KS, patients' interindividual differences in terms of health status will result in a better management of this chromosomal disease. The aim of this review is to provide an update on both genetic and clinical phenotype and their interrelationships.

  19. Genetic Regulation of Phenotypic Plasticity and Canalisation in Yeast Growth.

    Science.gov (United States)

    Yadav, Anupama; Dhole, Kaustubh; Sinha, Himanshu

    2016-01-01

    The ability of a genotype to show diverse phenotypes in different environments is called phenotypic plasticity. Phenotypic plasticity helps populations to evade extinctions in novel environments, facilitates adaptation and fuels evolution. However, most studies focus on understanding the genetic basis of phenotypic regulation in specific environments. As a result, while it's evolutionary relevance is well established, genetic mechanisms regulating phenotypic plasticity and their overlap with the environment specific regulators is not well understood. Saccharomyces cerevisiae is highly sensitive to the environment, which acts as not just external stimulus but also as signalling cue for this unicellular, sessile organism. We used a previously published dataset of a biparental yeast population grown in 34 diverse environments and mapped genetic loci regulating variation in phenotypic plasticity, plasticity QTL, and compared them with environment-specific QTL. Plasticity QTL is one whose one allele exhibits high plasticity whereas the other shows a relatively canalised behaviour. We mapped phenotypic plasticity using two parameters-environmental variance, an environmental order-independent parameter and reaction norm (slope), an environmental order-dependent parameter. Our results show a partial overlap between pleiotropic QTL and plasticity QTL such that while some plasticity QTL are also pleiotropic, others have a significant effect on phenotypic plasticity without being significant in any environment independently. Furthermore, while some plasticity QTL are revealed only in specific environmental orders, we identify large effect plasticity QTL, which are order-independent such that whatever the order of the environments, one allele is always plastic and the other is canalised. Finally, we show that the environments can be divided into two categories based on the phenotypic diversity of the population within them and the two categories have differential regulators of

  20. The Genetics of Phenotypic Plasticity. XIV. Coevolution.

    Science.gov (United States)

    Scheiner, Samuel M; Gomulkiewicz, Richard; Holt, Robert D

    2015-05-01

    Plastic changes in organisms' phenotypes can result from either abiotic or biotic effectors. Biotic effectors create the potential for a coevolutionary dynamic. Through the use of individual-based simulations, we examined the coevolutionary dynamic of two species that are phenotypically plastic. We explored two modes of biotic and abiotic interactions: ecological interactions that determine the form of natural selection and developmental interactions that determine phenotypes. Overall, coevolution had a larger effect on the evolution of phenotypic plasticity than plasticity had on the outcome of coevolution. Effects on the evolution of plasticity were greater when the fitness-maximizing coevolutionary outcomes were antagonistic between the species pair (predator-prey interactions) than when those outcomes were augmenting (competitive or mutualistic). Overall, evolution in the context of biotic interactions reduced selection for plasticity even when trait development was responding to just the abiotic environment. Thus, the evolution of phenotypic plasticity must always be interpreted in the full context of a species' ecology. Our results show how the merging of two theory domains--coevolution and phenotypic plasticity--can deepen our understanding of both and point to new empirical research.

  1. Phenotypes, genome wide markers and structured genetic populations; a means to understand economically important traits in beta vulgaris and to inform the process of germplasm enhancement

    Science.gov (United States)

    Although hybrid seed systems in beet have been widely adopted due to profitability and productivity, the population remains the operational unit of beet improvement and thus characterizing populations in terms of markers and phenotypes is critical for novel trait discovery and eventual deployment of...

  2. Methods for Analyzing Multivariate Phenotypes in Genetic Association Studies.

    Science.gov (United States)

    Yang, Qiong; Wang, Yuanjia

    2012-05-01

    This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Multivariate phenotypes are frequently encountered in genetic association studies. The purpose of analyzing multivariate phenotypes usually includes discovery of novel genetic variants of pleiotropy effects, that is, affecting multiple phenotypes, and the ultimate goal of uncovering the underlying genetic mechanism. In recent years, there have been new method development and application of existing statistical methods to such phenotypes. In this paper, we provide a review of the available methods for analyzing association between a single marker and a multivariate phenotype consisting of the same type of components (e.g., all continuous or all categorical) or different types of components (e.g., some are continuous and others are categorical). We also reviewed causal inference methods designed to test whether the detected association with the multivariate phenotype is truly pleiotropy or the genetic marker exerts its effects on some phenotypes through affecting the others.

  3. Improving Phenotypic Prediction by Combining Genetic and Epigenetic Associations

    NARCIS (Netherlands)

    Shah, Sonia; Bonder, Marc J.; Marioni, Riccardo E.; Zhu, Zhihong; McRae, Allan F.; Zhernakova, Alexandra; Harris, Sarah E.; Liewald, Dave; Henders, Anjali K.; Mendelson, Michael M.; Liu, Chunyu; Joehanes, Roby; Liang, Liming; Levy, Daniel; Martin, Nicholas G.; Starr, John M.; Wijmenga, Cisca; Wray, Naomi R.; Yang, Jian; Montgomery, Grant W.; Franke, Lude; Deary, Ian J.; Visscher, Peter M.

    2015-01-01

    We tested whether DNA-methylation profiles account for inter-individual variation in body mass index (BMI) and height and whether they predict these phenotypes over and above genetic factors. Genetic predictors were derived from published summary results from the largest genome-wide association stud

  4. The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities.

    Science.gov (United States)

    Chong, Jessica X; Buckingham, Kati J; Jhangiani, Shalini N; Boehm, Corinne; Sobreira, Nara; Smith, Joshua D; Harrell, Tanya M; McMillin, Margaret J; Wiszniewski, Wojciech; Gambin, Tomasz; Coban Akdemir, Zeynep H; Doheny, Kimberly; Scott, Alan F; Avramopoulos, Dimitri; Chakravarti, Aravinda; Hoover-Fong, Julie; Mathews, Debra; Witmer, P Dane; Ling, Hua; Hetrick, Kurt; Watkins, Lee; Patterson, Karynne E; Reinier, Frederic; Blue, Elizabeth; Muzny, Donna; Kircher, Martin; Bilguvar, Kaya; López-Giráldez, Francesc; Sutton, V Reid; Tabor, Holly K; Leal, Suzanne M; Gunel, Murat; Mane, Shrikant; Gibbs, Richard A; Boerwinkle, Eric; Hamosh, Ada; Shendure, Jay; Lupski, James R; Lifton, Richard P; Valle, David; Nickerson, Deborah A; Bamshad, Michael J

    2015-08-06

    Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying ∼50% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  5. Recommendations for using standardised phenotypes in genetic association studies

    Directory of Open Access Journals (Sweden)

    Naylor Melissa G

    2009-07-01

    Full Text Available Abstract Genetic association studies of complex traits often rely on standardised quantitative phenotypes, such as percentage of predicted forced expiratory volume and body mass index to measure an underlying trait of interest (eg lung function, obesity. These phenotypes are appealing because they provide an easy mechanism for comparing subjects, although such standardisations may not be the best way to control for confounders and other covariates. We recommend adjusting raw or standardised phenotypes within the study population via regression. We illustrate through simulation that optimal power in both population- and family-based association tests is attained by using the residuals from within-study adjustment as the complex trait phenotype. An application of family-based association analysis of forced expiratory volume in one second, and obesity in the Childhood Asthma Management Program data, illustrates that power is maintained or increased when adjusted phenotype residuals are used instead of typical standardised quantitative phenotypes.

  6. Genetic Factors in Systemic Lupus Erythematosus: Contribution to Disease Phenotype

    Science.gov (United States)

    Ceccarelli, Fulvia; Perricone, Carlo; Borgiani, Paola; Ciccacci, Cinzia; Rufini, Sara; Cipriano, Enrica; Alessandri, Cristiano; Spinelli, Francesca Romana; Sili Scavalli, Antonio; Novelli, Giuseppe; Valesini, Guido; Conti, Fabrizio

    2015-01-01

    Genetic factors exert an important role in determining Systemic Lupus Erythematosus (SLE) susceptibility, interplaying with environmental factors. Several genetic studies in various SLE populations have identified numerous susceptibility loci. From a clinical point of view, SLE is characterized by a great heterogeneity in terms of clinical and laboratory manifestations. As widely demonstrated, specific laboratory features are associated with clinical disease subset, with different severity degree. Similarly, in the last years, an association between specific phenotypes and genetic variants has been identified, allowing the possibility to elucidate different mechanisms and pathways accountable for disease manifestations. However, except for Lupus Nephritis (LN), no studies have been designed to identify the genetic variants associated with the development of different phenotypes. In this review, we will report data currently known about this specific association. PMID:26798662

  7. Challenging behavior: Behavioral phenotypes of some genetic syndromes

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    Buha Nataša

    2014-01-01

    Full Text Available Challenging behavior in individuals with mental retardation (MR is relatively frequent, and represents a significant obstacle to adaptive skills. The frequency of specific forms and manifestations of challenging behavior can depend on a variety of personal and environmental factors. There are several prominent theoretical models regarding the etiology of challenging behavior and psychopathology in persons with MR: behavioral, developmental, socio-cultural and biological. The biological model emphasizes the physiological, biochemical and genetic factors as the potential source of challenging behavior. The progress in the field of genetics and neuroscience has opened the opportunity to study and discover the neurobiological basis of phenotypic characteristics. Genetic syndromes associated with MR can be followed by a specific set of problems and disorders which constitutes their behavioral phenotype. The aim of this paper was to present challenging behaviors that manifest in the most frequently studied syndromes: Down syndrome, Fragile X syndrome, Williams syndrome, Prader-Willi syndrome and Angelman syndrome. The concept of behavioral phenotype implies a higher probability of manifesting specific developmental characteristics and specific behaviors in individuals with a certain genetic syndrome. Although the specific set of (possible problems and disorders is distinctive for the described genetic syndromes, the connection between genetics and behavior should be viewed through probabilistic dimension. The probabilistic concept takes into consideration the possibility of intra-syndrome variability in the occurrence, intensity and time onset of behavioral characteristics, at which the higher variability the lower is the specificity of the genetic syndrome. Identifying the specific pattern of behavior can be most important for the process of early diagnosis and prognosis. In addition, having knowledge about behavioral phenotype can be a landmark in

  8. Quantifying the contribution of genetic variants for survival phenotypes.

    Science.gov (United States)

    Müller, Martina; Döring, Angela; Küchenhoff, Helmut; Lamina, Claudia; Malzahn, Dörthe; Bickeböller, Heike; Vollmert, Caren; Klopp, Norman; Meisinger, Christa; Heinrich, Joachim; Kronenberg, Florian; Wichmann, H Erich; Heid, Iris M

    2008-09-01

    Particularly in studies based on population representative samples, it is of major interest what impact a genetic variant has on the phenotype of interest, which cannot be answered by mere association estimates alone. One possible measure for quantifying the phenotype's variance explained by the genetic variant is R(2). However, for survival outcomes, no clear definition of R(2) is available in the presence of censored observations. We selected three criteria proposed for this purpose in the literature and compared their performance for single nucleotide polymorphism (SNP) data through simulation studies and for mortality data with candidate SNPs in the general population-based KORA cohort. The evaluated criteria were based on: (1) the difference of deviance residuals, (2) the variation of individual survival curves, and (3) the variation of Schoenfeld residuals. Our simulation studies included various censoring and genetic scenarios. The simulation studies revealed that the deviance residuals' criterion had a high dependence on the censoring percentage, was generally not limited to the range [0; 1] and therefore lacked interpretation as a percentage of explained variation. The second criterion (variation of survival curves) hardly reached values above 60%. Our requirements were best fulfilled by the criterion based on Schoenfeld residuals. Our mortality data analysis also supported the findings in simulation studies. With the criterion based on Schoenfeld residuals, we recommend a powerful and flexible tool for genetic epidemiological studies to refine genetic association studies by judging the contribution of genetic variants to survival phenotype.

  9. Genetic and phenotypic diversity in breast tumor metastases

    NARCIS (Netherlands)

    Almendro, Vanessa; Kim, Hee Jung; Cheng, Yu-Kang; Gönen, Mithat; Itzkovitz, Shalev; Argani, Pedram; van Oudenaarden, Alexander; Sukumar, Saraswati; Michor, Franziska; Polyak, Kornelia

    2014-01-01

    Metastatic disease is the main cause of cancer-related mortality due to almost universal therapeutic resistance. Despite its high clinical relevance, our knowledge of how cancer cell populations change during metastatic progression is limited. Here, we investigated intratumor genetic and phenotypic

  10. Genetic and phenotypic diversity in breast tumor metastases

    NARCIS (Netherlands)

    Almendro, Vanessa; Kim, Hee Jung; Cheng, Yu-Kang; Gönen, Mithat; Itzkovitz, Shalev; Argani, Pedram; van Oudenaarden, Alexander; Sukumar, Saraswati; Michor, Franziska; Polyak, Kornelia

    2014-01-01

    Metastatic disease is the main cause of cancer-related mortality due to almost universal therapeutic resistance. Despite its high clinical relevance, our knowledge of how cancer cell populations change during metastatic progression is limited. Here, we investigated intratumor genetic and phenotypic

  11. Genetic association in multivariate phenotypic data: power in five models

    NARCIS (Netherlands)

    Minica, C.C.; Boomsma, D.I.; van der Sluis, S.; Dolan, C.V.

    2010-01-01

    This article concerns the power of various data analytic strategies to detect the effect of a single genetic variant (GV) in multivariate data. We simulated exactly fitting monozygotic and dizygotic phenotypic data according to single and two common factor models, and simplex models. We calculated t

  12. Behavioral Genetic Toolkits: Toward the Evolutionary Origins of Complex Phenotypes.

    Science.gov (United States)

    Rittschof, C C; Robinson, G E

    2016-01-01

    The discovery of toolkit genes, which are highly conserved genes that consistently regulate the development of similar morphological phenotypes across diverse species, is one of the most well-known observations in the field of evolutionary developmental biology. Surprisingly, this phenomenon is also relevant for a wide array of behavioral phenotypes, despite the fact that these phenotypes are highly complex and regulated by many genes operating in diverse tissues. In this chapter, we review the use of the toolkit concept in the context of behavior, noting the challenges of comparing behaviors and genes across diverse species, but emphasizing the successes in identifying genetic toolkits for behavior; these successes are largely attributable to the creative research approaches fueled by advances in behavioral genomics. We have two general goals: (1) to acknowledge the groundbreaking progress in this field, which offers new approaches to the difficult but exciting challenge of understanding the evolutionary genetic basis of behaviors, some of the most complex phenotypes known, and (2) to provide a theoretical framework that encompasses the scope of behavioral genetic toolkit studies in order to clearly articulate the research questions relevant to the toolkit concept. We emphasize areas for growth and highlight the emerging approaches that are being used to drive the field forward. Behavioral genetic toolkit research has elevated the use of integrative and comparative approaches in the study of behavior, with potentially broad implications for evolutionary biologists and behavioral ecologists alike.

  13. Social-Cognition and the Broad Autism Phenotype: Identifying Genetically Meaningful Phenotypes

    Science.gov (United States)

    Losh, Molly; Piven, Joseph

    2007-01-01

    Background: Strong evidence from twin and family studies suggests that the genetic liability to autism may be expressed through personality and language characteristics qualitatively similar, but more subtly expressed than those defining the full syndrome. This study examined behavioral features of this "broad autism phenotype" (BAP) in relation…

  14. Kidney aging: from phenotype to genetics.

    Science.gov (United States)

    Buemi, Michele; Nostro, Lorena; Aloisi, Carmela; Cosentini, Vincenzo; Criseo, Manila; Frisina, Nicola

    2005-01-01

    Aging is a physiological process that causes structural and functional changes in human body systems, sometimes leading to various organ failure. As far as the kidney is concerned, both genetic factors and environmental agents may influence the tissues damage in elderly people and the related loss of function. On the other hand, functional adaptations to structural changes appear to be compromised by co-morbid conditions that are frequently found in elderly people, such as atherosclerosis and hypertension. It is not yet known whether physiological aging is inevitably accompanied by a decline in renal function or how rapidly it might happen. The discovery of molecular mechanisms responsible for tissue damage in aging could offer new perspectives on interventions. The role of nitric oxide, oxidative stress, the renin-angiotensin system, changes in length of telomeres, and klotho gene expression are important subjects for further in-depth studies about aging. A better understanding of physiological renal aging could improve the clinical approach to this process and widen the therapeutic possibilities offered by transplantation.

  15. Genetic mapping of quantitative phenotypic traits in Saccharomyces cerevisiae.

    Science.gov (United States)

    Swinnen, Steve; Thevelein, Johan M; Nevoigt, Elke

    2012-03-01

    Saccharomyces cerevisiae has become a favorite production organism in industrial biotechnology presenting new challenges to yeast engineers in terms of introducing advantageous traits such as stress tolerances. Exploring subspecies diversity of S. cerevisiae has identified strains that bear industrially relevant phenotypic traits. Provided that the genetic basis of such phenotypic traits can be identified inverse engineering allows the targeted modification of production strains. Most phenotypic traits of interest in S. cerevisiae strains are quantitative, meaning that they are controlled by multiple genetic loci referred to as quantitative trait loci (QTL). A straightforward approach to identify the genetic basis of quantitative traits is QTL mapping which aims at the allocation of the genetic determinants to regions in the genome. The application of high-density oligonucleotide arrays and whole-genome re-sequencing to detect genetic variations between strains has facilitated the detection of large numbers of molecular markers thus allowing high-resolution QTL mapping over the entire genome. This review focuses on the basic principle and state of the art of QTL mapping in S. cerevisiae. Furthermore we discuss several approaches developed during the last decade that allow down-scaling of the regions identified by QTL mapping to the gene level. We also emphasize the particular challenges of QTL mapping in nonlaboratory strains of S. cerevisiae.

  16. A Unifying Model for the Analysis of Phenotypic, Genetic and Geographic Data

    DEFF Research Database (Denmark)

    Guillot, Gilles; Rena, Sabrina; Ledevin, Ronan

    2012-01-01

    Recognition of evolutionary units (species, populations) requires integrating several kinds of data such as genetic or phenotypic markers or spatial information, in order to get a comprehensive view concerning the dierentiation of the units. We propose a statistical model with a double original a...

  17. Genetic neurological channelopathies: molecular genetics and clinical phenotypes.

    Science.gov (United States)

    Spillane, J; Kullmann, D M; Hanna, M G

    2016-01-01

    Evidence accumulated over recent years has shown that genetic neurological channelopathies can cause many different neurological diseases. Presentations relating to the brain, spinal cord, peripheral nerve or muscle mean that channelopathies can impact on almost any area of neurological practice. Typically, neurological channelopathies are inherited in an autosomal dominant fashion and cause paroxysmal disturbances of neurological function, although the impairment of function can become fixed with time. These disorders are individually rare, but an accurate diagnosis is important as it has genetic counselling and often treatment implications. Furthermore, the study of less common ion channel mutation-related diseases has increased our understanding of pathomechanisms that is relevant to common neurological diseases such as migraine and epilepsy. Here, we review the molecular genetic and clinical features of inherited neurological channelopathies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  18. Phenotype in 18 Danish subjects with genetically verified CHARGE syndrome

    DEFF Research Database (Denmark)

    Husu, E; Hove, Hd; Farholt, Stense

    2012-01-01

    Husu E, Hove HD, Farholt S, Bille M, Tranebjaerg L, Vogel I, Kreiborg S. Phenotype in 18 Danish subjects with genetically verified CHARGE syndrome. CHARGE (coloboma of the eye, heart defects, choanal atresia, retarded growth and development, genital hypoplasia and ear anomalies and/or hearing loss...... problems (12/15) were other frequent cranial nerve dysfunctions. Three-dimensional reconstructions of MRI scans showed temporal bone abnormalities in >85%. CHARGE syndrome present a broad phenotypic spectrum, although some clinical features are more frequently occurring than others. Here, we suggest...

  19. A new method to infer causal phenotype networks using QTL and phenotypic information.

    Directory of Open Access Journals (Sweden)

    Huange Wang

    Full Text Available In the context of genetics and breeding research on multiple phenotypic traits, reconstructing the directional or causal structure between phenotypic traits is a prerequisite for quantifying the effects of genetic interventions on the traits. Current approaches mainly exploit the genetic effects at quantitative trait loci (QTLs to learn about causal relationships among phenotypic traits. A requirement for using these approaches is that at least one unique QTL has been identified for each trait studied. However, in practice, especially for molecular phenotypes such as metabolites, this prerequisite is often not met due to limited sample sizes, high noise levels and small QTL effects. Here, we present a novel heuristic search algorithm called the QTL+phenotype supervised orientation (QPSO algorithm to infer causal directions for edges in undirected phenotype networks. The two main advantages of this algorithm are: first, it does not require QTLs for each and every trait; second, it takes into account associated phenotypic interactions in addition to detected QTLs when orienting undirected edges between traits. We evaluate and compare the performance of QPSO with another state-of-the-art approach, the QTL-directed dependency graph (QDG algorithm. Simulation results show that our method has broader applicability and leads to more accurate overall orientations. We also illustrate our method with a real-life example involving 24 metabolites and a few major QTLs measured on an association panel of 93 tomato cultivars. Matlab source code implementing the proposed algorithm is freely available upon request.

  20. Translating inter-individual genetic variation to biological function in complex phenotypes

    DEFF Research Database (Denmark)

    Yadav, Rachita

    . The project work discussed in chapter 6 is aimed towards understanding the various underlying differences in obesity responses in fat cells from different white adipose tissue depots under diet-induced and genetic obesity by decoding the global epigenetic modifications. The fourth section of this thesis work...... examines epigenetic, genetic, transcriptomic and proteomic variations within different multifactorial diseases and this pivotal information is then annotated and associated to its corresponding phenotype. Childhood asthma and obesity are the two main phenotypic themes in this thesis. In the first section...... artificial neural network (ANN) based methodology of selecting genetic and clinical features with predictive power for childhood asthma. The goal of these studies is to understand the complex genetics of childhood asthma. The third part of this thesis (chapters 5 and 6) focuses on various mechanisms involved...

  1. [Research progress on the phenotype informative SNP in forensic science].

    Science.gov (United States)

    Liu, Yu-Xuan; Hu, Qing-Qing; Ma, Hong-Du; Huang, Dai-Xin

    2014-10-01

    Single nucleotide polymorphism (SNP) refers to the single base sequence variation in specific location of the human genome. Phenotype informative SNP has gradually become one of the research hot spots in forensic science. In this paper, the forensic research situation and application prospect of phenotype informative SNP in the characteristics of hair, eye and skin color, height, and facial feature are reviewed.

  2. Environment Changes Genetic Effects on Respiratory Conditions and Allergic Phenotypes

    DEFF Research Database (Denmark)

    Song, Yong; Schwager, Michelle J; Backer, Vibeke

    2017-01-01

    separated population. We evaluated 18 single nucleotide polymorphisms (SNPs) corresponding to 8 genes (ADAM33, ALOX5, LT-α, LTC4S, NOS1, ORMDL3, TBXA2R and TNF-α), the lung function and five respiratory/allergic conditions (ever asthma, bronchitis, rhinitis, dermatitis and atopy) in two populations of Inuit...... associated with bronchitis risk. LT-α SNP rs2844484 was related to dermatitis susceptibility and was significantly influenced by the place of residence. The observed gene-phenotype relationships were exclusively present in one population and absent in the other population. We conclude that the genotype......-phenotype associations relating to bronchitis and allergy susceptibility are dependent on the environment and that environmental factors/lifestyles modify genetic predisposition and change the genetic effects on diseases....

  3. Genetically meaningful phenotypic subgroups in autism spectrum disorders.

    Science.gov (United States)

    Veatch, O J; Veenstra-Vanderweele, J; Potter, M; Pericak-Vance, M A; Haines, J L

    2014-03-01

    Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with strong evidence for genetic susceptibility. However, the effect sizes for implicated chromosomal loci are small, hard to replicate and current evidence does not explain the majority of the estimated heritability. Phenotypic heterogeneity could be one phenomenon complicating identification of genetic factors. We used data from the Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, Vineland Adaptive Behavior Scales, head circumferences, and ages at exams as classifying variables to identify more clinically similar subgroups of individuals with ASD. We identified two distinct subgroups of cases within the Autism Genetic Resource Exchange dataset, primarily defined by the overall severity of evaluated traits. In addition, there was significant familial clustering within subgroups (odds ratio, OR ≈ 1.38-1.42, P Autism Genome Project, we similarly identified two distinct subgroups of cases and confirmed this severity-based dichotomy. We also observed evidence for genetic contributions to subgroups identified in the replication dataset. Our results provide more effective methods of phenotype definition that should increase power to detect genetic factors influencing risk for ASD.

  4. Genetic and phenotypic diversity in breast tumor metastases.

    Science.gov (United States)

    Almendro, Vanessa; Kim, Hee Jung; Cheng, Yu-Kang; Gönen, Mithat; Itzkovitz, Shalev; Argani, Pedram; van Oudenaarden, Alexander; Sukumar, Saraswati; Michor, Franziska; Polyak, Kornelia

    2014-03-01

    Metastatic disease is the main cause of cancer-related mortality due to almost universal therapeutic resistance. Despite its high clinical relevance, our knowledge of how cancer cell populations change during metastatic progression is limited. Here, we investigated intratumor genetic and phenotypic heterogeneity during metastatic progression of breast cancer. We analyzed cellular genotypes and phenotypes at the single cell level by performing immunoFISH in intact tissue sections of distant metastatic tumors from rapid autopsy cases and from primary tumors and matched lymph node metastases collected before systemic therapy. We calculated the Shannon index of intratumor diversity in all cancer cells and within phenotypically distinct cell populations. We found that the extent of intratumor genetic diversity was similar regardless of the chromosomal region analyzed, implying that it may reflect an inherent property of the tumors. We observed that genetic diversity was highest in distant metastases and was generally concordant across lesions within the same patient, whereas treatment-naïve primary tumors and matched lymph node metastases were frequently genetically more divergent. In contrast, cellular phenotypes were more discordant between distant metastases than primary tumors and matched lymph node metastases. Diversity for 8q24 was consistently higher in HER2(+) tumors compared with other subtypes and in metastases of triple-negative tumors relative to primary sites. We conclude that our integrative method that couples ecologic models with experimental data in human tissue samples could be used for the improved prognostication of patients with cancer and for the design of more effective therapies for progressive disease.

  5. Sex differences in genetic architecture of complex phenotypes?

    Directory of Open Access Journals (Sweden)

    Jacqueline M Vink

    Full Text Available We examined sex differences in familial resemblance for a broad range of behavioral, psychiatric and health related phenotypes (122 complex traits in children and adults. There is a renewed interest in the importance of genotype by sex interaction in, for example, genome-wide association (GWA studies of complex phenotypes. If different genes play a role across sex, GWA studies should consider the effect of genetic variants separately in men and women, which affects statistical power. Twin and family studies offer an opportunity to compare resemblance between opposite-sex family members to the resemblance between same-sex relatives, thereby presenting a test of quantitative and qualitative sex differences in the genetic architecture of complex traits. We analyzed data on lifestyle, personality, psychiatric disorder, health, growth, development and metabolic traits in dizygotic (DZ same-sex and opposite-sex twins, as these siblings are perfectly matched for age and prenatal exposures. Sample size varied from slightly over 300 subjects for measures of brain function such as EEG power to over 30,000 subjects for childhood psychopathology and birth weight. For most phenotypes, sample sizes were large, with an average sample size of 9027 individuals. By testing whether the resemblance in DZ opposite-sex pairs is the same as in DZ same-sex pairs, we obtain evidence for genetic qualitative sex-differences in the genetic architecture of complex traits for 4% of phenotypes. We conclude that for most traits that were examined, the current evidence is that same the genes are operating in men and women.

  6. Genetic and phenotypic variation along an ecological gradient in lake trout Salvelinus namaycush

    Science.gov (United States)

    Baillie, Shauna M.; Muir, Andrew M.; Hansen, Michael J.; Krueger, Charles Conrad; Bentzen, Paul

    2016-01-01

    BackgroundAdaptive radiation involving a colonizing phenotype that rapidly evolves into at least one other ecological variant, or ecotype, has been observed in a variety of freshwater fishes in post-glacial environments. However, few studies consider how phenotypic traits vary with regard to neutral genetic partitioning along ecological gradients. Here, we present the first detailed investigation of lake trout Salvelinus namaycushthat considers variation as a cline rather than discriminatory among ecotypes. Genetic and phenotypic traits organized along common ecological gradients of water depth and geographic distance provide important insights into diversification processes in a lake with high levels of human disturbance from over-fishing.ResultsFour putative lake trout ecotypes could not be distinguished using population genetic methods, despite morphological differences. Neutral genetic partitioning in lake trout was stronger along a gradient of water depth, than by locality or ecotype. Contemporary genetic migration patterns were consistent with isolation-by-depth. Historical gene flow patterns indicated colonization from shallow to deep water. Comparison of phenotypic (Pst) and neutral genetic variation (Fst) revealed that morphological traits related to swimming performance (e.g., buoyancy, pelvic fin length) departed more strongly from neutral expectations along a depth gradient than craniofacial feeding traits. Elevated phenotypic variance with increasing water depth in pelvic fin length indicated possible ongoing character release and diversification. Finally, differences in early growth rate and asymptotic fish length across depth strata may be associated with limiting factors attributable to cold deep-water environments.ConclusionWe provide evidence of reductions in gene flow and divergent natural selection associated with water depth in Lake Superior. Such information is relevant for documenting intraspecific biodiversity in the largest freshwater lake

  7. Etiologic Ischemic Stroke Phenotypes in the NINDS Stroke Genetics Network

    Science.gov (United States)

    Ay, Hakan; Arsava, Ethem Murat; Andsberg, Gunnar; Benner, Thomas; Brown, Robert D.; Chapman, Sherita N.; Cole, John W.; Delavaran, Hossein; Dichgans, Martin; Engström, Gunnar; Giralt-Steinhauer, Eva; Grewal, Raji P.; Gwinn, Katrina; Jern, Christina; Jimenez-Conde, Jordi; Jood, Katarina; Katsnelson, Michael; Kissela, Brett; Kittner, Steven J.; Kleindorfer, Dawn O.; Labovitz, Daniel L.; Lanfranconi, Silvia; Lee, Jin-Moo; Lehm, Manuel; Lemmens, Robin; Levi, Chris; Li, Linxin; Lindgren, Arne; Markus, Hugh S.; McArdle, Patrick F.; Melander, Olle; Norrving, Bo; Peddareddygari, Leema Reddy; Pedersén, Annie; Pera, Joanna; Rannikmäe, Kristiina; Rexrode, Kathryn M.; Rhodes, David; Rich, Stephen S.; Roquer, Jaume; Rosand, Jonathan; Rothwell, Peter M.; Rundek, Tatjana; Sacco, Ralph L.; Schmidt, Reinhold; Schürks, Markus; Seiler, Stephan; Sharma, Pankaj; Slowik, Agnieszka; Sudlow, Cathie; Thijs, Vincent; Woodfield, Rebecca; Worrall, Bradford B.; Meschia, James F.

    2014-01-01

    Background and Purpose NINDS Stroke Genetics Network (SiGN) is an international consortium of ischemic stroke studies that aims to generate high quality phenotype data to identify the genetic basis of etiologic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. Methods Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major etiologic groups without weighting towards the most likely cause) and causative ischemic stroke subtypes in 16,954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded re-adjudication of 1509 randomly selected cases. Results The distribution of etiologic categories varied by study, age, sex, and race (pstroke etiology (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (kappa 0.72, 95%CI:0.69-0.75) and phenotypic classifications (kappa 0.73, 95%CI:0.70-0.75). Conclusions This study demonstrates that etiologic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a stroke patient does not necessarily mean that it is the cause of stroke. PMID:25378430

  8. Genetics of resistant hypertension: a novel pharmacogenomics phenotype.

    Science.gov (United States)

    El Rouby, Nihal; Cooper-DeHoff, Rhonda M

    2015-09-01

    Resistant hypertension (RHTN), defined as an uncontrolled blood pressure despite the use of multiple antihypertensive medications, is an increasing clinical problem associated with increased cardiovascular (CV) risk, including stroke and target organ damage. Genetic variability in blood pressure (BP)-regulating genes and pathways may, in part, account for the variability in BP response to antihypertensive agents, when taken alone or in combination, and may contribute to the RHTN phenotype. Pharmacogenomics focuses on the identification of genetic factors responsible for inter-individual variability in drug response. Expanding pharmacogenomics research to include patients with RHTN taking multiple BP-lowering medications may identify genetic markers associated with RHTN. To date, the available evidence surrounding pharmacogenomics in RHTN is limited and primarily focused on candidate genes. In this review, we summarize the most current data in RHTN pharmacogenomics and offer some recommendations on how to advance the field.

  9. Using genetic networks and homology to understand the evolution of phenotypic traits.

    Science.gov (United States)

    McCune, Amy R; Schimenti, John C

    2012-03-01

    Homology can have different meanings for different kinds of biologists. A phylogenetic view holds that homology, defined by common ancestry, is rigorously identified through phylogenetic analysis. Such homologies are taxic homologies (=synapomorphies). A second interpretation, "biological homology" emphasizes common ancestry through the continuity of genetic information underlying phenotypic traits, and is favored by some developmental geneticists. A third kind of homology, deep homology, was recently defined as "the sharing of the genetic regulatory apparatus used to build morphologically and phylogenetically disparate features." Here we explain the commonality among these three versions of homology. We argue that biological homology, as evidenced by a conserved gene regulatory network giving a trait its "essential identity" (a Character Identity Network or "ChIN") must also be a taxic homology. In cases where a phenotypic trait has been modified over the course of evolution such that homology (taxic) is obscured (e.g. jaws are modified gill arches), a shared underlying ChIN provides evidence of this transformation. Deep homologies, where molecular and cellular components of a phenotypic trait precede the trait itself (are phylogenetically deep relative to the trait), are also taxic homologies, undisguised. Deep homologies inspire particular interest for understanding the evolutionary assembly of phenotypic traits. Mapping these deeply homologous building blocks on a phylogeny reveals the sequential steps leading to the origin of phenotypic novelties. Finally, we discuss how new genomic technologies will revolutionize the comparative genomic study of non-model organisms in a phylogenetic context, necessary to understand the evolution of phenotypic traits.

  10. Difference in MSA phenotype distribution between populations: genetics or environment?

    Science.gov (United States)

    Ozawa, Tetsutaro; Revesz, Tamas; Paviour, Dominic; Lees, Andrew J; Quinn, Niall; Tada, Mari; Kakita, Akiyoshi; Onodera, Osamu; Wakabayashi, Koichi; Takahashi, Hitoshi; Nishizawa, Masatoyo; Holton, Janice L

    2012-01-01

    The reasons for the differences in emphasis on striatonigral or olivopontocerebellar involvement in multiple system atrophy (MSA) remain to be determined. Semi-quantitative pathological analyses carried out in the United Kingdom and Japan demonstrated that olivopontocerebellar-predominant pathology was more frequent in Japanese MSA than British MSA. This observation provides evidence for a difference in phenotype distribution between British and Japanese patients with definite MSA. Studies of the natural history and epidemiology of MSA carried out in various populations have revealed that the relative prevalences of clinical subtypes of MSA probably differ among populations; the majority of MSA patients diagnosed in Europe have predominant parkinsonism (MSA-P), while the majority of MSA patients diagnosed in Asia have predominant cerebellar ataxia (MSA-C). Although potential drawbacks to the published frequencies of clinical subtypes and pathological subtypes should be considered because of selection biases, the difference demonstrated in pathological subtype is also consistent with the differences in clinical subtype of MSA demonstrated between Europe and Asia. Modest alterations in susceptibility factors may contribute to the difference in MSA phenotype distribution between populations. Synergistic interactions between genetic risk variants and environmental toxins responsible for parkinsonism or cerebellar dysfunction should therefore be explored. Further investigations are needed to determine the environmental, genetic, and epigenetic factors that account for the differences in clinicopathological phenotype of MSA among different populations.

  11. Superoxide dismutase phenotypes in duodenal ulcers: A genetic marker?

    Directory of Open Access Journals (Sweden)

    Sulekha S

    2006-01-01

    Full Text Available Background:Cu-Zn superoxide dismutases are antioxidative defensive enzymes that catalyze the reduction of superoxide anions to hydrogen peroxide. Aim:The study focuses on the association of electromorph of superoxide dismutase with duodenal ulcers, which result due to an imbalance between aggressive and defensive factors. Materials and Methods:Endoscopically confirmed 210 duodenal ulcer patients and 185 healthy individuals for comparative analysis were considered for the present study. Phenotyping of superoxide dismutase was carried out by subjecting the RBC membranes to polyacrylamide gel electrophoresis, using appropriate staining protocols. Results:Statistical analysis of SOD phenotypes revealed a significant increase of SOD AFNx012 allele and Superoxide dismutases (SOD 2-2 phenotype in duodenal ulcer group. Among these individuals, a predominance of Helicobacter pylori infection was observed. The increased preponderance of homozygotes can be explained on the basis of reduced and altered enzyme activity, which may lead to disturbance in homeostasis of antioxidant/oxidant culminating in high lipid peroxidative gastric mucosal tissue damage and ulceration. No variation in the distribution of SOD phenotypes with respect to Helicobacter pylori indicates the role of Mn-SOD rather than Cu-Zn SOD in the Helicobacter pylori infected cases as reported earlier. Conclusions:Superoxide dismutase as a genetic marker / gene modifier, encoding for an antioxidant enzyme in maintaining tissue homeostasis of the gastric mucosa is discussed.

  12. The genetic basis of hair whorl, handedness, and other phenotypes

    Science.gov (United States)

    Hatfield, J.S.

    2006-01-01

    Evidence is presented that RHO, RHCE, and other RH genes, may be interesting candidates to consider when searching for the genetic basis of hair whorl rotation (i.e., clockwise or counterclockwise), handedness (i.e., right handed, left handed or ambidextrous), speech laterality (i.e., right brained or left brained), speech dyslexia (e.g., stuttering), sexual orientation (i.e., heterosexual, homosexual, bisexual, or transsexual), schizophrenia, bipolar disorder, and autism spectrum disorder. Such evidence involves the need for a genetic model that includes maternal immunization to explain some of the empirical results reported in the literature. The complex polymorphisms present among the maternally immunizing RH genes can then be used to explain other empirical results. Easily tested hypotheses are suggested, based upon genotypic (but not phenotypic) frequencies of the RH genes. In particular, homozygous dominant individuals are expected to be less common or lacking entirely among the alternative phenotypes. If it is proven that RH genes are involved in brain architecture, it will have a profound effect upon our understanding of the development and organization of the asymmetrical vertebrate brain and may eventually lead to a better understanding of the developmental processes which occur to produce the various alternative phenotypes discussed here. In addition, if RH genes are shown to be involved in the production of these phenotypes, then the evolutionary studies can be performed to demonstrate the beneficial effect of the recessive alleles of RHO and RHCE, and why human evolution appears to be selecting for the recessive alleles even though an increase in the frequency of such alleles may imply lower average fecundity among some individuals possessing them.

  13. Phenotypic and Genetic Effects of Contrasting Ethanol Environments on Physiological and Developmental Traits in Drosophila melanogaster

    Science.gov (United States)

    Castañeda, Luis E.; Nespolo, Roberto F.

    2013-01-01

    A central problem in evolutionary physiology is to understand the relationship between energy metabolism and fitness-related traits. Most attempts to do so have been based on phenotypic correlations that are not informative for the evolutionary potential of natural populations. Here, we explored the effect of contrasting ethanol environments on physiological and developmental traits, their genetic (co)variances and genetic architecture in Drosophila melanogaster. Phenotypic and genetic parameters were estimated in two populations (San Fernando and Valdivia, Chile), using a half-sib family design where broods were split into ethanol-free and ethanol-supplemented conditions. Our findings show that metabolic rate, body mass and development times were sensitive (i.e., phenotypic plasticity) to ethanol conditions and dependent on population origin. Significant heritabilities were found for all traits, while significant genetic correlations were only found between larval and total development time and between development time and metabolic rate for flies of the San Fernando population developed in ethanol-free conditions. Posterior analyses indicated that the G matrices differed between ethanol conditions for the San Fernando population (mainly explained by differences in genetic (co)variances of developmental traits), whereas the Valdivia population exhibited similar G matrices between ethanol conditions. Our findings suggest that ethanol-free environment increases the energy available to reduce development time. Therefore, our results indicate that environmental ethanol could modify the process of energy allocation, which could have consequences on the evolutionary response of natural populations of D. melanogaster. PMID:23505567

  14. Phenotypic and genetic effects of contrasting ethanol environments on physiological and developmental traits in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Luis E Castañeda

    Full Text Available A central problem in evolutionary physiology is to understand the relationship between energy metabolism and fitness-related traits. Most attempts to do so have been based on phenotypic correlations that are not informative for the evolutionary potential of natural populations. Here, we explored the effect of contrasting ethanol environments on physiological and developmental traits, their genetic (covariances and genetic architecture in Drosophila melanogaster. Phenotypic and genetic parameters were estimated in two populations (San Fernando and Valdivia, Chile, using a half-sib family design where broods were split into ethanol-free and ethanol-supplemented conditions. Our findings show that metabolic rate, body mass and development times were sensitive (i.e., phenotypic plasticity to ethanol conditions and dependent on population origin. Significant heritabilities were found for all traits, while significant genetic correlations were only found between larval and total development time and between development time and metabolic rate for flies of the San Fernando population developed in ethanol-free conditions. Posterior analyses indicated that the G matrices differed between ethanol conditions for the San Fernando population (mainly explained by differences in genetic (covariances of developmental traits, whereas the Valdivia population exhibited similar G matrices between ethanol conditions. Our findings suggest that ethanol-free environment increases the energy available to reduce development time. Therefore, our results indicate that environmental ethanol could modify the process of energy allocation, which could have consequences on the evolutionary response of natural populations of D. melanogaster.

  15. [Paternal GNAS mutations: Which phenotypes? What genetic counseling?].

    Science.gov (United States)

    Kottler, Marie-Laure

    2015-05-01

    Parental imprinting and the type of the genetic alteration play a determinant role in the phenotype expression of GNAS locus associated to pseudohypoparathyroidism (PHP). GNAS locus gives rise to several different messenger RNA transcripts that are derived from the paternal allele, the maternal allele, or both and can be either coding or non-coding. As a consequence, GNAS mutations lead to a wide spectrum of phenotypes. An alteration in the coding sequence of the gene leads to a haplo-insufficiency and a dysmorphic phenotype (Albright's syndrome or AHO). AHO is a clinical syndrome defined by specific physical features including short stature, obesity, round-shaped face, subcutaneous ossifications, brachymetarcapy (mainly of the 4th and 5th ray). If the alteration is on the maternal allele, there is a hormonal resistance to the PTH at the kidney level and to the TSH at the thyroid level. The phenotype is known as pseudohypoparathyroidism type 1a (PHP1a). If the alteration is on the paternal allele, there are few clinical signs with no hormonal resistance and the phenotype is known as pseudopseudo hypoparathyroidism (pseudo-PPHP). Heterozygous GNAS mutations on the paternal GNAS allele were associated with intra uterin growth retardation (IUGR). Moreover, birth weights were lower with paternal GNAS mutations affecting exon 2-13 than with exon 1/intron 1 mutations suggesting a role for loss of function XLαs. Progressive osseous heteroplasia (POH) is a rare disease of ectopic bone formation, characterized by cutaneous and subcutaneous ossifications progressing towards deep connective and muscular tissues. POH is caused by a heterozygous GNAS inactivating mutation and has been associated with paternal inheritance. However, genotype/phenotype correlations suggest that there is no direct correlation between the ossifying process and parental origin, as there is high variability in heterotopic ossification. Clinical heterogeneity makes genetic counseling a very delicate

  16. Genetic variations strongly influence phenotypic outcome in the mouse retina.

    Directory of Open Access Journals (Sweden)

    Austin S Jelcick

    Full Text Available Variation in genetic background can significantly influence the phenotypic outcome of both disease and non-disease associated traits. Additionally, differences in temporal and strain specific gene expression can also contribute to phenotypes in the mammalian retina. This is the first report of microarray based cross-strain analysis of gene expression in the retina investigating genetic background effects. Microarray analyses were performed on retinas from the following mouse strains: C57BL6/J, AKR/J, CAST/EiJ, and NOD.NON-H2(-nb1 at embryonic day 18.5 (E18.5 and postnatal day 30.5 (P30.5. Over 3000 differentially expressed genes were identified between strains and developmental stages. Differential gene expression was confirmed by qRT-PCR, Western blot, and immunohistochemistry. Three major gene networks were identified that function to regulate retinal or photoreceptor development, visual perception, cellular transport, and signal transduction. Many of the genes in these networks are implicated in retinal diseases such as bradyopsia, night-blindness, and cone-rod dystrophy. Our analysis revealed strain specific variations in cone photoreceptor cell patterning and retinal function. This study highlights the substantial impact of genetic background on both development and function of the retina and the level of gene expression differences tolerated for normal retinal function. These strain specific genetic variations may also be present in other tissues. In addition, this study will provide valuable insight for the development of more accurate models for human retinal diseases.

  17. Behavioral phenotypes of genetic mouse models of autism.

    Science.gov (United States)

    Kazdoba, T M; Leach, P T; Crawley, J N

    2016-01-01

    More than a hundred de novo single gene mutations and copy-number variants have been implicated in autism, each occurring in a small subset of cases. Mutant mouse models with syntenic mutations offer research tools to gain an understanding of the role of each gene in modulating biological and behavioral phenotypes relevant to autism. Knockout, knockin and transgenic mice incorporating risk gene mutations detected in autism spectrum disorder and comorbid neurodevelopmental disorders are now widely available. At present, autism spectrum disorder is diagnosed solely by behavioral criteria. We developed a constellation of mouse behavioral assays designed to maximize face validity to the types of social deficits and repetitive behaviors that are central to an autism diagnosis. Mouse behavioral assays for associated symptoms of autism, which include cognitive inflexibility, anxiety, hyperactivity, and unusual reactivity to sensory stimuli, are frequently included in the phenotypic analyses. Over the past 10 years, we and many other laboratories around the world have employed these and additional behavioral tests to phenotype a large number of mutant mouse models of autism. In this review, we highlight mouse models with mutations in genes that have been identified as risk genes for autism, which work through synaptic mechanisms and through the mTOR signaling pathway. Robust, replicated autism-relevant behavioral outcomes in a genetic mouse model lend credence to a causal role for specific gene contributions and downstream biological mechanisms in the etiology of autism.

  18. [Genetic analysis of an individual with para-Bombay phenotype].

    Science.gov (United States)

    Lin, Jia-jin; Huang, Ying; Zhu, Sui-yong

    2013-04-01

    To study genetic characteristics of an individual with para-Bombay phenotype and her family members. ABO and H antigens were detected with routine serological techniques.The entire coding region of FUT1 gene was amplified by polymerase chain reaction (PCR). PCR products was purified with enzymes digestion and directly sequenced. The RBCs of the proband did not agglutinate with H antibody. The proband therefore has a para-Bombay phenotype (Bmh). Direct sequencing indicated the FUT1 sequence of the proband contained a homozygous 547-552 del AG and heterozygous 814A>G mutation, which gave rise to two haplotypes of 547-552delAG, 547-552delAG and 814A>G. The ABO blood type of the proband' s mother and sisters were all B.Sequencing of the FUT1 gene has found heterozygous 547-552 del AG, 814A>G mutations in the mother and elder sister, and heterozygous 547-552 del AG mutation in her younger sister. The FUT1 547-552 del AG and 814 A>G mutations of the proband were inherited from her mother. A complex mutation of the FUT1 gene consisting of 547-55 del AG and 814 A>G has been identified in an individual with para-Bombay phenotype.

  19. Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection

    Science.gov (United States)

    MacDuff, Donna A; Reese, Tiffany A; Kimmey, Jacqueline M; Weiss, Leslie A; Song, Christina; Zhang, Xin; Kambal, Amal; Duan, Erning; Carrero, Javier A; Boisson, Bertrand; Laplantine, Emmanuel; Israel, Alain; Picard, Capucine; Colonna, Marco; Edelson, Brian T; Sibley, L David; Stallings, Christina L; Casanova, Jean-Laurent; Iwai, Kazuhiro; Virgin, Herbert W

    2015-01-01

    Variation in the presentation of hereditary immunodeficiencies may be explained by genetic or environmental factors. Patients with mutations in HOIL1 (RBCK1) present with amylopectinosis-associated myopathy with or without hyper-inflammation and immunodeficiency. We report that barrier-raised HOIL-1-deficient mice exhibit amylopectin-like deposits in the myocardium but show minimal signs of hyper-inflammation. However, they show immunodeficiency upon acute infection with Listeria monocytogenes, Toxoplasma gondii or Citrobacter rodentium. Increased susceptibility to Listeria was due to HOIL-1 function in hematopoietic cells and macrophages in production of protective cytokines. In contrast, HOIL-1-deficient mice showed enhanced control of chronic Mycobacterium tuberculosis or murine γ-herpesvirus 68 (MHV68), and these infections conferred a hyper-inflammatory phenotype. Surprisingly, chronic infection with MHV68 complemented the immunodeficiency of HOIL-1, IL-6, Caspase-1 and Caspase-1;Caspase-11-deficient mice following Listeria infection. Thus chronic herpesvirus infection generates signs of auto-inflammation and complements genetic immunodeficiency in mutant mice, highlighting the importance of accounting for the virome in genotype-phenotype studies. DOI: http://dx.doi.org/10.7554/eLife.04494.001 PMID:25599590

  20. The genetics of phenotypic plasticity. XIII. Interactions with developmental instability.

    Science.gov (United States)

    Scheiner, Samuel M

    2014-04-01

    In a heterogeneous environment, natural selection on a trait can lead to a variety of outcomes, including phenotypic plasticity and bet-hedging through developmental instability. These outcomes depend on the magnitude and pattern of that heterogeneity and the spatial and temporal distribution of individuals. However, we do not know if and how those two outcomes might interact with each other. I examined the joint evolution of plasticity and instability through the use of an individual-based simulation in which each could be genetically independent or pleiotropically linked. When plasticity and instability were determined by different loci, the only effect on the evolution of plasticity was the elimination of plasticity as a bet-hedging strategy. In contrast, the effects on the evolution of instability were more substantial. If conditions were such that the population was likely to evolve to the optimal reaction norm, then instability was disfavored. Instability was favored only when the lack of a reliable environmental cue disfavored plasticity. When plasticity and instability were determined by the same loci, instability acted as a strong limitation on the evolution of plasticity. Under some conditions, selection for instability resulted in maladaptive plasticity. Therefore, before testing any models of plasticity or instability evolution, or interpreting empirical patterns, it is important to know the ecological, life history, developmental, and genetic contexts of trait phenotypic plasticity and developmental instability.

  1. Pangenesis as a source of new genetic information. The history of a now disproven theory.

    Science.gov (United States)

    Bergman, Gerald

    2006-01-01

    Evolution is based on natural selection of existing biological phenotypic traits. Natural selection can only eliminate traits. It cannot create new ones, requiring a theory to explain the origin of new genetic information. The theory of pangenesis was a major attempt to explain the source of new genetic information required to produce phenotypic variety. This theory, advocated by Darwin as the main source of genetic variety, has now been empirically disproved. It is currently a theory mainly of interest to science historians.

  2. Toward conservation of genetic and phenotypic diversity in Japanese sticklebacks.

    Science.gov (United States)

    Kitano, Jun; Mori, Seiichi

    2016-10-13

    Stickleback fishes have been established as a leading model system for studying the genetic mechanisms that underlie naturally occurring phenotypic diversification. Because of the tremendous diversification achieved by stickleback species in various environments, different geographical populations have unique phenotypes and genotypes, which provide us with unique opportunities for evolutionary genetic research. Among sticklebacks, Japanese species have several unique characteristics that have not been found in other populations. The sympatric marine threespine stickleback species Gasterosteus aculeatus and G. nipponicus (Japan Sea stickleback) are a good system for speciation research. Gasterosteus nipponicus also has several unique characteristics, such as neo-sex chromosomes and courtship behaviors, that differ from those of G. aculeatus. Several freshwater populations derived from G. aculeatus (Hariyo threespine stickleback) inhabit spring-fed ponds and streams in central Honshu and exhibit year-round reproduction, which has never been observed in other stickleback populations. Four species of ninespine stickleback, including Pungitius tymensis and the freshwater, brackish water and Omono types of the P. pungitius-P. sinensis complex, are also excellent model systems for speciation research. Anthropogenic alteration of environments, however, has exposed several Japanese stickleback populations to the risk of extinction and has actually led to extinction of several populations and species. Pungitius kaibarae, which is endemic to East Asia, used to inhabit Kyoto and Hyogo prefectures, but is now extinct. Causes of extinction include depletion of spring water, landfill of habitats, and construction of river-mouth weirs. Here, we review the importance of Japanese sticklebacks as genetic resources, the status of several endangered stickleback populations and species, and the factors putting these populations at risk.

  3. Deep phenotyping unveils hidden traits and genetic relations in subtle mutants

    Science.gov (United States)

    San-Miguel, Adriana; Kurshan, Peri T.; Crane, Matthew M.; Zhao, Yuehui; McGrath, Patrick T.; Shen, Kang; Lu, Hang

    2016-11-01

    Discovering mechanistic insights from phenotypic information is critical for the understanding of biological processes. For model organisms, unlike in cell culture, this is currently bottlenecked by the non-quantitative nature and perceptive biases of human observations, and the limited number of reporters that can be simultaneously incorporated in live animals. An additional challenge is that isogenic populations exhibit significant phenotypic heterogeneity. These difficulties limit genetic approaches to many biological questions. To overcome these bottlenecks, we developed tools to extract complex phenotypic traits from images of fluorescently labelled subcellular landmarks, using C. elegans synapses as a test case. By population-wide comparisons, we identified subtle but relevant differences inaccessible to subjective conceptualization. Furthermore, the models generated testable hypotheses of how individual alleles relate to known mechanisms or belong to new pathways. We show that our model not only recapitulates current knowledge in synaptic patterning but also identifies novel alleles overlooked by traditional methods.

  4. [Leber's hereditary optic neuropathy - phenotype, genetics, therapeutic options].

    Science.gov (United States)

    Gallenmüller, C; Klopstock, T

    2014-03-01

    Leber's hereditary optic neuropathy is a rare genetic disorder affecting the retinal ganglion cells leading to a persistent severe bilateral loss of visual acuity within weeks or months. Males are much more likely to be affected than females, disease onset in most cases takes place between age 15 and 35 years. The disease is caused by point mutations in the mitochondrial DNA. The penetrance of the disease is incomplete, i.e., not all mutation carriers develop clinical symptoms. The phenotype is relatively uniform, but age at onset, severity and prognosis may vary even within the same family. Environmental and endocrine factors, optic disc anatomy as well as mitochondrial and nuclear genetic factors are discussed to influence penetrance as well as interindividual and intrafamilial variability. However, only cigarette smoking and excessive alcohol consumption have been shown to trigger disease onset. The disease is characterised by a central visual field defect, impaired colour vision and fundoscopically a peripapillary microangiopathy in the acute phase. Most patients end up after some months with a severe visual loss below 0.1 and in most cases there is no significant improvement of visual acuity in the course. In rare cases patients experience a mostly partial visual recovery which depends on the type of mutation. For confirmation of the diagnosis a detailed ophthalmological examination with fundoscopy, family history and genetic analysis of the mitochondrial DNA is needed. To date, there is no proven causal therapy, but at early disease stages treatment with idebenone can be tried.

  5. Smallpox virus plaque phenotypes: genetic, geographical and case fatality relationships.

    Science.gov (United States)

    Olson, Victoria A; Karem, Kevin L; Smith, Scott K; Hughes, Christine M; Damon, Inger K

    2009-04-01

    Smallpox (infection with Orthopoxvirus variola) remains a feared illness more than 25 years after its eradication. Historically, case-fatality rates (CFRs) varied between outbreaks (<1 to approximately 40 %), the reasons for which are incompletely understood. The extracellular enveloped virus (EEV) form of orthopoxvirus progeny is hypothesized to disseminate infection. Investigations with the closely related Orthopoxvirus vaccinia have associated increased comet formation (EEV production) with increased mouse mortality (pathogenicity). Other vaccinia virus genetic manipulations which affect EEV production inconsistently support this association. However, antisera against vaccinia virus envelope protect mice from lethal challenge, further supporting a critical role for EEV in pathogenicity. Here, we show that the increased comet formation phenotypes of a diverse collection of variola viruses associate with strain phylogeny and geographical origin, but not with increased outbreak-related CFRs; within clades, there may be an association of plaque size with CFR. The mechanisms for variola virus pathogenicity probably involves multiple host and pathogen factors.

  6. Aarskog-Scott syndrome: phenotypic and genetic heterogeneity

    Directory of Open Access Journals (Sweden)

    Ignacio Briceno

    2016-03-01

    Full Text Available Aarskog-Scott syndrome (AAS is a rare developmental disorder which primarily affects males and has a relative prevalence of 1 in 25,000 in the general population. AAS patients usually present with developmental complications including short stature and facial, skeletal and urogenital anomalies. The spectrum of genotype-phenotype correlations in AAS is unclear and mutations of the FGD1 gene on the proximal short arm of chromosome X account for only 20% of the incidence of the disorder. Failure to identify pathogenic variants in patients referred for FGD1 screening suggests heterogeneity underlying pathophysiology of the condition. Furthermore, overlapping features of AAS with several other developmental disorders increase the complexity of diagnosis. Cytoskeletal signaling may be involved in the pathophysiology of AAS. The FGD1 protein family has a role in activation of CDC42 (Cell Division Control protein 42 homolog which has a core function in remodeling of extracellular matrix and the transcriptional activation of many modulators of development. Therefore, mutations in components in the EGFR1 (Epidermal Growth Factor Receptor 1 signaling pathway, to which CDC42 belongs, may contribute to pathophysiology. Parallel sequencing strategies (so-called next generation sequencing or high throughput sequencing enables simultaneous production of millions of sequencing reads that enormously facilitate cost-effective identification of cryptic mutations in heterogeneous monogenic disorders. Here we review the source of phenotypic and genetic heterogeneity in the context of AAS and discuss the applicability of next generation sequencing for identification of novel mutations underlying AAS.

  7. Genetic Determinism vs. Phenotypic Plasticity in Protist Morphology.

    Science.gov (United States)

    Mulot, Matthieu; Marcisz, Katarzyna; Grandgirard, Lara; Lara, Enrique; Kosakyan, Anush; Robroek, Bjorn J M; Lamentowicz, Mariusz; Payne, Richard J; Mitchell, Edward A D

    2017-02-23

    Untangling the relationships between morphology and phylogeny is key to building a reliable taxonomy, but is especially challenging for protists, where the existence of cryptic or pseudocryptic species makes finding relevant discriminant traits difficult. Here we use Hyalosphenia papilio (a testate amoeba) as a model species to investigate the contribution of phylogeny and phenotypic plasticity in its morphology. We study the response of H. papilio morphology (shape and pores number) to environmental variables in (i) a manipulative experiment with controlled conditions (water level), (ii) an observational study of a within-site natural ecological gradient (water level), and (iii) an observational study across 37 European peatlands (climate). We showed that H. papilio morphology is correlated to environmental conditions (climate and water depth) as well as geography, while no relationship between morphology and phylogeny was brought to light. The relative contribution of genetic inheritance and phenotypic plasticity in shaping morphology varies depending on the taxonomic group and the trait under consideration. Thus, our data call for a reassessment of taxonomy based on morphology alone. This clearly calls for a substantial increase in taxonomic research on these globally still under-studied organisms leading to a reassessment of estimates of global microbial eukaryotic diversity.

  8. The genetic basis of alcoholism: multiple phenotypes, many genes, complex networks.

    Science.gov (United States)

    Morozova, Tatiana V; Goldman, David; Mackay, Trudy F C; Anholt, Robert R H

    2012-02-20

    Alcoholism is a significant public health problem. A picture of the genetic architecture underlying alcohol-related phenotypes is emerging from genome-wide association studies and work on genetically tractable model organisms.

  9. The genetic basis of alcoholism: multiple phenotypes, many genes, complex networks

    OpenAIRE

    Morozova, Tatiana V.; Goldman, David; Mackay, Trudy FC; Anholt, Robert RH

    2012-01-01

    Alcoholism is a significant public health problem. A picture of the genetic architecture underlying alcohol-related phenotypes is emerging from genome-wide association studies and work on genetically tractable model organisms.

  10. Pathogenic Ischemic Stroke Phenotypes in the NINDS-Stroke Genetics Network

    National Research Council Canada - National Science Library

    Ay, Hakan; Arsava, Ethem Murat; Andsberg, Gunnar; Benner, Thomas; Brown, Jr, Robert D; Chapman, Sherita N; Cole, John W; Delavaran, Hossein; Dichgans, Martin; Engström, Gunnar; Giralt-Steinhauer, Eva; Grewal, Raji P; Gwinn, Katrina; Jern, Christina; Jimenez-Conde, Jordi; Jood, Katarina; Katsnelson, Michael; Kissela, Brett; Kittner, Steven J; Kleindorfer, Dawn O; Labovitz, Daniel L; Lanfranconi, Silvia; Lee, Jin-Moo; Lehm, Manuel; Lemmens, Robin; Levi, Chris; Li, Linxin; Lindgren, Arne; Markus, Hugh S; McArdle, Patrick F; Melander, Olle; Norrving, Bo; Peddareddygari, Leema Reddy; Pedersén, Annie; Pera, Joanna; Rannikmäe, Kristiina; Rexrode, Kathryn M; Rhodes, David; Rich, Stephen S; Roquer, Jaume; Rosand, Jonathan; Rothwell, Peter M; Rundek, Tatjana; Sacco, Ralph L; Schmidt, Reinhold; Schürks, Markus; Seiler, Stephan; Sharma, Pankaj; Slowik, Agnieszka; Sudlow, Cathie; Thijs, Vincent; Woodfield, Rebecca; Worrall, Bradford B; Meschia, James F

    2014-01-01

    ...)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes...

  11. Genetic and phenotypic consequences of introgression between humans and Neanderthals.

    Science.gov (United States)

    Wills, Christopher

    2011-01-01

    Strong evidence for introgression of Neanderthal genes into parts of the modern human gene pool has recently emerged. The evidence indicates that some populations of modern humans have received infusions of genes from two different groups of Neanderthals. One of these Neanderthal groups lived in the Middle East and Central Europe and the other group (the Denisovans) is known to have lived in Central Asia and was probably more widespread. This review examines two questions. First, how were these introgressions detected and what does the genetic evidence tell us about their nature and extent? We will see that an unknown but possibly large fraction of the entire Neanderthal gene complement may have survived in modern humans. Even though each modern European and Asian carries only a few percent of genes that can be traced back to Neanderthals, different individuals carry different subgroups of these introgressed genes. Second, what is the likelihood that this Neanderthal genetic legacy has had phenotypic effects on modern humans? We examine evidence for and against the possibility that some of the surviving fragments of Neanderthal genomes have been preserved by natural selection, and we explore the ways in which more evidence bearing on this question will become available in the future.

  12. [Genetic information and future medicine].

    Science.gov (United States)

    Sakurai, Akihiro

    2012-11-01

    Rapid technological advances in genetic analysis have revealed the genetic background of various diseases. Elucidation of the genes responsible for a disease enables better clinical management of the disease and helps to develop targeted drugs. Also, early diagnosis and management of at-risk family members can be made by identification of a genetic disease in the proband. On the other hand, genetic issues often cause psychological distress to the family. To perform genetic testing appropriately and to protect patients and family members from any harm, guidelines for genetic testing were released from the alliance of Japanese genetics-related academic societies in 2003. As genetic testing is becoming incorporated into clinical practice more broadly, the guideline was revised and released by the Japanese Society of Medical Sciences in 2011. All medical professionals in Japan are expected to follow this guideline.

  13. The phenotypic difference discards sib-pair QTL linkage information

    Energy Technology Data Exchange (ETDEWEB)

    Wright, F.A. [Univ. of California, San Diego, CA (United States)]|[Univ. of Texas, El Paso, TX (United States)

    1997-03-01

    Kruglyak and Lander provide an important synthesis of methods for (IBD) sib-pair linkage mapping, with an emphasis on the use of complete multipoint inheritance information for each sib pair. These procedures are implemented in the computer program MAPMAKER/SIBS, which performs interval mapping for dichotomous and quantitative traits. The authors present three methods for mapping quantitative trait loci (QTLs): a variant of the commonly used Haseman-Elston regression approach, a maximum-likelihood procedure involving variance components, and a rank-based nonparametric procedure. These approaches and related work use the magnitude of the difference in the sibling phenotype values for each sib pair as the observation for analysis. Linkage is detected if siblings sharing more alleles IBD have similar phenotypes (i.e., a small difference in the phenotype values), while siblings sharing fewer alleles IBD have less similar phenotypes. Such techniques have been used to detect linkage for a number of quantitative traits. However, the exclusive reliance on the phenotypic differences may be due in large part to historical inertia. A likelihood argument is presented here to show that, under certain classical assumptions, the phenotypic differences do not contain the full likelihood information for QTL mapping. Furthermore, considerable gains in power to detect linkage can be achieved with an expanded likelihood model. The development here is related to previous work, which incorporates the full set of phenotypic data using likelihood and robust quasi-likelihood methods. The purpose of this letter is not to endorse a particular approach but to spur research in alternative and perhaps more powerful linkage tests. 17 refs.

  14. eCOMPAGT – efficient Combination and Management of Phenotypes and Genotypes for Genetic Epidemiology

    Directory of Open Access Journals (Sweden)

    Specht Günther

    2009-05-01

    Full Text Available Abstract Background High-throughput genotyping and phenotyping projects of large epidemiological study populations require sophisticated laboratory information management systems. Most epidemiological studies include subject-related personal information, which needs to be handled with care by following data privacy protection guidelines. In addition, genotyping core facilities handling cooperative projects require a straightforward solution to monitor the status and financial resources of the different projects. Description We developed a database system for an efficient combination and management of phenotypes and genotypes (eCOMPAGT deriving from genetic epidemiological studies. eCOMPAGT securely stores and manages genotype and phenotype data and enables different user modes with different rights. Special attention was drawn on the import of data deriving from TaqMan and SNPlex genotyping assays. However, the database solution is adjustable to other genotyping systems by programming additional interfaces. Further important features are the scalability of the database and an export interface to statistical software. Conclusion eCOMPAGT can store, administer and connect phenotype data with all kinds of genotype data and is available as a downloadable version at http://dbis-informatik.uibk.ac.at/ecompagt.

  15. Understanding mammalian genetic systems: the challenge of phenotyping in the mouse.

    Directory of Open Access Journals (Sweden)

    Steve D M Brown

    2006-08-01

    Full Text Available Understanding mammalian genetic systems is predicated on the determination of the relationship between genetic variation and phenotype. Several international programmes are under way to deliver mutations in every gene in the mouse genome. The challenge for mouse geneticists is to develop approaches that will provide comprehensive phenotype datasets for these mouse mutant libraries. Several factors are critical to success in this endeavour. It will be important to catalogue assay and environment and where possible to adopt standardised procedures for phenotyping tests along with common environmental conditions to ensure comparable datasets of phenotypes. Moreover, the scale of the task underlines the need to invest in technological development improving both the speed and cost of phenotyping platforms. In addition, it will be necessary to develop new informatics standards that capture the phenotype assay as well as other factors, genetic and environmental, that impinge upon phenotype outcome.

  16. A synthetic framework for modeling the genetic basis of phenotypic plasticity and its costs.

    Science.gov (United States)

    Zhai, Yi; Lv, Yafei; Li, Xin; Wu, Weimiao; Bo, Wenhao; Shen, Dengfeng; Xu, Fang; Pang, Xiaoming; Zheng, Bingsong; Wu, Rongling

    2014-01-01

    The phenotype of an individual is controlled not only by its genes, but also by the environment in which it grows. A growing body of evidence shows that the extent to which phenotypic changes are driven by the environment, known as phenotypic plasticity, is also under genetic control, but an overall picture of genetic variation for phenotypic plasticity remains elusive. Here, we develop a model for mapping quantitative trait loci (QTLs) that regulate environment-induced plastic response. This model enables geneticists to test whether there exist actual QTLs that determine phenotypic plasticity and, if there are, further test how plasticity QTLs control the costs of plastic response by dissecting the genetic correlation of phenotypic plasticity and trait value. The model was used to analyze real data for grain yield of winter wheat (Triticum aestivum), leading to the detection of pleiotropic QTLs and epistatic QTLs that affect phenotypic plasticity and its cost in this crop.

  17. Signal function drives phenotypic and genetic diversity: the effects of signalling individual identity, quality or behavioural strategy.

    Science.gov (United States)

    Tibbetts, Elizabeth A; Mullen, Sean P; Dale, James

    2017-07-05

    Animal coloration is influenced by selection pressures associated with communication. During communication, signallers display traits that inform receivers and modify receiver behaviour in ways that benefit signallers. Here, we discuss how selection on signallers to convey different kinds of information influences animal phenotypes and genotypes. Specifically, we address the phenotypic and genetic consequences of communicating three different kinds of information: individual identity, behavioural strategy and quality. Previous work has shown signals that convey different kinds of information differ in terms of the (i) type of selection acting on signallers (e.g. directional, stabilizing, or negative frequency dependent), and (ii) developmental basis of signals (i.e. heritability, genetic architecture). These differences result in signals that convey different information having consistently different phenotypic properties, including the amount, modality and continuity of intraspecific variation. Understanding how communication influences animal phenotypes may allow researchers to quickly identify putative functions of colour variation prior to experimentation. Signals that convey different information will also have divergent evolutionary consequences. For example, signalling individual identity can increase genetic diversity, signalling quality may decrease diversity, and signalling strategy can constrain adaptation and contribute to speciation. Considering recent advances in genomic resources, our framework highlights new opportunities to resolve the evolutionary consequences of selection on communication across diverse taxa and signal types.This article is part of the themed issue 'Animal coloration: production, perception, function and application'. © 2017 The Author(s).

  18. Combining high-throughput phenotyping and genome-wide association studies to reveal natural genetic variation in rice.

    Science.gov (United States)

    Yang, Wanneng; Guo, Zilong; Huang, Chenglong; Duan, Lingfeng; Chen, Guoxing; Jiang, Ni; Fang, Wei; Feng, Hui; Xie, Weibo; Lian, Xingming; Wang, Gongwei; Luo, Qingming; Zhang, Qifa; Liu, Qian; Xiong, Lizhong

    2014-10-08

    Even as the study of plant genomics rapidly develops through the use of high-throughput sequencing techniques, traditional plant phenotyping lags far behind. Here we develop a high-throughput rice phenotyping facility (HRPF) to monitor 13 traditional agronomic traits and 2 newly defined traits during the rice growth period. Using genome-wide association studies (GWAS) of the 15 traits, we identify 141 associated loci, 25 of which contain known genes such as the Green Revolution semi-dwarf gene, SD1. Based on a performance evaluation of the HRPF and GWAS results, we demonstrate that high-throughput phenotyping has the potential to replace traditional phenotyping techniques and can provide valuable gene identification information. The combination of the multifunctional phenotyping tools HRPF and GWAS provides deep insights into the genetic architecture of important traits.

  19. Intention to seek information on cancer genetics

    Directory of Open Access Journals (Sweden)

    J.E. Andrews

    2005-01-01

    Full Text Available Objective. The public has a high interest in seeking personal genetic information, which holds implications for health information seeking research and health care policy. Rapid advances in cancer genetics research promise early detection, prevention and treatment, yet consumers may have greater difficulty finding and using the information they may need to make informed decisions regarding their personal health and the future of their families. Design. A statewide telephone survey was conducted of non-institutionalized Kentucky residents 18 years of age or older to investigate factors associated with the intention to seek cancer genetics information, including the need for such information seeking help. Results. The results show that intention to seek cancer genetics information, if testing were readily available, is moderately high (62.5% of those responding; n=835, and that status as a racial minority, the perception that cancer runs in one's family, and frequent worrying about cancer risk are statistically significant predictors of intent to seek genetics information. Conclusion. . We argue that an already complex health information environment will be even more difficult for individuals to navigate as genetic research becomes more ubiquitous in health care. An increase in demand for genetics information in various forms, as suggested by these results and those of other studies, implies that enduring intervention strategies are needed to help individuals acquire necessary health information literacy skills, with special attention given to racial minorities.

  20. Absolute pitch exhibits phenotypic and genetic overlap with synesthesia.

    Science.gov (United States)

    Gregersen, Peter K; Kowalsky, Elena; Lee, Annette; Baron-Cohen, Simon; Fisher, Simon E; Asher, Julian E; Ballard, David; Freudenberg, Jan; Li, Wentian

    2013-05-15

    Absolute pitch (AP) and synesthesia are two uncommon cognitive traits that reflect increased neuronal connectivity and have been anecdotally reported to occur together in an individual. Here we systematically evaluate the occurrence of synesthesia in a population of 768 subjects with documented AP. Out of these 768 subjects, 151 (20.1%) reported synesthesia, most commonly with color. These self-reports of synesthesia were validated in a subset of 21 study subjects, using an established methodology. We further carried out combined linkage analysis of 53 multiplex families with AP and 36 multiplex families with synesthesia. We observed a peak NPL LOD = 4.68 on chromosome 6q, as well as evidence of linkage on chromosome 2, using a dominant model. These data establish the close phenotypic and genetic relationship between AP and synesthesia. The chromosome 6 linkage region contains 73 genes; several leading candidate genes involved in neurodevelopment were investigated by exon resequencing. However, further studies will be required to definitively establish the identity of the causative gene(s) in the region.

  1. Role of phenotypic and genetic testing in managing clopidogrel therapy.

    Science.gov (United States)

    Chan, Noel C; Eikelboom, John W; Ginsberg, Jeffrey S; Lauw, Mandy N; Vanassche, Thomas; Weitz, Jeffrey I; Hirsh, Jack

    2014-07-31

    The P2Y12 inhibitors, clopidogrel, prasugrel, and ticagrelor, are administered in fixed doses without laboratory monitoring. Randomized trials in acute coronary syndrome have shown that prasugrel and ticagrelor are more effective than standard-dose clopidogrel. Nonetheless, standard-dose clopidogrel remains widely used because it causes less bleeding and is less expensive. Patients treated with standard-dose clopidogrel have substantial variability in platelet inhibition, which is partly explained by genetic polymorphisms encoding CYP2C19, the hepatic enzyme involved in biotransformation of clopidogrel to its active metabolite. Some advocate tailoring P2Y12 inhibitor therapy according to the results of routine laboratory testing. Although there is good evidence for analytic, biological, and clinical validity of several phenotypic and genotypic biomarkers, the benefit of a management strategy that incorporates routine biomarker testing over standard of care without such testing remains unproven. Appropriately designed, adequately powered trials are needed but face the challenges of feasibility, cost, and the progressive switch from clopidogrel to prasugrel or ticagrelor.

  2. TOMATOMA Update: Phenotypic and Metabolite Information in the Micro-Tom Mutant Resource.

    Science.gov (United States)

    Shikata, Masahito; Hoshikawa, Ken; Ariizumi, Tohru; Fukuda, Naoya; Yamazaki, Yukiko; Ezura, Hiroshi

    2016-01-01

    TOMATOMA (http://tomatoma.nbrp.jp/) is a tomato mutant database providing visible phenotypic data of tomato mutant lines generated by ethylmethane sulfonate (EMS) treatment or γ-ray irradiation in the genetic background of Micro-Tom, a small and rapidly growing variety. To increase mutation efficiency further, mutagenized M3 seeds were subjected to a second round of EMS treatment; M3M1 populations were generated. These plants were self-pollinated, and 4,952 lines of M3M2 mutagenized seeds were generated. We checked for visible phenotypes in the M3M2 plants, and 618 mutant lines with 1,194 phenotypic categories were identified. In addition to the phenotypic information, we investigated Brix values and carotenoid contents in the fruits of individual mutants. Of 466 samples from 171 mutant lines, Brix values and carotenoid contents were between 3.2% and 11.6% and 6.9 and 37.3 µg g(-1) FW, respectively. This metabolite information concerning the mutant fruits would be useful in breeding programs as well as for the elucidation of metabolic regulation. Researchers are able to browse and search this phenotypic and metabolite information and order seeds of individual mutants via TOMATOMA. Our new Micro-Tom double-mutagenized populations and the metabolic information could provide a valuable genetic toolkit to accelerate tomato research and potential breeding programs. © The Author 2015. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  3. Use of genetic data to infer population-specific ecological and phenotypic traits from mixed aggregations.

    Directory of Open Access Journals (Sweden)

    Paul Moran

    Full Text Available Many applications in ecological genetics involve sampling individuals from a mixture of multiple biological populations and subsequently associating those individuals with the populations from which they arose. Analytical methods that assign individuals to their putative population of origin have utility in both basic and applied research, providing information about population-specific life history and habitat use, ecotoxins, pathogen and parasite loads, and many other non-genetic ecological, or phenotypic traits. Although the question is initially directed at the origin of individuals, in most cases the ultimate desire is to investigate the distribution of some trait among populations. Current practice is to assign individuals to a population of origin and study properties of the trait among individuals within population strata as if they constituted independent samples. It seemed that approach might bias population-specific trait inference. In this study we made trait inferences directly through modeling, bypassing individual assignment. We extended a Bayesian model for population mixture analysis to incorporate parameters for the phenotypic trait and compared its performance to that of individual assignment with a minimum probability threshold for assignment. The Bayesian mixture model outperformed individual assignment under some trait inference conditions. However, by discarding individuals whose origins are most uncertain, the individual assignment method provided a less complex analytical technique whose performance may be adequate for some common trait inference problems. Our results provide specific guidance for method selection under various genetic relationships among populations with different trait distributions.

  4. Multiple genetic interaction experiments provide complementary information useful for gene function prediction.

    Directory of Open Access Journals (Sweden)

    Magali Michaut

    Full Text Available Genetic interactions help map biological processes and their functional relationships. A genetic interaction is defined as a deviation from the expected phenotype when combining multiple genetic mutations. In Saccharomyces cerevisiae, most genetic interactions are measured under a single phenotype - growth rate in standard laboratory conditions. Recently genetic interactions have been collected under different phenotypic readouts and experimental conditions. How different are these networks and what can we learn from their differences? We conducted a systematic analysis of quantitative genetic interaction networks in yeast performed under different experimental conditions. We find that networks obtained using different phenotypic readouts, in different conditions and from different laboratories overlap less than expected and provide significant unique information. To exploit this information, we develop a novel method to combine individual genetic interaction data sets and show that the resulting network improves gene function prediction performance, demonstrating that individual networks provide complementary information. Our results support the notion that using diverse phenotypic readouts and experimental conditions will substantially increase the amount of gene function information produced by genetic interaction screens.

  5. Genetic susceptibility and genotype-phenotype association in 588 Danish children with inflammatory bowel disease

    DEFF Research Database (Denmark)

    Jakobsen, C; Cleynen, I; Andersen, Susanne Pia;

    2014-01-01

    AIM: To investigate the association between known inflammatory bowel disease (IBD)-associated genetic variants and development of paediatric IBD, and specific clinical sub-phenotypes. MATERIAL AND METHODS: In this case-control study we included IBD patients ... retrieved and clinical information was extracted. DNA was obtained from Guthrie cards from the Danish National Neonatal Screening Biobank (PKU-biobanken) at Statens Serum Institut and from blood samples. RESULTS: A total of 588 IBD patients (244 Crohn's disease (CD), 318 ulcerative colitis (UC) and 26 IBD...... associated with disease localisation, medical treatment or surgery after correcting for multiple analyses. CONCLUSION: We found an association between CD and three previously published genetic variants and replicated the association with the paediatric specific ZMIZ1 gene. No Bonferroni corrected significant...

  6. [Phenotype-based genetic association studies (PGAS): a new approach to understanding the genotype contribution to schizophrenic phenotypes].

    Science.gov (United States)

    Ehrenreich, H

    2013-05-01

    Schizophrenias are diagnosed purely clinically. The biological basis for this clinical entity is still fully unknown. Genetic studies have revealed some interesting hints but have not led to the identification of actual disease genotypes. On the contrary, it has become more and more probable that widely differing genotype constellations together with manifold environmental factors can trigger schizophrenia according to the motto "many roads lead to Rome...". Thus, new strategies that allow a better insight into complex genotype-phenotype relationships, e. g. PGAS (phenotype-based genetic associations studies) are urgently needed. PGAS became possible on the basis of the GRAS data collection, the as yet largest worldwide phenotypical databank of schizophrenic patients. First PGAS proof-of-concept results on cognition or development-relevant genes are already available.

  7. Genetic and Environmental Regulation on Longitudinal Change of Metabolic Phenotypes in Danish and Chinese Adult Twins

    DEFF Research Database (Denmark)

    Li, Shuxia; Kyvik, Kirsten Ohm; Pang, Zengchang

    2016-01-01

    OBJECTIVE: The rate of change in metabolic phenotypes can be highly indicative of metabolic disorders and disorder-related modifications. We analyzed data from longitudinal twin studies on multiple metabolic phenotypes in Danish and Chinese twins representing two populations of distinct ethnic...... environmental contribution to blood pressure but no genetic contribution to longitudinal change in body mass traits. CONCLUSION: Our results emphasize the major contribution of unique environment to the observed intra-individual variation in all metabolic phenotypes in both samples, and meanwhile reveal...... differential patterns of genetic and common environmental regulation on changes over time in metabolic phenotypes across the two samples....

  8. What monozygotic twins discordant for phenotype illustrate about mechanisms influencing genetic forms of neurodegeneration

    NARCIS (Netherlands)

    Ketelaar, M. E.; Hofstra, R. M. W.; Hayden, M. R.

    2012-01-01

    As monozygotic (MZ) twins are believed to be genetically identical, discordance for disease phenotype between MZ twins has been used in genetic research to understand the contribution of genetic vs environmental factors in disease development. However, recent studies show that MZ twins can differ bo

  9. The genetics of maternal care: direct and indirect genetic effects on phenotype in the dung beetle Onthophagus taurus.

    Science.gov (United States)

    Hunt, John; Simmons, Leigh W

    2002-05-14

    While theoretical models of the evolution of parental care are based on the assumption of underlying genetic variance, surprisingly few quantitative genetic studies of this life-history trait exist. Estimation of the degree of genetic variance in parental care is important because it can be a significant source of maternal effects, which, if genetically based, represent indirect genetic effects. A major prediction of indirect genetic effect theory is that traits without heritable variation can evolve because of the heritable environmental variation that indirect genetic effects provide. In the dung beetle, Onthophagus taurus, females provide care to offspring by provisioning a brood mass. The size of the brood mass has pronounced effects on offspring phenotype. Using a half-sib breeding design we show that the weight of the brood mass females produce exhibits significant levels of additive genetic variance due to sires. However, variance caused by dams is considerably larger, demonstrating that maternal effects are also important. Body size exhibited low additive genetic variance. However, body size exerts a strong maternal influence on the weight of brood masses produced, accounting for 22% of the nongenetic variance in offspring body size. Maternal body size also influenced the number of offspring produced but there was no genetic variance for this trait. Offspring body size and brood mass weight exhibited positive genetic and phenotypic correlations. We conclude that both indirect genetic effects, via maternal care, and nongenetic maternal effects, via female size, play important roles in the evolution of phenotype in this species.

  10. Genetic and phenotypic parameters of body weight in Zandi sheep

    African Journals Online (AJOL)

    DR. TONUKARI NYEROVWO

    2011-11-02

    Nov 2, 2011 ... from the Khojir Sheep Breeding Station, Tehran, Iran. Number of ..... food intake and performance in the young lamb; although this trend was not also .... genetic parameters and genetic trends for live weight and fleece traits.

  11. Phenotypic characterization and genetic diversity of Flavobacterium columnare isolated from red tilapia, Oreochromis sp. in Thailand

    Science.gov (United States)

    Flavobacterium columnare is the etiologic agent of columnaris disease and severely affects various freshwater aquaculture fish species worldwide. The objectives of this study were to determine the phenotypic characteristics and genetic variability among F. columnare isolates isolated from red tilapi...

  12. In-depth metabolic phenotyping of genetically engineered mouse models in obesity and diabetes.

    Science.gov (United States)

    Lee, Hui-Young; Jeong, Kyeong-Hoon; Choi, Cheol Soo

    2014-10-01

    The world-wide prevalence of obesity and diabetes has increased sharply during the last two decades. Accordingly, the metabolic phenotyping of genetically engineered mouse models is critical for evaluating the functional roles of target genes in obesity and diabetes, and for developing new therapeutic targets. In this review, we discuss the practical meaning of metabolic phenotyping, the strategy of choosing appropriate tests, and considerations when designing and performing metabolic phenotyping in mice.

  13. Movement disorders in 2014 : Genetic advances spark a revolution in dystonia phenotyping

    NARCIS (Netherlands)

    de Koning, Tom J; Tijssen, Marina A J

    2015-01-01

    Genetic revelations in 2014 are testing traditional classification systems for movement disorders, and our approach to clinical diagnostics. Mutations in dystonia-associated genes lead to a spectrum of disorders with different phenotypes, underscoring the need for stringent clinical phenotyping of p

  14. Symptom dimensions as alternative phenotypes to address genetic heterogeneity in schizophrenia and bipolar disorder.

    Science.gov (United States)

    Labbe, Aurélie; Bureau, Alexandre; Moreau, Isabel; Roy, Marc-André; Chagnon, Yvon; Maziade, Michel; Merette, Chantal

    2012-11-01

    This study introduces a novel way to use the lifetime ratings of symptoms of psychosis, mania and depression in genetic linkage analysis of schizophrenia (SZ) and bipolar disorder (BP). It suggests using a latent class model developed for family data to define more homogeneous symptom subtypes that are influenced by a smaller number of genes that will thus be more easily detectable. In a two-step approach, we proposed: (i) to form homogeneous clusters of subjects based on the symptom dimensions and (ii) to use the information from these homogeneous clusters in linkage analysis. This framework was applied to a unique SZ and BP sample composed of 1278 subjects from 48 large kindreds from the Eastern Quebec population. The results suggest that our strategy has the power to increase linkage signals previously obtained using the diagnosis as phenotype and allows for a better characterization of the linkage signals. This is the case for a linkage signal, which we formerly obtained in chromosome 13q and enhanced using the dimension mania. The analysis also suggests that the methods may detect new linkage signals not previously uncovered by using diagnosis alone, as in chromosomes 2q (delusion), 15q (bizarre behavior), 7p (anhedonia) and 9q (delusion). In the case of the 15q and 2q region, the results coincide with linkage signals detected in other studies. Our results support the view that dissecting phenotypic heterogeneity by modeling symptom dimensions may provide new insights into the genetics of SZ and BP.

  15. The role of genetic information in personalized medicine.

    Science.gov (United States)

    Gamma, Alex

    2013-01-01

    Personalized medicine is the latest promise of a gene-centered biomedicine to provide treatments custom-tailored to the specific needs of patients. Although surrounded by much hype, personalized medicine at present lacks the empirical and theoretical foundations necessary to render it a realistic long-term perspective. In particular, the role of genetic data and the relationship between causal understanding, prediction, prevention, and treatment of a disease need clarifying. This article critically examines the concept of information in genetics and its relation to modern-day genetic determinism, using pharmacogenetics, personalized medicine's core discipline, as a test case. The article concludes that: (1) genetic knowledge does not constitute a privileged basis for personalized medicine because there is an a priori complete causal parity of genetic and nongenetic resources of development; and (2) prediction, prevention, and treatment all depend on a causal-mechanistic understanding that will follow only from integrating data across the whole gamut of developmental factors-genetic and non-genetic. In a future successful personalized medicine, genes will have no special status, either as determinants of phenotype, markers of disease or as targets of treatment.

  16. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

    Science.gov (United States)

    Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke; Schumm, L Philip; Zeissig, Sebastian; Ahmad, Tariq; Andersen, Vibeke; Andrews, Jane M; Annese, Vito; Brand, Stephan; Brant, Steven R; Cho, Judy H; Daly, Mark J; Dubinsky, Marla; Duerr, Richard H; Ferguson, Lynnette R; Franke, Andre; Gearry, Richard B; Goyette, Philippe; Hakonarson, Hakon; Halfvarson, Jonas; Hov, Johannes R; Huang, Hailang; Kennedy, Nicholas A; Kupcinskas, Limas; Lawrance, Ian C; Lee, James C; Satsangi, Jack; Schreiber, Stephan; Théâtre, Emilie; van der Meulen-de Jong, Andrea E; Weersma, Rinse K; Wilson, David C; Parkes, Miles; Vermeire, Severine; Rioux, John D; Mansfield, John; Silverberg, Mark S; Radford-Smith, Graham; McGovern, Dermot P B; Barrett, Jeffrey C; Lees, Charlie W

    2016-01-01

    Summary Background Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. Findings After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for

  17. The phenotypic and genetic structure of depression and anxiety disorder symptoms in childhood, adolescence, and young adulthood.

    Science.gov (United States)

    Waszczuk, Monika A; Zavos, Helena M S; Gregory, Alice M; Eley, Thalia C

    2014-08-01

    internalizing factor influencing depression and all anxiety subscales emerged, alongside a small significant genetic fear factor. These results provide preliminary evidence for different phenotypic and genetic structures of internalizing disorder symptoms in childhood, adolescence, and young adulthood, with depression and anxiety becoming more associated from adolescence. The results inform molecular genetics research and transdiagnostic treatment approaches. The findings affirm the need to continue examining the classification of mood and anxiety disorders in diagnostic systems.

  18. A quantitative genetic analysis of intermediate asthma phenotypes

    DEFF Research Database (Denmark)

    Thomsen, S.F.; Ferreira, M.A.R.; Kyvik, K.O.

    2009-01-01

    to the observed data using maximum likelihood methods. RESULTS: Additive genetic factors explained 67% of the variation in FeNO, 43% in airway responsiveness, 22% in airway obstruction, and 81% in serum total IgE. In general, traits had genetically and environmentally distinct variance structures. The most...

  19. GPA-MDS: A Visualization Approach to Investigate Genetic Architecture among Phenotypes Using GWAS Results.

    Science.gov (United States)

    Wei, Wei; Ramos, Paula S; Hunt, Kelly J; Wolf, Bethany J; Hardiman, Gary; Chung, Dongjun

    2016-01-01

    Genome-wide association studies (GWAS) have identified tens of thousands of genetic variants associated with hundreds of phenotypes and diseases, which have provided clinical and medical benefits to patients with novel biomarkers and therapeutic targets. Recently, there has been accumulating evidence suggesting that different complex traits share a common risk basis, namely, pleiotropy. Previously, a statistical method, namely, GPA (Genetic analysis incorporating Pleiotropy and Annotation), was developed to improve identification of risk variants and to investigate pleiotropic structure through a joint analysis of multiple GWAS datasets. While GPA provides a statistically rigorous framework to evaluate pleiotropy between phenotypes, it is still not trivial to investigate genetic relationships among a large number of phenotypes using the GPA framework. In order to address this challenge, in this paper, we propose a novel approach, GPA-MDS, to visualize genetic relationships among phenotypes using the GPA algorithm and multidimensional scaling (MDS). This tool will help researchers to investigate common etiology among diseases, which can potentially lead to development of common treatments across diseases. We evaluate the proposed GPA-MDS framework using a simulation study and apply it to jointly analyze GWAS datasets examining 18 unique phenotypes, which helps reveal the shared genetic architecture of these phenotypes.

  20. Conflict between genetic and phenotypic differentiation: the evolutionary history of a 'lost and rediscovered' shorebird.

    Directory of Open Access Journals (Sweden)

    Frank E Rheindt

    Full Text Available Understanding and resolving conflicts between phenotypic and genetic differentiation is central to evolutionary research. While phenotypically monomorphic species may exhibit deep genetic divergences, some morphologically distinct taxa lack notable genetic differentiation. Here we conduct a molecular investigation of an enigmatic shorebird with a convoluted taxonomic history, the White-faced Plover (Charadrius alexandrinus dealbatus, widely regarded as a subspecies of the Kentish Plover (C. alexandrinus. Described as distinct in 1863, its name was consistently misapplied in subsequent decades until taxonomic clarification ensued in 2008. Using a recently proposed test of species delimitation, we reconfirm the phenotypic distinctness of dealbatus. We then compare three mitochondrial and seven nuclear DNA markers among 278 samples of dealbatus and alexandrinus from across their breeding range and four other closely related plovers. We fail to find any population genetic differentiation between dealbatus and alexandrinus, whereas the other species are deeply diverged at the study loci. Kentish Plovers join a small but growing list of species for which low levels of genetic differentiation are accompanied by the presence of strong phenotypic divergence, suggesting that diagnostic phenotypic characters may be encoded by few genes that are difficult to detect. Alternatively, gene expression differences may be crucial in producing different phenotypes whereas neutral differentiation may be lagging behind.

  1. Precision phenotyping of biomass accumulation in triticale reveals temporal genetic patterns of regulation

    Science.gov (United States)

    Busemeyer, Lucas; Ruckelshausen, Arno; Möller, Kim; Melchinger, Albrecht E.; Alheit, Katharina V.; Maurer, Hans Peter; Hahn, Volker; Weissmann, Elmar A.; Reif, Jochen C.; Würschum, Tobias

    2013-08-01

    To extend agricultural productivity by knowledge-based breeding and tailor varieties adapted to specific environmental conditions, it is imperative to improve our ability to assess the dynamic changes of the phenome of crops under field conditions. To this end, we have developed a precision phenotyping platform that combines various sensors for a non-invasive, high-throughput and high-dimensional phenotyping of small grain cereals. This platform yielded high prediction accuracies and heritabilities for biomass of triticale. Genetic variation for biomass accumulation was dissected with 647 doubled haploid lines derived from four families. Employing a genome-wide association mapping approach, two major quantitative trait loci (QTL) for biomass were identified and the genetic architecture of biomass accumulation was found to be characterized by dynamic temporal patterns. Our findings highlight the potential of precision phenotyping to assess the dynamic genetics of complex traits, especially those not amenable to traditional phenotyping.

  2. Genetic and Environmental Regulation on Longitudinal Change of Metabolic Phenotypes in Danish and Chinese Adult Twins.

    Science.gov (United States)

    Li, Shuxia; Kyvik, Kirsten Ohm; Pang, Zengchang; Zhang, Dongfeng; Duan, Haiping; Tan, Qihua; Hjelmborg, Jacob; Kruse, Torben; Dalgård, Christine

    2016-01-01

    The rate of change in metabolic phenotypes can be highly indicative of metabolic disorders and disorder-related modifications. We analyzed data from longitudinal twin studies on multiple metabolic phenotypes in Danish and Chinese twins representing two populations of distinct ethnic, cultural, social-economic backgrounds and geographical environments. The study covered a relatively large sample of 502 pairs of Danish adult twins followed up for a long period of 12 years with a mean age at intake of 38 years (range: 18-65) and a total of 181 Chinese adult twin pairs traced for about 7 years with a mean baseline age of 39.5 years (range: 23-64). The classical twin models were fitted to the longitudinal change in each phenotypephenotype) to estimate the genetic and environmental contributions to the variation in Δphenotype. Moderate to high contributions by the unique environment were estimated for all phenotypes in both Danish (from 0.51 for low density lipoprotein cholesterol up to 0.72 for triglycerides) and Chinese (from 0.41 for triglycerides up to 0.73 for diastolic blood pressure) twins; low to moderate genetic components were estimated for long-term change in most of the phenotypes in Danish twins except for triglycerides and hip circumference. Compared with Danish twins, the Chinese twins tended to have higher genetic control over the longitudinal changes in lipids (except high density lipoprotein cholesterol) and glucose, higher unique environmental contribution to blood pressure but no genetic contribution to longitudinal change in body mass traits. Our results emphasize the major contribution of unique environment to the observed intra-individual variation in all metabolic phenotypes in both samples, and meanwhile reveal differential patterns of genetic and common environmental regulation on changes over time in metabolic phenotypes across the two samples.

  3. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders

    DEFF Research Database (Denmark)

    Wolff, Markus; Johannesen, Katrine M; Hedrich, Ulrike B S

    2017-01-01

    for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (...). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients....... In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers...

  4. Longitudinal investigation into genetics in the conservation of metabolic phenotypes in Danish and Chinese twins

    DEFF Research Database (Denmark)

    Li, Shuxia; Kyvik, Kirsten Ohm; Duan, Haiping

    2016-01-01

    twin study on long-term stability of metabolic phenotypes in Danish and Chinese twins identified a common pattern of high genetic control over phenotype conservation, and at the same time revealed population-specific patterns of genetic and common environmental regulation on the variance as well...... for 12 years and Chinese twins traced for 7 years. The study covered a relatively large sample of 502 pairs of Danish adult twins with a mean age at intake of 38 years and a total of 181 Chinese adult twin pairs with a mean baseline age of 39.5 years. Bivariate twin models were fitted to the longitudinal...... estimated in both Danish (h2>0.75 except fasting blood glucose) and Chinese (h2>0.72 except blood pressure) twins; moderate to high genetic contribution to phenotype variation at the two time points were also estimated except for the low genetic regulation on glucose in Danish and on blood pressure...

  5. Analysis of malaria parasite phenotypes using experimental genetic crosses of Plasmodium falciparum

    OpenAIRE

    Ranford-Cartwright, Lisa C; Mwangi, Jonathan M.

    2012-01-01

    We review the principles of linkage analysis of experimental genetic crosses and their application to Plasmodium falciparum. Three experimental genetic crosses have been performed using the human malaria parasite P. falciparum. Linkage analysis of the progeny of these crosses has been used to identify parasite genes important in phenotypes such as drug resistance, parasite growth and virulence, and transmission to mosquitoes. The construction and analysis of genetic maps has been used to char...

  6. Online genetic databases informing human genome epidemiology

    Directory of Open Access Journals (Sweden)

    Higgins Julian PT

    2007-07-01

    Full Text Available Abstract Background With the advent of high throughput genotyping technology and the information available via projects such as the human genome sequencing and the HapMap project, more and more data relevant to the study of genetics and disease risk will be produced. Systematic reviews and meta-analyses of human genome epidemiology studies rely on the ability to identify relevant studies and to obtain suitable data from these studies. A first port of call for most such reviews is a search of MEDLINE. We examined whether this could be usefully supplemented by identifying databases on the World Wide Web that contain genetic epidemiological information. Methods We conducted a systematic search for online databases containing genetic epidemiological information on gene prevalence or gene-disease association. In those containing information on genetic association studies, we examined what additional information could be obtained to supplement a MEDLINE literature search. Results We identified 111 databases containing prevalence data, 67 databases specific to a single gene and only 13 that contained information on gene-disease associations. Most of the latter 13 databases were linked to MEDLINE, although five contained information that may not be available from other sources. Conclusion There is no single resource of structured data from genetic association studies covering multiple diseases, and in relation to the number of studies being conducted there is very little information specific to gene-disease association studies currently available on the World Wide Web. Until comprehensive data repositories are created and utilized regularly, new data will remain largely inaccessible to many systematic review authors and meta-analysts.

  7. PHENOPSIS DB: an Information System for Arabidopsis thaliana phenotypic data in an environmental context

    Directory of Open Access Journals (Sweden)

    Massonnet Catherine

    2011-05-01

    Full Text Available Abstract Background Renewed interest in plant × environment interactions has risen in the post-genomic era. In this context, high-throughput phenotyping platforms have been developed to create reproducible environmental scenarios in which the phenotypic responses of multiple genotypes can be analysed in a reproducible way. These platforms benefit hugely from the development of suitable databases for storage, sharing and analysis of the large amount of data collected. In the model plant Arabidopsis thaliana, most databases available to the scientific community contain data related to genetic and molecular biology and are characterised by an inadequacy in the description of plant developmental stages and experimental metadata such as environmental conditions. Our goal was to develop a comprehensive information system for sharing of the data collected in PHENOPSIS, an automated platform for Arabidopsis thaliana phenotyping, with the scientific community. Description PHENOPSIS DB is a publicly available (URL: http://bioweb.supagro.inra.fr/phenopsis/ information system developed for storage, browsing and sharing of online data generated by the PHENOPSIS platform and offline data collected by experimenters and experimental metadata. It provides modules coupled to a Web interface for (i the visualisation of environmental data of an experiment, (ii the visualisation and statistical analysis of phenotypic data, and (iii the analysis of Arabidopsis thaliana plant images. Conclusions Firstly, data stored in the PHENOPSIS DB are of interest to the Arabidopsis thaliana community, particularly in allowing phenotypic meta-analyses directly linked to environmental conditions on which publications are still scarce. Secondly, data or image analysis modules can be downloaded from the Web interface for direct usage or as the basis for modifications according to new requirements. Finally, the structure of PHENOPSIS DB provides a useful template for the development

  8. Genetic and phenotypic population divergence on a microgeographic scale in brown trout.

    Science.gov (United States)

    Stelkens, Rike B; Jaffuel, Geoffrey; Escher, Matthias; Wedekind, Claus

    2012-06-01

    Salmonid populations of many rivers are rapidly declining. One possible explanation is that habitat fragmentation increases genetic drift and reduces the populations' potential to adapt to changing environmental conditions. We measured the genetic and eco-morphological diversity of brown trout (Salmo trutta) in a Swiss stream system, using multivariate statistics and Bayesian clustering. We found large genetic and phenotypic variation within only 40 km of stream length. Eighty-eight percent of all pairwise F(ST) comparisons and 50% of the population comparisons in body shape were significant. High success rates of population assignment tests confirmed the distinctiveness of populations in both genotype and phenotype. Spatial analysis revealed that divergence increased with waterway distance, the number of weirs, and stretches of poor habitat between sampling locations, but effects of isolation-by-distance and habitat fragmentation could not be fully disentangled. Stocking intensity varied between streams but did not appear to erode genetic diversity within populations. A lack of association between phenotypic and genetic divergence points to a role of local adaptation or phenotypically plastic responses to habitat heterogeneity. Indeed, body shape could be largely explained by topographic stream slope, and variation in overall phenotype matched the flow regimes of the respective habitats.

  9. Phenotypic plasticity and epigenetic marking: an assessment of evidence for genetic accommodation.

    Science.gov (United States)

    Schlichting, Carl D; Wund, Matthew A

    2014-03-01

    The relationship between genotype (which is inherited) and phenotype (the target of selection) is mediated by environmental inputs on gene expression, trait development, and phenotypic integration. Phenotypic plasticity or epigenetic modification might influence evolution in two general ways: (1) by stimulating evolutionary responses to environmental change via population persistence or by revealing cryptic genetic variation to selection, and (2) through the process of genetic accommodation, whereby natural selection acts to improve the form, regulation, and phenotypic integration of novel phenotypic variants. We provide an overview of models and mechanisms for how such evolutionary influences may be manifested both for plasticity and epigenetic marking. We point to promising avenues of research, identifying systems that can best be used to address the role of plasticity in evolution, as well as the need to apply our expanding knowledge of genetic and epigenetic mechanisms to our understanding of how genetic accommodation occurs in nature. Our review of a wide variety of studies finds widespread evidence for evolution by genetic accommodation.

  10. Genetic and Phenotypic Characterization of a Salmonella enterica serovar Enteritidis Emerging Strain with Superior Intra-macrophage Replication Phenotype

    Science.gov (United States)

    Shomer, Inna; Avisar, Alon; Desai, Prerak; Azriel, Shalhevet; Smollan, Gill; Belausov, Natasha; Keller, Nathan; Glikman, Daniel; Maor, Yasmin; Peretz, Avi; McClelland, Michael; Rahav, Galia; Gal-Mor, Ohad

    2016-01-01

    Salmonella enterica serovar Enteritidis (S. Enteritidis) is one of the ubiquitous Salmonella serovars worldwide and a major cause of food-born outbreaks, which are often associated with poultry and poultry derivatives. Here we report a nation-wide S. Enteritidis clonal outbreak that occurred in Israel during the last third of 2015. Pulsed field gel electrophoresis and whole genome sequencing identified genetically related strains that were circulating in Israel as early as 2008. Global comparison linked this outbreak strain to several clinical and marine environmental isolates that were previously isolated in California and Canada, indicating that similar strains are prevalent outside of Israel. Phenotypic comparison between the 2015 outbreak strain and other clinical and reference S. Enteritidis strains showed only limited intra-serovar phenotypic variation in growth in rich medium, invasion into Caco-2 cells, uptake by J774.1A macrophages, and host cell cytotoxicity. In contrast, significant phenotypic variation was shown among different S. Enteritidis isolates when biofilm-formation, motility, invasion into HeLa cells and uptake by THP-1 human macrophages were studied. Interestingly, the 2015 outbreak clone was found to possess superior intra-macrophage replication ability within both murine and human macrophages in comparison to the other S. Enteritidis strains studied. This phenotype is likely to play a role in the virulence and host-pathogen interactions of this emerging clone. PMID:27695450

  11. Developmental cognitive genetics: how psychology can inform genetics and vice versa.

    Science.gov (United States)

    Bishop, Dorothy V M

    2006-07-01

    Developmental neuropsychology is concerned with uncovering the underlying basis of developmental disorders such as specific language impairment (SLI), developmental dyslexia, and autistic disorder. Twin and family studies indicate that genetic influences play an important part in the aetiology of all of these disorders, yet progress in identifying genes has been slow. One way forward is to cut loose from conventional clinical criteria for diagnosing disorders and to focus instead on measures of underlying cognitive mechanisms. Psychology can inform genetics by clarifying what the key dimensions are for heritable phenotypes. However, it is not a one-way street. By using genetically informative designs, one can gain insights about causal relationships between different cognitive deficits. For instance, it has been suggested that low-level auditory deficits cause phonological problems in SLI. However, a twin study showed that, although both types of deficit occur in SLI, they have quite different origins, with environmental factors more important for auditory deficit, and genes more important for deficient phonological short-term memory. Another study found that morphosyntactic deficits in SLI are also highly heritable, but have different genetic origins from impairments of phonological short-term memory. A genetic perspective shows that a search for the underlying cause of developmental disorders may be misguided, because they are complex and heterogeneous and are associated with multiple risk factors that only cause serious disability when they occur in combination.

  12. The evolution of phenotypes and genetic parameters under preferential mating

    Science.gov (United States)

    Roff, Derek A; Fairbairn, Daphne J

    2014-01-01

    This article extends and adds more realism to Lande's analytical model for evolution under mate choice by using individual-based simulations in which females sample a finite number of males and the genetic architecture of the preference and preferred trait evolves. The simulations show that the equilibrium heritabilities of the preference and preferred trait and the genetic correlation between them (rG), depend critically on aspects of the mating system (the preference function, mode of mate choice, choosiness, and number of potential mates sampled), the presence or absence of natural selection on the preferred trait, and the initial genetic parameters. Under some parameter combinations, preferential mating increased the heritability of the preferred trait, providing a possible resolution for the lek paradox. The Kirkpatrick–Barton approximation for rG proved to be biased downward, but the realized genetic correlations were also low, generally <0.2. Such low values of rG indicate that coevolution of the preference and preferred trait is likely to be very slow and subject to significant stochastic variation. Lande's model accurately predicted the incidence of runaway selection in the simulations, except where preferences were relative and the preferred trait was subject to natural selection. In these cases, runaways were over- or underestimated, depending on the number of males sampled. We conclude that rapid coevolution of preferences and preferred traits is unlikely in natural populations, but that the parameter combinations most conducive to it are most likely to occur in lekking species. PMID:25077025

  13. Genetical Genomics of Plants: From Genotype to Phenotype

    NARCIS (Netherlands)

    Joosen, R.V.L.; Ligterink, W.; Hilhorst, H.W.M.; Keurentjes, J.J.B.

    2013-01-01

    Natural variation provides a valuable resource to study the genetic regulation of quantitative traits. In quantitative trait locus (QTL) analyses this variation, captured in segregating mapping populations, is used to identify the genomic regions affecting these traits. The identification of the cau

  14. Inherited Platelet Function Disorders: Algorithms for Phenotypic and Genetic Investigation.

    Science.gov (United States)

    Gresele, Paolo; Bury, Loredana; Falcinelli, Emanuela

    2016-04-01

    Inherited platelet function disorders (IPFDs) manifest with mucocutaneous bleeding and are frequently difficult to diagnose due to their heterogeneity, the complexity of the platelet activation pathways and a lack of standardization of the platelet function laboratory assays and of their use for this purpose. A rational diagnostic approach to IPFDs should follow an algorithm where clinical examination and a stepwise laboratory evaluation play a crucial role. A streamlined panel of laboratory tests, with consecutive steps of increasing level of complexity, allows the phenotypic characterization of most IPFDs. A first-line diagnosis of a significant fraction of the IPFD may be made also at nonspecialized centers by using relatively simple tests, including platelet count, peripheral blood smear, light transmission aggregometry, measurement of platelet granule content and release, and the expression of glycoproteins by flow cytometry. Some of the most complex, second- and third-step tests may be performed only in highly specialized laboratories. Genotyping, including the widespread application of next-generation sequencing, has enabled discovery in the last few years of several novel genes associated with platelet disorders and this method may eventually become a first-line diagnostic approach; however, a preliminary clinical and laboratory phenotypic characterization nowadays still remains crucial for diagnosis of IPFDs.

  15. Genetic studies of two inherited human phenotypes : Hearing loss and monoamine oxidase activity

    OpenAIRE

    Balciuniene, Jorune

    2001-01-01

    This thesis focuses on the identification of genetic factors underlying two inherited human phenotypes: hearing loss and monoamine oxidase activity. Non-syndromic hearing loss segregating in a Swedish family was tested for linkage to 13 previously reported candidate loci for hearing disabilities. Linkage was found to two loci: DFNA12 (llq22-q24) and DFNA2 (lp32). A detailed analysis of the phenotypes and haplotypes shared by the affected individuals supported the hypothesis of digenic inheri...

  16. Phenotypic, genetic, and environmental relationships between self-reported talents and measured intelligence.

    Science.gov (United States)

    Schermer, Julie Aitken; Johnson, Andrew M; Jang, Kerry L; Vernon, Philip A

    2015-02-01

    The relationship between self-report abilities and measured intelligence was examined at both the phenotypic (zero-order) level as well as at the genetic and environmental levels. Twins and siblings (N = 516) completed a timed intelligence test and a self-report ability questionnaire, which has previously been found to produce 10 factors, including: politics, interpersonal relationships, practical tasks, intellectual pursuits, academic skills, entrepreneur/business, domestic skills, vocal abilities, and creativity. At the phenotypic level, the correlations between the ability factor scores and intelligence ranged from 0.01 to 0.42 (between self-report academic abilities and verbal intelligence). Further analyses found that some of the phenotypic relationships between self-report ability scores and measured intelligence also had significant correlations at the genetic and environmental levels, suggesting that some of the observed relationships may be due to common genetic and/or environmental factors.

  17. Genetic variants and early cigarette smoking and nicotine dependence phenotypes in adolescents.

    Science.gov (United States)

    O'Loughlin, Jennifer; Sylvestre, Marie-Pierre; Labbe, Aurélie; Low, Nancy C; Roy-Gagnon, Marie-Hélène; Dugas, Erika N; Karp, Igor; Engert, James C

    2014-01-01

    While the heritability of cigarette smoking and nicotine dependence (ND) is well-documented, the contribution of specific genetic variants to specific phenotypes has not been closely examined. The objectives of this study were to test the associations between 321 tagging single-nucleotide polymorphisms (SNPs) that capture common genetic variation in 24 genes, and early smoking and ND phenotypes in novice adolescent smokers, and to assess if genetic predictors differ across these phenotypes. In a prospective study of 1294 adolescents aged 12-13 years recruited from ten Montreal-area secondary schools, 544 participants who had smoked at least once during the 7-8 year follow-up provided DNA. 321 single-nucleotide polymorphisms (SNPs) in 24 candidate genes were tested for an association with number of cigarettes smoked in the past 3 months, and with five ND phenotypes (a modified version of the Fagerstrom Tolerance Questionnaire, the ICD-10 and three clusters of ND symptoms representing withdrawal symptoms, use of nicotine for self-medication, and a general ND/craving symptom indicator). The pattern of SNP-gene associations differed across phenotypes. Sixteen SNPs in seven genes (ANKK1, CHRNA7, DDC, DRD2, COMT, OPRM1, SLC6A3 (also known as DAT1)) were associated with at least one phenotype with a p-value genetic predictors differ, specific cigarette smoking and ND phenotypes should be distinguished in genetic studies in adolescents. Fifteen of the 16 top-ranked SNPs identified in this study were from loci involved in dopaminergic pathways (ANKK1/DRD2, DDC, COMT, OPRM1, and SLC6A3). Dopaminergic pathways may be salient during early smoking and the development of ND.

  18. Evolutionary triangulation: informing genetic association studies with evolutionary evidence.

    Science.gov (United States)

    Huang, Minjun; Graham, Britney E; Zhang, Ge; Harder, Reed; Kodaman, Nuri; Moore, Jason H; Muglia, Louis; Williams, Scott M

    2016-01-01

    Genetic studies of human diseases have identified many variants associated with pathogenesis and severity. However, most studies have used only statistical association to assess putative relationships to disease, and ignored other factors for evaluation. For example, evolution is a factor that has shaped disease risk, changing allele frequencies as human populations migrated into and inhabited new environments. Since many common variants differ among populations in frequency, as does disease prevalence, we hypothesized that patterns of disease and population structure, taken together, will inform association studies. Thus, the population distributions of allelic risk variants should reflect the distributions of their associated diseases. Evolutionary Triangulation (ET) exploits this evolutionary differentiation by comparing population structure among three populations with variable patterns of disease prevalence. By selecting populations based on patterns where two have similar rates of disease that differ substantially from a third, we performed a proof of principle analysis for this method. We examined three disease phenotypes, lactase persistence, melanoma, and Type 2 diabetes mellitus. We show that for lactase persistence, a phenotype with a simple genetic architecture, ET identifies the key gene, lactase. For melanoma, ET identifies several genes associated with this disease and/or phenotypes related to it, such as skin color genes. ET was less obviously successful for Type 2 diabetes mellitus, perhaps because of the small effect sizes in known risk loci and recent environmental changes that have altered disease risk. Alternatively, ET may have revealed new genes involved in conferring disease risk for diabetes that did not meet nominal GWAS significance thresholds. We also compared ET to another method used to filter for phenotype associated genes, population branch statistic (PBS), and show that ET performs better in identifying genes known to associate with

  19. Elevated oxidative membrane damage associated with genetic modifiers of Lyst-mutant phenotypes.

    Directory of Open Access Journals (Sweden)

    Colleen M Trantow

    2010-07-01

    Full Text Available LYST is a large cytosolic protein that influences the biogenesis of lysosome-related organelles, and mutation of the encoding gene, LYST, can cause Chediak-Higashi syndrome. Recently, Lyst-mutant mice were recognized to also exhibit an iris disease resembling exfoliation syndrome, a common cause of glaucoma in humans. Here, Lyst-mutant iris phenotypes were used in a search for genes that influence Lyst pathways. In a candidate gene-driven approach, albino Lyst-mutant mice homozygous for a mutation in Tyr, whose product is key to melanin synthesis within melanosomes, exhibited complete rescue of Lyst-mutant iris phenotypes. In a genetic background-driven approach using a DBA/2J strain of congenic mice, an interval containing Tyrp1 enhanced Lyst-dependent iris phenotypes. Thus, both experimental approaches implicated the melanosome, an organelle that is a potential source of oxidative stress, as contributing to the disease phenotype. Confirming an association with oxidative damage, Lyst mutation resulted in genetic context-sensitive changes in iris lipid hydroperoxide levels, being lowest in albino and highest in DBA/2J mice. Surprisingly, the DBA/2J genetic background also exposed a late-onset neurodegenerative phenotype involving cerebellar Purkinje-cell degeneration. These results identify an association between oxidative damage to lipid membranes and the severity of Lyst-mutant phenotypes, revealing a new mechanism that contributes to pathophysiology involving LYST.

  20. Syndromic albinism: a review of genetics and phenotypes.

    Science.gov (United States)

    Scheinfeld, Noah S

    2003-12-01

    There are several syndromes of albinism associated with systemic pathology. These include Chediak-Higashi Syndrome (CHS), Hermansky-Pudlack Syndrome (HPS), Griscelli Syndrome (GS), Elejalde Syndrome (ES) and Cross-McKusick-Breen Syndrome (CMBS). In the last several years the genetic defects underlying some of these syndromes have been described. HPS is related to 7 genes in humans. GS is related to 3 genes: MYOVA, Rab-27A, and melanophilin (Mlph). CHS is related to one gene: LYST. The genetic defects in ES and CMBS are yet to be defined. Syndromic forms of albinism are associated with defects in the packaging of melanin and other cellular proteins. As such they are distinct from oculocutaneous albinism, which is associated with defects in the production of melanin (e.g., TRP1, P gene, and tyrosinase).

  1. Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases

    Science.gov (United States)

    Hoehndorf, Robert; Schofield, Paul N.; Gkoutos, Georgios V.

    2015-06-01

    Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.

  2. Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases

    KAUST Repository

    Hoehndorf, Robert

    2015-06-08

    Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.

  3. The Baldwin effect and genetic assimilation: revisiting two mechanisms of evolutionary change mediated by phenotypic plasticity.

    Science.gov (United States)

    Crispo, Erika

    2007-11-01

    Two different, but related, evolutionary theories pertaining to phenotypic plasticity were proposed by James Mark Baldwin and Conrad Hal Waddington. Unfortunately, these theories are often confused with one another. Baldwin's notion of organic selection posits that plasticity influences whether an individual will survive in a new environment, thus dictating the course of future evolution. Heritable variations can then be selected upon to direct phenotypic evolution (i.e., "orthoplasy"). The combination of these two processes (organic selection and orthoplasy) is now commonly referred to as the "Baldwin effect." Alternately, Waddington's genetic assimilation is a process whereby an environmentally induced phenotype, or "acquired character," becomes canalized through selection acting upon the developmental system. Genetic accommodation is a modern term used to describe the process of heritable changes that occur in response to a novel induction. Genetic accommodation is a key component of the Baldwin effect, and genetic assimilation is a type of genetic accommodation. I here define both the Baldwin effect and genetic assimilation in terms of genetic accommodation, describe cases in which either should occur in nature, and propose that each could play a role in evolutionary diversification.

  4. Phenotyping the Genetic Diversity of Wild Agave Species that Coexist in the Same Spatial Region

    Directory of Open Access Journals (Sweden)

    Elí Secundino PORRAS-RAMÍREZ

    2016-12-01

    Full Text Available Phenotypic characteristics are important to identify species and provide valuable information for the uses in plant breeding. The aim of this study was to characterize through morphological traits the genetic diversity of the Agave genus under wild and semi-wild culture conditions in Maguey Largo region in Oaxaca, Mexico. Through field trips, eleven morphological characteristics of the Agave species were recorded. Principal component analysis (PCA, phylogenetic trees, and correlation analyses, were performed. Seven wild species were identified: Agave potatorum Zucc., A. seemanniana, A. nussaviorum subsp. nussaviorum, A. angustifolia Haw., A. marmorata Roezl., A. karwinskii Zucc. and A. americana var. Americana. Also, a semi-wild unclassified specie Agave sp. was found. The values of the first four principal components in the PCA explain more than 89% of the total morphological variance. The dendrogram of the agglomerative hierarchical clustering (AHC shown a high similarity between the species and divide them in two main cluster with one unassociated specie (A. karwinskii Miahuatlán shape. Following the different analyses done, we observed a very close relationship between A. potatorum and A. nussaviorum, and dissociated from A. seemanniana, which are belonging to the “Tobala” complex and never described before. The results obtained in this work suggest a great genetic diversity expressed in a wide morphological variety of agaves in Oaxaca; which can be used in futures molecular studies.

  5. Prediction of quantitative phenotypes based on genetic networks: a case study in yeast sporulation

    Directory of Open Access Journals (Sweden)

    Shen Li

    2010-09-01

    Full Text Available Abstract Background An exciting application of genetic network is to predict phenotypic consequences for environmental cues or genetic perturbations. However, de novo prediction for quantitative phenotypes based on network topology is always a challenging task. Results Using yeast sporulation as a model system, we have assembled a genetic network from literature and exploited Boolean network to predict sporulation efficiency change upon deleting individual genes. We observe that predictions based on the curated network correlate well with the experimentally measured values. In addition, computational analysis reveals the robustness and hysteresis of the yeast sporulation network and uncovers several patterns of sporulation efficiency change caused by double gene deletion. These discoveries may guide future investigation of underlying mechanisms. We have also shown that a hybridized genetic network reconstructed from both temporal microarray data and literature is able to achieve a satisfactory prediction accuracy of the same quantitative phenotypes. Conclusions This case study illustrates the value of predicting quantitative phenotypes based on genetic network and provides a generic approach.

  6. Searching Online Mendelian Inheritance in Man (OMIM) for information on genetic loci involved in human disease.

    Science.gov (United States)

    Baxevanis, Andreas D

    2012-04-01

    Online Mendelian Inheritance in Man (OMIM) is a comprehensive compendium of information on human genes and genetic disorders, with a particular emphasis on the interplay between observed phenotypes and underlying genotypes. This unit focuses on the basic methodology for formulating OMIM searches and illustrates the types of information that can be retrieved from OMIM, including descriptions of clinical manifestations resulting from genetic abnormalities. This unit also provides information on additional relevant medical and molecular biology databases. A basic knowledge of OMIM should be part of the armamentarium of physicians and scientists with an interest in research on the clinical aspects of genetic disorders.

  7. Is Ankyrin a genetic risk factor for psychiatric phenotypes?

    Directory of Open Access Journals (Sweden)

    Stöber Gerald

    2011-06-01

    Full Text Available Abstract Background Genome wide association studies reported two single nucleotide polymorphisms in ANK3 (rs9804190 and rs10994336 as independent genetic risk factors for bipolar disorder. Another SNP in ANK3 (rs10761482 was associated with schizophrenia in a large European sample. Within the debate on common susceptibility genes for schizophrenia and bipolar disorder, we tried to investigate common findings by analyzing association of ANK3 with schizophrenia, bipolar disorder and unipolar depression. Methods We genotyped three single nucleotide polymorphisms (SNPs in ANK3 (rs9804190, rs10994336, and rs10761482 in a case-control sample of German descent including 920 patients with schizophrenia, 400 with bipolar affective disorder, 220 patients with unipolar depression according to ICD 10 and 480 healthy controls. Sample was further differentiated according to Leonhard's classification featuring disease entities with specific combination of bipolar and psychotic syndromes. Results We found no association of rs9804190 and rs10994336 with bipolar disorder, unipolar depression or schizophrenia. In contrast to previous findings rs10761482 was associated with bipolar disorder (p = 0.015 but not with schizophrenia or unipolar depression. We observed no association with disease entities according to Leonhard's classification. Conclusion Our results support a specific genetic contribution of ANK3 to bipolar disorder though we failed to replicate findings for schizophrenia. We cannot confirm ANK3 as a common risk factor for different diseases.

  8. Autosomal dominant cyclic hematopoiesis: Genetics, phenotype, and natural history

    Energy Technology Data Exchange (ETDEWEB)

    Palmer, S.E.; Stephens, K.; Dale, D.C. [Univ. of Washington, Seattle, WA (United States)

    1994-09-01

    Autosomal dominant cyclic hematopoiesis (ADCH; cyclic neutropenia) is a rare disorder manifested by transient neutropenia that recurs every three weeks. To facilitate mapping the ADCH gene by genetic linkage analysis, we studied 9 ADCH families with 42 affected individuals. Pedigrees revealed AD inheritance with no evidence for decreased penetrance. Similar intra- and interfamilial variable expression was observed, with no evidence to support heterogeneity. At least 3 families displayed apparent new mutations. Many adults developed chronic neutropenia, while offspring always cycled during childhood. Children displayed recurrent oral ulcers, gingivitis, lymphadenopathy, fever, and skin and other infections with additional symptoms. Interestingly, there were no cases of neonatal infection. Some children required multiple hospitalizations for treatment. Four males under age 18 died of Clostridium sepsis following necrotizing enterocolitis; all had affected mothers. No other deaths due to ADCH were found; most had improvement of symptoms and infections as adults. Adults experienced increased tooth loss prior to age 30 (16 out of 27 adults, with 9 edentulous). No increase in myelodysplasia, malignancy, or congenital anomalies was observed. Recombinant G-CSF treatment resulted in dramatic improvement of symptoms and infections. The results suggest that ADCH is not a benign disorder, especially in childhood, and abdominal pain requires immediate evaluation. Diagnosis of ADCH requires serial blood counts in the proband and at least one CBC in relatives to exclude similar disorders. Genetic counseling requires specific histories as well as CBCs of each family member at risk to determine status regardless of symptom history, especially to assess apparent new mutations.

  9. Reversible non-genetic phenotypic heterogeneity in bacterial quorum sensing.

    Science.gov (United States)

    Pradhan, Binod B; Chatterjee, Subhadeep

    2014-05-01

    Bacteria co-ordinate their social behaviour in a density-dependent manner by production of diffusible signal molecules by a process known as quorum sensing (QS). It is generally assumed that in homogenous environments and at high cell density, QS synchronizes cells in the population to perform collective social tasks in unison which maximize the benefit at the inclusive fitness of individuals. However, evolutionary theory predicts that maintaining phenotypic heterogeneity in performing social tasks is advantageous as it can serve as a bet-hedging survival strategy. Using Pseudomonas syringae and Xanthomonas campestris as model organisms, which use two diverse classes of QS signals, we show that two distinct subpopulations of QS-responsive and non-responsive cells exist in the QS-activated population. Addition of excess exogenous QS signal does not significantly alter the distribution of QS-responsive and non-responsive cells in the population. We further show that progeny of cells derived from these subpopulations also exhibited heterogeneous distribution patterns similar to their respective parental strains. Overall, these results support the model that bacteria maintain QS-responsive and non-responsive subpopulations at high cell densities in a bet-hedging strategy to simultaneously perform functions that are both positively and negatively regulated by QS to improve their fitness in fluctuating environments.

  10. Habitat Fragmentation Differentially Affects Genetic Variation, Phenotypic Plasticity and Survival in Populations of a Gypsum Endemic.

    Science.gov (United States)

    Matesanz, Silvia; Rubio Teso, María Luisa; García-Fernández, Alfredo; Escudero, Adrián

    2017-01-01

    Habitat fragmentation, i.e., fragment size and isolation, can differentially alter patterns of neutral and quantitative genetic variation, fitness and phenotypic plasticity of plant populations, but their effects have rarely been tested simultaneously. We assessed the combined effects of size and connectivity on these aspects of genetic and phenotypic variation in populations of Centaurea hyssopifolia, a narrow endemic gypsophile that previously showed performance differences associated with fragmentation. We grew 111 maternal families sampled from 10 populations that differed in their fragment size and connectivity in a common garden, and characterized quantitative genetic variation, phenotypic plasticity to drought for key functional traits, and plant survival, as a measure of population fitness. We also assessed neutral genetic variation within and among populations using eight microsatellite markers. Although C. hyssopifolia is a narrow endemic gypsophile, we found substantial neutral genetic variation and quantitative variation for key functional traits. The partition of genetic variance indicated that a higher proportion of variation was found within populations, which is also consistent with low population differentiation in molecular markers, functional traits and their plasticity. This, combined with the generally small effect of habitat fragmentation suggests that gene flow among populations is not restricted, despite large differences in fragment size and isolation. Importantly, population's similarities in genetic variation and plasticity did not reflect the lower survival observed in isolated populations. Overall, our results indicate that, although the species consists of genetically variable populations able to express functional plasticity, such aspects of adaptive potential may not always reflect populations' survival. Given the differential effects of habitat connectivity on functional traits, genetic variation and fitness, our study highlights

  11. Habitat Fragmentation Differentially Affects Genetic Variation, Phenotypic Plasticity and Survival in Populations of a Gypsum Endemic

    Directory of Open Access Journals (Sweden)

    Silvia Matesanz

    2017-05-01

    Full Text Available Habitat fragmentation, i.e., fragment size and isolation, can differentially alter patterns of neutral and quantitative genetic variation, fitness and phenotypic plasticity of plant populations, but their effects have rarely been tested simultaneously. We assessed the combined effects of size and connectivity on these aspects of genetic and phenotypic variation in populations of Centaurea hyssopifolia, a narrow endemic gypsophile that previously showed performance differences associated with fragmentation. We grew 111 maternal families sampled from 10 populations that differed in their fragment size and connectivity in a common garden, and characterized quantitative genetic variation, phenotypic plasticity to drought for key functional traits, and plant survival, as a measure of population fitness. We also assessed neutral genetic variation within and among populations using eight microsatellite markers. Although C. hyssopifolia is a narrow endemic gypsophile, we found substantial neutral genetic variation and quantitative variation for key functional traits. The partition of genetic variance indicated that a higher proportion of variation was found within populations, which is also consistent with low population differentiation in molecular markers, functional traits and their plasticity. This, combined with the generally small effect of habitat fragmentation suggests that gene flow among populations is not restricted, despite large differences in fragment size and isolation. Importantly, population’s similarities in genetic variation and plasticity did not reflect the lower survival observed in isolated populations. Overall, our results indicate that, although the species consists of genetically variable populations able to express functional plasticity, such aspects of adaptive potential may not always reflect populations’ survival. Given the differential effects of habitat connectivity on functional traits, genetic variation and fitness

  12. Phenotype-Based Genetic Association Studies (PGAS)-Towards Understanding the Contribution of Common Genetic Variants to Schizophrenia Subphenotypes.

    Science.gov (United States)

    Ehrenreich, Hannelore; Nave, Klaus-Armin

    2014-02-27

    Neuropsychiatric diseases ranging from schizophrenia to affective disorders and autism are heritable, highly complex and heterogeneous conditions, diagnosed purely clinically, with no supporting biomarkers or neuroimaging criteria. Relying on these "umbrella diagnoses", genetic analyses, including genome-wide association studies (GWAS), were undertaken but failed to provide insight into the biological basis of these disorders. "Risk genotypes" of unknown significance with low odds ratios of mostly definition of biological subgroups of mental diseases. For that purpose, the GRAS (Göttingen Research Association for Schizophrenia) data collection was initiated in 2005. With >3000 phenotypical data points per patient, it comprises the world-wide largest currently available schizophrenia database (N > 1200), combining genome-wide SNP coverage and deep phenotyping under highly standardized conditions. First PGAS results on normal genetic variants, relevant for e.g., cognition or catatonia, demonstrated proof-of-concept. Presently, an autistic subphenotype of schizophrenia is being defined where an unfortunate accumulation of normal genotypes, so-called pro-autistic variants of synaptic genes, explains part of the phenotypical variance. Deep phenotyping and comprehensive clinical data sets, however, are expensive and it may take years before PGAS will complement conventional GWAS approaches in psychiatric genetics.

  13. Genetic Studies of Quantitative MCI and AD Phenotypes in ADNI: Progress, Opportunities, and Plans

    Science.gov (United States)

    Saykin, Andrew J.; Shen, Li; Yao, Xiaohui; Kim, Sungeun; Nho, Kwangsik; Risacher, Shannon L.; Ramanan, Vijay K.; Foroud, Tatiana M.; Faber, Kelly M.; Sarwar, Nadeem; Munsie, Leanne M.; Hu, Xiaolan; Soares, Holly D.; Potkin, Steven G.; Thompson, Paul M.; Kauwe, John S.K.; Kaddurah-Daouk, Rima; Green, Robert C.; Toga, Arthur W.; Weiner, Michael W.

    2015-01-01

    INTRODUCTION Genetic data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) has been crucial in advancing the understanding of AD pathophysiology. Here we provide an update on sample collection, scientific progress and opportunities, conceptual issues, and future plans. METHODS Lymphoblastoid cell lines and DNA and RNA samples from blood have been collected and banked, and data and biosamples have been widely disseminated. To date, APOE genotyping, genome-wide association study (GWAS), and whole exome and whole genome sequencing (WES, WGS) data have been obtained and disseminated. RESULTS ADNI genetic data have been downloaded thousands of times and over 300 publications have resulted, including reports of large scale GWAS by consortia to which ADNI contributed. Many of the first applications of quantitative endophenotype association studies employed ADNI data, including some of the earliest GWAS and pathway-based studies of biospecimen and imaging biomarkers, as well as memory and other clinical/cognitive variables. Other contributions include some of the first WES and WGS data sets and reports in healthy controls, MCI, and AD. DISCUSSION Numerous genetic susceptibility and protective markers for AD and disease biomarkers have been identified and replicated using ADNI data, and have heavily implicated immune, mitochondrial, cell cycle/fate, and other biological processes. Early sequencing studies suggest that rare and structural variants are likely to account for significant additional phenotypic variation. Longitudinal analyses of transcriptomic, proteomic, metabolomic, and epigenomic changes will also further elucidate dynamic processes underlying preclinical and prodromal stages of disease. Integration of this unique collection of multi-omics data within a systems biology framework will help to separate truly informative markers of early disease mechanisms and potential novel therapeutic targets from the vast background of less relevant biological

  14. Effects of birthplace and individual genetic admixture on lung volume and exercise phenotypes of Peruvian Quechua.

    Science.gov (United States)

    Brutsaert, Tom D; Parra, Esteban; Shriver, Mark; Gamboa, Alfredo; Palacios, Jose-Antonio; Rivera, Maria; Rodriguez, Ivette; León-Velarde, Fabiola

    2004-04-01

    Forced vital capacity (FVC) and maximal exercise response were measured in two populations of Peruvian males (age, 18-35 years) at 4,338 m who differed by the environment in which they were born and raised, i.e., high altitude (Cerro de Pasco, Peru, BHA, n = 39) and sea level (Lima, Peru, BSL, n = 32). BSL subjects were transported from sea level to 4,338 m, and were evaluated within 24 hr of exposure to hypobaric hypoxia. Individual admixture level (ADMIX, % Spanish ancestry) was estimated for each subject, using 22 ancestry-informative genetic markers and also by skin reflectance measurement (MEL). Birthplace accounted for the approximately 10% larger FVC (P < 0.001), approximately 15% higher maximal oxygen consumption (VO(2)max, ml.min(-1).kg(-1)) (P < 0.001), and approximately 5% higher arterial oxygen saturation during exercise (SpO(2)) (P < 0.001) of BHA subjects. ADMIX was low in both study groups, averaging 9.5 +/- 2.6% and 2.1 +/- 0.3% in BSL and BHA subjects, respectively. Mean underarm MEL was significantly higher in the BSL group (P < 0.001), despite higher ADMIX. ADMIX was not associated with any study phenotype, but study power was not sufficient to evaluate hypotheses of genetic adaptation via the ADMIX variable. MEL and FVC were positively correlated in the BHA (P = 0.035) but not BSL (P = 0.335) subjects. However, MEL and ADMIX were not correlated across the entire study sample (P = 0.282). In summary, results from this study emphasize the importance of developmental adaptation to high altitude. While the MEL-FVC correlation may reflect genetic adaptation to high altitude, study results suggest that alternate (environmental) explanations be considered.

  15. The evolution of phenotypic plasticity: genealogy of a debate in genetics.

    Science.gov (United States)

    Nicoglou, Antonine

    2015-04-01

    The paper describes the context and the origin of a particular debate that concerns the evolution of phenotypic plasticity. In 1965, British biologist A. D. Bradshaw proposed a widely cited model intended to explain the evolution of norms of reaction, based on his studies of plant populations. Bradshaw's model went beyond the notion of the "adaptive norm of reaction" discussed before him by Dobzhansky and Schmalhausen by suggesting that "plasticity"--the ability of a phenotype to be modified by the environment--should be genetically determined. To prove Bradshaw's hypothesis, it became necessary for some authors to identify the pressures exerted by natural selection on phenotypic plasticity in particular traits, and thus to model its evolution. In this paper, I contrast two different views, based on quantitative genetic models, proposed in the mid-1980s: Russell Lande and Sara Via's conception of phenotypic plasticity, which assumes that the evolution of plasticity is linked to the evolution of the plastic trait itself, and Samuel Scheiner and Richard Lyman's view, which assumes that the evolution of plasticity is independent from the evolution of the trait. I show how the origin of this specific debate, and different assumptions about the evolution of phenotypic plasticity, depended on Bradshaw's definition of plasticity and the context of quantitative genetics. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Relaxed genetic constraint is ancestral to the evolution of phenotypic plasticity.

    Science.gov (United States)

    Leichty, Aaron R; Pfennig, David W; Jones, Corbin D; Pfennig, Karin S

    2012-07-01

    Phenotypic plasticity--the capacity of a single genotype to produce different phenotypes in response to varying environmental conditions--is widespread. Yet, whether, and how, plasticity impacts evolutionary diversification is unclear. According to a widely discussed hypothesis, plasticity promotes rapid evolution because genes expressed differentially across different environments (i.e., genes with "biased" expression) experience relaxed genetic constraint and thereby accumulate variation faster than do genes with unbiased expression. Indeed, empirical studies confirm that biased genes evolve faster than unbiased genes in the same genome. An alternative hypothesis holds, however, that the relaxed constraint and faster evolutionary rates of biased genes may be a precondition for, rather than a consequence of, plasticity's evolution. Here, we evaluated these alternative hypotheses by characterizing evolutionary rates of biased and unbiased genes in two species of frogs that exhibit a striking form of phenotypic plasticity. We also characterized orthologs of these genes in four species of frogs that had diverged from the two plastic species before the plasticity evolved. We found that the faster evolutionary rates of biased genes predated the evolution of the plasticity. Furthermore, biased genes showed greater expression variance than did unbiased genes, suggesting that they may be more dispensable. Phenotypic plasticity may therefore evolve when dispensable genes are co-opted for novel function in environmentally induced phenotypes. Thus, relaxed genetic constraint may be a cause--not a consequence--of the evolution of phenotypic plasticity, and thereby contribute to the evolution of novel traits.

  17. The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype.

    NARCIS (Netherlands)

    Rueda, B.; Broen, J.; Simeon, C.; Hesselstrand, R.; Diaz, B.; Suarez, H.; Ortego-Centeno, N.; Riemekasten, G.; Fonollosa, V.; Vonk, M.C.; Hoogen, F.H.J. van den; Sanchez-Roman, J.; Aguirre-Zamorano, M.A.; Garcia-Portales, R.; Pros, A.; Camps, M.T.; Gonzalez-Gay, M.A.; Coenen, M.J.H.; Airo, P.; Beretta, L.; Scorza, R.; Laar, J. van; Gonzalez-Escribano, M.F.; Nelson, J.L.; Radstake, T.R.D.J.; Martin, J.

    2009-01-01

    The aim of this study was to investigate the possible role of STAT4 gene in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. A total of 1317 SSc patients [896 with limited cutaneous SSc (lcSSc) and 421 with diffuse cutaneous SSc (dcSSc)] and 3113 healthy c

  18. Parapatric genetic introgression and phenotypic assimilation: testing conditions for introgression between Hercules beetles (Dynastes, Dynastinae).

    Science.gov (United States)

    Huang, Jen-Pan

    2016-11-01

    The prevalence and consequences of genetic introgression between species have been intensively debated. I used Hercules beetles as examples to test for conditions that may be associated with the occurrence of introgression. RADseq data were used to reconstruct the species tree and history of introgression between Hercules beetles. Image data from museum specimens were used to investigate the phenotypic similarity of two adaptive traits between species from two distinct climatic realms (Nearctic vs. Neotropical). Genetic introgression was identified between Hercules beetles living in geographic proximity (parapatric). Phylogenetic relatedness and phenotypic similarity did not predict nor preclude genetic introgression between species. Phenotypic assimilation in body coloration was evident between distantly related Hercules beetles codistributed in Central America, where directional introgression was also statistically supported from the putative donor to receiver lineages. The number of introgressed loci was significantly higher between species with than without phenotypic similarity. I discuss the implications of recent studies on adaptive genetic introgression by providing supporting evidence from the Hercules beetle system.

  19. Genetic and phenotypically flexible components of seasonal variation in immune function

    NARCIS (Netherlands)

    Versteegh, M. A.; Helm, B.; Kleynhans, E. J.; Gwinner, E.; Tieleman, B. I.

    2014-01-01

    Animals cope with seasonal variation in environmental factors by adjustments of physiology and life history. When seasonal variation is partly predictable, such adjustments can be based on a genetic component or be phenotypically flexible. Animals have to allocate limited resources over different de

  20. Genetic variation in variability: phenotypic variability of fledging weight and its evolution in a songbird population

    NARCIS (Netherlands)

    Mulder, H.A.; Gienapp, P; Visser, ME

    2016-01-01

    Variation in traits is essential for natural selection to operate and genetic and environmental effects can contribute to this phenotypic variation. From domesticated populations, we know that families can differ in their level of within-family variance, which leads to the intriguing situation that

  1. Genetic variation in variability : phenotypic variability of fledging weight and its evolution in a songbird population

    NARCIS (Netherlands)

    Mulder, Han A.; Gienapp, P; Visser, Marcel

    2016-01-01

    Variation in traits is essential for natural selection to operate and genetic and environmental effects can contribute to this phenotypic variation. From domesticated populations we know that families can differ in their level of within-family variance, which leads to the intriguing situation that w

  2. The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype.

    NARCIS (Netherlands)

    Rueda, B.; Broen, J.; Simeon, C.; Hesselstrand, R.; Diaz, B.; Suarez, H.; Ortego-Centeno, N.; Riemekasten, G.; Fonollosa, V.; Vonk, M.C.; Hoogen, F.H.J. van den; Sanchez-Roman, J.; Aguirre-Zamorano, M.A.; Garcia-Portales, R.; Pros, A.; Camps, M.T.; Gonzalez-Gay, M.A.; Coenen, M.J.H.; Airo, P.; Beretta, L.; Scorza, R.; Laar, J. van; Gonzalez-Escribano, M.F.; Nelson, J.L.; Radstake, T.R.D.J.; Martin, J.

    2009-01-01

    The aim of this study was to investigate the possible role of STAT4 gene in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. A total of 1317 SSc patients [896 with limited cutaneous SSc (lcSSc) and 421 with diffuse cutaneous SSc (dcSSc)] and 3113 healthy

  3. Pedimap: Software for the Visualization of Genetic and Phenotypic Data in Pedigrees

    NARCIS (Netherlands)

    Voorrips, R.E.; Bink, M.C.A.M.; Weg, van de W.E.

    2012-01-01

    Pedimap is a user-friendly software tool for visualizing phenotypic and genotypic data for related individuals linked in pedigrees. Genetic data can include marker scores, Identity-by-Descent probabilities, and marker linkage map positions, allowing the visualization of haplotypes through lineages.

  4. GENETIC BACKGROUND BUT NOT METALLOTHIONEIN PHENOTYPE DICTATES SENSITIVITY TO CADMIUM-INDUCED TESTICULAR INJURY IN MICE

    Science.gov (United States)

    Genetic Background but not Metallothionein Phenotype Dictates Sensitivity to Cadmium-Induced Testicular Injury in MiceJie Liu1,2, Chris Corton3, David J. Dix4, Yaping Liu1, Michael P. Waalkes2 and Curtis D. Klaassen1 ABSTRACTParenteral administrati...

  5. An interview study of phenotypic characterization of genetically-modified mice.

    NARCIS (Netherlands)

    Thon, R.; Vondeling, H.; Lassen, J.; Hansen, A.K.; Ritskes-Hoitinga, M.

    2009-01-01

    An interview study was carried out with the aim of clarifying the reasons for the limited use of phenotypic characterization of genetically-modified mice (GMM) and identifying issues hindering its implementation. A total of 15 users of GMM participated in semi-structured face-to-face interviews, whi

  6. Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

    NARCIS (Netherlands)

    Rietveld, Cornelius A; Esko, Tõnu; Davies, Gail; Pers, Tune H; Turley, Patrick; Benyamin, Beben; Chabris, Christopher F; Emilsson, Valur; Johnson, Andrew D; Lee, James J; de Leeuw, Christiaan; Marioni, Riccardo E; Medland, Sarah E; Miller, Michael B; Rostapshova, Olga; van der Lee, Sven J; Vinkhuyzen, Anna A E; Amin, Najaf; Conley, Dalton; Derringer, Jaime; van Duijn, Cornelia M; Fehrmann, Rudolf; Franke, Lude; Glaeser, Edward L; Hansell, Narelle K; Hayward, Caroline; Iacono, William G; Ibrahim-Verbaas, Carla; Jaddoe, Vincent; Karjalainen, Juha; Laibson, David; Lichtenstein, Paul; Liewald, David C; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; McMahon, George; Pedersen, Nancy L; Pinker, Steven; Porteous, David J; Posthuma, Danielle; Rivadeneira, Fernando; Smith, Blair H; Starr, John M; Tiemeier, Henning; Timpson, Nicholas J; Trzaskowski, Maciej; Uitterlinden, André G; Verhulst, Frank C; Ward, Mary E; Wright, Margaret J; Davey Smith, George; Deary, Ian J; Johannesson, Magnus; Plomin, Robert; Visscher, Peter M; Benjamin, Daniel J; Cesarini, David; Koellinger, Philipp D

    2014-01-01

    We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated

  7. Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

    NARCIS (Netherlands)

    Rietveld, Cornelius A; Esko, Tõnu; Davies, Gail; Pers, Tune H; Turley, Patrick; Benyamin, Beben; Chabris, Christopher F; Emilsson, Valur; Johnson, Andrew D; Lee, James J; de Leeuw, Christiaan; Marioni, Riccardo E; Medland, Sarah E; Miller, Michael B; Rostapshova, Olga; van der Lee, Sven J; Vinkhuyzen, Anna A E; Amin, Najaf; Conley, Dalton; Derringer, Jaime; van Duijn, Cornelia M; Fehrmann, Rudolf; Franke, Lude; Glaeser, Edward L; Hansell, Narelle K; Hayward, Caroline; Iacono, William G; Ibrahim-Verbaas, Carla; Jaddoe, Vincent; Karjalainen, Juha; Laibson, David; Lichtenstein, Paul; Liewald, David C; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; McMahon, George; Pedersen, Nancy L; Pinker, Steven; Porteous, David J; Posthuma, Danielle; Rivadeneira, Fernando; Smith, Blair H; Starr, John M; Tiemeier, Henning; Timpson, Nicholas J; Trzaskowski, Maciej; Uitterlinden, André G; Verhulst, Frank C; Ward, Mary E; Wright, Margaret J; Davey Smith, George; Deary, Ian J; Johannesson, Magnus; Plomin, Robert; Visscher, Peter M; Benjamin, Daniel J; Cesarini, David; Koellinger, Philipp D

    2014-01-01

    We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated

  8. Comparison of genetics, phenotypic and behavioral properties of eubacteria and archaebacteria

    Directory of Open Access Journals (Sweden)

    HAMID KAZEMIAN

    2016-06-01

    Full Text Available Background: The genome of the bacteria has considerable diversity and change over the time. With the advancement of bioinformatics science possibility of the vast comparison to living organisms has risen. In this study we compared some of the genetic, phenotypic and behavioral properties of archaebacteria and eubacteria. Methods: Genomic Information of 286 species of archaebacteria and 122 species of eubacteria were collected from the NCBI National Center for Biotechnology Information( site. Mean of gene size, gene number, protein number and  C + G content compared in the two groups of archaebacteria and eubacteria.  Association of genomic characterization of bacteria with several other characteristics were analyzed using SPSS statistical software version 19. Results: There was significant association between means discrepancy in two group. The genome size of eubacteria and archaebacteria have significant association with some of the characteristics of bacteria, such as the C + G content, the number of proteins, genes and habitats of the bacteria. As well as there was significant association between genome size and features such as number of pseudogene, mobility and type of breathing in eubacteria but not in archaebacteria. Conclusion: Many characteristics  of eubacteria and archaebacteria are significantly associated with genomic properties. Comparison genomics of bacteria will help in identification of evolutionary origins as well as differences between different categories of bacterial.

  9. Phenopolis: an open platform for harmonization and analysis of genetic and phenotypic data.

    Science.gov (United States)

    Pontikos, Nikolas; Yu, Jing; Moghul, Ismail; Withington, Lucy; Blanco-Kelly, Fiona; Vulliamy, Tom; Wong, Tsz Lun Ernest; Murphy, Cian; Cipriani, Valentina; Fiorentino, Alessia; Arno, Gavin; Greene, Daniel; Jacobsen, Julius O B; Clark, Tristan; Gregory, David S; Nemeth, Andrea M; Halford, Stephanie; Inglehearn, Chris F; Downes, Susan; Black, Graeme C; Webster, Andrew R; Hardcastle, Alison J; Plagnol, Vincent

    2017-08-01

    Phenopolis is an open-source web server providing an intuitive interface to genetic and phenotypic databases. It integrates analysis tools such as variant filtering and gene prioritization based on phenotype. The Phenopolis platform will accelerate clinical diagnosis, gene discovery and encourage wider adoption of the Human Phenotype Ontology in the study of rare genetic diseases. A demo of the website is available at https://phenopolis.github.io . If you wish to install a local copy, source code and installation instruction are available at https://github.com/phenopolis . The software is implemented using Python, MongoDB, HTML/Javascript and various bash shell scripts. n.pontikos@ucl.ac.uk. Supplementary data are available at Bioinformatics online.

  10. Phenotype-Based Genetic Association Studies (PGAS—Towards Understanding the Contribution of Common Genetic Variants to Schizophrenia Subphenotypes

    Directory of Open Access Journals (Sweden)

    Hannelore Ehrenreich

    2014-02-01

    Full Text Available Neuropsychiatric diseases ranging from schizophrenia to affective disorders and autism are heritable, highly complex and heterogeneous conditions, diagnosed purely clinically, with no supporting biomarkers or neuroimaging criteria. Relying on these “umbrella diagnoses”, genetic analyses, including genome-wide association studies (GWAS, were undertaken but failed to provide insight into the biological basis of these disorders. “Risk genotypes” of unknown significance with low odds ratios of mostly <1.2 were extracted and confirmed by including ever increasing numbers of individuals in large multicenter efforts. Facing these results, we have to hypothesize that thousands of genetic constellations in highly variable combinations with environmental co-factors can cause the individual disorder in the sense of a final common pathway. This would explain why the prevalence of mental diseases is so high and why mutations, including copy number variations, with a higher effect size than SNPs, constitute only a small part of variance. Elucidating the contribution of normal genetic variation to (disease phenotypes, and so re-defining disease entities, will be extremely labor-intense but crucial. We have termed this approach PGAS (“phenotype-based genetic association studies”. Ultimate goal is the definition of biological subgroups of mental diseases. For that purpose, the GRAS (Göttingen Research Association for Schizophrenia data collection was initiated in 2005. With >3000 phenotypical data points per patient, it comprises the world-wide largest currently available schizophrenia database (N > 1200, combining genome-wide SNP coverage and deep phenotyping under highly standardized conditions. First PGAS results on normal genetic variants, relevant for e.g., cognition or catatonia, demonstrated proof-of-concept. Presently, an autistic subphenotype of schizophrenia is being defined where an unfortunate accumulation of normal genotypes, so

  11. Narcissism predicts impulsive buying: phenotypic and genetic evidence.

    Science.gov (United States)

    Cai, Huajian; Shi, Yuanyuan; Fang, Xiang; Luo, Yu L L

    2015-01-01

    Impulsive buying makes billions of dollars for retail businesses every year, particularly in an era of thriving e-commerce. Narcissism, characterized by impulsivity and materialism, may serve as a potential antecedent to impulsive buying. To test this hypothesis, two studies examined the relationship between narcissism and impulsive buying. In Study 1, we surveyed an online sample and found that while adaptive narcissism was not correlated with impulsive buying, maladaptive narcissism was significantly predictive of the impulsive buying tendency. By investigating 304 twin pairs, Study 2 showed that global narcissism and its two components, adaptive and maladaptive narcissism, as well as the impulsive buying tendency were heritable. The study found, moreover, that the connections between global narcissism and impulsive buying, and between maladaptive narcissism and impulsive buying were genetically based. These findings not only establish a link between narcissism and impulsive buying but also help to identify the origins of the link. The present studies deepen our understanding of narcissism, impulsive buying, and their interrelationship.

  12. Narcissism predicts impulsive buying: phenotypic and genetic evidence

    Directory of Open Access Journals (Sweden)

    Huajian eCai

    2015-07-01

    Full Text Available Impulsive buying makes billions of dollars for retail businesses every year, particularly in an era of thriving e-commerce. Narcissism, characterized by impulsivity and materialism, may serve as a potential antecedent to impulsive buying. To test this hypothesis, two studies examined the relationship between narcissism and impulsive buying. In study 1, we surveyed narcissism and the impulsive buying tendency among an online sample and found that while adaptive narcissism was not correlated with impulsive buying, maladaptive narcissism was significantly predictive of the impulsive buying tendency. By investigating narcissism and the impulsive buying tendency in 304 twin pairs, study 2 showed that global narcissism and its two components, adaptive and maladaptive narcissism, as well as the impulsive buying tendency were heritable. The study found, moreover, that the connections between global narcissism and impulsive buying, and between maladaptive narcissism and impulsive buying were genetically based. These findings not only establish a link between narcissism and impulsive buying but also help to identify the origins of the link. The present studies deepen our understanding of narcissism, impulsive buying, and their interrelationship.

  13. Narcissism predicts impulsive buying: phenotypic and genetic evidence

    Science.gov (United States)

    Cai, Huajian; Shi, Yuanyuan; Fang, Xiang; Luo, Yu L. L.

    2015-01-01

    Impulsive buying makes billions of dollars for retail businesses every year, particularly in an era of thriving e-commerce. Narcissism, characterized by impulsivity and materialism, may serve as a potential antecedent to impulsive buying. To test this hypothesis, two studies examined the relationship between narcissism and impulsive buying. In Study 1, we surveyed an online sample and found that while adaptive narcissism was not correlated with impulsive buying, maladaptive narcissism was significantly predictive of the impulsive buying tendency. By investigating 304 twin pairs, Study 2 showed that global narcissism and its two components, adaptive and maladaptive narcissism, as well as the impulsive buying tendency were heritable. The study found, moreover, that the connections between global narcissism and impulsive buying, and between maladaptive narcissism and impulsive buying were genetically based. These findings not only establish a link between narcissism and impulsive buying but also help to identify the origins of the link. The present studies deepen our understanding of narcissism, impulsive buying, and their interrelationship. PMID:26217251

  14. Estimating genetic correlations based on phenotypic data: a simulation-based method

    Indian Academy of Sciences (India)

    Elias Zintzaras

    2011-04-01

    Knowledge of genetic correlations is essential to understand the joint evolution of traits through correlated responses to selection, a difficult and seldom, very precise task even with easy-to-breed species. Here, a simulation-based method to estimate genetic correlations and genetic covariances that relies only on phenotypic measurements is proposed. The method does not require any degree of relatedness in the sampled individuals. Extensive numerical results suggest that the propose method may provide relatively efficient estimates regardless of sample sizes and contributions from common environmental effects.

  15. Information theory and the ethylene genetic network.

    Science.gov (United States)

    González-García, José S; Díaz, José

    2011-10-01

    The original aim of the Information Theory (IT) was to solve a purely technical problem: to increase the performance of communication systems, which are constantly affected by interferences that diminish the quality of the transmitted information. That is, the theory deals only with the problem of transmitting with the maximal precision the symbols constituting a message. In Shannon's theory messages are characterized only by their probabilities, regardless of their value or meaning. As for its present day status, it is generally acknowledged that Information Theory has solid mathematical foundations and has fruitful strong links with Physics in both theoretical and experimental areas. However, many applications of Information Theory to Biology are limited to using it as a technical tool to analyze biopolymers, such as DNA, RNA or protein sequences. The main point of discussion about the applicability of IT to explain the information flow in biological systems is that in a classic communication channel, the symbols that conform the coded message are transmitted one by one in an independent form through a noisy communication channel, and noise can alter each of the symbols, distorting the message; in contrast, in a genetic communication channel the coded messages are not transmitted in the form of symbols but signaling cascades transmit them. Consequently, the information flow from the emitter to the effector is due to a series of coupled physicochemical processes that must ensure the accurate transmission of the message. In this review we discussed a novel proposal to overcome this difficulty, which consists of the modeling of gene expression with a stochastic approach that allows Shannon entropy (H) to be directly used to measure the amount of uncertainty that the genetic machinery has in relation to the correct decoding of a message transmitted into the nucleus by a signaling pathway. From the value of H we can define a function I that measures the amount of

  16. Information theory and the ethylene genetic network

    Science.gov (United States)

    González-García, José S

    2011-01-01

    The original aim of the Information Theory (IT) was to solve a purely technical problem: to increase the performance of communication systems, which are constantly affected by interferences that diminish the quality of the transmitted information. That is, the theory deals only with the problem of transmitting with the maximal precision the symbols constituting a message. In Shannon's theory messages are characterized only by their probabilities, regardless of their value or meaning. As for its present day status, it is generally acknowledged that Information Theory has solid mathematical foundations and has fruitful strong links with Physics in both theoretical and experimental areas. However, many applications of Information Theory to Biology are limited to using it as a technical tool to analyze biopolymers, such as DNA, RNA or protein sequences. The main point of discussion about the applicability of IT to explain the information flow in biological systems is that in a classic communication channel, the symbols that conform the coded message are transmitted one by one in an independent form through a noisy communication channel, and noise can alter each of the symbols, distorting the message; in contrast, in a genetic communication channel the coded messages are not transmitted in the form of symbols but signaling cascades transmit them. Consequently, the information flow from the emitter to the effector is due to a series of coupled physicochemical processes that must ensure the accurate transmission of the message. In this review we discussed a novel proposal to overcome this difficulty, which consists of the modeling of gene expression with a stochastic approach that allows Shannon entropy (H) to be directly used to measure the amount of uncertainty that the genetic machinery has in relation to the correct decoding of a message transmitted into the nucleus by a signaling pathway. From the value of H we can define a function I that measures the amount of

  17. [Genetic components and the uncertainty of the phenotypic realization of the mass of newborns in domestic pigs Sus scrofa L].

    Science.gov (United States)

    Nikitin, S V; Kniazev, S P; Ermolaev, V I

    2014-01-01

    In this article, we discuss the features of the genetic determination of a continuous quantitative trait, the mass of newborn offspring in populations of the domestic pig. We defined several components that determine the phenotypic trait, such as the maternal effect, complete dominance, interaction of the parental alleles in the genotype of the offspring, and the uncertainty of phenotypic realization of genotype. We found that a phenotypic trait of high genetic determinacy can also have a maximum range in phenotypic realization, in which case each genotype encountered in the population can realize within the entire range of possible phenotypes.

  18. Phenotypic and Genetic Associations between Reading Comprehension, Decoding Skills, and ADHD Dimensions: Evidence from Two Population-Based Studies

    Science.gov (United States)

    Plourde, Vickie; Boivin, Michel; Forget-Dubois, Nadine; Brendgen, Mara; Vitaro, Frank; Marino, Cecilia; Tremblay, Richard T.; Dionne, Ginette

    2015-01-01

    Background: The phenotypic and genetic associations between decoding skills and ADHD dimensions have been documented but less is known about the association with reading comprehension. The aim of the study is to document the phenotypic and genetic associations between reading comprehension and ADHD dimensions of inattention and…

  19. Phenotypic and Genetic Associations between Reading Comprehension, Decoding Skills, and ADHD Dimensions: Evidence from Two Population-Based Studies

    Science.gov (United States)

    Plourde, Vickie; Boivin, Michel; Forget-Dubois, Nadine; Brendgen, Mara; Vitaro, Frank; Marino, Cecilia; Tremblay, Richard T.; Dionne, Ginette

    2015-01-01

    Background: The phenotypic and genetic associations between decoding skills and ADHD dimensions have been documented but less is known about the association with reading comprehension. The aim of the study is to document the phenotypic and genetic associations between reading comprehension and ADHD dimensions of inattention and…

  20. Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy

    Directory of Open Access Journals (Sweden)

    Claudia Gonzaga-Jauregui

    2015-08-01

    Full Text Available Charcot-Marie-Tooth (CMT disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ∼45% (17/37 of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.

  1. Exome sequence analysis suggests genetic burden contributes to phenotypic variability and complex neuropathy

    Science.gov (United States)

    Gonzaga-Jauregui, Claudia; Harel, Tamar; Gambin, Tomasz; Kousi, Maria; Griffin, Laurie B.; Francescatto, Ludmila; Ozes, Burcak; Karaca, Ender; Jhangiani, Shalini; Bainbridge, Matthew N.; Lawson, Kim S.; Pehlivan, Davut; Okamoto, Yuji; Withers, Marjorie; Mancias, Pedro; Slavotinek, Anne; Reitnauer, Pamela J; Goksungur, Meryem T.; Shy, Michael; Crawford, Thomas O.; Koenig, Michel; Willer, Jason; Flores, Brittany N.; Pediaditrakis, Igor; Us, Onder; Wiszniewski, Wojciech; Parman, Yesim; Antonellis, Anthony; Muzny, Donna M.; Katsanis, Nicholas; Battaloglu, Esra; Boerwinkle, Eric; Gibbs, Richard A.; Lupski, James R.

    2015-01-01

    Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ~45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy associated genes in subjects versus controls; confirmed in a second ethnically discrete neuropathy cohort, suggesting mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HMPVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity. PMID:26257172

  2. Genetic variants and early cigarette smoking and nicotine dependence phenotypes in adolescents.

    Directory of Open Access Journals (Sweden)

    Jennifer O'Loughlin

    Full Text Available While the heritability of cigarette smoking and nicotine dependence (ND is well-documented, the contribution of specific genetic variants to specific phenotypes has not been closely examined. The objectives of this study were to test the associations between 321 tagging single-nucleotide polymorphisms (SNPs that capture common genetic variation in 24 genes, and early smoking and ND phenotypes in novice adolescent smokers, and to assess if genetic predictors differ across these phenotypes.In a prospective study of 1294 adolescents aged 12-13 years recruited from ten Montreal-area secondary schools, 544 participants who had smoked at least once during the 7-8 year follow-up provided DNA. 321 single-nucleotide polymorphisms (SNPs in 24 candidate genes were tested for an association with number of cigarettes smoked in the past 3 months, and with five ND phenotypes (a modified version of the Fagerstrom Tolerance Questionnaire, the ICD-10 and three clusters of ND symptoms representing withdrawal symptoms, use of nicotine for self-medication, and a general ND/craving symptom indicator.The pattern of SNP-gene associations differed across phenotypes. Sixteen SNPs in seven genes (ANKK1, CHRNA7, DDC, DRD2, COMT, OPRM1, SLC6A3 (also known as DAT1 were associated with at least one phenotype with a p-value <0.01 using linear mixed models. After permutation and FDR adjustment, none of the associations remained statistically significant, although the p-values for the association between rs557748 in OPRM1 and the ND/craving and self-medication phenotypes were both 0.076.Because the genetic predictors differ, specific cigarette smoking and ND phenotypes should be distinguished in genetic studies in adolescents. Fifteen of the 16 top-ranked SNPs identified in this study were from loci involved in dopaminergic pathways (ANKK1/DRD2, DDC, COMT, OPRM1, and SLC6A3.Dopaminergic pathways may be salient during early smoking and the development of ND.

  3. Methods of Sports Genetics: dermatoglyphic analysis of human fingerprints (information 1

    Directory of Open Access Journals (Sweden)

    Serhiyenko L.P.

    2010-02-01

    Full Text Available The article provides data on the dermatoglyphic analysis of human fingerprints. The most informative dermatoglyphic traits of fingerprints are defined. They can be used as genetic markers to prognosticate sports endowments. The recommendations to use the technology of dermatoglyphic analysis of human fingerprints in sports genetics are given. There are certain national and racial differences in phenotypical expressed of dermatoglyphics of digit patterns.

  4. Study of genetics, phenotypic and behavioral properties of eubacteria and archaebacteria

    Directory of Open Access Journals (Sweden)

    Hamid Kazemian

    2016-06-01

    Full Text Available Background: The genome of the bacteria has considerable diversity in terms of sequence of nucleotide bases and change over the time. With the advancement of bioinformatics science possibility of the vast comparison to living organisms has risen. During the last two decades many information about genome sequencing of pathogenic and non-pathogenic bacteria have been published. Using this information and to find connections between them and many phenotypic characteristics and behavior of bacteria could be used in many studies. In this study we compared some of the genetic, phenotypic and behavioral properties of archaebacteria and eubacteria. Methods: In this analytical study, genomic Information of 286 species of archaebacteria and 122 species of eubacteria were collected from the NCBI (National Center for Biotechnology Information site which was conducted in April to June 2015. Mean of gene size, gene number, protein number and C+G content compared in the two groups of archaebacteria and eubacteria. Association of genomic characterization of bacteria with several other characteristics were analyzed using SPSS statistical software version 19 (Chicago, IL, USA. For this purpose, the Pearson correlation coefficient (Pearson, Student’s t-test and ANOVA test (One-way analysis of variance was used. The P values less than 0.05 was considered as significant level. Results: There was significant association between means discrepancy in two group (P= 0.01. The genome size of eubacteria and archaebacteria have significant association with some of the characteristics of bacteria, such as the C+G content, the number of proteins, genes and habitats of the bacteria (P= 0.01. As well as there was significant association between genome size and features such as number of pseudogene, mobility and type of breathing in eubacteria (P= 0.01 but not in archaebacterial (P˃ 0.05. Conclusion: Many characteristics of eubacteria and archaebacteria are significantly

  5. The relative contribution of environmental and genetic factors to phenotypic variation in familial Mediterranean fever (FMF).

    Science.gov (United States)

    Ben-Zvi, Ilan; Brandt, Benny; Berkun, Yackov; Lidar, Merav; Livneh, Avi

    2012-01-10

    Familial Mediterranean fever (FMF) is an autosomal recessive disease, caused by mutations in the FMF gene MEFV (MEditerranean FeVer). It has a large phenotypic diversity even in patients with similar genotypes. Despite evidence that environmental factors (EFs) and genetic factors, including MEFV mutations (such as M694V, E148Q) and background modifier genes (MGs), affect the clinical manifestations of FMF, the relative contribution of each remains unknown. To investigate the relative contribution of environmental and genetic factors to the phenotype of FMF, we compared the intra-pair clinical concordance of 10 mono and 7 dizygotic twins with FMF. The part played by EFs was determined by the phenotypic discordance of the monozygous twins, and the MGs effect was determined by deducing the environmental effect, computed for MZ twins, from the phenotypic discordance of the dizygous twins. The mean±SD of intra-pair concordance was higher in the MZ than in DZ twin group (88.1±13.2 vs. 70.7±14.1 respectively, P valueFMF is estimated as 11.9%±6.6% and the MGs effect as 17.4%±15.5% in average. In FMF the phenotype is affected by MEFV mutations, MGs and EFs in an estimated ratio of about 6:1.5:1 respectively. Copyright © 2011 Elsevier B.V. All rights reserved.

  6. Trichophyton tonsurans strains from Brazil: phenotypic heterogeneity, genetic homology, and detection of virulence genes.

    Science.gov (United States)

    Sidrim, José Julio Costa; Rocha, Marcos Fábio Gadelha; Leite, João Jaime Giffoni; Maranhão, Fernanda Cristina de Albuquerque; Lima, Rita Amanda Chaves; Castelo-Branco, Débora de Souza Collares Maia; Bandeira, Tereza de Jesus Pinheiro Gomes; Cordeiro, Rossana de Aguiar; Brilhante, Raimunda Sâmia Nogueira

    2013-11-01

    The objective of this study was to establish the phenotypical and molecular patterns of clinical isolates of Trichophyton tonsurans circulating in the state of Ceará, northeastern Brazil. For this purpose, 25 T. tonsurans strains isolated from independent cases of tinea capitis in children were phenotypically evaluated regarding their macro- and micro-morphological characteristics, vitamin requirements, urease production, and antifungal susceptibility. The molecular characterization was carried out with random amplified polymorphic DNA molecular markers and M13 fingerprinting. The presence of the genes CarbM14, Sub2, CER, URE, ASP, PBL, and LAC, which encode enzymes related to fungal virulence, was also evaluated. Finally, melanin production was assessed through specific staining. The data obtained demonstrated that these T. tonsurans strains have considerable phenotypical variation, although they showed a low degree of genetic polymorphism according to the markers used. The genes CarbM14, Sub2, CER, and URE were detected in all the analyzed strains. The gene LAC was also identified in all the strains, and melanin synthesis was phenotypically confirmed. The strains were susceptible to antifungals, especially itraconazole (GM = 0.06 μg/mL) and ketoconazole (GM = 0.24 μg/mL). Therefore, T. tonsurans strains can present great phenotypical heterogeneity, even in genetically similar isolates. Moreover, the presence of the LAC gene indicates the possible participation of melanin in the pathogenesis of these dermatophytes.

  7. Punctuated emergences of genetic and phenotypic innovations in eumetazoan, bilaterian, euteleostome, and hominidae ancestors.

    Science.gov (United States)

    Wenger, Yvan; Galliot, Brigitte

    2013-01-01

    Phenotypic traits derive from the selective recruitment of genetic materials over macroevolutionary times, and protein-coding genes constitute an essential component of these materials. We took advantage of the recent production of genomic scale data from sponges and cnidarians, sister groups from eumetazoans and bilaterians, respectively, to date the emergence of human proteins and to infer the timing of acquisition of novel traits through metazoan evolution. Comparing the proteomes of 23 eukaryotes, we find that 33% human proteins have an ortholog in nonmetazoan species. This premetazoan proteome associates with 43% of all annotated human biological processes. Subsequently, four major waves of innovations can be inferred in the last common ancestors of eumetazoans, bilaterians, euteleostomi (bony vertebrates), and hominidae, largely specific to each epoch, whereas early branching deuterostome and chordate phyla show very few innovations. Interestingly, groups of proteins that act together in their modern human functions often originated concomitantly, although the corresponding human phenotypes frequently emerged later. For example, the three cnidarians Acropora, Nematostella, and Hydra express a highly similar protein inventory, and their protein innovations can be affiliated either to traits shared by all eumetazoans (gut differentiation, neurogenesis); or to bilaterian traits present in only some cnidarians (eyes, striated muscle); or to traits not identified yet in this phylum (mesodermal layer, endocrine glands). The variable correspondence between phenotypes predicted from protein enrichments and observed phenotypes suggests that a parallel mechanism repeatedly produce similar phenotypes, thanks to novel regulatory events that independently tie preexisting conserved genetic modules.

  8. Evidence for multiple genetic forms with similar eyeless phenotypes in the blind cavefish, Astyanax mexicanus.

    Science.gov (United States)

    Dowling, Thomas E; Martasian, David P; Jeffery, William R

    2002-04-01

    A diverse group of animals has adapted to caves and lost their eyes and pigmentation, but little is known about how these animals and their striking phenotypes have evolved. The teleost Astyanax mexicanus consists of an eyed epigean form (surface fish) and at least 29 different populations of eyeless hypogean forms (cavefish). Current alternative hypotheses suggest that adaptation to cave environments may have occurred either once or multiple times during the evolutionary history of this species. If the latter is true, the unique phenotypes of different cave-dwelling populations may result from convergence of form, and different genetic changes and developmental processes may have similar morphological consequences. Here we report an analysis of variation in the mitochondrial NADH dehydrogenase 2 (ND2) gene among different surface fish and cavefish populations. The results identify a minimum of two genetically distinctive cavefish lineages with similar eyeless phenotypes. The distinction between these divergent forms is supported by differences in the number of rib-bearing thoracic vertebrae in their axial skeletons. The geographic distribution of ND2 haplotypes is consistent with roles for multiple founder events and introgressive hybridization in the evolution of cave-related phenotypes. The existence of multiple genetic lineages makes A. mexicanus an excellent model to study convergence and the genes and developmental pathways involved in the evolution of the eye and pigment degeneration.

  9. Genetic diversity assessment of sesame core collection in China by phenotype and molecular markers and extraction of a mini-core collection

    Directory of Open Access Journals (Sweden)

    Zhang Yanxin

    2012-11-01

    Full Text Available Abstract Background Sesame (Sesamum indicum L. is one of the four major oil crops in China. A sesame core collection (CC was established in China in 2000, but no complete study on its genetic diversity has been carried out at either the phenotypic or molecular level. To provide technical guidance, a theoretical basis for further collection, effective protection, reasonable application, and a complete analysis of sesame genetic resources, a genetic diversity assessment of the sesame CC in China was conducted using phenotypic and molecular data and by extracting a sesame mini-core collection (MC. Results Results from a genetic diversity assessment of sesame CC in China were significantly inconsistent at the phenotypic and molecular levels. A Mantel test revealed the insignificant correlation between phenotype and molecular marker information (r = 0.0043, t = 0.1320, P = 0.5525. The Shannon-Weaver diversity index (I and Nei genetic diversity index (h were higher (I = 0.9537, h = 0.5490 when calculated using phenotypic data from the CC than when using molecular data (I = 0.3467, h = 0.2218. A mini-core collection (MC containing 184 accessions was extracted based on both phenotypic and molecular data, with a low mean difference percentage (MD, 1.64%, low variance difference percentage (VD, 22.58%, large variable rate of coefficient of variance (VR, 114.86%, and large coincidence rate of range (CR, 95.76%. For molecular data, the diversity indices and the polymorphism information content (PIC for the MC were significantly higher than for the CC. Compared to an alternative random sampling strategy, the advantages of capturing genetic diversity and validation by extracting a MC using an advanced maximization strategy were proven. Conclusions This study provides a comprehensive characterization of the phenotypic and molecular genetic diversities of the sesame CC in China. A MC was extracted using both phenotypic and molecular data. Low MD% and VD%, and

  10. Genetic diversity assessment of sesame core collection in China by phenotype and molecular markers and extraction of a mini-core collection

    Science.gov (United States)

    2012-01-01

    Background Sesame (Sesamum indicum L.) is one of the four major oil crops in China. A sesame core collection (CC) was established in China in 2000, but no complete study on its genetic diversity has been carried out at either the phenotypic or molecular level. To provide technical guidance, a theoretical basis for further collection, effective protection, reasonable application, and a complete analysis of sesame genetic resources, a genetic diversity assessment of the sesame CC in China was conducted using phenotypic and molecular data and by extracting a sesame mini-core collection (MC). Results Results from a genetic diversity assessment of sesame CC in China were significantly inconsistent at the phenotypic and molecular levels. A Mantel test revealed the insignificant correlation between phenotype and molecular marker information (r = 0.0043, t = 0.1320, P = 0.5525). The Shannon-Weaver diversity index (I) and Nei genetic diversity index (h) were higher (I = 0.9537, h = 0.5490) when calculated using phenotypic data from the CC than when using molecular data (I = 0.3467, h = 0.2218). A mini-core collection (MC) containing 184 accessions was extracted based on both phenotypic and molecular data, with a low mean difference percentage (MD, 1.64%), low variance difference percentage (VD, 22.58%), large variable rate of coefficient of variance (VR, 114.86%), and large coincidence rate of range (CR, 95.76%). For molecular data, the diversity indices and the polymorphism information content (PIC) for the MC were significantly higher than for the CC. Compared to an alternative random sampling strategy, the advantages of capturing genetic diversity and validation by extracting a MC using an advanced maximization strategy were proven. Conclusions This study provides a comprehensive characterization of the phenotypic and molecular genetic diversities of the sesame CC in China. A MC was extracted using both phenotypic and molecular data. Low MD% and VD%, and large VR% and CR

  11. Genetic diversity assessment of sesame core collection in China by phenotype and molecular markers and extraction of a mini-core collection.

    Science.gov (United States)

    Zhang, Yanxin; Zhang, Xiurong; Che, Zhuo; Wang, Linhai; Wei, Wenliang; Li, Donghua

    2012-11-15

    Sesame (Sesamum indicum L.) is one of the four major oil crops in China. A sesame core collection (CC) was established in China in 2000, but no complete study on its genetic diversity has been carried out at either the phenotypic or molecular level. To provide technical guidance, a theoretical basis for further collection, effective protection, reasonable application, and a complete analysis of sesame genetic resources, a genetic diversity assessment of the sesame CC in China was conducted using phenotypic and molecular data and by extracting a sesame mini-core collection (MC). Results from a genetic diversity assessment of sesame CC in China were significantly inconsistent at the phenotypic and molecular levels. A Mantel test revealed the insignificant correlation between phenotype and molecular marker information (r = 0.0043, t = 0.1320, P = 0.5525). The Shannon-Weaver diversity index (I) and Nei genetic diversity index (h) were higher (I = 0.9537, h = 0.5490) when calculated using phenotypic data from the CC than when using molecular data (I = 0.3467, h = 0.2218). A mini-core collection (MC) containing 184 accessions was extracted based on both phenotypic and molecular data, with a low mean difference percentage (MD, 1.64%), low variance difference percentage (VD, 22.58%), large variable rate of coefficient of variance (VR, 114.86%), and large coincidence rate of range (CR, 95.76%). For molecular data, the diversity indices and the polymorphism information content (PIC) for the MC were significantly higher than for the CC. Compared to an alternative random sampling strategy, the advantages of capturing genetic diversity and validation by extracting a MC using an advanced maximization strategy were proven. This study provides a comprehensive characterization of the phenotypic and molecular genetic diversities of the sesame CC in China. A MC was extracted using both phenotypic and molecular data. Low MD% and VD%, and large VR% and CR% suggested that the MC

  12. Genetic difference in HLA-DR phenotypes between coeliac disease and transitory gluten intolerance.

    OpenAIRE

    Meuli, R; Pichler, W J; Gaze, H; Lentze, M J

    1995-01-01

    Genetic differences in HLA phenotypes were studied in coeliac disease to investigate why some patients do not react with mucosal damage after gluten challenge. Forty five children with coeliac disease and 16 with transitory gluten intolerance were typed; 76 subjects served as controls. HLA phenotypes in children with coeliac disease had significantly higher proportions of DR3/X and DR5/7 than controls (48.8% v 11.8% and 26.7% v 5.3%). Children with transitory gluten intolerance had lower DR3/...

  13. Independent genetic control of maize (Zea mays L.) kernel weight determination and its phenotypic plasticity.

    Science.gov (United States)

    Alvarez Prado, Santiago; Sadras, Víctor O; Borrás, Lucas

    2014-08-01

    Maize kernel weight (KW) is associated with the duration of the grain-filling period (GFD) and the rate of kernel biomass accumulation (KGR). It is also related to the dynamics of water and hence is physiologically linked to the maximum kernel water content (MWC), kernel desiccation rate (KDR), and moisture concentration at physiological maturity (MCPM). This work proposed that principles of phenotypic plasticity can help to consolidated the understanding of the environmental modulation and genetic control of these traits. For that purpose, a maize population of 245 recombinant inbred lines (RILs) was grown under different environmental conditions. Trait plasticity was calculated as the ratio of the variance of each RIL to the overall phenotypic variance of the population of RILs. This work found a hierarchy of plasticities: KDR ≈ GFD > MCPM > KGR > KW > MWC. There was no phenotypic and genetic correlation between traits per se and trait plasticities. MWC, the trait with the lowest plasticity, was the exception because common quantitative trait loci were found for the trait and its plasticity. Independent genetic control of a trait per se and genetic control of its plasticity is a condition for the independent evolution of traits and their plasticities. This allows breeders potentially to select for high or low plasticity in combination with high or low values of economically relevant traits.

  14. The alignment between phenotypic plasticity, the major axis of genetic variation and the response to selection.

    Science.gov (United States)

    Lind, Martin I; Yarlett, Kylie; Reger, Julia; Carter, Mauricio J; Beckerman, Andrew P

    2015-10-07

    Phenotypic plasticity is the ability of a genotype to produce more than one phenotype in order to match the environment. Recent theory proposes that the major axis of genetic variation in a phenotypically plastic population can align with the direction of selection. Therefore, theory predicts that plasticity directly aids adaptation by increasing genetic variation in the direction favoured by selection and reflected in plasticity. We evaluated this theory in the freshwater crustacean Daphnia pulex, facing predation risk from two contrasting size-selective predators. We estimated plasticity in several life-history traits, the G matrix of these traits, the selection gradients on reproduction and survival, and the predicted responses to selection. Using these data, we tested whether the genetic lines of least resistance and the predicted response to selection aligned with plasticity. We found predator environment-specific G matrices, but shared genetic architecture across environments resulted in more constraint in the G matrix than in the plasticity of the traits, sometimes preventing alignment of the two. However, as the importance of survival selection increased, the difference between environments in their predicted response to selection increased and resulted in closer alignment between the plasticity and the predicted selection response. Therefore, plasticity may indeed aid adaptation to new environments.

  15. Using text mining techniques to extract phenotypic information from the PhenoCHF corpus

    OpenAIRE

    Alnazzawi, Noha; Thompson, Paul; Batista-Navarro, Riza; Ananiadou, Sophia

    2015-01-01

    Background Phenotypic information locked away in unstructured narrative text presents significant barriers to information accessibility, both for clinical practitioners and for computerised applications used for clinical research purposes. Text mining (TM) techniques have previously been applied successfully to extract different types of information from text in the biomedical domain. They have the potential to be extended to allow the extraction of information relating to phenotypes from fre...

  16. Destabilizing protein polymorphisms in the genetic background direct phenotypic expression of mutant SOD1 toxicity.

    Directory of Open Access Journals (Sweden)

    Tali Gidalevitz

    2009-03-01

    Full Text Available Genetic background exerts a strong modulatory effect on the toxicity of aggregation-prone proteins in conformational diseases. In addition to influencing the misfolding and aggregation behavior of the mutant proteins, polymorphisms in putative modifier genes may affect the molecular processes leading to the disease phenotype. Mutations in SOD1 in a subset of familial amyotrophic lateral sclerosis (ALS cases confer dominant but clinically variable toxicity, thought to be mediated by misfolding and aggregation of mutant SOD1 protein. While the mechanism of toxicity remains unknown, both the nature of the SOD1 mutation and the genetic background in which it is expressed appear important. To address this, we established a Caenorhabditis elegans model to systematically examine the aggregation behavior and genetic interactions of mutant forms of SOD1. Expression of three structurally distinct SOD1 mutants in C. elegans muscle cells resulted in the appearance of heterogeneous populations of aggregates and was associated with only mild cellular dysfunction. However, introduction of destabilizing temperature-sensitive mutations into the genetic background strongly enhanced the toxicity of SOD1 mutants, resulting in exposure of several deleterious phenotypes at permissive conditions in a manner dependent on the specific SOD1 mutation. The nature of the observed phenotype was dependent on the temperature-sensitive mutation present, while its penetrance reflected the specific combination of temperature-sensitive and SOD1 mutations. Thus, the specific toxic phenotypes of conformational disease may not be simply due to misfolding/aggregation toxicity of the causative mutant proteins, but may be defined by their genetic interactions with cellular pathways harboring mildly destabilizing missense alleles.

  17. Dissecting the catatonia phenotype in psychotic and mood disorders on the basis of familial-genetic factors.

    Science.gov (United States)

    Peralta, Victor; Fañanás, Lourdes; Martín-Reyes, Migdyrai; Cuesta, Manuel J

    2017-09-14

    This study examines the familial aggregation (familiality) of different phenotypic definitions of catatonia in a sample of multiplex families with psychotic and mood disorders. Participants were probands with a lifetime diagnosis of a DSM-IV functional psychotic disorder, their parents and at least one first-degree relative with a psychotic disorder. The study sample included 441 families comprising 2703 subjects, of whom 1094 were affected and 1609 unaffected. Familiality (h(2)) was estimated by linear mixed models using family membership as a random effect, with h(2) indicating the portion of phenotypic variance accounted for by family membership. Familiality estimates highly varied for individual catatonia signs (h(2)=0.17-0.65), principal component analysis-derived factors (h(2)=0.29-0.49), number of catatonia signs present (h(2)=0.03-0.43) and severity of the catatonia syndrome (h(2)=0.25-0.59). Phenotypes maximizing familiality estimates included individual signs (mutism and rigidity, both h(2)=0.65), presence of ≥5 catatonia signs (h(2)=0.43), a classical catatonia factor (h(2)=0.49), a DSM-IV catatonia syndrome at a severity level of moderate or higher (h(2)=0.59) and the diagnostic construct of psychosis with prominent catatonia features (h(2)=0.56). Familiality estimates of a DSM-IV catatonia syndrome did not significantly differ across the diagnostic categories of psychotic and mood disorders (h(2)=0.40-0.47). The way in which catatonia is defined has a strong impact on familiality estimates with some catatonia phenotypes exhibiting substantial familial aggregation, which may inform about the most adequate phenotypes for molecular studies. From a familial-genetic perspective, the catatonia phenotype in psychotic and mood disorders has a transdiagnostic character. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Phenotype Similarity Regression for Identifying the Genetic Determinants of Rare Diseases

    Science.gov (United States)

    Greene, Daniel; Richardson, Sylvia; Turro, Ernest

    2016-01-01

    Rare genetic disorders, which can now be studied systematically with affordable genome sequencing, are often caused by high-penetrance rare variants. Such disorders are often heterogeneous and characterized by abnormalities spanning multiple organ systems ascertained with variable clinical precision. Existing methods for identifying genes with variants responsible for rare diseases summarize phenotypes with unstructured binary or quantitative variables. The Human Phenotype Ontology (HPO) allows composite phenotypes to be represented systematically but association methods accounting for the ontological relationship between HPO terms do not exist. We present a Bayesian method to model the association between an HPO-coded patient phenotype and genotype. Our method estimates the probability of an association together with an HPO-coded phenotype characteristic of the disease. We thus formalize a clinical approach to phenotyping that is lacking in standard regression techniques for rare disease research. We demonstrate the power of our method by uncovering a number of true associations in a large collection of genome-sequenced and HPO-coded cases with rare diseases. PMID:26924528

  19. Phenotype Similarity Regression for Identifying the Genetic Determinants of Rare Diseases.

    Science.gov (United States)

    Greene, Daniel; Richardson, Sylvia; Turro, Ernest

    2016-03-01

    Rare genetic disorders, which can now be studied systematically with affordable genome sequencing, are often caused by high-penetrance rare variants. Such disorders are often heterogeneous and characterized by abnormalities spanning multiple organ systems ascertained with variable clinical precision. Existing methods for identifying genes with variants responsible for rare diseases summarize phenotypes with unstructured binary or quantitative variables. The Human Phenotype Ontology (HPO) allows composite phenotypes to be represented systematically but association methods accounting for the ontological relationship between HPO terms do not exist. We present a Bayesian method to model the association between an HPO-coded patient phenotype and genotype. Our method estimates the probability of an association together with an HPO-coded phenotype characteristic of the disease. We thus formalize a clinical approach to phenotyping that is lacking in standard regression techniques for rare disease research. We demonstrate the power of our method by uncovering a number of true associations in a large collection of genome-sequenced and HPO-coded cases with rare diseases.

  20. Genetic information and insurance: some ethical issues.

    Science.gov (United States)

    O'Neill, O

    1997-08-29

    Life is risky, and insurance provides one of the best developed ways of controlling risks. By pooling, and so transferring risks, those who turn out to suffer antecedently uncertain harms can be assured in advance that they will be helped if those harms arise; they can then plan their lives and activities with confidence that they are less at the mercy of ill fortune. Both publicly organized and commercial insurance can organize the pooling of risk in ways that are beneficial for all concerned. They provide standard ways of securing fundamental ethical values such as solidarity and mutuality. Although policy holders do not know or contract with one another, each benefits from the contribution of others to a shared scheme for pooling and so controlling risk. Although there is a limit to the degree to which commercially-based insurance, where premiums depend on risk level, can go beyond mutuality towards solidarity, in practice it too often achieves a measure of solidarity by taking a broad brush approach to pooling risk. However, the ordinary practices of insurance, and in particular of commercial insurance, also raise ethical questions. These may be put in simple terms by contrasting the way in which an insurance market discriminates between different people, on the basis of characteristics that (supposedly) determine their risk level, and our frequent abhorrence of discrimination, in particular on the basis on religious, racial and gender characteristics. Are the discriminations on which insurance practice relies upon as standard acceptable or not? The increasing availability of genetic information, which testing (of individuals) and screening (of populations) may provide, could lend urgency to these questions. Genetic information may provide a way of obtaining more accurate assessment of individual risks to health and life. This information could be used to discriminate more finely between the risk levels of different individuals, and then to alter the

  1. Evidence of phenotypic and genetic relationships between sociality, emotional reactivity and production traits in Japanese quail.

    Directory of Open Access Journals (Sweden)

    Julien Recoquillay

    Full Text Available The social behavior of animals, which is partially controlled by genetics, is one of the factors involved in their adaptation to large breeding groups. To understand better the relationships between different social behaviors, fear behaviors and production traits, we analyzed the phenotypic and genetic correlations of these traits in Japanese quail by a second generation crossing of two lines divergently selected for their social reinstatement behavior. Analyses of results for 900 individuals showed that the phenotypic correlations between behavioral traits were low with the exception of significant correlations between sexual behavior and aggressive pecks both at phenotypic (0.51 and genetic (0.90 levels. Significant positive genetic correlations were observed between emotional reactivity toward a novel object and sexual (0.89 or aggressive (0.63 behaviors. The other genetic correlations were observed mainly between behavioral and production traits. Thus, the level of emotional reactivity, estimated by the duration of tonic immobility, was positively correlated with weight at 17 and 65 days of age (0.76 and 0.79, respectively and with delayed egg laying onset (0.74. In contrast, a higher level of social reinstatement behavior was associated with an earlier egg laying onset (-0.71. In addition, a strong sexual motivation was correlated with an earlier laying onset (-0.68 and a higher number of eggs laid (0.82. A low level of emotional reactivity toward a novel object and also a higher aggressive behavior were genetically correlated with a higher number of eggs laid (0.61 and 0.58, respectively. These results bring new insights into the complex determinism of social and emotional reactivity behaviors in birds and their relationships with production traits. Furthermore, they highlight the need to combine animal welfare and production traits in selection programs by taking into account traits of sociability and emotional reactivity.

  2. Genomic imprinting: genetic mechanisms and phenotypic consequences in Prader-Willi and Angelman syndromes

    Directory of Open Access Journals (Sweden)

    Cintia Fridman

    2000-12-01

    Full Text Available Chromosomal 15q11-q13 region is of great interest in Human Genetics because many structural rearrangements have been described for it (deletions, duplications and translocations leading to phenotypes resulting in conditions such as the Prader-Willi (PWS and Angelman (AS syndromes which were the first human diseases found to be related to the differential expression of parental alleles (genomic imprinting. Contrary to Mendelian laws where the parental inheritance of genetic information does not influence gene expression, genomic imprinting is characterized by DNA modifications that produce different phenotypes depending on the parental origin of the mutation. Clinical manifestation of PWS appears when the loss of paternally expressed genes occurs and AS results from the loss of a maternally expressed gene. Different genetic mechanisms can lead to PWS or AS, such as deletions, uniparental disomy or imprinting mutation. In AS patients an additional class occurs with mutations on the UBE3A gene. Studies of PWS and AS patients can help us to understand the imprinting process, so that other genomic regions with similar characteristics can be located, and different syndromes can have their genetic mechanisms elucidated.O segmento cromossômico 15q11-q13 é de grande interesse em Genética Humana uma vez que diversos rearranjos estruturais têm sido descritos nessa região (deleções, duplicações e translocações resultando em fenótipos diferentes como os das síndromes de Prader-Willi (PWS e Angelman (AS, que foram as primeiras doenças humanas a serem relacionadas com a expressão diferencial de alelos parentais (imprinting genômico. Contrário às leis de Mendel onde a herança parental da informação genética não influencia a expressão gênica, o imprinting genômico é caracterizado por modificações no DNA que produzem diferentes fenótipos dependendo da origem parental da mutação. A manifestação clínica da PWS aparece quando

  3. Genetic Similarities between Compulsive Overeating and Addiction Phenotypes: A Case for "Food Addiction"?

    Science.gov (United States)

    Carlier, Nina; Marshe, Victoria S; Cmorejova, Jana; Davis, Caroline; Müller, Daniel J

    2015-12-01

    There exists a continuous spectrum of overeating, where at the extremes there are casual overindulgences and at the other a 'pathological' drive to consume palatable foods. It has been proposed that pathological eating behaviors may be the result of addictive appetitive behavior and loss of ability to regulate the consumption of highly processed foods containing refined carbohydrates, fats, salt, and caffeine. In this review, we highlight the genetic similarities underlying substance addiction phenotypes and overeating compulsions seen in individuals with binge eating disorder. We relate these similarities to findings from neuroimaging studies on reward processing and clinical diagnostic criteria based on addiction phenotypes. The abundance of similarities between compulsive overeating and substance addictions puts forth a case for a 'food addiction' phenotype as a valid, diagnosable disorder.

  4. Pedimap: software for the visualization of genetic and phenotypic data in pedigrees.

    Science.gov (United States)

    Voorrips, Roeland E; Bink, Marco C A M; van de Weg, W Eric

    2012-01-01

    Pedimap is a user-friendly software tool for visualizing phenotypic and genotypic data for related individuals linked in pedigrees. Genetic data can include marker scores, Identity-by-Descent probabilities, and marker linkage map positions, allowing the visualization of haplotypes through lineages. The pedigrees can accommodate all types of inheritance, including selfing, cloning, and repeated backcrossing, and all ploidy levels are supported. Visual association of the genetic data with phenotypic data simplifies the exploration of large data sets, thereby improving breeding decision making. Data are imported from text files; in addition data exchange with other software packages (FlexQTL(TM) and GenomeStudio(TM)) is possible. Instructions for use and an executable version compatible with the Windows platform are available for free from http://www.plantbreeding.wur.nl/UK/software_pedimap.html.

  5. Punctuated Emergences of Genetic and Phenotypic Innovations in Eumetazoan, Bilaterian, Euteleostome, and Hominidae Ancestors

    OpenAIRE

    Wenger, Yvan; Galliot, Brigitte

    2013-01-01

    Phenotypic traits derive from the selective recruitment of genetic materials over macroevolutionary times, and protein-coding genes constitute an essential component of these materials. We took advantage of the recent production of genomic scale data from sponges and cnidarians, sister groups from eumetazoans and bilaterians, respectively, to date the emergence of human proteins and to infer the timing of acquisition of novel traits through metazoan evolution. Comparing the proteomes of 23 eu...

  6. Computational approaches for the genetic and phenotypic characterization of a Saccharomyces cerevisiae wine yeast collection.

    Science.gov (United States)

    Franco-Duarte, R; Umek, L; Zupan, B; Schuller, D

    2009-12-01

    Within this study, we have used a set of computational techniques to relate the genotypes and phenotypes of natural populations of Saccharomyces cerevisiae, using allelic information from 11 microsatellite loci and results from 24 phenotypic tests. A group of 103 strains was obtained from a larger S. cerevisiae winemaking strain collection by clustering with self-organizing maps. These strains were further characterized regarding their allelic combinations for 11 microsatellites and analysed in phenotypic screens that included taxonomic criteria (carbon and nitrogen assimilation tests, growth at different temperatures) and tests with biotechnological relevance (ethanol resistance, H(2)S or aromatic precursors formation). Phenotypic variability was rather high and each strain showed a unique phenotypic profile. The results, expressed as optical density (A(640)) after 22 h of growth, were in agreement with taxonomic data, although with some exceptions, since few strains were capable of consuming arabinose and ribose to a small extent. Based on microsatellite allelic information, naïve Bayesian classifier correctly assigned (AUC = 0.81, p 0.75). Subgroups were found for strains with low ethanol resistance, growth at 30 degrees C and growth in media containing galactose, raffinose or urea. The results demonstrate that computational approaches can be used to establish genotype-phenotype relations and to make predictions about a strain's biotechnological potential.

  7. ESTIMATION OF PHENOTYPIC AND GENETIC CORRELATIONS FOR QUALITY TRAITS IN A WHEAT POPULATION

    Directory of Open Access Journals (Sweden)

    Dario Novoselović

    2012-06-01

    Full Text Available The objective of this paper was to estimate phenotypic and genetic correlations in order to improve existing wheat quality breeding methodology in early generations. For this purpose, one-year trial with population of 143 recombinant inbred lines from crossing combination Bezostaja/Klara was carried out on Osijek and Slavonski Brod locations in 2008/09 year. Among analyzed traits (grain protein content, wet gluten content, gluten index, mid-line peak time -MPT, mid-line peak height -MPH and mid-line tail width -MTW consistent positive phenotypic and genetic pattern of correlations was found between grain protein content and wet gluten content, negative between gluten index with grain protein content and wet gluten content, and positive between grain protein content and wet gluten content with MPT and MPH. Conformity of the phenotypic and genetic correlations was confirmed by Mantel test on both locations (for Osijek r=0.81** and for Slavonski Brod r=0.88**.

  8. Structural mapping: how to study the genetic architecture of a phenotypic trait through its formation mechanism.

    Science.gov (United States)

    Tong, Chunfa; Shen, Lianying; Lv, Yafei; Wang, Zhong; Wang, Xiaoling; Feng, Sisi; Li, Xin; Sui, Yihan; Pang, Xiaoming; Wu, Rongling

    2014-01-01

    Traditional approaches for genetic mapping are to simply associate the genotypes of a quantitative trait locus (QTL) with the phenotypic variation of a complex trait. A more mechanistic strategy has emerged to dissect the trait phenotype into its structural components and map specific QTLs that control the mechanistic and structural formation of a complex trait. We describe and assess such a strategy, called structural mapping, by integrating the internal structural basis of trait formation into a QTL mapping framework. Electrical impedance spectroscopy (EIS) has been instrumental for describing the structural components of a phenotypic trait and their interactions. By building robust mathematical models on circuit EIS data and embedding these models within a mixture model-based likelihood for QTL mapping, structural mapping implements the EM algorithm to obtain maximum likelihood estimates of QTL genotype-specific EIS parameters. The uniqueness of structural mapping is to make it possible to test a number of hypotheses about the pattern of the genetic control of structural components. We validated structural mapping by analyzing an EIS data collected for QTL mapping of frost hardiness in a controlled cross of jujube trees. The statistical properties of parameter estimates were examined by simulation studies. Structural mapping can be a powerful alternative for genetic mapping of complex traits by taking account into the biological and physical mechanisms underlying their formation.

  9. Distinct subspecies or phenotypic plasticity? Genetic and morphological differentiation of mountain honey bees in East Africa.

    Science.gov (United States)

    Gruber, Karl; Schöning, Caspar; Otte, Marianne; Kinuthia, Wanja; Hasselmann, Martin

    2013-09-01

    Identifying the forces shaping intraspecific phenotypic and genotypic divergence are of key importance in evolutionary biology. Phenotypic divergence may result from local adaptation or, especially in species with strong gene flow, from pronounced phenotypic plasticity. Here, we examine morphological and genetic divergence among populations of the western honey bee Apis mellifera in the topographically heterogeneous East African region. The currently accepted "mountain refugia hypothesis" states that populations living in disjunct montane forests belong to a different lineage than those in savanna habitats surrounding these forests. We obtained microsatellite data, mitochondrial sequences, and morphometric data from worker honey bees collected from feral colonies in three montane forests and corresponding neighboring savanna regions in Kenya. Honey bee colonies from montane forests showed distinct worker morphology compared with colonies in savanna areas. Mitochondrial sequence data did not support the existence of the two currently accepted subspecies. Furthermore, analyses of the microsatellite data with a Bayesian clustering method did not support the existence of two source populations as it would be expected under the mountain refugia scenario. Our findings suggest that phenotypic plasticity rather than distinct ancestry is the leading cause behind the phenotypic divergence observed between montane forest and savanna honey bees. Our study thus corroborates the idea that high gene flow may select for increased plasticity.

  10. Local versus Generalized Phenotypes in Two Sympatric Aurelia Species: Understanding Jellyfish Ecology Using Genetics and Morphometrics.

    Science.gov (United States)

    Chiaverano, Luciano M; Bayha, Keith W; Graham, William M

    2016-01-01

    For individuals living in environmentally heterogeneous environments, a key component for adaptation and persistence is the extent of phenotypic differentiation in response to local environmental conditions. In order to determine the extent of environmentally induced morphological variation in a natural population distributed along environmental gradients, it is necessary to account for potential genetic differences contributing to morphological differentiation. In this study, we set out to quantify geographic morphological variation in the moon jellyfish Aurelia exposed at the extremes of a latitudinal environmental gradient in the Gulf of Mexico (GoM). We used morphological data based on 28 characters, and genetic data taken from mitochondrial cytochrome oxidase I (COI) and nuclear internal transcribed spacer 1 (ITS-1). Molecular analyses revealed the presence of two genetically distinct species of Aurelia co-occurring in the GoM: Aurelia sp. 9 and Aurelia c.f. sp. 2, named for its divergence from (for COI) and similarity to (for ITS-1) Aurelia sp. 2 (Brazil). Neither species exhibited significant population genetic structure between the Northern and the Southeastern Gulf of Mexico; however, they differed greatly in the degree of geographic morphological variation. The morphology of Aurelia sp. 9 exhibited ecophenotypic plasticity and varied significantly between locations, while morphology of Aurelia c.f. sp. 2 was geographically invariant (i.e., canalized). The plastic, generalist medusae of Aurelia sp. 9 are likely able to produce environmentally-induced, "optimal" phenotypes that confer high relative fitness in different environments. In contrast, the non-plastic generalist individuals of Aurelia c.f. sp. 2 likely produce environmentally-independent phenotypes that provide the highest fitness across environments. These findings suggest the two Aurelia lineages co-occurring in the GoM were likely exposed to different past environmental conditions (i

  11. Local versus Generalized Phenotypes in Two Sympatric Aurelia Species: Understanding Jellyfish Ecology Using Genetics and Morphometrics.

    Directory of Open Access Journals (Sweden)

    Luciano M Chiaverano

    Full Text Available For individuals living in environmentally heterogeneous environments, a key component for adaptation and persistence is the extent of phenotypic differentiation in response to local environmental conditions. In order to determine the extent of environmentally induced morphological variation in a natural population distributed along environmental gradients, it is necessary to account for potential genetic differences contributing to morphological differentiation. In this study, we set out to quantify geographic morphological variation in the moon jellyfish Aurelia exposed at the extremes of a latitudinal environmental gradient in the Gulf of Mexico (GoM. We used morphological data based on 28 characters, and genetic data taken from mitochondrial cytochrome oxidase I (COI and nuclear internal transcribed spacer 1 (ITS-1. Molecular analyses revealed the presence of two genetically distinct species of Aurelia co-occurring in the GoM: Aurelia sp. 9 and Aurelia c.f. sp. 2, named for its divergence from (for COI and similarity to (for ITS-1 Aurelia sp. 2 (Brazil. Neither species exhibited significant population genetic structure between the Northern and the Southeastern Gulf of Mexico; however, they differed greatly in the degree of geographic morphological variation. The morphology of Aurelia sp. 9 exhibited ecophenotypic plasticity and varied significantly between locations, while morphology of Aurelia c.f. sp. 2 was geographically invariant (i.e., canalized. The plastic, generalist medusae of Aurelia sp. 9 are likely able to produce environmentally-induced, "optimal" phenotypes that confer high relative fitness in different environments. In contrast, the non-plastic generalist individuals of Aurelia c.f. sp. 2 likely produce environmentally-independent phenotypes that provide the highest fitness across environments. These findings suggest the two Aurelia lineages co-occurring in the GoM were likely exposed to different past environmental conditions

  12. Information capacity of genetic regulatory elements

    Science.gov (United States)

    Tkačik, Gašper; Callan, Curtis G., Jr.; Bialek, William

    2008-07-01

    Changes in a cell’s external or internal conditions are usually reflected in the concentrations of the relevant transcription factors. These proteins in turn modulate the expression levels of the genes under their control and sometimes need to perform nontrivial computations that integrate several inputs and affect multiple genes. At the same time, the activities of the regulated genes would fluctuate even if the inputs were held fixed, as a consequence of the intrinsic noise in the system, and such noise must fundamentally limit the reliability of any genetic computation. Here we use information theory to formalize the notion of information transmission in simple genetic regulatory elements in the presence of physically realistic noise sources. The dependence of this “channel capacity” on noise parameters, cooperativity and cost of making signaling molecules is explored systematically. We find that, in the range of parameters probed by recent in vivo measurements, capacities higher than one bit should be achievable. It is of course generally accepted that gene regulatory elements must, in order to function properly, have a capacity of at least one bit. The central point of our analysis is the demonstration that simple physical models of noisy gene transcription, with realistic parameters, can indeed achieve this capacity: it was not self-evident that this should be so. We also demonstrate that capacities significantly greater than one bit are possible, so that transcriptional regulation need not be limited to simple “on-off” components. The question whether real systems actually exploit this richer possibility is beyond the scope of this investigation.

  13. Speciation in the highlands of Mexico: genetic and phenotypic divergence in the Mexican jay (Aphelocoma ultramarina).

    Science.gov (United States)

    McCormack, J E; Peterson, A T; Bonaccorso, E; Smith, T B

    2008-05-01

    The pine-oak woodlands of the Mexican highlands harbour significant biological diversity, yet little is known about the evolutionary history of organisms inhabiting this region. We assessed genetic and phenotypic differentiation in 482 individuals representing 27 populations of the Mexican jay (Aphelocoma ultramarina) - a widespread bird species of the Mexican highlands - to test whether populations in the central and northern Mexican sierras display discrete breaks between groups, which would be consistent with a role for the different mountain chains in divergence and speciation. We found abrupt breaks in mitochondrial DNA (mtDNA; ND2 and control region) delineating four major genetic groups found in the Sierra Madre Occidental, Sierra Madre Oriental, southern Central Plateau (Bajio), and Transvolcanic Belt. These mtDNA groups were largely corroborated by data from nuclear microsatellites and phenotypic data, except that clades from the Central Plateau and Sierra Madre Oriental showed clinal change in these data sets. Uncertainty about the mutation rate for our mitochondrial markers warrants considerable caution with regard to estimating divergence times, but the major genetic groups appear to have split before the most extreme period of glacial cycling that marked the last 0.7 million years and after Mexico's period of major mountain formation. The fact that some genetic breaks do not coincide with well-known geographic barriers suggests a role for ecology in divergence and speciation, and we discuss implications for taxonomy and conservation.

  14. Discovering Pair-Wise Genetic Interactions: An Information Theory-Based Approach

    Science.gov (United States)

    Ignac, Tomasz M.; Skupin, Alexander; Sakhanenko, Nikita A.; Galas, David J.

    2014-01-01

    Phenotypic variation, including that which underlies health and disease in humans, results in part from multiple interactions among both genetic variation and environmental factors. While diseases or phenotypes caused by single gene variants can be identified by established association methods and family-based approaches, complex phenotypic traits resulting from multi-gene interactions remain very difficult to characterize. Here we describe a new method based on information theory, and demonstrate how it improves on previous approaches to identifying genetic interactions, including both synthetic and modifier kinds of interactions. We apply our measure, called interaction distance, to previously analyzed data sets of yeast sporulation efficiency, lipid related mouse data and several human disease models to characterize the method. We show how the interaction distance can reveal novel gene interaction candidates in experimental and simulated data sets, and outperforms other measures in several circumstances. The method also allows us to optimize case/control sample composition for clinical studies. PMID:24670935

  15. Pathogenic ischemic stroke phenotypes in the NINDS-stroke genetics network.

    Science.gov (United States)

    Ay, Hakan; Arsava, Ethem Murat; Andsberg, Gunnar; Benner, Thomas; Brown, Robert D; Chapman, Sherita N; Cole, John W; Delavaran, Hossein; Dichgans, Martin; Engström, Gunnar; Giralt-Steinhauer, Eva; Grewal, Raji P; Gwinn, Katrina; Jern, Christina; Jimenez-Conde, Jordi; Jood, Katarina; Katsnelson, Michael; Kissela, Brett; Kittner, Steven J; Kleindorfer, Dawn O; Labovitz, Daniel L; Lanfranconi, Silvia; Lee, Jin-Moo; Lehm, Manuel; Lemmens, Robin; Levi, Chris; Li, Linxin; Lindgren, Arne; Markus, Hugh S; McArdle, Patrick F; Melander, Olle; Norrving, Bo; Peddareddygari, Leema Reddy; Pedersén, Annie; Pera, Joanna; Rannikmäe, Kristiina; Rexrode, Kathryn M; Rhodes, David; Rich, Stephen S; Roquer, Jaume; Rosand, Jonathan; Rothwell, Peter M; Rundek, Tatjana; Sacco, Ralph L; Schmidt, Reinhold; Schürks, Markus; Seiler, Stephan; Sharma, Pankaj; Slowik, Agnieszka; Sudlow, Cathie; Thijs, Vincent; Woodfield, Rebecca; Worrall, Bradford B; Meschia, James F

    2014-12-01

    NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases. The distribution of pathogenic categories varied by study, age, sex, and race (Pstroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (κ 0.72; 95% confidence interval, 0.69-0.75) and phenotypic classifications (κ 0.73; 95% confidence interval, 0.70-0.75). This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke. © 2014 American Heart Association, Inc.

  16. [Angelman syndrome: physical characteristics and behavioural phenotype in 37 patients with confirmed genetic diagnosis].

    Science.gov (United States)

    Galván-Manso, M; Campistol, J; Monros, E; Póo, P; Vernet, A M; Pineda, M; Sans, A; Colomer, J; Conill, J J; Sanmartí, F X

    Angelman syndrome (AS) is characterised by mental retardation, ataxic gait, epilepsy, absence of language and a special series of physical traits behavioural phenotype. Its incidence is estimated as one in every 20,000 individuals. On the basis of discoveries made in molecular biology, patients can be classified as belonging to five types: deletion, paternal uniparental disomy (UPD), imprinting defects, mutation of the UBE3A ubiquitin protein ligase gene and unidentified mechanism (15% 20% of patients). Some studies report significant correlations between the phenotype and the genetic cause. We reviewed, retrospectively, 37 patients suffering from AS with a positive genetic study and who had been controlled for at least two years in the Neurological Service at the Hospital Sant Joan de D u. Data was collected on physical characteristics, behavioural phenotype, type of communication, sleep disorders and the medication they needed, as well as epilepsy, start age, types of seizures, medication, schooling and social integration. 87% of cases were due to de novo deletion, 8% were caused by UPD, and 5% had their origins in imprinting defects. The average age of diagnosis was 6.5 years. The sleep disorders present in 48% of the patients required medication in 67% of cases, and 95% presented epilepsy. The most frequent seizures were myoclonic, tonic clonic and atonic. The electroencephalogram (EEG) was the characteristic found in the AS in 68%. The most effective treatment was afforded by valproate and clonazepam. As regards the phenotype, no differences were found according to the genetic alteration. The most effective treatment for the sleep disorders was melatonin. Epilepsy was an almost constant finding in our series, as was cognitive affectation. Lastly, it must be pointed out that educational and socio occupational integration is difficult for patients suffering from AS.

  17. Phenotypic evolution by distance in fluctuating environments: The contribution of dispersal, selection and random genetic drift.

    Science.gov (United States)

    Engen, Steinar; Sæther, Bernt-Erik

    2016-06-01

    Here we analyze how dispersal, genetic drift, and adaptation to the local environment affect the geographical differentiation of a quantitative character through natural selection using a spatial dynamic model for the evolution of the distribution of mean breeding values in space and time. The variation in optimal phenotype is described by local Ornstein-Uhlenbeck processes with a given spatial autocorrelation. Selection and drift are assumed to be governed by phenotypic variation within areas with a given mean breeding value and constant additive genetic variance. Between such neighboring areas there will be white noise variation in mean breeding values, while the variation at larger distances has a spatial structure and a spatial scale that we investigate. The model is analyzed by solving balance equations for the stationary distribution of mean breeding values. We also present scaling results for the spatial autocovariance function for mean breeding values as well as that for the covariance between mean breeding value and the optimal phenotype expressing local adaption. Our results show in particular how these spatial scales depend on population density. For large densities the spatial scale of fluctuations in mean breeding values have similarities with corresponding results in population dynamics, where the effect of migration on spatial scales may be large if the local strength of density regulation is small. In our evolutionary model strength of density regulation corresponds to strength of local selection so that weak local selection may produce large spatial scales of autocovariances. Genetic drift and stochastic migration are shown to act through the population size within a characteristic area with much smaller variation in optimal phenotypes than in the whole population.

  18. Genetic Variation in Autophagy-Related Genes Influences the Risk and Phenotype of Buruli Ulcer.

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    Carlos Capela

    2016-04-01

    Full Text Available Buruli ulcer (BU is a severe necrotizing human skin disease caused by Mycobacterium ulcerans. Clinically, presentation is a sum of these diverse pathogenic hits subjected to critical immune-regulatory mechanisms. Among them, autophagy has been demonstrated as a cellular process of critical importance. Since microtubules and dynein are affected by mycolactone, the critical pathogenic exotoxin produced by M. ulcerans, cytoskeleton-related changes might potentially impair the autophagic process and impact the risk and progression of infection.Genetic variants in the autophagy-related genes NOD2, PARK2 and ATG16L1 has been associated with susceptibility to mycobacterial diseases. Here, we investigated their association with BU risk, its severe phenotypes and its progression to an ulcerative form.Genetic variants were genotyped using KASPar chemistry in 208 BU patients (70.2% with an ulcerative form and 28% in severe WHO category 3 phenotype and 300 healthy endemic controls.The rs1333955 SNP in PARK2 was significantly associated with increased susceptibility to BU [odds ratio (OR, 1.43; P = 0.05]. In addition, both the rs9302752 and rs2066842 SNPs in NOD2 gee significantly increased the predisposition of patients to develop category 3 (OR, 2.23; P = 0.02; and OR 12.7; P = 0.03, respectively, whereas the rs2241880 SNP in ATG16L1 was found to significantly protect patients from presenting the ulcer phenotype (OR, 0.35; P = 0.02.Our findings indicate that specific genetic variants in autophagy-related genes influence susceptibility to the development of BU and its progression to severe phenotypes.

  19. Regulating genetic information--exploring the options in legal theory.

    Science.gov (United States)

    2014-12-01

    Ground-breaking genetic discoveries and technological advances have introduced a new world of genetic exploration, and technological advances have facilitated the discovery of the genetic basis of a myriad of diseases. Genetic testing promises to potentially revolutionise health care and offer the potential ofpersonalised medicine. Genetic technology may also offer the means to detect potential future disabilities. In light of rapid advances in genetic science and technology, questions arise as to whether an appropriate framework exists to protect the interests of individuals, prevent the misuse of genetic information by interested third parties, and also to encourage further advances in genetic science. In consideration of rapidly advancing genetic technologies and the ethical and legal concerns that arise, this article examines the regulation of genetic information, primarily from a theoretical perspective. It explores the preferable mode of regulation and choice of regulatory frameworks in legal theory, including non-discrimination, privacy and property.

  20. Parallel Genetic and Phenotypic Evolution of DNA Superhelicity in Experimental Populations of Escherichia coli

    DEFF Research Database (Denmark)

    Crozat, Estelle; Winkworth, Cynthia; Gaffé, Joël

    2010-01-01

    DNA supercoiling is the master function that interconnects chromosome structure and global gene transcription. This function has recently been shown to be under strong selection in Escherichia coli. During the evolution of 12 initially identical populations propagated in a defined environment...... for 20,000 generations, parallel increases in DNA supercoiling were observed in ten populations. The genetic changes associated with the increased supercoiling were examined in one population, and beneficial mutations in the genes topA (encoding topoisomerase I) and fis (encoding a histone-like protein......) were identified. To elucidate the molecular basis and impact of these changes, we quantified the level of genetic, phenotypic, and molecular parallelism linked to DNA supercoiling in all 12 evolving populations. First, sequence determination of DNA topology-related loci revealed strong genetic...

  1. [Modern evolutional developmental biology: mechanical and molecular genetic or phenotypic approaches?].

    Science.gov (United States)

    Vorob'eva, É I

    2010-01-01

    Heightened interest in the evolutionary problems of developmental biology in the 1980s was due to the success of molecular genetics and disappointment in the synthetic theory of evolution, where the chapters of embryology and developmental biology seem to have been left out. Modern evo-devo, which turned out to be antipodean to the methodology of the synthetic theory of evolution, propagandized in the development of evolutionary problems only the mechanical and molecular genetic approach to the evolution of ontogenesis, based on cellular and intercellular interactions. The phonotypical approach to the evaluation of evolutionary occurrences in ontogenesis, which aids in the joining of the genetic and epigenetic levels of research, the theory of natural selection, the nomogenetic conception, and the problem of the wholeness of the organism in onto- and phylogenesis may be against this. The phenotypic approach to ontogenesis is methodologically the most perspective for evolutionary developmental biology.

  2. Genetic and environmental dissections of sub-phenotypes of metabolic syndrome in the chinese population: a twin-based heritability study

    DEFF Research Database (Denmark)

    Duan, Haiping; Pang, Zengchang; Zhang, Dongfeng

    2011-01-01

    Objective: We perform a comprehensive heritability study on multiple phenotypes related to metabolic syndrome using Chinese twins to assess the genetic and environmental effects in determining the variation and covariation of the phenotypes in the Chinese population. Methods: The studied sample...... of the phenotypes. Conclusions: Our results showed significant genetic contributions to the sub-phenotypes of metabolic syndrome. Although pleiotropic genetic control may exist for some physiologically similar phenotypes, our results do not support a common genetic mechanism among the phenotypes covered in our...

  3. Personality as an intermediate phenotype for genetic dissection of alcohol use disorder.

    Science.gov (United States)

    Oreland, Lars; Lagravinese, Gianvito; Toffoletto, Simone; Nilsson, Kent W; Harro, Jaanus; Robert Cloninger, C; Comasco, Erika

    2017-01-04

    Genetic and environmental interactive influences on predisposition to develop alcohol use disorder (AUD) account for the high heterogeneity among AUD patients and make research on the risk and resiliency factors complicated. Several attempts have been made to identify the genetic basis of AUD; however, only few genetic polymorphisms have consistently been associated with AUD. Intermediate phenotypes are expected to be in-between proxies of basic neuronal biological processes and nosological symptoms of AUD. Personality is likely to be a top candidate intermediate phenotype for the dissection of the genetic underpinnings of different subtypes of AUD. To date, 38 studies have investigated personality traits, commonly assessed by the Cloninger's Tridimensional Personality Questionnaire (TPQ) or Temperament and Character Inventory (TCI), in relation to polymorphisms of candidate genes of neurotransmitter systems in alcohol-dependent patients. Particular attention has been given to the functional polymorphism of the serotonin transporter gene (5-HTTLPR), however, leading to contradictory results, whereas results with polymorphisms in other candidate monoaminergic genes (e.g., tryptophan hydroxylase, serotonin receptors, monoamine oxidases, dopamine receptors and transporter) are sparse. Only one genome-wide association study has been performed so far and identified the ABLIM1 gene of relevance for novelty seeking, harm avoidance and reward dependence in alcohol-dependent patients. Studies investigating genetic factors together with personality could help to define more homogenous subgroups of AUD patients and facilitate treatment strategies. This review also urges the scientific community to combine genetic data with psychobiological and environmental data to further dissect the link between personality and AUD.

  4. Inference of Tumor Evolution during Chemotherapy by Computational Modeling and In Situ Analysis of Genetic and Phenotypic Cellular Diversity

    Directory of Open Access Journals (Sweden)

    Vanessa Almendro

    2014-02-01

    Full Text Available Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and posttreatment samples. We also observed significant changes in the spatial distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution.

  5. Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity.

    Science.gov (United States)

    Almendro, Vanessa; Cheng, Yu-Kang; Randles, Amanda; Itzkovitz, Shalev; Marusyk, Andriy; Ametller, Elisabet; Gonzalez-Farre, Xavier; Muñoz, Montse; Russnes, Hege G; Helland, Aslaug; Rye, Inga H; Borresen-Dale, Anne-Lise; Maruyama, Reo; van Oudenaarden, Alexander; Dowsett, Mitchell; Jones, Robin L; Reis-Filho, Jorge; Gascon, Pere; Gönen, Mithat; Michor, Franziska; Polyak, Kornelia

    2014-02-13

    Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and posttreatment samples. We also observed significant changes in the spatial distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution.

  6. Working-memory endophenotype and dyslexia-associated genetic variant predict dyslexia phenotype.

    Science.gov (United States)

    Männel, Claudia; Meyer, Lars; Wilcke, Arndt; Boltze, Johannes; Kirsten, Holger; Friederici, Angela D

    2015-10-01

    Developmental dyslexia, a severe impairment of literacy acquisition, is known to have a neurological basis and a strong genetic background. However, effects of individual genetic variations on dyslexia-associated deficits are only moderate and call for the assessment of the genotype's impact on mediating neuro-endophenotypes by the imaging genetics approach. Using voxel-based morphometry (VBM) in German participants with and without dyslexia, we investigated gray matter changes and their association with impaired phonological processing, such as reduced verbal working memory. These endophenotypical alterations were, together with dyslexia-associated genetic variations, examined on their suitability as potential predictors of dyslexia. We identified two gray matter clusters in the left posterior temporal cortex related to verbal working memory capacity. Regional cluster differences correlated with genetic risk variants in TNFRSF1B. High-genetic-risk participants exhibit a structural predominance of auditory-association areas relative to auditory-sensory areas, which may partly compensate for deficient early auditory-sensory processing stages of verbal working memory. The reverse regional predominance observed in low-genetic-risk participants may in turn reflect reliance on these early auditory-sensory processing stages. Logistic regression analysis further supported that regional gray matter differences and genetic risk interact in the prediction of individuals' diagnostic status: With increasing genetic risk, the working-memory related structural predominance of auditory-association areas relative to auditory-sensory areas classifies participants with dyslexia versus control participants. Focusing on phonological deficits in dyslexia, our findings suggest endophenotypical changes in the left posterior temporal cortex could comprise novel pathomechanisms for verbal working memory-related processes translating TNFRSF1B genotype into the dyslexia phenotype.

  7. Genetic architecture for human aggression: A study of gene-phenotype relationship in OMIM.

    Science.gov (United States)

    Zhang-James, Yanli; Faraone, Stephen V

    2016-07-01

    Genetic studies of human aggression have mainly focused on known candidate genes and pathways regulating serotonin and dopamine signaling and hormonal functions. These studies have taught us much about the genetics of human aggression, but no genetic locus has yet achieved genome-significance. We here present a review based on a paradoxical hypothesis that studies of rare, functional genetic variations can lead to a better understanding of the molecular mechanisms underlying complex multifactorial disorders such as aggression. We examined all aggression phenotypes catalogued in Online Mendelian Inheritance in Man (OMIM), an Online Catalog of Human Genes and Genetic Disorders. We identified 95 human disorders that have documented aggressive symptoms in at least one individual with a well-defined genetic variant. Altogether, we retrieved 86 causal genes. Although most of these genes had not been implicated in human aggression by previous studies, the most significantly enriched canonical pathways had been previously implicated in aggression (e.g., serotonin and dopamine signaling). Our findings provide strong evidence to support the causal role of these pathways in the pathogenesis of aggression. In addition, the novel genes and pathways we identified suggest additional mechanisms underlying the origins of human aggression. Genome-wide association studies with very large samples will be needed to determine if common variants in these genes are risk factors for aggression. © 2015 Wiley Periodicals, Inc.

  8. Genome-wide genetic interaction analysis of glaucoma using expert knowledge derived from human phenotype networks.

    Science.gov (United States)

    Hu, Ting; Darabos, Christian; Cricco, Maria E; Kong, Emily; Moore, Jason H

    2015-01-01

    The large volume of GWAS data poses great computational challenges for analyzing genetic interactions associated with common human diseases. We propose a computational framework for characterizing epistatic interactions among large sets of genetic attributes in GWAS data. We build the human phenotype network (HPN) and focus around a disease of interest. In this study, we use the GLAUGEN glaucoma GWAS dataset and apply the HPN as a biological knowledge-based filter to prioritize genetic variants. Then, we use the statistical epistasis network (SEN) to identify a significant connected network of pairwise epistatic interactions among the prioritized SNPs. These clearly highlight the complex genetic basis of glaucoma. Furthermore, we identify key SNPs by quantifying structural network characteristics. Through functional annotation of these key SNPs using Biofilter, a software accessing multiple publicly available human genetic data sources, we find supporting biomedical evidences linking glaucoma to an array of genetic diseases, proving our concept. We conclude by suggesting hypotheses for a better understanding of the disease.

  9. Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis

    Science.gov (United States)

    Simeone, Ines; Anjum, Samreen; Mokrab, Younes; Bertucci, François; Finetti, Pascal; Curigliano, Giuseppe; Cerulo, Luigi; Tomei, Sara; Delogu, Lucia Gemma; Maccalli, Cristina; Miller, Lance D.; Ceccarelli, Michele

    2017-01-01

    ABSTRACT Cancer immunotherapy is revolutionizing the clinical management of several tumors, but has demonstrated limited activity in breast cancer. The development of more effective treatments is hindered by incomplete knowledge of the genetic determinant of immune responsiveness. To fill this gap, we mined copy number alteration, somatic mutation, and expression data from The Cancer Genome Atlas (TCGA). By using RNA-sequencing data from 1,004 breast cancers, we defined distinct immune phenotypes characterized by progressive expression of transcripts previously associated with immune-mediated rejection. The T helper 1 (Th-1) phenotype (ICR4), which also displays upregulation of immune-regulatory transcripts such as PDL1, PD1, FOXP3, IDO1, and CTLA4, was associated with prolonged patients' survival. We validated these findings in an independent meta-cohort of 1,954 breast cancer gene expression data. Chromosome segment 4q21, which includes genes encoding for the Th-1 chemokines CXCL9-11, was significantly amplified only in the immune favorable phenotype (ICR4). The mutation and neoantigen load progressively decreased from ICR4 to ICR1 but could not fully explain immune phenotypic differences. Mutations of TP53 were enriched in the immune favorable phenotype (ICR4). Conversely, the presence of MAP3K1 and MAP2K4 mutations were tightly associated with an immune-unfavorable phenotype (ICR1). Using both the TCGA and the validation dataset, the degree of MAPK deregulation segregates breast tumors according to their immune disposition. These findings suggest that mutation-driven perturbations of MAPK pathways are linked to the negative regulation of intratumoral immune response in breast cancer. Modulations of MAPK pathways could be experimentally tested to enhance breast cancer immune sensitivity. PMID:28344865

  10. Grocery Store Genetics: A PCR-Based Genetics Lab that Links Genotype to Phenotype

    Science.gov (United States)

    Briju, Betsy J.; Wyatt, Sarah E.

    2015-01-01

    Instructors often present Mendelian genetics and molecular biology separately. As a result, students often fail to connect the two topics in a tangible manner. We have adopted a simple experiment to help link these two important topics in a basic biology course, using red and white onions bought from a local grocery store. A lack of red coloration…

  11. Grocery Store Genetics: A PCR-Based Genetics Lab that Links Genotype to Phenotype

    Science.gov (United States)

    Briju, Betsy J.; Wyatt, Sarah E.

    2015-01-01

    Instructors often present Mendelian genetics and molecular biology separately. As a result, students often fail to connect the two topics in a tangible manner. We have adopted a simple experiment to help link these two important topics in a basic biology course, using red and white onions bought from a local grocery store. A lack of red coloration…

  12. Genetic epidemiology, prevalence, and genotype–phenotype correlations in the Swedish population with osteogenesis imperfecta

    Science.gov (United States)

    Lindahl, Katarina; Åström, Eva; Rubin, Carl-Johan; Grigelioniene, Giedre; Malmgren, Barbro; Ljunggren, Östen; Kindmark, Andreas

    2015-01-01

    Osteogenesis imperfecta (OI) is a rare hereditary bone fragility disorder, caused by collagen I mutations in 90% of cases. There are no comprehensive genotype–phenotype studies on >100 families outside North America, and no population-based studies determining the genetic epidemiology of OI. Here, detailed clinical phenotypes were recorded, and the COL1A1 and COL1A2 genes were analyzed in 164 Swedish OI families (223 individuals). Averages for bone mineral density (BMD), height and yearly fracture rate were calculated and related to OI and mutation type. N-terminal helical mutations in both the α1- and α2-chains were associated with the absence of dentinogenesis imperfecta (P95% of the complete Swedish pediatric OI population. The prevalence of OI types I, III, and IV was 5.16, 0.89, and 1.35/100 000, respectively (7.40/100 000 overall), corresponding to what has been estimated but not unequivocally proven in any population. Collagen I mutation analysis was performed in the family of 97% of known cases, with causative mutations found in 87%. Qualitative mutations caused 32% of OI type I. The data reported here may be helpful to predict phenotype, and describes for the first time the genetic epidemiology in >95% of an entire OI population. PMID:25944380

  13. Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta.

    Science.gov (United States)

    Lindahl, Katarina; Åström, Eva; Rubin, Carl-Johan; Grigelioniene, Giedre; Malmgren, Barbro; Ljunggren, Östen; Kindmark, Andreas

    2015-08-01

    Osteogenesis imperfecta (OI) is a rare hereditary bone fragility disorder, caused by collagen I mutations in 90% of cases. There are no comprehensive genotype-phenotype studies on >100 families outside North America, and no population-based studies determining the genetic epidemiology of OI. Here, detailed clinical phenotypes were recorded, and the COL1A1 and COL1A2 genes were analyzed in 164 Swedish OI families (223 individuals). Averages for bone mineral density (BMD), height and yearly fracture rate were calculated and related to OI and mutation type. N-terminal helical mutations in both the α1- and α2-chains were associated with the absence of dentinogenesis imperfecta (P95% of the complete Swedish pediatric OI population. The prevalence of OI types I, III, and IV was 5.16, 0.89, and 1.35/100 000, respectively (7.40/100 000 overall), corresponding to what has been estimated but not unequivocally proven in any population. Collagen I mutation analysis was performed in the family of 97% of known cases, with causative mutations found in 87%. Qualitative mutations caused 32% of OI type I. The data reported here may be helpful to predict phenotype, and describes for the first time the genetic epidemiology in >95% of an entire OI population.

  14. Genetic and phenotypic trends of fertility traits for Holstein dairy population in warm and temperate climate

    Directory of Open Access Journals (Sweden)

    Rabie Rahbar

    2016-04-01

    Full Text Available The main objective of this study was to investigate genetic and phenotypic trends for fertility traits in Holstein dairy population under warm and temperate climate. Fertility traits were: success in first service, gestation length, number of inseminations, insemination outcome, calving interval, calving birth weight and days open. The edited data set included up to 23,402 records from 9,486 cows. The mean and standard deviation for fertility traits were 0.32 ± 0.003, 278.2 ± 5.58, 2.73 ± 1.94,0.31 ± 0.001, 415.99 ± 79.62, 40.4 ± 6.08 and 140.36 ± 76.16 for success in first service, gestation length, number of inseminations, insemination outcome, calving interval, calving birth weight and days open, respectively. In general, there were decreasing genetic trends for all traits over the years. On the other hand, there were decreasing phenotypic trend for days open, calving interval, gestation length, number of inseminations and calving birth weight, but estimates of phenotypic trends were positive for success in first service and insemination outcome over the years. It was concluded decreased trend for days open, calving interval, gestation length, number of inseminations and calving birth weight and increased trend for success in first service and insemination outcome traits over time indicated that Holstein dairy producers in warm and temperate climate were successful in managing and improving in nutrition during 1999 to 2013.

  15. The genetic diversity and phenotypic characterisation of Streptococcus agalactiae isolates from Rio de Janeiro, Brazil

    Directory of Open Access Journals (Sweden)

    Ana Beatriz de Almeida Corrêa

    2011-12-01

    Full Text Available Streptococcus agalactiae isolates are more common among pregnant women, neonates and nonpregnant adults with underlying diseases compared to other demographic groups. In this study, we evaluate the genetic and phenotypic diversity in S. agalactiae strains from Rio de Janeiro (RJ that were isolated from asymptomatic carriers. We analysed these S. agalactiae strains using pulsed-field gel electrophoresis (PFGE, serotyping and antimicrobial susceptibility testing, as well as by determining the macrolide resistance phenotype, and detecting the presence of the ermA/B, mefA/E and lnuB genes. The serotypes Ia, II, III and V were the most prevalent serotypes observed. The 60 strains analysed were susceptible to penicillin, vancomycin and levofloxacin. Resistance to clindamycin, chloramphenicol, erythromycin, rifampin and tetracycline was observed. Among the erythromycin and/or clindamycin resistant strains, the ermA, ermB and mefA/E genes were detected and the constitutive macrolides, lincosamides and streptogramin B-type resistance was the most prevalent phenotype observed. The lnuB gene was not detected in any of the strains studied. We found 56 PFGE electrophoretic profiles and only 22 of them were allocated in polymorphism patterns. This work presents data on the genetic diversity and prevalent capsular serotypes among RJ isolates. Approximately 85% of these strains came from pregnant women; therefore, these data may be helpful in developing future prophylaxis and treatment strategies for neonatal syndromes in RJ.

  16. [Molecular genetic basis for para-Bombay phenotypes in two cases].

    Science.gov (United States)

    He, Yang-Ming; Xu, Xian-Guo; Zhu, Fa-Ming; Yan, Li-Xing

    2007-06-01

    This study was purposed to investigate the molecular genetics basis for para-Bombay phenotype. The para-Bombay phenotype of two probands was identified by routine serological techniques. The full coding region of alpha (1, 2) fucosyltransferase gene (FUT1 and FUT2) in the probands was amplified by polymerase chain reaction and the amplified fragments were directly sequenced, meanwhile the mutations of FUT1 were also identified by TOPO TA cloning sequence method. The results indicated that two heterozygous mutations were detected by directly sequencing in two probands: AG deletion at position 547 - 552 and C to T mutation at position 658. Two different mutations were confirmed to be true compound heterozygotes with each mutation on a separate homologous chromosome by TOPO TA cloning sequence method. AG deletion at position 547 - 552 caused a reading frame shift and a premature stop codon. C658T mutation resulted in Arg-->Cys at amino acid position 220. It is suggested that the FUT1 mutation of two probands are compound heterozygous mutation with different chromosomes, which are named h1h3 and may be the genetics basis of para-Bombay phenotype.

  17. Does Degree of Gyrification Underlie the Phenotypic and Genetic Associations between Cortical Surface Area and Cognitive Ability?

    Science.gov (United States)

    Docherty, Anna R.; Hagler, Donald J.; Panizzon, Matthew S.; Neale, Michael C.; Eyler, Lisa T.; Fennema-Notestine, Christine; Franz, Carol E.; Jak, Amy; Lyons, Michael J.; Rinker, Daniel A.; Thompson, Wesley K.; Tsuang, Ming T.; Dale, Anders M.; Kremen, William S.

    2015-01-01

    The phenotypic and genetic relationship between global cortical size and general cognitive ability (GCA) appears to be driven by surface area (SA) and not cortical thickness (CT). Gyrification (cortical folding) is an important property of the cortex that helps to increase SA within a finite space, and may also improve connectivity by reducing distance between regions. Hence, gyrification may be what underlies the SA-GCA relationship. In previous phenotypic studies, a 3-dimensional gyrification index (3DGI) has been positively associated with cognitive ability and negatively associated with mild cognitive impairment, Alzheimer’s disease, and psychiatric disorders affecting cognition. However, the differential genetic associations of 3DGI and SA with GCA are still unclear. We examined the heritability of 3DGI, and the phenotypic, genetic, and environmental associations of 3DGI with SA and GCA in a large sample of adult male twins (N = 512). Nearly 85% of the variance in 3DGI was due to genes, and 3DGI had a strong phenotypic and genetic association with SA. Both 3DGI and total SA had positive phenotypic correlations with GCA. However, the SA-GCA correlation remained significant after controlling for 3DGI, but not the other way around. There was also significant genetic covariance between SA and GCA, but not between 3DGI and GCA. Thus, despite the phenotypic and genetic associations between 3DGI and SA, our results do not support the hypothesis that gyrification underlies the association between SA and GCA. PMID:25433211

  18. Regulating genetic privacy in the online health information era.

    Science.gov (United States)

    Magnusson, Roger S

    2002-01-01

    As the clinical implications of the genetic components of disease come to be better understood, there is likely to be a significant increase in the volume of genetic information held within clinical records. As patient health care records, in turn, come on-line as part of broader health information networks, there is likely to be considerable pressure in favour of special laws protecting genetic privacy. This paper reviews some of the privacy challenges posed by electronic health records, some government initiatives in this area, and notes the impact that developments in genetic testing will have upon the 'genetic content' of e-health records. Despite the sensitivity of genetic information, the paper argues against a policy of 'genetic exceptionalism', and its implications for genetic privacy laws.

  19. Genetics of kidney disease and related cardiometabolic phenotypes in Zuni Indians: The Zuni Kidney Project

    Directory of Open Access Journals (Sweden)

    Sandra L Laston

    2015-01-01

    Full Text Available The objective of this study is to identify genetic factors associated with chronic kidney disease (CKD and related cardiometabolic phenotypes among participants of the Genetics of Kidney Disease in Zuni Indians study. The study was conducted as a community-based participatory research project in the Zuni Indians, a small endogamous tribe in rural New Mexico. We recruited 998 members from 28 extended multigenerational families, ascertained through probands with CKD who had at least one sibling with CKD. We used the Illumina Infinium Human1M-Duo v3.0 BeadChips to type 1.1 million single nucleotide polymorphisms (SNPs. Prevalence estimates for CKD, hyperuricemia, diabetes and hypertension were 24%, 30%, 17% and 34%, respectively. We found a significant (p<1.58 × 10-7 association for a SNP in a novel gene for serum creatinine (PTPLAD2. We replicated significant associations for genes with serum uric acid (SLC2A9, triglyceride levels (APOA1, BUD13, ZNF259, and total cholesterol (PVRL2. We found novel suggestive associations (p<1.58 × 10-6 for SNPs in genes with systolic (OLFML2B, and diastolic blood pressure (NFIA. We identified a series of genes associated with CKD and related cardiometabolic phenotypes among Zuni Indians, a population with a high prevalence of kidney disease. Illuminating genetic variations that modulate the risk for these disorders may ultimately provide a basis for novel preventive strategies and therapeutic interventions.

  20. Quantitative Assessment of Eye Phenotypes for Functional Genetic Studies Using Drosophila melanogaster

    Science.gov (United States)

    Iyer, Janani; Wang, Qingyu; Le, Thanh; Pizzo, Lucilla; Grönke, Sebastian; Ambegaokar, Surendra S.; Imai, Yuzuru; Srivastava, Ashutosh; Troisí, Beatriz Llamusí; Mardon, Graeme; Artero, Ruben; Jackson, George R.; Isaacs, Adrian M.; Partridge, Linda; Lu, Bingwei; Kumar, Justin P.; Girirajan, Santhosh

    2016-01-01

    About two-thirds of the vital genes in the Drosophila genome are involved in eye development, making the fly eye an excellent genetic system to study cellular function and development, neurodevelopment/degeneration, and complex diseases such as cancer and diabetes. We developed a novel computational method, implemented as Flynotyper software (http://flynotyper.sourceforge.net), to quantitatively assess the morphological defects in the Drosophila eye resulting from genetic alterations affecting basic cellular and developmental processes. Flynotyper utilizes a series of image processing operations to automatically detect the fly eye and the individual ommatidium, and calculates a phenotypic score as a measure of the disorderliness of ommatidial arrangement in the fly eye. As a proof of principle, we tested our method by analyzing the defects due to eye-specific knockdown of Drosophila orthologs of 12 neurodevelopmental genes to accurately document differential sensitivities of these genes to dosage alteration. We also evaluated eye images from six independent studies assessing the effect of overexpression of repeats, candidates from peptide library screens, and modifiers of neurotoxicity and developmental processes on eye morphology, and show strong concordance with the original assessment. We further demonstrate the utility of this method by analyzing 16 modifiers of sine oculis obtained from two genome-wide deficiency screens of Drosophila and accurately quantifying the effect of its enhancers and suppressors during eye development. Our method will complement existing assays for eye phenotypes, and increase the accuracy of studies that use fly eyes for functional evaluation of genes and genetic interactions. PMID:26994292

  1. Approaches for the identification of genetic modifiers of nutrient dependent phenotypes: Examples from folate

    Directory of Open Access Journals (Sweden)

    Amanda J. Macfarlane

    2014-07-01

    Full Text Available By combining the sciences of nutrition, bioinformatics, genomics, population genetics and epidemiology, nutrigenomics is improving our understanding of how diet and nutrient intake can interact with or modify gene expression and disease risk. In this review, we explore various approaches to examine gene-nutrient interactions and the modifying role of nutrient consumption, as they relate to nutrient status and disease risk in human populations. Two common approaches include the use of SNPs in candidate genes to identify their association with nutritional status or disease outcomes, or genome wide association studies to identify genetic polymorphisms associated with a given phenotype. Here, we examine the results of various gene-nutrient interaction studies, the association of genetic polymorphisms with disease expression and the identification of nutritional factors that modify gene-dependent disease phenotypes. We have focussed on specific examples from investigations of the interactions of folate and B-vitamin consumption and polymorphisms in the genes of B vitamin dependent enzymes and their association with disease risk, followed by an examination of the strengths and limitations of the methods employed. We also present suggestions for future studies, including an approach from an on-going large scale study, to examine the interaction of nutrient intake and genotypic variation and their impact on nutritional status.

  2. Large animal models of rare genetic disorders: sheep as phenotypically relevant models of human genetic disease.

    Science.gov (United States)

    Pinnapureddy, Ashish R; Stayner, Cherie; McEwan, John; Baddeley, Olivia; Forman, John; Eccles, Michael R

    2015-09-02

    Animals that accurately model human disease are invaluable in medical research, allowing a critical understanding of disease mechanisms, and the opportunity to evaluate the effect of therapeutic compounds in pre-clinical studies. Many types of animal models are used world-wide, with the most common being small laboratory animals, such as mice. However, rodents often do not faithfully replicate human disease, despite their predominant use in research. This discordancy is due in part to physiological differences, such as body size and longevity. In contrast, large animal models, including sheep, provide an alternative to mice for biomedical research due to their greater physiological parallels with humans. Completion of the full genome sequences of many species, and the advent of Next Generation Sequencing (NGS) technologies, means it is now feasible to screen large populations of domesticated animals for genetic variants that resemble human genetic diseases, and generate models that more accurately model rare human pathologies. In this review, we discuss the notion of using sheep as large animal models, and their advantages in modelling human genetic disease. We exemplify several existing naturally occurring ovine variants in genes that are orthologous to human disease genes, such as the Cln6 sheep model for Batten disease. These, and other sheep models, have contributed significantly to our understanding of the relevant human disease process, in addition to providing opportunities to trial new therapies in animals with similar body and organ size to humans. Therefore sheep are a significant species with respect to the modelling of rare genetic human disease, which we summarize in this review.

  3. Rapid phenotyping of knockout mice to identify genetic determinants of bone strength

    Science.gov (United States)

    Freudenthal, Bernard; Logan, John; Croucher, Peter I

    2016-01-01

    The genetic determinants of osteoporosis remain poorly understood, and there is a large unmet need for new treatments in our ageing society. Thus, new approaches for gene discovery in skeletal disease are required to complement the current genome-wide association studies in human populations. The International Knockout Mouse Consortium (IKMC) and the International Mouse Phenotyping Consortium (IMPC) provide such an opportunity. The IKMC generates knockout mice representing each of the known protein-coding genes in C57BL/6 mice and, as part of the IMPC initiative, the Origins of Bone and Cartilage Disease project identifies mutants with significant outlier skeletal phenotypes. This initiative will add value to data from large human cohorts and provide a new understanding of bone and cartilage pathophysiology, ultimately leading to the identification of novel drug targets for the treatment of skeletal disease. PMID:27535945

  4. The molecular genetics and neurobiology of developmental dyslexia as model of a complex phenotype.

    Science.gov (United States)

    Kere, Juha

    2014-09-19

    Among complex disorders, those concerning neuropsychiatric phenotypes involve particular challenges compared to disorders with more easily distinguished clinical signs and measures. One such common and unusually challenging phenotype to disentangle genetically is developmental dyslexia (DD), or reading disability, defined as the inability to learn to read and write for an otherwise normally intelligent child with normal senses and educational opportunity. There is presently ample evidence for the strongly biological etiology for DD, and a dozen susceptibility genes have been suggested. Many of these genes point to common but previously unsuspected biological mechanisms, such as neuronal migration and cilia functions. I discuss here the state-of-the-art in genomic and neurobiological aspects of DD research, starting with short general background to its history.

  5. Genetic ablation of NMDA receptor subunit NR3B in mouse reveals motoneuronal and nonmotoneuronal phenotypes.

    Science.gov (United States)

    Niemann, Stephan; Kanki, Hiroaki; Fukui, Yasuyuki; Takao, Keizo; Fukaya, Masahiro; Hynynen, Meri N; Churchill, Michael J; Shefner, Jeremy M; Bronson, Roderick T; Brown, Robert H; Watanabe, Masahiko; Miyakawa, Tsuyoshi; Itohara, Shigeyoshi; Hayashi, Yasunori

    2007-09-01

    NR3B is a modulatory subunit of the NMDA receptor, abundantly expressed in both cranial and spinal somatic motoneurons and at lower levels in other regions of the brain as well. Recently, we found the human NR3B gene (GRIN3B) to be highly genetically heterogeneous, and that approximately 10% of the normal European-American population lacks NR3B due to homozygous occurrence of a null allele in the gene. Therefore, it is especially important to understand the phenotypic consequences of the genetic loss of NR3B in both humans and animal models. We here provide results of behavioral analysis of mice genetically lacking NR3B, which is an ideal animal model due to homogeneity in genetic and environmental background. The NR3B(-/-) mice are viable and fertile. Consistent with the expression of NR3B in somatic motoneurons, the NR3B(-/-) mice showed a moderate but significant impairment in motor learning or coordination, and decreased activity in their home cages. Remarkably, the NR3B(-/-) mice showed a highly increased social interaction with their familiar cage mates in their home cage but moderately increased anxiety-like behaviour and decreased social interaction in a novel environment, consistent with the inhibitory role of NR3B on the functions of NMDA receptors. This work is the first reporting of the functional significance of NR3B in vivo and may give insight into the contribution of genetic variability of NR3B in the phenotypic heterogeneity among human population.

  6. Identifying Genetic Sources of Phenotypic Heterogeneity in Orofacial Clefts by Targeted Sequencing.

    Science.gov (United States)

    Carlson, Jenna C; Taub, Margaret A; Feingold, Eleanor; Beaty, Terri H; Murray, Jeffrey C; Marazita, Mary L; Leslie, Elizabeth J

    2017-07-17

    Orofacial clefts (OFCs), including nonsyndromic cleft lip with or without cleft palate (NSCL/P), are common birth defects. NSCL/P is highly heterogeneous with multiple phenotypic presentations. Two common subtypes of NSCL/P are cleft lip (CL) and cleft lip with cleft palate (CLP) which have different population prevalence. Similarly, NSCL/P can be divided into bilateral and unilateral clefts, with unilateral being the most common. Individuals with unilateral NSCL/P are more likely to be affected on the left side of the upper lip, but right side affection also occurs. Moreover, NSCL/P is twice as common in males as in females. The goal of this study is to discover genetic variants that have different effects in case subgroups. We conducted both common variant and rare variant analyses in 1034 individuals of Asian ancestry with NSCL/P, examining four sources of heterogeneity within CL/P: cleft type, sex, laterality, and side. We identified several regions associated with subtype differentiation: cleft type differences in 8q24 (p = 1.00 × 10(-4) ), laterality differences in IRF6, a gene previously implicated with wound healing (p = 2.166 × 10(-4) ), sex differences and side of unilateral CL differences in FGFR2 (p = 3.00 × 10(-4) ; p = 6.00 × 10(-4) ), and sex differences in VAX1 (p < 1.00 × 10(-4) ) among others. Many of the regions associated with phenotypic modification were either adjacent to or overlapping functional elements based on ENCODE chromatin marks and published craniofacial enhancers. We have identified multiple common and rare variants as potential phenotypic modifiers of NSCL/P, and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs. Birth Defects Research 109:1030-1038, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  7. Multivariate genetic analysis of atopy phenotypes in a selected sample of twins

    DEFF Research Database (Denmark)

    Thomsen, SF; Ulrik, Charlotte Suppli; Kyvik, KO

    2006-01-01

    BACKGROUND: Atopic traits often co-occur and this can potentially be caused by common aetiological relationships between traits, i.e. a common genetic or a common environmental background. OBJECTIVE: To estimate to what extent the same genetic and environmental factors influence wheeze, rhinitis...... traits were estimated and latent factor models of genetic and environmental effects were fitted to the observed data using maximum likelihood methods. RESULTS: The various phenotypic correlations between wheeze, rhinitis, AHR and posSPT were all significant and ranged between 0.50 and 0.86. Traits...... that showed highest genetic correlations were wheeze-rhinitis (rho(A)=0.95), wheeze-AHR (rho(A)=0.85) and rhinitis-posSPT (rho(A)=0.92), whereas lower genetic correlations were observed for rhinitis-AHR (rho(A)=0.43) and AHR-posSPT (rho(A)=0.59). Traits with a high degree of environmental sharing were...

  8. Phenotypic and genetic characterization of a novel phenotype in pigs characterized by juvenile hairlessness and age dependent emphysema

    DEFF Research Database (Denmark)

    Bruun, Camilla S.; Jørgensen, Claus B.; Bay, Lene

    2008-01-01

    ß6-/- knockout phenotype seen in mice, the two genes encoding the two subunits of integrin avß6, i.e. ITGB6 and ITGAV, were considered candidate genes for this trait. Results: The mutated pig phenotype is characterized by hairlessness until puberty, thin skin with few hair follicles and absence...... resembling the integrin ß6-/- knockout phenotype seen in mice has been characterized in the pig. The candidate region on SSC15 has been confirmed by linkage analysis but molecular and functional analyses have excluded that the mutated phenotype is caused by structural mutations in or ablation of any...

  9. Demographic, phenotypic, and genetic characteristics of centenarians in Okinawa and Japan: Part 1-centenarians in Okinawa.

    Science.gov (United States)

    Willcox, Bradley J; Willcox, Donald Craig; Suzuki, Makoto

    2017-07-01

    A study of elderly Okinawans has been carried out by the Okinawa Centenarian Study (OCS) research group for over four decades. The OCS began in 1975 as a population-based study of centenarians (99-year-olds and older) and other selected elderly persons residing in the main island of the Japanese prefecture of Okinawa. As of 2015, over 1000 centenarians have been examined. By several measures of health and longevity the Okinawans can claim to be the world's healthiest and longest-lived people. In this paper we explore the demographic, phenotypic, and genetic characteristics of this fascinating population. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. [Phenotypic variability in a family with genetically verified familial hemiplegic migraine type 2].

    Science.gov (United States)

    Hogaard, Nina; Klit, Henriette; Vogel, Ida; Thelle, Thomas

    2015-01-26

    After playing handball, a 13-year-old girl developed a comatose condition during 7-10 days with hemiparesis and aphasia. From age three to nine she was treated for partial epilepsy. She never had symptoms of migraine. Her father had childhood epilepsy and at the age of 40 and 44 he experienced two attacks with prolonged coma, fever, seizures, hemiparesis and aphasia. His mother had symptoms of severe hemiplegic migraine. Father and daughter were genetically tested and an earlier described mutation in ATP1A2 gene was found. These cases illustrate the phenotypic variability in familial hemiplegic migraine type 2.

  11. Predicting brain structure in population-based samples with biologically informed genetic scores for schizophrenia.

    Science.gov (United States)

    Van der Auwera, Sandra; Wittfeld, Katharina; Shumskaya, Elena; Bralten, Janita; Zwiers, Marcel P; Onnink, A Marten H; Usberti, Niccolo; Hertel, Johannes; Völzke, Henry; Völker, Uwe; Hosten, Norbert; Franke, Barbara; Grabe, Hans J

    2017-04-01

    Schizophrenia is associated with brain structural abnormalities including gray and white matter volume reductions. Whether these alterations are caused by genetic risk variants for schizophrenia is unclear. Previous attempts to detect associations between polygenic factors for schizophrenia and structural brain phenotypes in healthy subjects have been negative or remain non-replicated. In this study, we used genetic risk scores that were based on the accumulated effect of selected risk variants for schizophrenia belonging to specific biological systems like synaptic function, neurodevelopment, calcium signaling, and glutamatergic neurotransmission. We hypothesized that this "biologically informed" approach would provide the missing link between genetic risk for schizophrenia and brain structural phenotypes. We applied whole-brain voxel-based morphometry (VBM) analyses in two population-based target samples and subsequent regions of interest (ROIs) analyses in an independent replication sample (total N = 2725). No consistent association between the genetic scores and brain volumes were observed in the investigated samples. These results suggest that in healthy subjects with a higher genetic risk for schizophrenia additional factors apart from common genetic variants (e.g., infection, trauma, rare genetic variants, or gene-gene interactions) are required to induce structural abnormalities of the brain. Further studies are recommended to test for possible gene-gene or gene-environment effects. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  12. Quantitative Seq-LGS: Genome-Wide Identification of Genetic Drivers of Multiple Phenotypes in Malaria Parasites

    KAUST Repository

    Abkallo, Hussein M.

    2016-10-01

    Identifying the genetic determinants of phenotypes that impact on disease severity is of fundamental importance for the design of new interventions against malaria. Traditionally, such discovery has relied on labor-intensive approaches that require significant investments of time and resources. By combining Linkage Group Selection (LGS), quantitative whole genome population sequencing and a novel mathematical modeling approach (qSeq-LGS), we simultaneously identified multiple genes underlying two distinct phenotypes, identifying novel alleles for growth rate and strain specific immunity (SSI), while removing the need for traditionally required steps such as cloning, individual progeny phenotyping and marker generation. The detection of novel variants, verified by experimental phenotyping methods, demonstrates the remarkable potential of this approach for the identification of genes controlling selectable phenotypes in malaria and other apicomplexan parasites for which experimental genetic crosses are amenable.

  13. Blue eyes in lemurs and humans: same phenotype, different genetic mechanism

    DEFF Research Database (Denmark)

    Bradley, Brenda J; Pedersen, Anja; Mundy, Nicholas I

    2009-01-01

    Almost all mammals have brown or darkly-pigmented eyes (irises), but among primates, there are some prominent blue-eyed exceptions. The blue eyes of some humans and lemurs are a striking example of convergent evolution of a rare phenotype on distant branches of the primate tree. Recent work...... on humans indicates that blue eye color is associated with, and likely caused by, a single nucleotide polymorphism (rs12913832) in an intron of the gene HERC2, which likely regulates expression of the neighboring pigmentation gene OCA2. This raises the immediate question of whether blue eyes in lemurs might...... have a similar genetic basis. We addressed this by sequencing the homologous genetic region in the blue-eyed black lemur (Eulemur macaco flavifrons; N = 4) and the closely-related black lemur (Eulemur macaco macaco; N = 4), which has brown eyes. We then compared a 166-bp segment corresponding...

  14. Prevalence and genetic analysis of phenotypically Vi- negative Salmonella typhi isolates in children from Kathmandu, Nepal.

    Science.gov (United States)

    Pulickal, Anoop S; Callaghan, Martin J; Kelly, Dominic F; Maskey, Mitu; Mahat, Sandeep; Hamaluba, Mainga; Dongol, Sabina; Adhikari, Neelam; Thorson, Stephen; Basynat, Buddha; Murdoch, David R; Farrar, Jeremy J; Pollard, Andrew J

    2013-08-01

    The Vi capsular polysaccharide (ViPS) protects Salmonella enterica subspecies enterica serotype Typhi (S.Typhi) in vivo by multiple mechanisms. Recent microbiological reports from typhoid endemic countries suggest that acapsulate S.Typhi may occur in nature and contribute to clinical typhoid fever that is indistinguishable from disease caused by capsulate strains. The prevalence and genetic basis of ViPS-negative S.Typhi isolates in children from Kathmandu, Nepal, were tested in 68 isolates. Although 5.9% of isolates tested negative for capsular expression by slide agglutination tests, a novel multiplex PCR assay and individual PCR analyses demonstrated the presence of all 14 genes responsible for the synthesis, transportation and regulation of the ViPS. These data suggest that phenotypically acapsulate S.Typhi may not have a genetic basis for the same.

  15. Laboratory Evolution to Alternating Substrate Environments Yields Distinct Phenotypic and Genetic Adaptive Strategies

    DEFF Research Database (Denmark)

    Sandberg, Troy E.; Lloyd, Colton J.; Palsson, Bernhard O.

    2017-01-01

    Adaptive laboratory evolution (ALE) experiments are often designed to maintain a static culturing environment to minimize confounding variables that could influence the adaptive process, but dynamic nutrient conditions occur frequently in natural and bioprocessing settings. To study the nature...... of carbon substrate fitness tradeoffs, we evolved batch cultures of Escherichia coli via serial propagation into tubes alternating between glucose and either xylose, glycerol, or acetate. Genome sequencing of evolved cultures revealed several genetic changes preferentially selected for under dynamic...... to the observed distinct adaptive strategies. This study gives insight into the population dynamics of adaptation in an alternating environment and into the underlying metabolic and genetic mechanisms. Furthermore, ALE-generated optimized strains have phenotypes with potential industrial bioprocessing...

  16. Phenotypic and genetic evidence for a unifactorial structure of spatial abilities.

    Science.gov (United States)

    Rimfeld, Kaili; Shakeshaft, Nicholas G; Malanchini, Margherita; Rodic, Maja; Selzam, Saskia; Schofield, Kerry; Dale, Philip S; Kovas, Yulia; Plomin, Robert

    2017-03-07

    Spatial abilities encompass several skills differentiable from general cognitive ability (g). Importantly, spatial abilities have been shown to be significant predictors of many life outcomes, even after controlling for g. To date, no studies have analyzed the genetic architecture of diverse spatial abilities using a multivariate approach. We developed "gamified" measures of diverse putative spatial abilities. The battery of 10 tests was administered online to 1,367 twin pairs (age 19-21) from the UK-representative Twins Early Development Study (TEDS). We show that spatial abilities constitute a single factor, both phenotypically and genetically, even after controlling for g This spatial ability factor is highly heritable (69%). We draw three conclusions: (i) The high heritability of spatial ability makes it a good target for gene-hunting research; (ii) some genes will be specific to spatial ability, independent of g; and (iii) these genes will be associated with all components of spatial ability.

  17. Genetic Causes of Phenotypic Adaptation to the Second Fermentation of Sparkling Wines in Saccharomyces cerevisiae

    Science.gov (United States)

    Martí-Raga, Maria; Peltier, Emilien; Mas, Albert; Beltran, Gemma; Marullo, Philippe

    2016-01-01

    Hybridization is known to improve complex traits due to heterosis and phenotypic robustness. However, these phenomena have been rarely explained at the molecular level. Here, the genetic determinism of Saccharomyces cerevisiae fermentation performance was investigated using a QTL mapping approach on an F1-progeny population. Three main QTL were detected, with positive alleles coming from both parental strains. The heterosis effect found in the hybrid was partially explained by three loci showing pseudooverdominance and dominance effects. The molecular dissection of those QTL revealed that the adaptation to second fermentation is related to pH, lipid, or osmotic regulation. Our results suggest that the stressful conditions of second fermentation have driven the selection of rare genetic variants adapted to maintain yeast cell homeostasis and, in particular, to low pH conditions. PMID:27903630

  18. Genetic Causes of Phenotypic Adaptation to the Second Fermentation of Sparkling Wines in Saccharomyces cerevisiae

    Directory of Open Access Journals (Sweden)

    Maria Martí-Raga

    2017-02-01

    Full Text Available Hybridization is known to improve complex traits due to heterosis and phenotypic robustness. However, these phenomena have been rarely explained at the molecular level. Here, the genetic determinism of Saccharomyces cerevisiae fermentation performance was investigated using a QTL mapping approach on an F1-progeny population. Three main QTL were detected, with positive alleles coming from both parental strains. The heterosis effect found in the hybrid was partially explained by three loci showing pseudooverdominance and dominance effects. The molecular dissection of those QTL revealed that the adaptation to second fermentation is related to pH, lipid, or osmotic regulation. Our results suggest that the stressful conditions of second fermentation have driven the selection of rare genetic variants adapted to maintain yeast cell homeostasis and, in particular, to low pH conditions.

  19. When three traits make a line: evolution of phenotypic plasticity and genetic assimilation through linear reaction norms in stochastic environments.

    Science.gov (United States)

    Ergon, T; Ergon, R

    2017-03-01

    Genetic assimilation emerges from selection on phenotypic plasticity. Yet, commonly used quantitative genetics models of linear reaction norms considering intercept and slope as traits do not mimic the full process of genetic assimilation. We argue that intercept-slope reaction norm models are insufficient representations of genetic effects on linear reaction norms and that considering reaction norm intercept as a trait is unfortunate because the definition of this trait relates to a specific environmental value (zero) and confounds genetic effects on reaction norm elevation with genetic effects on environmental perception. Instead, we suggest a model with three traits representing genetic effects that, respectively, (i) are independent of the environment, (ii) alter the sensitivity of the phenotype to the environment and (iii) determine how the organism perceives the environment. The model predicts that, given sufficient additive genetic variation in environmental perception, the environmental value at which reaction norms tend to cross will respond rapidly to selection after an abrupt environmental change, and eventually becomes equal to the new mean environment. This readjustment of the zone of canalization becomes completed without changes in genetic correlations, genetic drift or imposing any fitness costs of maintaining plasticity. The asymptotic evolutionary outcome of this three-trait linear reaction norm generally entails a lower degree of phenotypic plasticity than the two-trait model, and maximum expected fitness does not occur at the mean trait values in the population.

  20. A new system identification approach to identify genetic variants in sequencing studies for a binary phenotype.

    Science.gov (United States)

    Kang, Guolian; Bi, Wenjian; Zhao, Yanlong; Zhang, Ji-Feng; Yang, Jun J; Xu, Heng; Loh, Mignon L; Hunger, Stephen P; Relling, Mary V; Pounds, Stanley; Cheng, Cheng

    2014-01-01

    We propose in this paper a set-valued (SV) system model, which is a generalized form of logistic (LG) and Probit (Probit) regression, to be considered as a method for discovering genetic variants, especially rare genetic variants in next-generation sequencing studies, for a binary phenotype. We propose a new SV system identification method to estimate all underlying key system parameters for the Probit model and compare it with the LG model in the setting of genetic association studies. Across an extensive series of simulation studies, the Probit method maintained type I error control and had similar or greater power than the LG method, which is robust to different distributions of noise: logistic, normal, or t distributions. Additionally, the Probit association parameter estimate was 2.7-46.8-fold less variable than the LG log-odds ratio association parameter estimate. Less variability in the association parameter estimate translates to greater power and robustness across the spectrum of minor allele frequencies (MAFs), and these advantages are the most pronounced for rare variants. For instance, in a simulation that generated data from an additive logistic model with an odds ratio of 7.4 for a rare single nucleotide polymorphism with a MAF of 0.005 and a sample size of 2,300, the Probit method had 60% power whereas the LG method had 25% power at the α = 10(-6) level. Consistent with these simulation results, the set of variants identified by the LG method was a subset of those identified by the Probit method in two example analyses. Thus, we suggest the Probit method may be a competitive alternative to the LG method in genetic association studies such as candidate gene, genome-wide, or next-generation sequencing studies for a binary phenotype.

  1. A New System Identification Approach to Identifying Genetic Variants in Sequencing Studies for A Binary Phenotype

    Science.gov (United States)

    Kang, Guolian; Bi, Wenjian; Zhao, Yanlong; Zhang, Ji-Feng; Yang, Jun J.; Xu, Heng; Loh, Mignon L.; Hunger, Stephen P.; Relling, Mary V.; Pounds, Stanley; Cheng, Cheng

    2014-01-01

    We propose in this paper a set-valued (SV) system model, which is a generalized form of Logistic (LG) and Probit (Probit) regression, to be considered as a method for discovering genetic variants, especially rare genetic variants in next generation sequencing studies, for a binary phenotype. We propose a new set-valued system identification method to estimate all the underlying key system parameters for the Probit model and compare it with the LG model in the setting of genetic association studies. Across an extensive series of simulation studies, the Probit method maintained Type I error control and had similar or greater power than the LG method which is robust to different distributions of noise: logistic, normal or t distributions. Additionally, the Probit association parameter estimate was 2.7–46.8 fold less variable than the LG log-odds ratio association parameter estimate. Less variability in the association parameter estimate translates to greater power and robustness across the spectrum of minor allele frequencies (MAFs), and these advantages are the most pronounced for rare variants. For instance, in a simulation that generated data from an additive logistic model with odds ratio of 7.4 for a rare single nucleotide polymorphism with a MAF of 0.005 and a sample size of 2300, the Probit method had 60% power whereas the LG method had 25% power at the α=10−6 level. Consistent with these simulation results, the set of variants identified by the LG method was a subset of those identified by the Probit method in two example analyses. Thus, we suggest the Probit method may be a competitive alternative to the LG method in genetic association studies such as candidate gene, genome-wide, or next generation sequencing studies for a binary phenotype. PMID:25096228

  2. Subspecies delineation amid phenotypic, geographic and genetic discordance in a songbird.

    Science.gov (United States)

    Walsh, Jennifer; Lovette, Irby J; Winder, Virginia; Elphick, Chris S; Olsen, Brian J; Shriver, Gregory; Kovach, Adrienne I

    2017-03-01

    Understanding the processes that drive divergence within and among species is a long-standing goal in evolutionary biology. Traditional approaches to assessing differentiation rely on phenotypes to identify intra- and interspecific variation, but many species express subtle morphological gradients in which boundaries among forms are unclear. This intraspecific variation may be driven by differential adaptation to local conditions and may thereby reflect the evolutionary potential within a species. Here, we combine genetic and morphological data to evaluate intraspecific variation within the Nelson's (Ammodramus nelsoni) and salt marsh (Ammodramus caudacutus) sparrow complex, a group with populations that span considerable geographic distributions and a habitat gradient. We evaluated genetic structure among and within five putative subspecies of A. nelsoni and A. caudacutus using a reduced-representation sequencing approach to generate a panel of 1929 SNPs among 69 individuals. Although we detected morphological differences among some groups, individuals sorted along a continuous phenotypic gradient. In contrast, the genetic data identified three distinct clusters corresponding to populations that inhabit coastal salt marsh, interior freshwater marsh and coastal brackish-water marsh habitats. These patterns support the current species-level recognition but do not match the subspecies-level taxonomy within each species-a finding which may have important conservation implications. We identified loci exhibiting patterns of elevated divergence among and within these species, indicating a role for local selective pressures in driving patterns of differentiation across the complex. We conclude that this evidence for adaptive variation among subspecies warrants the consideration of evolutionary potential and genetic novelty when identifying conservation units for this group. © 2017 John Wiley & Sons Ltd.

  3. Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis.

    Science.gov (United States)

    Lo, Sarah M; Choi, Murim; Liu, Jun; Jain, Dhanpat; Boot, Rolf G; Kallemeijn, Wouter W; Aerts, Johannes M F G; Pashankar, Farzana; Kupfer, Gary M; Mane, Shrikant; Lifton, Richard P; Mistry, Pramod K

    2012-05-17

    Gaucher disease (GD), an inherited macrophage glycosphingolipidosis, manifests with an extraordinary variety of phenotypes that show imperfect correlation with mutations in the GBA gene. In addition to the classic manifestations, patients suffer from increased susceptibility to hematologic and nonhematologic malignancies. The mechanism(s) underlying malignancy in GD is not known, but is postulated to be secondary to macrophage dysfunction and immune dysregulation arising from lysosomal accumulation of glucocerebroside. However, there is weak correlation between GD/cancer phenotype and the systemic burden of glucocerebroside-laden macrophages. Therefore, we hypothesized that genetic modifier(s) may underlie the GD/cancer phenotype. In the present study, the genetic basis of GD/T-cell acute lymphoblastic lymphoma in 2 affected siblings was deciphered through genomic analysis. GBA gene sequencing revealed homozygosity for a novel mutation, D137N. Whole-exome capture and massively parallel sequencing combined with homozygosity mapping identified a homozygous novel mutation in the MSH6 gene that leads to constitutional mismatch repair deficiency syndrome and increased cancer risk. Enzyme studies demonstrated that the D137N mutation in GBA is a pathogenic mutation, and immunohistochemistry confirmed the absence of the MSH6 protein. Therefore, precise phenotype annotation followed by individual genome analysis has the potential to identify genetic modifiers of GD, facilitate personalized management, and provide novel insights into disease pathophysiology.

  4. APPLICATION OF THE INFORMATION THEORY AND COGNITIVE TECHNOLOGIES FOR SOLVING PROBLEMS OF GENETICS (on the example of calculation of the amount of information in the genes about characteristics and properties of the various indigenous grape varieties

    Directory of Open Access Journals (Sweden)

    Lutsenko Y. V.

    2016-09-01

    Full Text Available It is well known that genetics studies the mechanisms of variation/heredity and widely uses the concept of "genetic information". While genetics considers the information as the content of the genetic code - structure of DNA and RNA included in the cell of a living organism. Genetics examines the mechanisms of recording, copying, readout of genetic information, the possibility of its modification and its influence on the characteristics and properties of the organism. In conversational and scientific language we know phrases, such as "Genes contain information about the characteristics/properties of the body." Paradoxically, we see no attempts to determine the amount of information contained in specific genes on specific characteristics or phenotypic properties of the organism. It would seem that the application of information theory in genetics is a completely natural and suggests itself. More strange that there are practically no works devoted to the application of information theory for solving problems of genetics. This article is intended, to some extent, to fill this gap on the example of calculating the amount of information in the genes of the characteristics or properties of different grape varieties. It examines the application of automated system-cognitive analysis (ASC-analysis, its mathematical model – system of information theory and software tools – intellectual system called "Eidos" for solving one of the important tasks of genetics: determine the amount of information contained in the genes on various phenotypic characteristics/properties of the grapes. To solve this problem, we perform the following steps: 1 cognitive-targeted structuring of the subject area; 2 the formalization of the subject area, i.e. development of classification and descriptive dials and graduations and training samples; 3 synthesis and verification of information model, reflecting the amount of information in the genes on the phenotypic

  5. [Study on the molecular genetics basis for one para-Bombay phenotype].

    Science.gov (United States)

    Hong, Xiao-Zhen; Shao, Xiao-Chun; Xu, Xian-Guo; Hu, Qing-Fa; Wu, Jun-Jie; Zhu, Fa-Ming; Fu, Qi-Hua; Yan, Li-Xing

    2005-12-01

    To investigate the molecular genetics basis for one para-Bombay phenotype, the red blood cell phenotype of the proband was characterized by standard serological techniques. Exon 6 and 7 of ABO gene, the entire coding region of FUT1 gene and FUT2 gene were amplified by polymerase chain reaction from genomic DNA of the proband respectively. The PCR products were purified by agarose gels and directly sequenced. The PCR-SSP and genescan were performed to confirm the mutations detected by sequencing. The results showed that the proband ABO genotype was A(102)A(102). Two heterozygous mutations of FUT1 gene, an A to G transition at position 682 and AG deletion at position 547-552 were detected in the proband. A682G could cause transition of Met-->Val at amino acid position 228, AG deletion at position 547-552 caused a reading frame shift and a premature stop codon. The FUT2 genotype was heterozygous for a functional allele Se(357) and a weakly functional allele Se(357), 385 (T/T homozygous at position 357 and A/T heterozygous at 385 position). It is concluded that the compound heterozygous mutation--a novel A682G missense mutation and a 547-552 del AG is the molecular mechanism of this para-Bombay phenotype.

  6. MSH1-induced non-genetic variation provides a source of phenotypic diversity in Sorghum bicolor.

    Directory of Open Access Journals (Sweden)

    Roberto de la Rosa Santamaria

    Full Text Available MutS Homolog 1 (MSH1 encodes a plant-specific protein that functions in mitochondria and chloroplasts. We showed previously that disruption or suppression of the MSH1 gene results in a process of developmental reprogramming that is heritable and non-genetic in subsequent generations. In Arabidopsis, this developmental reprogramming process is accompanied by striking changes in gene expression of organellar and stress response genes. This developmentally reprogrammed state, when used in crossing, results in a range of variation for plant growth potential. Here we investigate the implications of MSH1 modulation in a crop species. We found that MSH1-mediated phenotypic variation in Sorghum bicolor is heritable and potentially valuable for crop breeding. We observed phenotypic variation for grain yield, plant height, flowering time, panicle architecture, and above-ground biomass. Focusing on grain yield and plant height, we found some lines that appeared to respond to selection. Based on amenability of this system to implementation in a range of crops, and the scope of phenotypic variation that is derived, our results suggest that MSH1 suppression provides a novel approach for breeding in crops.

  7. Using text mining techniques to extract phenotypic information from the PhenoCHF corpus.

    Science.gov (United States)

    Alnazzawi, Noha; Thompson, Paul; Batista-Navarro, Riza; Ananiadou, Sophia

    2015-01-01

    Phenotypic information locked away in unstructured narrative text presents significant barriers to information accessibility, both for clinical practitioners and for computerised applications used for clinical research purposes. Text mining (TM) techniques have previously been applied successfully to extract different types of information from text in the biomedical domain. They have the potential to be extended to allow the extraction of information relating to phenotypes from free text. To stimulate the development of TM systems that are able to extract phenotypic information from text, we have created a new corpus (PhenoCHF) that is annotated by domain experts with several types of phenotypic information relating to congestive heart failure. To ensure that systems developed using the corpus are robust to multiple text types, it integrates text from heterogeneous sources, i.e., electronic health records (EHRs) and scientific articles from the literature. We have developed several different phenotype extraction methods to demonstrate the utility of the corpus, and tested these methods on a further corpus, i.e., ShARe/CLEF 2013. Evaluation of our automated methods showed that PhenoCHF can facilitate the training of reliable phenotype extraction systems, which are robust to variations in text type. These results have been reinforced by evaluating our trained systems on the ShARe/CLEF corpus, which contains clinical records of various types. Like other studies within the biomedical domain, we found that solutions based on conditional random fields produced the best results, when coupled with a rich feature set. PhenoCHF is the first annotated corpus aimed at encoding detailed phenotypic information. The unique heterogeneous composition of the corpus has been shown to be advantageous in the training of systems that can accurately extract phenotypic information from a range of different text types. Although the scope of our annotation is currently limited to a single

  8. Research on Modeling of Genetic Networks Based on Information Measurement

    Institute of Scientific and Technical Information of China (English)

    ZHANG Guo-wei; SHAO Shi-huang; ZHANG Ying; LI Hai-ying

    2006-01-01

    As the basis of network of biology organism, the genetic network is concerned by many researchers.Current modeling methods to genetic network, especially the Boolean networks modeling method are analyzed. For modeling the genetic network, the information theory is proposed to mining the relations between elements in network. Through calculating the values of information entropy and mutual entropy in a case, the effectiveness of the method is verified.

  9. Yellow fever virus: genetic and phenotypic diversity and implications for detection, prevention and therapy.

    Science.gov (United States)

    Beasley, David W C; McAuley, Alexander J; Bente, Dennis A

    2015-03-01

    Yellow fever virus (YFV) is the prototypical hemorrhagic fever virus, yet our understanding of its phenotypic diversity and any molecular basis for observed differences in disease severity and epidemiology is lacking, when compared to other arthropod-borne and haemorrhagic fever viruses. This is, in part, due to the availability of safe and effective vaccines resulting in basic YFV research taking a back seat to those viruses for which no effective vaccine occurs. However, regular outbreaks occur in endemic areas, and the spread of the virus to new, previously unaffected, areas is possible. Analysis of isolates from endemic areas reveals a strong geographic association for major genotypes, and recent epidemics have demonstrated the emergence of novel sequence variants. This review aims to outline the current understanding of YFV genetic and phenotypic diversity and its sources, as well as the available animal models for characterizing these differences in vivo. The consequences of genetic diversity for detection and diagnosis of yellow fever and development of new vaccines and therapeutics are discussed.

  10. Phenotypic assortment in wild primate networks: implications for the dissemination of information.

    Science.gov (United States)

    Carter, Alecia J; Lee, Alexander E G; Marshall, Harry H; Ticó, Miquel Torrents; Cowlishaw, Guy

    2015-05-01

    Individuals' access to social information can depend on their social network. Homophily-a preference to associate with similar phenotypes-may cause assortment within social networks that could preclude information transfer from individuals who generate information to those who would benefit from acquiring it. Thus, understanding phenotypic assortment may lead to a greater understanding of the factors that could limit the transfer of information between individuals. We tested whether there was assortment in wild baboon (Papio ursinus) networks, using data collected from two troops over 6 years for six phenotypic traits-boldness, age, dominance rank, sex and the propensity to generate/exploit information-using two methods for defining a connection between individuals-time spent in proximity and grooming. Our analysis indicated that assortment was more common in grooming than proximity networks. In general, there was homophily for boldness, age, rank and the propensity to both generate and exploit information, but heterophily for sex. However, there was considerable variability both between troops and years. The patterns of homophily we observed for these phenotypes may impede information transfer between them. However, the inconsistency in the strength of assortment between troops and years suggests that the limitations to information flow may be quite variable.

  11. Genetic variations and miRNA-target interactions contribute to natural phenotypic variations in Populus.

    Science.gov (United States)

    Chen, Jinhui; Xie, Jianbo; Chen, Beibei; Quan, Mingyang; Li, Ying; Li, Bailian; Zhang, Deqiang

    2016-10-01

    Variation in regulatory factors, including microRNAs (miRNAs), contributes to variation in quantitative and complex traits. However, in plants, variants in miRNAs and their target genes that contribute to natural phenotypic variation, and the underlying regulatory networks, remain poorly characterized. We investigated the associations and interactions of single-nucleotide polymorphisms (SNPs) in miRNAs and their target genes with phenotypes in 435 individuals from a natural population of Populus. We used RNA-seq to identify 217 miRNAs differentially expressed in a tension wood system, and identified 1196 candidate target genes; degradome sequencing confirmed 60 of the target sites. In addition, 72 miRNA-target pairs showed significant co-expression. Gene ontology (GO) term analysis showed that most of the genes in the co-regulated pairs participate in biological regulation. Genome resequencing found 5383 common SNPs (frequency ≥ 0.05) in 139 miRNAs and 31 037 SNPs in 819 target genes. Single-SNP association analyses identified 232 significant associations between wood traits (P ≤ 0.05) and SNPs in 102 miRNAs and 1387 associations with 478 target genes. Among these, 102 miRNA-target pairs associated with the same traits. Multi-SNP associations found 102 epistatic pairs associated with traits. Furthermore, a reconstructed regulatory network contained 12 significantly co-expressed pairs, including eight miRNAs and nine targets associated with traits. Lastly, both expression and genetic association showed that miR156i, miR156j, miR396a and miR6445b were involved in the formation of tension wood. This study shows that variants in miRNAs and target genes contribute to natural phenotypic variation and annotated roles and interactions of miRNAs and their target genes by genetic association analysis. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

  12. Genetic heterogeneity among slow acetylator N-acetyltransferase 2 phenotypes in cryopreserved human hepatocytes.

    Science.gov (United States)

    Doll, Mark A; Hein, David W

    2017-07-01

    Genetic polymorphisms in human N-acetyltransferase 2 (NAT2) modify the metabolism of numerous drugs and carcinogens. These genetic polymorphisms modify both drug efficacy and toxicity and cancer risk associated with carcinogen exposure. Previous studies have suggested phenotypic heterogeneity among different NAT2 slow acetylator genotypes. NAT2 phenotype was investigated in vitro and in situ in samples of human hepatocytes obtained from various NAT2 slow and intermediate NAT2 acetylator genotypes. NAT2 gene dose response (NAT2*5B/*5B > NAT2*5B/*6A > NAT2*6A/*6A) was observed towards the N-acetylation of the NAT2-specific drug sulfamethazine by human hepatocytes both in vitro and in situ. N-acetylation of 4-aminobiphenyl, an arylamine carcinogen substrate for both N-acetyltransferase 1 and NAT2, showed the same trend both in vitro and in situ although the differences were not significant (p > 0.05). The N-acetylation of the N-acetyltransferase 1-specific substrate p-aminobenzoic acid did not follow this trend. In comparisons of NAT2 intermediate acetylator genotypes, differences in N-acetylation between NAT2*4/*5B and NAT2*4/*6B hepatocytes were not observed in vitro or in situ towards any of these substrates. These results further support phenotypic heterogeneity among NAT2 slow acetylator genotypes, consistent with differential risks of drug failure or toxicity and cancer associated with carcinogen exposure.

  13. Genetic background of nonmutant Piebald-Virol-Glaxo rats does not influence nephronophthisis phenotypes

    Directory of Open Access Journals (Sweden)

    Yengkopiong JP

    2013-02-01

    Full Text Available Jada Pasquale Yengkopiong, Joseph Daniel Wani LakoJohn Garang Memorial University of Science and Technology, Faculty of Science and Technology, Bor, Jonglei State, Republic of South SudanBackground: Nephronophthisis (NPHP, which affects multiple organs, is a hereditary cystic kidney disease (CKD, characterized by interstitial fibrosis and numerous fluid-filled cysts in the kidneys. It is caused by mutations in NPHP genes, which encode for ciliary proteins known as nephrocystins. The disorder affects many people across the world and leads to end-stage renal disease. The aim of this study was to determine if the genetic background of the nonmutant female Piebald-Virol-Glaxo (PVG/Seac-/- rat influences phenotypic inheritance of NPHP from mutant male Lewis polycystic kidney rats.Methods: Mating experiments were performed between mutant Lewis polycystic kidney male rats with CKD and nonmutant PVG and Wistar Kyoto female rats without cystic kidney disease to raise second filial and backcross 1 progeny, respectively. Rats that developed cystic kidneys were identified. Systolic blood pressure was determined in each rat at 12 weeks of age using the tail and cuff method. After euthanasia, blood samples were collected and chemistry was determined. Histological examination of the kidneys, pancreas, and liver of rats with and without cystic kidney disease was performed.Results: It was established that the genetic background of nonmutant female PVG rats did not influence the phenotypic inheritance of the CKD from mutant male Lewis polycystic kidney rats. The disease arose as a result of a recessive mutation in a single gene (second filial generation, CKD = 13, non-CKD = 39, Χ2 = 0.00, P ≥ 0.97; backcross 1 generation, CKD = 67, non-CKD = 72, Χ2 = 0.18, P > 0.05 and inherited as NPHP. The rats with CKD developed larger fluid-filled cystic kidneys, higher systolic blood pressure, and anemia, but there were no extrarenal cysts and disease did not lead to

  14. Skin-Based DNA Repair Phenotype for Cancer Risk from GCR in Genetically Diverse Populations

    Science.gov (United States)

    Guiet, Elodie; Viger, Louise; Snijders, Antoine; Costes, Sylvian V.

    2017-01-01

    Predicting cancer risk associated with cosmic radiation remains a mission-critical challenge for NASA radiation health scientists and mission planners. Epidemiological data are lacking and risk methods do not take individual radiation sensitivity into account. In our approach we hypothesize that genetic factors strongly influence risk of cancer from space radiation and that biomarkers reflecting DNA damage and cell death are ideal tools to predict risk and monitor potential health effects post-flight. At this workshop, we will be reporting the work we have done over the first 9 months of this proposal. Skin cells from 15 different strains of mice already characterized for radiation-induced cancer sensitivity (B6C3F; BALB/cByJ, C57BL/6J, CBA/CaJ, C3H/HeMsNrsf), and 10 strains from the DOE collaborative cross-mouse model were expanded from ear biopsy and cultivated until Passage 3. On average, 3 males and 3 females for each strain were expanded and frozen for further characterization at the NSRL beam line during the NSRL16C run for three LET (350 MeV/n Si, 350 MeV/n Ar and 600 MeV/n Fe) and two ion fluences (1 and 3 particles per cell). The mice work has established new metrics for the usage of Radiation Induced Foci as a marker for various aspect of DNA repair deficiencies. In year 2, we propose to continue characterization of the mouse lines with low LET to identify loci specific to high- versus low- LET and establish genetic linkage for the various DNA repair biomarkers. Correlation with cancer risk from each animals strain and gender will also be investigated. On the human side, we will start characterizing the DNA damage response induced ex-vivo in 200 human's blood donors for radiation sensitivity with a tentative 500 donors by the end of this project. All ex-vivo phenotypic data will be correlated to genetic characterization of each individual human donors using SNP arrays characterization as done for mice. Similarly, ex-vivo phenotypic features from mice will

  15. Mapping Phenotypic Information in Heterogeneous Textual Sources to a Domain-Specific Terminological Resource.

    Science.gov (United States)

    Alnazzawi, Noha; Thompson, Paul; Ananiadou, Sophia

    2016-01-01

    Biomedical literature articles and narrative content from Electronic Health Records (EHRs) both constitute rich sources of disease-phenotype information. Phenotype concepts may be mentioned in text in multiple ways, using phrases with a variety of structures. This variability stems partly from the different backgrounds of the authors, but also from the different writing styles typically used in each text type. Since EHR narrative reports and literature articles contain different but complementary types of valuable information, combining details from each text type can help to uncover new disease-phenotype associations. However, the alternative ways in which the same concept may be mentioned in each source constitutes a barrier to the automatic integration of information. Accordingly, identification of the unique concepts represented by phrases in text can help to bridge the gap between text types. We describe our development of a novel method, PhenoNorm, which integrates a number of different similarity measures to allow automatic linking of phenotype concept mentions to known concepts in the UMLS Metathesaurus, a biomedical terminological resource. PhenoNorm was developed using the PhenoCHF corpus-a collection of literature articles and narratives in EHRs, annotated for phenotypic information relating to congestive heart failure (CHF). We evaluate the performance of PhenoNorm in linking CHF-related phenotype mentions to Metathesaurus concepts, using a newly enriched version of PhenoCHF, in which each phenotype mention has an expert-verified link to a concept in the UMLS Metathesaurus. We show that PhenoNorm outperforms a number of alternative methods applied to the same task. Furthermore, we demonstrate PhenoNorm's wider utility, by evaluating its ability to link mentions of various other types of medically-related information, occurring in texts covering wider subject areas, to concepts in different terminological resources. We show that PhenoNorm can maintain

  16. What drivers phenotypic divergence in Leymus chinensis (Poaceae) on large-scale gradient, climate or genetic differentiation?

    Science.gov (United States)

    Yuan, Shan; Ma, Linna; Guo, Chengyuan; Wang, Renzhong

    2016-05-01

    Elucidating the driving factors among-population divergence is an important task in evolutionary biology, however the relative contribution from natural selection and neutral genetic differentiation has been less debated. A manipulation experiment was conducted to examine whether the phenotypic divergence of Leymus chinensis depended on climate variations or genetic differentiations at 18 wild sites along a longitudinal gradient from 114 to 124°E in northeast China and at common garden condition of transplantation. Demographical, morphological and physiological phenotypes of 18 L. chinensis populations exhibited significant divergence along the gradient, but these divergent variations narrowed significantly at the transplantation. Moreover, most of the phenotypes were significantly correlated with mean annual precipitation and temperature in wild sites, suggesting that climatic variables played vital roles in phenotypic divergence of the species. Relative greater heterozygosity (HE), genotype evenness (E) and Shannon-Wiener diversity (I) in western group of populations suggested that genetic differentiation also drove phenotypic divergence of the species. However, neutral genetic differentiation (FST = 0.041) was greatly lower than quantitative differentiation (QST = 0.199), indicating that divergent selection/climate variable was the main factor in determining the phenotypic divergence of the species along the large-scale gradient.

  17. Optimizing the creation of base populations for aquaculture breeding programs using phenotypic and genomic data and its consequences on genetic progress.

    Science.gov (United States)

    Fernández, Jesús; Toro, Miguel Á; Sonesson, Anna K; Villanueva, Beatriz

    2014-01-01

    The success of an aquaculture breeding program critically depends on the way in which the base population of breeders is constructed since all the genetic variability for the traits included originally in the breeding goal as well as those to be included in the future is contained in the initial founders. Traditionally, base populations were created from a number of wild strains by sampling equal numbers from each strain. However, for some aquaculture species improved strains are already available and, therefore, mean phenotypic values for economically important traits can be used as a criterion to optimize the sampling when creating base populations. Also, the increasing availability of genome-wide genotype information in aquaculture species could help to refine the estimation of relationships within and between candidate strains and, thus, to optimize the percentage of individuals to be sampled from each strain. This study explores the advantages of using phenotypic and genome-wide information when constructing base populations for aquaculture breeding programs in terms of initial and subsequent trait performance and genetic diversity level. Results show that a compromise solution between diversity and performance can be found when creating base populations. Up to 6% higher levels of phenotypic performance can be achieved at the same level of global diversity in the base population by optimizing the selection of breeders instead of sampling equal numbers from each strain. The higher performance observed in the base population persisted during 10 generations of phenotypic selection applied in the subsequent breeding program.

  18. Optimizing the creation of base populations for aquaculture breeding programs using phenotypic and genomic data and its consequences on genetic progress

    Directory of Open Access Journals (Sweden)

    Jesús eFernández

    2014-11-01

    Full Text Available The success of an aquaculture breeding program critically depends on the way in which the base population of breeders is constructed since all the genetic variability for the traits included originally in the breeding goal as well as those to be included in the future is contained in those initial founders. Traditionally base populations were created from a number of wild strains by sampling equal numbers from each strain. However, for some aquaculture species improved strains are already available and therefore, mean phenotypic values for economically important traits can be used as a criterion to optimize the sampling when creating base populations. Also, the increasing availability of genome-wide genotype information in aquaculture species could help to refine the estimation of relationships within and between candidate strains and, thus, to optimize the percentage of individuals to be sampled from each strain. This study explores the advantages of using phenotypic and genome-wide information when constructing base populations for aquaculture breeding programs in terms of initial and subsequent trait performance and genetic diversity level. Results show that a compromise solution between diversity and performance can be found when creating base populations. Up to 6% higher levels of phenotypic performance can be achieved at the same level of global diversity in the base population by optimizing the selection of breeders instead of sampling equal numbers from each strain. The higher performance observed in the base population persisted during ten generations of phenotypic selection applied in the subsequent breeding program.

  19. Integration of Genetic and Phenotypic Data in 48 Lineages of Philippine Birds Shows Heterogeneous Divergence Processes and Numerous Cryptic Species.

    Science.gov (United States)

    Campbell, Kyle K; Braile, Thomas; Winker, Kevin

    2016-01-01

    The Philippine Islands are one of the most biologically diverse archipelagoes in the world. Current taxonomy, however, may underestimate levels of avian diversity and endemism in these islands. Although species limits can be difficult to determine among allopatric populations, quantitative methods for comparing phenotypic and genotypic data can provide useful metrics of divergence among populations and identify those that merit consideration for elevation to full species status. Using a conceptual approach that integrates genetic and phenotypic data, we compared populations among 48 species, estimating genetic divergence (p-distance) using the mtDNA marker ND2 and comparing plumage and morphometrics of museum study skins. Using conservative speciation thresholds, pairwise comparisons of genetic and phenotypic divergence suggested possible species-level divergences in more than half of the species studied (25 out of 48). In speciation process space, divergence routes were heterogeneous among taxa. Nearly all populations that surpassed high genotypic divergence thresholds were Passeriformes, and non-Passeriformes populations surpassed high phenotypic divergence thresholds more commonly than expected by chance. Overall, there was an apparent logarithmic increase in phenotypic divergence with respect to genetic divergence, suggesting the possibility that divergence among these lineages may initially be driven by divergent selection in this allopatric system. Also, genetic endemism was high among sampled islands. Higher taxonomy affected divergence in genotype and phenotype. Although broader lineage, genetic, phenotypic, and numeric sampling is needed to further explore heterogeneity among divergence processes and to accurately assess species-level diversity in these taxa, our results support the need for substantial taxonomic revisions among Philippine birds. The conservation implications are profound.

  20. Integration of Genetic and Phenotypic Data in 48 Lineages of Philippine Birds Shows Heterogeneous Divergence Processes and Numerous Cryptic Species.

    Directory of Open Access Journals (Sweden)

    Kyle K Campbell

    Full Text Available The Philippine Islands are one of the most biologically diverse archipelagoes in the world. Current taxonomy, however, may underestimate levels of avian diversity and endemism in these islands. Although species limits can be difficult to determine among allopatric populations, quantitative methods for comparing phenotypic and genotypic data can provide useful metrics of divergence among populations and identify those that merit consideration for elevation to full species status. Using a conceptual approach that integrates genetic and phenotypic data, we compared populations among 48 species, estimating genetic divergence (p-distance using the mtDNA marker ND2 and comparing plumage and morphometrics of museum study skins. Using conservative speciation thresholds, pairwise comparisons of genetic and phenotypic divergence suggested possible species-level divergences in more than half of the species studied (25 out of 48. In speciation process space, divergence routes were heterogeneous among taxa. Nearly all populations that surpassed high genotypic divergence thresholds were Passeriformes, and non-Passeriformes populations surpassed high phenotypic divergence thresholds more commonly than expected by chance. Overall, there was an apparent logarithmic increase in phenotypic divergence with respect to genetic divergence, suggesting the possibility that divergence among these lineages may initially be driven by divergent selection in this allopatric system. Also, genetic endemism was high among sampled islands. Higher taxonomy affected divergence in genotype and phenotype. Although broader lineage, genetic, phenotypic, and numeric sampling is needed to further explore heterogeneity among divergence processes and to accurately assess species-level diversity in these taxa, our results support the need for substantial taxonomic revisions among Philippine birds. The conservation implications are profound.

  1. Genetic and Epigenetic Tumor Suppressor Gene Silencing Are Distinct Molecular Phenotypes Driven by Growth Promoting Mutations in Nonsmall Cell Lung Cancer

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    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.

  2. Genetic and phenotypic characterization of manufacturing seeds for a tetravalent dengue vaccine (DENVax.

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    Claire Y-H Huang

    Full Text Available BACKGROUND: We have developed a manufacturing strategy that can improve the safety and genetic stability of recombinant live-attenuated chimeric dengue vaccine (DENVax viruses. These viruses, containing the pre-membrane (prM and envelope (E genes of dengue serotypes 1-4 in the replicative background of the attenuated dengue-2 PDK-53 vaccine virus candidate, were manufactured under cGMP. METHODOLOGY/PRINCIPAL FINDINGS: After deriving vaccine viruses from RNA-transfected Vero cells, six plaque-purified viruses for each serotype were produced. The plaque-purified strains were then analyzed to select one stock for generation of the master seed. Full genetic and phenotypic characterizations of the master virus seeds were conducted to ensure these viruses retained the previously identified attenuating determinants and phenotypes of the vaccine viruses. We also assessed vector competence of the vaccine viruses in sympatric (Thai Aedes aegypti mosquito vectors. CONCLUSION/SIGNIFICANCE: All four serotypes of master vaccine seeds retained the previously defined safety features, including all three major genetic loci of attenuation, small plaques, temperature sensitivity in mammalian cells, reduced replication in mosquito cell cultures, and reduced neurovirulence in new-born mice. In addition, the candidate vaccine viruses demonstrated greatly reduced infection and dissemination in Aedes aegypti mosquitoes, and are not likely to be transmissible by these mosquitoes. This manufacturing strategy has successfully been used to produce the candidate tetravalent vaccine, which is currently being tested in human clinical trials in the United States, Central and South America, and Asia.

  3. Genetic and phenotypically flexible components of seasonal variation in immune function.

    Science.gov (United States)

    Versteegh, M A; Helm, B; Kleynhans, E J; Gwinner, E; Tieleman, B I

    2014-05-01

    Animals cope with seasonal variation in environmental factors by adjustments of physiology and life history. When seasonal variation is partly predictable, such adjustments can be based on a genetic component or be phenotypically flexible. Animals have to allocate limited resources over different demands, including immune function. Accordingly, immune traits could change seasonally, and such changes could have a genetic component that differs between environments. We tested this hypothesis in genotypically distinct groups of a widespread songbird, the stonechat (Saxicola torquata). We compared variation in immunity during 1 year in long-distance migrants, short-distance migrants, tropical residents and hybrids in a common garden environment. Additionally, we investigated phenotypically flexible responses to temperature by applying different temperature regimes to one group. We assessed constitutive immunity by measuring hemagglutination, hemolysis, haptoglobin and bactericidal ability against Escherichia coli and Staphylococcus aureus. Genotypic groups differed in patterns of variation of all measured immune indices except haptoglobin. Hybrids differed from, but were rarely intermediate to, parental subspecies. Temperature treatment only influenced patterns of hemolysis and bactericidal ability against E. coli. We conclude that seasonal variation in constitutive immunity has a genetic component, that heredity does not follow simple Mendelian rules, and that some immune measures are relatively rigid while others are more flexible. Furthermore, our results support the idea that seasonal variability in constitutive immunity is associated with variability in environment and annual-cycle demands. This study stresses the importance of considering seasonal variation in immune function in relation to the ecology and life history of the organism of interest.

  4. The genetics of phenotypic plasticity. XI. Joint evolution of plasticity and dispersal rate.

    Science.gov (United States)

    Scheiner, Samuel M; Barfield, Michael; Holt, Robert D

    2012-08-01

    In a spatially heterogeneous environment, the rate at which individuals move among habitats affects whether selection favors phenotypic plasticity or genetic differentiation, with high dispersal rates favoring trait plasticity. Until now, in theoretical explorations of plasticity evolution, dispersal rate has been treated as a fixed, albeit probabilistic, characteristic of a population, raising the question of what happens when the propensity to disperse and trait plasticity are allowed to evolve jointly. We examined the effects of their joint evolution on selection for plasticity using an individual-based computer simulation model. In the model, the environment consisted of a linear gradient of 50 demes with dispersal occurring either before or after selection. Individuals consisted of loci whose phenotypic expression either are affected by the environment (plastic) or are not affected (nonplastic), plus a locus determining the propensity to disperse. When dispersal rate and trait plasticity evolve jointly, the system tends to dichotomous outcomes of either high trait plasticity and high dispersal, or low trait plasticity and low dispersal. The outcome strongly depended on starting conditions, with high trait plasticity and dispersal favored when the system started at high values for either trait plasticity or dispersal rate (or both). Adding a cost of plasticity tended to drive the system to genetic differentiation, although this effect also depended on initial conditions. Genetic linkage between trait plasticity loci and dispersal loci further enhanced this strong dichotomy in evolutionary outcomes. All of these effects depended on organismal life history pattern, and in particular whether selection occurred before or after dispersal. These results can explain why adaptive trait plasticity is less common than might be expected.

  5. Disentangling the role of phenotypic plasticity and genetic divergence in contemporary ecotype formation during a biological invasion.

    Science.gov (United States)

    Lucek, Kay; Sivasundar, Arjun; Seehausen, Ole

    2014-09-01

    The occurrence of contemporary ecotype formation through adaptive divergence of populations within the range of an invasive species typically requires standing genetic variation but can be facilitated by phenotypic plasticity. The relative contributions of both of these to adaptive trait differentiation have rarely been simultaneously quantified in recently diverging vertebrate populations. Here we study a case of intraspecific divergence into distinct lake and stream ecotypes of threespine stickleback that evolved in the past 140 years within the invasive range in Switzerland. Using a controlled laboratory experiment with full-sib crosses and treatments mimicking a key feature of ecotypic niche divergence, we test if the phenotypic divergence that we observe in the wild results from phenotypic plasticity or divergent genetic predisposition. Our experimental groups show qualitatively similar phenotypic divergence as those observed among wild adults. The relative contribution of plasticity and divergent genetic predisposition differs among the traits studied, with traits related to the biomechanics of feeding showing a stronger genetic predisposition, whereas traits related to locomotion are mainly plastic. These results implicate that phenotypic plasticity and standing genetic variation interacted during contemporary ecotype formation in this case.

  6. Is genetic information relevantly different from other kinds of non-genetic information in the life insurance context?

    Science.gov (United States)

    Malpas, P J

    2008-07-01

    Within the medical, legal and bioethical literature, there has been an increasing concern that the information derived from genetic tests may be used to unfairly discriminate against individuals seeking various kinds of insurance; particularly health and life insurance. Consumer groups, the general public and those with genetic conditions have also expressed these concerns, specifically in the context of life insurance. While it is true that all insurance companies may have an interest in the information obtained from genetic tests, life insurers potentially have a very strong incentive to (want to) use genetic information to rate applicants, as individuals generally purchase their own cover and may want to take out very large policies. This paper critically focuses on genetic information in the context of life insurance. We consider whether genetic information differs in any relevant way from other kinds of non-genetic information required by and disclosed to life insurance companies by potential clients. We will argue that genetic information should not be treated any differently from other types of health information already collected from those wishing to purchase life insurance cover.

  7. Genetic information, non-discrimination, and privacy protections in genetic counseling practice.

    Science.gov (United States)

    Prince, Anya E R; Roche, Myra I

    2014-12-01

    The passage of the Genetic Information Non Discrimination Act (GINA) was hailed as a pivotal achievement that was expected to calm the fears of both patients and research participants about the potential misuse of genetic information. However, 6 years later, patient and provider awareness of legal protections at both the federal and state level remains discouragingly low, thereby, limiting their potential effectiveness. The increasing demand for genetic testing will expand the number of individuals and families who could benefit from obtaining accurate information about the privacy and anti-discriminatory protections that GINA and other laws extend. In this paper we describe legal protections that are applicable to individuals seeking genetic counseling, review the literature on patient and provider fears of genetic discrimination and examine their awareness and understandings of existing laws, and summarize how genetic counselors currently discuss genetic discrimination. We then present three genetic counseling cases to illustrate issues of genetic discrimination and provide relevant information on applicable legal protections. Genetic counselors have an unprecedented opportunity, as well as the professional responsibility, to disseminate accurate knowledge about existing legal protections to their patients. They can strengthen their effectiveness in this role by achieving a greater knowledge of current protections including being able to identify specific steps that can help protect genetic information.

  8. Genetic, phenotypic and environmental relationships between sow body weight and sow productivity traits.

    Science.gov (United States)

    Ferguson, P W; Harvey, W R; Irvin, K M

    1985-02-01

    Yorkshire and Duroc litter records were used to estimate genetic, phenotypic and environmental relationships between sow body weight and sow productivity traits. Two data sets with two subsets each were used to complete this study; 663 and 460 records included litter traits only, while 522 and 359 records also contained sow body weight for Yorkshires and Durocs, respectively. Heritability estimates for number born (NB), number born alive (NBA), total birth weight of live pigs (BWLIT), litter weight at 3 wk (WT3WK), sow weight at parturition (WTDAMPAR) and sow weight at weaning (WTDAMWN) were .24 +/- .14, .21 +/- .14, .42 +/- .16, .19 +/- .14, .72 +/- .21 and .42 +/- .18, respectively, for Yorkshires and .05 +/- .10, .04 +/- .10, .21 +/- .14, .25 +/- .15, .85 +/- .25 and .87 +/- .26, respectively, for the Durocs. Repeatability estimates for NB, NBA, BWLIT, WT3WK, WTDAMPAR and WTDAMWN were .13 +/- .06, .17 +/- .06, .27 +/- .06, .13 +/- .06, .64 +/- .05 and .54 +/- .05, respectively, for Yorkshires and .17 +/- .06, .21 +/- .06, .14 +/- .06, .17 +/- .06, .28 +/- .07 and .39 +/- .07, respectively, for Durocs. Genetic correlations among litter traits were high and positive in the Yorkshire data. Genetic correlations between NBA and WTDAMPAR, NBA and WTDAMWN, WT3WK and WTDAMPAR, and WT3WK and WTDAMWN were .37 +/- .25, .18 +/- .34, .60 +/- .29 and .29 +/- .45, respectively, in the Yorkshire data. Genetic correlations among litter traits in the Duroc analysis had large standard errors but were generally similar to the estimates obtained from the Yorkshire data. The genetic correlation between WTDAMPAR and WTDAMWN was .93 +/- .09 for Yorkshire sows. The primary conclusion from this study is that as selection increases sow productivity traits, there will be a positive correlated response in sow body weight.

  9. IQ heritability estimation: analyzing genetically-informative data with structural equation models.

    Science.gov (United States)

    Gallardo Pujol, David; García-Forero, Carlos; Kramp, Uwe; Maydeu-Olivares, Albert; Andrés-Pueyo, Antonio

    2007-02-01

    When analyzing genetic data, Structural Equations Modeling (SEM) provides a straightforward methodology to decompose phenotypic variance using a model-based approach. Furthermore, several models can be easily implemented, tested, and compared using SEM, allowing the researcher to obtain valuable information about the sources of variability. This methodology is briefly described and applied to re-analyze a Spanish set of IQ data using the biometric ACE model. In summary, we report heritability estimates that are consistent with those of previous studies and support substantial genetic contribution to phenotypic IQ; around 40% of the variance can be attributable to it. With regard to the environmental contribution, shared environment accounts for 50% of the variance, and non-shared environment accounts for the remaining 10%. These results are discussed in the text.

  10. Study on Dynamic Information of Animal Genetic Resources in China

    Institute of Scientific and Technical Information of China (English)

    MA Yue-hui; XU Gui-fang; WANG Duan-yun; LIU Hai-liang; YANG Yan

    2003-01-01

    The dynamic information of 331 animal genetic resources in 17 important animal genetic re-source provinces (regions) was analyzed. According to the population inbreeding coefficient, combiningwith the information of population dynamic change trend and cross degree, these genetic resources forthreatened degrees were classified. The results indicated that the population size of 138 breeds had in-creased, 147 breeds had decreased, 3 breeds were constant, 7 breeds (or varieties) were extinct, 9 breeds(or varieties) were critically endangered and needed urgently conserve, 50 breeds (or varieties) were endan-gered and should be conserved. We put forward a conservation and utilization plan for animal genetic re-sources.

  11. The role of inflammatory pathway genetic variation on maternal metabolic phenotypes during pregnancy.

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    Margrit Urbanek

    Full Text Available BACKGROUND: Since mediators of inflammation are associated with insulin resistance, and the risk of developing diabetes mellitus and gestational diabetes, we hypothesized that genetic variation in members of the inflammatory gene pathway impact glucose levels and related phenotypes in pregnancy. We evaluated this hypothesis by testing for association between genetic variants in 31 inflammatory pathway genes in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO cohort, a large multiethnic multicenter study designed to address the impact of glycemia less than overt diabetes on pregnancy outcome. RESULTS: Fasting, 1-hour, and 2-hour glucose, fasting and 1-hour C-peptide, and HbA1c levels were measured in blood samples obtained from HAPO participants during an oral glucose tolerance test at 24-32 weeks gestation. We tested for association between 458 SNPs mapping to 31 genes in the inflammatory pathway and metabolic phenotypes in 3836 European ancestry and 1713 Thai pregnant women. The strongest evidence for association was observed with TNF alpha and HbA1c (rs1052248; 0.04% increase per allele C; p-value = 4.4×10(-5, RETN and fasting plasma glucose (rs1423096; 0.7 mg/dl decrease per allele A; p-value = 1.1×10(-4, IL8 and 1 hr plasma glucose (rs2886920; 2.6 mg/dl decrease per allele T; p-value = 1.3×10(-4, ADIPOR2 and fasting C-peptide (rs2041139; 0.55 ug/L decrease per allele A; p-value = 1.4×10(-4, LEPR and 1-hour C-peptide (rs1171278; 0.62 ug/L decrease per allele T; p-value = 2.4×10(-4, and IL6 and 1-hour plasma glucose (rs6954897; -2.29 mg/dl decrease per allele G, p-value = 4.3×10(-4. CONCLUSIONS: Based on the genes surveyed in this study the inflammatory pathway is unlikely to have a strong impact on maternal metabolic phenotypes in pregnancy although variation in individual members of the pathway (e.g. RETN, IL8, ADIPOR2, LEPR, IL6, and TNF alpha, may contribute to metabolic phenotypes in pregnant women.

  12. Genetic variation in variability: Phenotypic variability of fledging weight and its evolution in a songbird population.

    Science.gov (United States)

    Mulder, Han A; Gienapp, Philip; Visser, Marcel E

    2016-09-01

    Variation in traits is essential for natural selection to operate and genetic and environmental effects can contribute to this phenotypic variation. From domesticated populations, we know that families can differ in their level of within-family variance, which leads to the intriguing situation that within-family variance can be heritable. For offspring traits, such as birth weight, this implies that within-family variance in traits can vary among families and can thus be shaped by natural selection. Empirical evidence for this in wild populations is however lacking. We investigated whether within-family variance in fledging weight is heritable in a wild great tit (Parus major) population and whether these differences are associated with fitness. We found significant evidence for genetic variance in within-family variance. The genetic coefficient of variation (GCV) was 0.18 and 0.25, when considering fledging weight a parental or offspring trait, respectively. We found a significant quadratic relationship between within-family variance and fitness: families with low or high within-family variance had lower fitness than families with intermediate within-family variance. Our results show that within-family variance can respond to selection and provides evidence for stabilizing selection on within-family variance. © 2016 The Author(s). Evolution © 2016 The Society for the Study of Evolution.

  13. Behavioral phenotypes of genetic syndromes with intellectual disability: comparison of adaptive profiles.

    Science.gov (United States)

    Di Nuovo, Santo; Buono, Serafino

    2011-10-30

    The study of distinctive and consistent behaviors in the most common genetic syndromes with intellectual disability is useful to explain abnormalities or associated psychiatric disorders. The behavioral phenotypes revealed outcomes totally or partially specific for each syndrome. The aim of our study was to compare similarities and differences in the adaptive profiles of the five most frequent genetic syndromes, i.e. Down syndrome, Williams syndrome, Angelman syndrome, Prader-Willi syndrome, and Fragile-X syndrome (fully mutated), taking into account the relation with chronological age and the overall IQ level. The research was carried out using the Vineland Adaptive Behavior Scale (beside the Wechsler Intelligence scales to obtain IQ) with a sample of 181 persons (107 males and 74 females) showing genetic syndromes and mental retardation. Syndrome-based groups were matched for chronological age and mental age (excluding the Angelman group, presenting with severe mental retardation). Similarities and differences in the adaptive profiles are described, relating them to IQs and maladaptive behaviors. The results might be useful in obtaining a global index of adjustment for the assessment of intellectual disability level as well as for educational guidance and rehabilitative plans. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  14. Temporal patterns of genetic and phenotypic variation in the epidemiologically important drone fly, Eristalis tenax.

    Science.gov (United States)

    Francuski, Lj; Matić, I; Ludoški, J; Milankov, V

    2011-06-01

    Eristalis tenax L. (Diptera: Syrphidae) is commonly known as the drone fly (adult) or rat-tailed maggot (immature). Both adults and immature stages are identified as potential mechanical vectors of mycobacterial pathogens, and early-stage maggots cause accidental myiasis. We compared four samples from Mount Fruška Gora, Serbia, with the aim of obtaining insights into the temporal variations and sexual dimorphism in the species. This integrative approach was based on allozyme loci, morphometric wing parameters (shape and size) and abdominal colour patterns. Consistent sexual dimorphism was observed, indicating that male specimens had lighter abdomens and smaller and narrower wings than females. The distribution of genetic diversity at polymorphic loci indicated genetic divergence among collection dates. Landmark-based geometric morphometrics revealed, contrary to the lack of divergence in wing size, significant wing shape variation throughout the year. In addition, temporal changes in the frequencies of the abdominal patterns observed are likely to relate to the biology of the species and ecological factors in the locality. Hence, the present study expands our knowledge of the genetic diversity and phenotypic plasticity of E. tenax. The quantification of such variability represents a step towards the evaluation of the adaptive potential of this species of medical and epidemiological importance.

  15. The W303 genetic background affects the isw2 delta mutant phenotype in Saccharomyces cerevisiae.

    Science.gov (United States)

    Trachtulcová, P; Frýdlová, I; Janatová, I; Dorosh, A; Hasek, J

    2003-01-01

    We performed detailed phenotypic analysis of the isw2 delta strains of the W303 genetic background and compared its results with those obtained previously in BY-derived genetic background. Shmoolike morphology was observed in the isw2 delta strain of alpha-mating type of the BY strains, but not in its W303-derived counterpart. On the other hand, derepression of a-specific genes in the isw2 delta (MAT alpha) strain was observed in both genetic backgrounds, although to a different extent. Unlike in BY-derived strain hyperactivation of the Ras2/cAMP pathway reduced invasiveness of the isw2 delta strain (MAT alpha) of the W303 background. Sensitivity to Calcofluor White indicating a cell wall-integrity defect was significantly increased in the isw2 delta strains of the W303 background in contrast to BY-derived strains. Our data indicate that the effects of the isw2 deletion strongly depend on the background in which the deletion, is made.

  16. Phenotypic Characterization and Genetic Dissection of Growth Period Traits in Soybean (Glycine max Using Association Mapping.

    Directory of Open Access Journals (Sweden)

    Zhangxiong Liu

    Full Text Available The growth period traits are important traits that affect soybean yield. The insights into the genetic basis of growth period traits can provide theoretical basis for cultivated area division, rational distribution, and molecular breeding for soybean varieties. In this study, genome-wide association analysis (GWAS was exploited to detect the quantitative trait loci (QTL for number of days to flowering (ETF, number of days from flowering to maturity (FTM, and number of days to maturity (ETM using 4032 single nucleotide polymorphism (SNP markers with 146 cultivars mainly from Northeast China. Results showed that abundant phenotypic variation was presented in the population, and variation explained by genotype, environment, and genotype by environment interaction were all significant for each trait. The whole accessions could be clearly clustered into two subpopulations based on their genetic relatedness, and accessions in the same group were almost from the same province. GWAS based on the unified mixed model identified 19 significant SNPs distributed on 11 soybean chromosomes, 12 of which can be consistently detected in both planting densities, and 5 of which were pleotropic QTL. Of 19 SNPs, 7 SNPs located in or close to the previously reported QTL or genes controlling growth period traits. The QTL identified with high resolution in this study will enrich our genomic understanding of growth period traits and could then be explored as genetic markers to be used in genomic applications in soybean breeding.

  17. Analysis of phenotype and genotype information for the diagnosis of Marfan syndrome.

    Science.gov (United States)

    Sheikhzadeh, S; Kade, C; Keyser, B; Stuhrmann, M; Arslan-Kirchner, M; Rybczynski, M; Bernhardt, A M; Habermann, C R; Hillebrand, M; Mir, T; Robinson, P N; Berger, J; Detter, C; Blankenberg, S; Schmidtke, J; von Kodolitsch, Y

    2012-09-01

    Marfan syndrome is considered a clinical diagnosis. Three diagnostic classifications comprising first, Marfan genotype with a causative FBN1 gene mutation; second, Marfan phenotype with clinical criteria of the original Ghent nosology (Ghent-1); and third, phenotype with clinical criteria of its current revision (Ghent-2) in 300 consecutive persons referred for confirmation or exclusion of Marfan syndrome (150 men, 150 women aged 35 ± 13 years) were used. Sequencing of TGBR1/2 genes was performed in 128 persons without FBN1 mutation. Marfan genotype was present in 140, Ghent-1 phenotype in 139, and Ghent-2 phenotype in 124 of 300 study patients. Marfan syndrome was confirmed in 94 and excluded in 129 persons consistently by all classifications, but classifications were discordant in 77 persons. With combined genotype and phenotype information confirmation of Marfan syndrome was finally achieved in 126 persons by Ghent-1 and in 125 persons by Ghent-2 among 140 persons with Marfan genotype, and exclusion was accomplished in 139 persons by Ghent-1 and in 141 persons by Ghent-2 among 160 persons without Marfan genotype. In total, genotype information changed final diagnoses in 22 persons with Ghent-1, and in 32 persons with Ghent-2. It is concluded that genotype information is essential for diagnosis or exclusion of Marfan syndrome.

  18. Communicating genetic information: a difficult challenge for future pediatricians

    Directory of Open Access Journals (Sweden)

    Shirsat Pratibha

    2007-06-01

    Full Text Available Abstract Background The role of the pediatrician as genetic counselor is ideal because pediatricians have medical knowledge and experience with genetic disorders (e.g. Down syndrome. Moreover, pediatricians can provide comprehensive care in a medical home to patients with genetic disorders. However, changes in the curriculum of the pediatric resident are necessary to address the future challenges of effectively communicating genetic information to patients. The objective of this study was to explore these challenges and make recommendations for training to adequately prepare pediatricians for their future role as genetic counselors. Methods Three reviewers independently searched PubMed, OVID, and Medline databases to identify articles describing the challenges of communicating genetic information to patients, published from 1960 to December 2005. After the publications were identified and reviewed, four major areas of interest were identified in order to categorize the findings. Results Twenty-five publications were identified during the literature search. From the review, the following categories were selected to organize the findings: (1 Inherent difficulties of communicating and comprehending genetic information; (2 Comprehension of genetic information by pediatricians; (3 Genetics training in residency programs; and (4 The effect of genetic information on the future role of pediatricians and potential legal implications. Conclusion Pediatricians and residents lack essential knowledge of genetics and communication skills for effective counseling of patients. The review indicated that successful communication of genetic information involves a number of important skills and considerations. It is likely that these skills and considerations are universally required for the communication of most complex specialized medical information. In the past, communication skills have not been considered a priority. Today, these skills have become a

  19. Identifying genetic marker sets associated with phenotypes via an efficient adaptive score test

    KAUST Repository

    Cai, T.

    2012-06-25

    In recent years, genome-wide association studies (GWAS) and gene-expression profiling have generated a large number of valuable datasets for assessing how genetic variations are related to disease outcomes. With such datasets, it is often of interest to assess the overall effect of a set of genetic markers, assembled based on biological knowledge. Genetic marker-set analyses have been advocated as more reliable and powerful approaches compared with the traditional marginal approaches (Curtis and others, 2005. Pathways to the analysis of microarray data. TRENDS in Biotechnology 23, 429-435; Efroni and others, 2007. Identification of key processes underlying cancer phenotypes using biologic pathway analysis. PLoS One 2, 425). Procedures for testing the overall effect of a marker-set have been actively studied in recent years. For example, score tests derived under an Empirical Bayes (EB) framework (Liu and others, 2007. Semiparametric regression of multidimensional genetic pathway data: least-squares kernel machines and linear mixed models. Biometrics 63, 1079-1088; Liu and others, 2008. Estimation and testing for the effect of a genetic pathway on a disease outcome using logistic kernel machine regression via logistic mixed models. BMC bioinformatics 9, 292-2; Wu and others, 2010. Powerful SNP-set analysis for case-control genome-wide association studies. American Journal of Human Genetics 86, 929) have been proposed as powerful alternatives to the standard Rao score test (Rao, 1948. Large sample tests of statistical hypotheses concerning several parameters with applications to problems of estimation. Mathematical Proceedings of the Cambridge Philosophical Society, 44, 50-57). The advantages of these EB-based tests are most apparent when the markers are correlated, due to the reduction in the degrees of freedom. In this paper, we propose an adaptive score test which up- or down-weights the contributions from each member of the marker-set based on the Z-scores of

  20. Fostering Informed Choice: Alleviating the Trauma of Genetic Abortions.

    Science.gov (United States)

    Asbury, Bret D

    2015-01-01

    Each year, thousands of pregnant women learn of fetal abnormalities through prenatal genetic analysis. This discovery--made after a woman has initially declined to exercise her right to abort an unwanted pregnancy—raises the difficult and heart-wrenching question of whether to terminate on genetic grounds. Women considering a genetic abortion rely on information and support from health care providers to assist them in making their choice. Though intended to be objective and nondirective, the support women receive frequently provides them within complete and incomprehensible information having the effect of encouraging them to abort genetically anomalous fetuses. As a result, genetic terminations--which cause severe and long-standing psychological impacts such as pathological grief, depression and post-traumatic stress—are often the result of something other than a fully informed choice.Congress and eleven states have recognized the importance of better informing choice by passing legislation aimed at providing clearer and more balanced information to expectant mothers learning of fetal genetic abnormalities. But existing legislative remedies do not adequately address this problem, and this inadequacy will become more pronounced in future years as increases in access to prenatal genetic analysis further stretch the capabilities of the available support services.This Article describes the unique characteristics of terminations for a fetal abnormality, their troubling and persistent psychological impacts,and the reasons why they will become more common in future years. It then offers proposals for how to reconfigure the prenatal genetic counseling landscape in order to reduce the incidence of genetic terminations based on incomplete or misleading information, thereby alleviating their distinct psychological costs. Its overall objective is to ensure that women learning of prenatal genetic abnormalities have access to complete and comprehensible information prior to

  1. Privacy and intra-familiy communication of genetic information.

    Science.gov (United States)

    Moniz, Helena

    2004-01-01

    The new knowledge (and predictions) created by DNA tests and the family nature of genetic information has already lead to a new problem: the intra-familiar communication of genetic data. This raises questions such as the following. Is there a duty to inform in cases when treatment is possible and the patient does not permit disclosure of genetic results to relatives? Is there an obligation to warn or merely an authorization (that could be used or not)? Could privacy protection be maintain as an individual interest but with some justified violations? A balance needs to be establishes between the interest of privacy and the need to disclose secret information.

  2. Genetic differences between the determinants of lipid profile phenotypes in African and European Americans: the Jackson Heart Study.

    Directory of Open Access Journals (Sweden)

    Rahul C Deo

    2009-01-01

    Full Text Available Genome-wide association analysis in populations of European descent has recently found more than a hundred genetic variants affecting risk for common disease. An open question, however, is how relevant the variants discovered in Europeans are to other populations. To address this problem for cardiovascular phenotypes, we studied a cohort of 4,464 African Americans from the Jackson Heart Study (JHS, in whom we genotyped both a panel of 12 recently discovered genetic variants known to predict lipid profile levels in Europeans and a panel of up to 1,447 ancestry informative markers allowing us to determine the African ancestry proportion of each individual at each position in the genome. Focusing on lipid profiles -- HDL-cholesterol (HDL-C, LDL-cholesterol (LDL-C, and triglycerides (TG -- we identified the lipoprotein lipase (LPL locus as harboring variants that account for interethnic variation in HDL-C and TG. In particular, we identified a novel common variant within LPL that is strongly associated with TG (p = 2.7 x 10(-6 and explains nearly 1% of the variability in this phenotype, the most of any variant in African Americans to date. Strikingly, the extensively studied "gain-of-function" S447X mutation at LPL, which has been hypothesized to be the major determinant of the LPL-TG genetic association and is in trials for human gene therapy, has a significantly diminished strength of biological effect when it is found on a background of African rather than European ancestry. These results suggest that there are other, yet undiscovered variants at the locus that are truly causal (and are in linkage disequilibrium with S447X or that work synergistically with S447X to modulate TG levels. Finally, we find systematically lower effect sizes for the 12 risk variants discovered in European populations on the African local ancestry background in JHS, highlighting the need for caution in the use of genetic variants for risk assessment across different

  3. Phenotypic and genetic characterization of a novel phenotype in pigs characterized by juvenile hairlessness and age dependent emphysema

    DEFF Research Database (Denmark)

    Bruun, Camilla S.; Jørgensen, Claus B.; Bay, Lene

    2008-01-01

    Background: A pig phenotype characterized by juvenile hairlessness, thin skin and age dependent lung emphysema has been discovered in a Danish pig herd. The trait shows autosomal co-dominant inheritance with all three genotypes distinguishable. Since the phenotype shows resemblance to the integrin...... of musculi arrectores pili, and at puberty or later localized areas of emphysema are seen in the lungs. Comparative mapping predicted that the porcine ITGB6 and ITGAV orthologs map to SSC15. In an experimentall family (n=113), showing segregation of the trait, the candidate region was confirmed by linkage...

  4. Multivariate genetic analysis of atopy phenotypes in a selected sample of twins

    DEFF Research Database (Denmark)

    Thomsen, SF; Ulrik, Charlotte Suppli; Kyvik, KO

    2006-01-01

    , airway hyper-responsiveness (AHR), and positive skin prick test (posSPT) in a sample of adult twins. METHODS: Within a sampling frame of 21,162 twin subjects, 20-49 years of age, from the Danish Twin Registry, a total of 575 subjects (256 intact pairs and 63 single twins), who either themselves and....../or their co-twins reported a history of asthma at a nationwide questionnaire survey, were clinically examined. Symptoms of wheeze and rhinitis were obtained by interview; airway responsiveness and skin test reactivity were measured using standard techniques. Correlations in liability between the different...... traits were estimated and latent factor models of genetic and environmental effects were fitted to the observed data using maximum likelihood methods. RESULTS: The various phenotypic correlations between wheeze, rhinitis, AHR and posSPT were all significant and ranged between 0.50 and 0.86. Traits...

  5. Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability.

    Science.gov (United States)

    Beckmann, Jacques S; Estivill, Xavier; Antonarakis, Stylianos E

    2007-08-01

    A considerable and unanticipated plasticity of the human genome, manifested as inter-individual copy number variation, has been discovered. These structural changes constitute a major source of inter-individual genetic variation that could explain variable penetrance of inherited (Mendelian and polygenic) diseases and variation in the phenotypic expression of aneuploidies and sporadic traits, and might represent a major factor in the aetiology of complex, multifactorial traits. For these reasons, an effort should be made to discover all common and rare copy number variants (CNVs) in the human population. This will also enable systematic exploration of both SNPs and CNVs in association studies to identify the genomic contributors to the common disorders and complex traits.

  6. Genetic and phenotypic characteristics of importance for clonal success and diversity in Salmonella

    DEFF Research Database (Denmark)

    Müller, Karoline

    dominance of certain clones. These epidemically successful clones are often resistant to antibiotics and associated with severe human illness. They pose a major threat to public health and lead to heavy economic losses. So far, little is known about the environmental and bacterial factors leading......, the isolates were categorized based on their antibiotic resistance pattern into quinolone resistant (Q; at least low level resistance to one fluoroquinolone), multidrug resistant (MR; resistant to four or more antibiotic agents), resistant (R; resistant to less than four antibiotic agents) and sensitive (S...... to freezing nor to dehydration appears to contribute to the epidemic success of Salmonella. MR and Q Salmonella seem to have a virulence or fitness advantage apart from the effect posed by the antibiotic resistance phenotype. Manuscript II describes a study aiming to identify genes and genetic structures in Q...

  7. Heritabilities and genetic and phenotypic correlations of litter uniformity and litter size in Large White sows

    Institute of Scientific and Technical Information of China (English)

    ZHANG Tian; ZHAO Ke-bin; WANG Li-xian; WANG Li-gang; SHI Hui-bi; YAN Hua; ZHANG Long-chao; LIU Xin; PU Lei; LIANG Jing; ZHANG Yue-bo

    2016-01-01

    Litter uniformity, which is usualy represented by within-litter weight coefifcient of variation at birth (CVB), could inlfuence litter performance of sows and the proiftability of pig enterprises. The objective of this study was to characterize CVB and its effect on other reproductive traits in Large White sows. Genetic parameters and genetic correlation of the reproductive traits, including CVB, within-litter weight coefifcient of variation at three weeks (CVT), total number born (TNB), number born alive (NBA), number born dead (NBD), gestation length (GL), piglet mortality at birth (M0), piglet mortality at three weeks (M3), total litter weight at birth (TLW0), and total litter weight at three weeks (TLW3) were estimated for 2032 Large White litters. The effects of parity and classiifed litter size on CVB, CVT, TNB, NBA, NBD, GL, M0, M3, TLW0, and TLW3 were also estimated. The heritabilities of these reproductive traits ranged from 0.06 to 0.17, with the lowest heritability for CVB and the highest heritability for TLW0. Phenotypic and genetic correlations between these reproductive traits were low to highly positive and negative (ranging from −0.03 to 0.93, and −0.53 to 0.93, respectively). The genetic correlations between TNB and CVB, and between M0 and CVB were 0.32 and 0.29, respectively. In addition, CVB was signiifcantly inlfuenced by parity and litter size class (P<0.05). Al the results suggest that piglet uniformity should be maintained in pig production practices and pig breeding programs.

  8. Relationship of disease-associated gene expression to cardiac phenotype is buffered by genetic diversity and chromatin regulation.

    Science.gov (United States)

    Karbassi, Elaheh; Monte, Emma; Chapski, Douglas J; Lopez, Rachel; Rosa Garrido, Manuel; Kim, Joseph; Wisniewski, Nicholas; Rau, Christoph D; Wang, Jessica J; Weiss, James N; Wang, Yibin; Lusis, Aldons J; Vondriska, Thomas M

    2016-08-01

    Expression of a cohort of disease-associated genes, some of which are active in fetal myocardium, is considered a hallmark of transcriptional change in cardiac hypertrophy models. How this transcriptome remodeling is affected by the common genetic variation present in populations is unknown. We examined the role of genetics, as well as contributions of chromatin proteins, to regulate cardiac gene expression and heart failure susceptibility. We examined gene expression in 84 genetically distinct inbred strains of control and isoproterenol-treated mice, which exhibited varying degrees of disease. Unexpectedly, fetal gene expression was not correlated with hypertrophic phenotypes. Unbiased modeling identified 74 predictors of heart mass after isoproterenol-induced stress, but these predictors did not enrich for any cardiac pathways. However, expanded analysis of fetal genes and chromatin remodelers as groups correlated significantly with individual systemic phenotypes. Yet, cardiac transcription factors and genes shown by gain-/loss-of-function studies to contribute to hypertrophic signaling did not correlate with cardiac mass or function in disease. Because the relationship between gene expression and phenotype was strain specific, we examined genetic contribution to expression. Strikingly, strains with similar transcriptomes in the basal heart did not cluster together in the isoproterenol state, providing comprehensive evidence that there are different genetic contributors to physiological and pathological gene expression. Furthermore, the divergence in transcriptome similarity versus genetic similarity between strains is organ specific and genome-wide, suggesting chromatin is a critical buffer between genetics and gene expression.

  9. Invited commentary: Personality phenotype and mortality--new avenues in genetic, social, and clinical epidemiology.

    Science.gov (United States)

    Chapman, Benjamin P

    2013-09-01

    In this issue of the Journal, Jokela et al. (Am J Epidemiol. 2013;178(5):667-675) scrutinize the association between personality phenotype and all-cause mortality in remarkable detail by using an "individual-participant meta-analysis" design. Across 7 large cohorts varying in demographics and methods of personality measurement, they find varying prospective associations for 4 dimensions of the five-factor (or "Big Five") model of personality, but robust and consistent prospective associations for Big Five dimension of "conscientiousness." Jokela et al. place an important exclamation point on a long era of study of this topic and hint directly and indirectly at new avenues for this line of research. I consider the following 3 areas particularly rife for further inquiry: the role of genetics in personality and health studies; the role of personality in social inequalities in health; and the health policy and clinical implications of work like that of Jokela et al., including the potential role of personality phenotype in the evolution of personalized medicine.

  10. Development, anatomy, and genetic control of some teratological phenotypes of Ranunculaceae flowers

    Directory of Open Access Journals (Sweden)

    Florian Jabbour

    2016-04-01

    Full Text Available Teratological organisms originate from developmental anomalies, and exhibit structures and a body organization that deviate from the species standard. These monsters give essential clues about the formation and evolutionary significance of the wild-type groundplan. We focus on flower terata, which can be affected in their sterile and/or fertile organs, with special emphasis on the Ranunculaceae. The diversity of perianth shapes and organizations in flowers of this family is huge, and is even increased when anomalies occur during organo- and/or morphogenesis. To begin with, we synthesize the observations and research conducted on the Ranunculacean floral terata, following the most recent phylogenetic framework published in 2016 by our team. Then, we report results regarding the morphology of developing meristems, the anatomy of buds, and the genetic control of selected teratological phenotypes of Ranunculaceae flowers. We focus on species and horticultural varieties belonging to the genera Aquilegia, Delphinium, and Nigella. Wildtype flowers of these species are actinomorphic (Aquilegia, Nigella or zygomorphic (Delphinium, spurred (Aquilegia, Delphinium or with pocket-like petals (Nigella. Last, we discuss the evolutionary potential of such teratological phenotypes when they occur in the wild.

  11. Genetic and phenotypic parameters estimated from Nebraska specific-pathogen-free swine field records.

    Science.gov (United States)

    David, P J; Johnson, R K; Socha, T E

    1983-11-01

    Records collected during 1971 through 1979 from 101,606 hogs raised in 18 Nebraska Specific Pathogen Free herds were analyzed. Traits considered were backfat at 100 kg (BF), weight at 140 d of age (WT) and, in some analyses, number of live pigs/litter at birth (NBA). The phenotypic correlation of BF and WT, averaged across herds, was -.07. The correlations between BF and NBA and between WT and NBA were .04 and -.05, respectively. Average phenotypic standard deviations for BF, WT and NBA were 2.6 mm, 8.8 kg and 2.0 pigs. Estimates of the heritability of BF and WT were lower than most estimates reported from university research herds. Within breed, herd and sex estimates of heritability ranged from -.22 and .51 (unweighted mean = .16 +/- .025) for BF and ranged from -.28 to .49 (mean = .16 +/- .016) for WT. Estimates of the genetic correlation between BF and WT were extremely variable (mean = -.62 +/- 14.3, range = -9.42 to 1.30) among breed-herd-sex subclasses.

  12. Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort.

    Science.gov (United States)

    Lindquist, S G; Schwartz, M; Batbayli, M; Waldemar, G; Nielsen, J E

    2009-08-01

    Autosomal dominantly transmitted Alzheimer's disease (AD) and frontotemporal dementia (FTD) are genetically heterogeneous disorders. To date, three genes have been identified in which mutations cause early-onset autosomal dominant inherited AD: APP, PSEN1, and PSEN2. Mutations in two genes on chromosome 17, the MAPT and the PGRN genes, are associated with autosomal dominant inherited FTD. The aim of this study was to characterize the mutation spectrum and describe genotype-phenotype correlations in families with inherited dementia. The identification of novel mutations and/or atypical genotype-phenotype correlations contributes to further characterizing the disorders. DNA-samples from the 90 index cases from a Danish referral-based cohort representing families with presumed autosomal dominant inherited AD or FTD were screened for mutations in the known genes with sequencing, denaturing high-performance liquid chromatography (DHPLC) and multiplex ligation-dependent probe amplification (MLPA) techniques. Seven presumed pathogenic mutations (two PSEN1, one PSEN2, one APP, one MAPT, and two PGRN) were identified, including a novel PSEN2 mutation (V393M). No dosage aberrations were identified.

  13. Mitochondrial genetics and hearing loss: the missing link between genotype and phenotype.

    Science.gov (United States)

    Fischel-Ghodsian, N

    1998-05-01

    Mitochondrial DNA mutations have been implicated in a great variety of diseases, including such common ones as diabetes, Parkinson's disease and Alzheimer's, but the pathophysiological pathway leading from a specific mutation to a specific phenotype has remained elusive. Individuals with the same mutation can fall along a clinical spectrum ranging from asymptomatic to severely affected, and can even have completely different diseases. Much of this phenotypic heterogeneity has been attributed to the heteroplasmic nature of mitochondrial mutations, with both normal and mutated mitochondrial chromosomes being present in different proportions and tissue distributions. Isolated hearing loss is one of the only mitochondrial disorders that can be caused by homoplasmic mutations (e.g., only mutated mitochondrial mutations are present in all tissues). This review will outline the relationship between mitochondrial mutations and hearing loss while showing that even in a homoplasmic model, the two basic questions of mitochondrial genetics, penetrance and tissue specificity, remain unanswered: Why does the same mutation cause severe hearing loss in some family members but not in others, and why is the ear the only organ affected?

  14. Genetic deletion of fibroblast growth factor 14 recapitulates phenotypic alterations underlying cognitive impairment associated with schizophrenia

    Science.gov (United States)

    Alshammari, T K; Alshammari, M A; Nenov, M N; Hoxha, E; Cambiaghi, M; Marcinno, A; James, T F; Singh, P; Labate, D; Li, J; Meltzer, H Y; Sacchetti, B; Tempia, F; Laezza, F

    2016-01-01

    Cognitive processing is highly dependent on the functional integrity of gamma-amino-butyric acid (GABA) interneurons in the brain. These cells regulate excitability and synaptic plasticity of principal neurons balancing the excitatory/inhibitory tone of cortical networks. Reduced function of parvalbumin (PV) interneurons and disruption of GABAergic synapses in the cortical circuitry result in desynchronized network activity associated with cognitive impairment across many psychiatric disorders, including schizophrenia. However, the mechanisms underlying these complex phenotypes are still poorly understood. Here we show that in animal models, genetic deletion of fibroblast growth factor 14 (Fgf14), a regulator of neuronal excitability and synaptic transmission, leads to loss of PV interneurons in the CA1 hippocampal region, a critical area for cognitive function. Strikingly, this cellular phenotype associates with decreased expression of glutamic acid decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) and also coincides with disrupted CA1 inhibitory circuitry, reduced in vivo gamma frequency oscillations and impaired working memory. Bioinformatics analysis of schizophrenia transcriptomics revealed functional co-clustering of FGF14 and genes enriched within the GABAergic pathway along with correlatively decreased expression of FGF14, PVALB, GAD67 and VGAT in the disease context. These results indicate that Fgf14−/− mice recapitulate salient molecular, cellular, functional and behavioral features associated with human cognitive impairment, and FGF14 loss of function might be associated with the biology of complex brain disorders such as schizophrenia. PMID:27163207

  15. The vascular phenotype in pseudoxanthoma elasticum and related disorders: Contribution of a genetic disease to the understanding of vascular calcification.

    Directory of Open Access Journals (Sweden)

    Georges eLeftheriotis

    2013-02-01

    Full Text Available Vascular calcification is a complex and dynamic process occurring in various physiological conditions such as aging and exercise or in acquired metabolic disorders like diabetes or chronic renal insufficiency. Arterial calcifications are also observed in several genetic diseases revealing the important role of unbalanced or defective anti- or pro-calcifying factors. Pseudoxanthoma elasticum (PXE is an inherited disease (OMIM 264800 characterized by elastic fiber fragmentation and calcification in various soft conjunctive tissues including the skin, eyes and arterial media. The PXE disease results from mutations in the ABCC6 gene, encoding an ATP-binding cassette transporter primarily expressed in the liver, kidneys suggesting that it is a prototypic metabolic soft-tissue calcifying disease of genetic origin. The clinical expression of the PXE arterial disease is characterized by an increased risk for coronary (myocardial infarction, cerebral (aneurysm and stroke and lower limb peripheral artery disease. However, the structural and functional changes in the arterial wall induced by PXE are still unexplained. The use of a recombinant mouse model inactivated for the Abcc6 gene is an important tool for the understanding of the PXE pathophysiology although the vascular impact in this model remains limited to date. Overlapping of the PXE phenotype with other inherited calcifying diseases could bring important informations to our comprehension of the PXE disease.

  16. Model selection emphasises the importance of non-chromosomal information in genetic studies.

    Directory of Open Access Journals (Sweden)

    Reda Rawi

    Full Text Available Ever since the case of the missing heritability was highlighted some years ago, scientists have been investigating various possible explanations for the issue. However, none of these explanations include non-chromosomal genetic information. Here we describe explicitly how chromosomal and non-chromosomal modifiers collectively influence the heritability of a trait, in this case, the growth rate of yeast. Our results show that the non-chromosomal contribution can be large, adding another dimension to the estimation of heritability. We also discovered, combining the strength of LASSO with model selection, that the interaction of chromosomal and non-chromosomal information is essential in describing phenotypes.

  17. Clinical phenotype in genetically confirmed von Willebrand disease type 2N patients reflects a haemophilia A phenotype

    NARCIS (Netherlands)

    Meegeren, M.E.R. van; Mancini, T.L.; Schoormans, S.C.M.; Haren, B.J.T. van; Duren, C. van; Diekstra, A.; Laros-van Gorkom, B.A.P.; Brons, P.P.; Simons, A.; Hoefsloot, L.H.; Heerde, W.L. van

    2015-01-01

    INTRODUCTION: Von Willebrand disease (VWD) type 2N is characterized by a defective binding of factor VIII (FVIII) to von Willebrand factor (VWF) resulting in diminished plasma FVIII levels and a clinical phenotype mimicking mild haemophilia A. Several mutations in the FVIII binding site of VWF have

  18. Genetic and Rare Diseases Information Center (GARD)

    Data.gov (United States)

    Federal Laboratory Consortium — NCATS collaborates with the National Human Genome Research Institute (NHGRI) to support GARD, a center designed to provide comprehensive information about rare and...

  19. Genetic and phenotypic variance and covariance components for methane emission and postweaning traits in Angus cattle.

    Science.gov (United States)

    Donoghue, K A; Bird-Gardiner, T; Arthur, P F; Herd, R M; Hegarty, R F

    2016-04-01

    Ruminants contribute 80% of the global livestock greenhouse gas (GHG) emissions mainly through the production of methane, a byproduct of enteric microbial fermentation primarily in the rumen. Hence, reducing enteric methane production is essential in any GHG emissions reduction strategy in livestock. Data on 1,046 young bulls and heifers from 2 performance-recording research herds of Angus cattle were analyzed to provide genetic and phenotypic variance and covariance estimates for methane emissions and production traits and to examine the interrelationships among these traits. The cattle were fed a roughage diet at 1.2 times their estimated maintenance energy requirements and measured for methane production rate (MPR) in open circuit respiration chambers for 48 h. Traits studied included DMI during the methane measurement period, MPR, and methane yield (MY; MPR/DMI), with means of 6.1 kg/d (SD 1.3), 132 g/d (SD 25), and 22.0 g/kg (SD 2.3) DMI, respectively. Four forms of residual methane production (RMP), which is a measure of actual minus predicted MPR, were evaluated. For the first 3 forms, predicted MPR was calculated using published equations. For the fourth (RMP), predicted MPR was obtained by regression of MPR on DMI. Growth and body composition traits evaluated were birth weight (BWT), weaning weight (WWT), yearling weight (YWT), final weight (FWT), and ultrasound measures of eye muscle area, rump fat depth, rib fat depth, and intramuscular fat. Heritability estimates were moderate for MPR (0.27 [SE 0.07]), MY (0.22 [SE 0.06]), and the RMP traits (0.19 [SE 0.06] for each), indicating that genetic improvement to reduce methane emissions is possible. The RMP traits and MY were strongly genetically correlated with each other (0.99 ± 0.01). The genetic correlation of MPR with MY as well as with the RMP traits was moderate (0.32 to 0.63). The genetic correlation between MPR and the growth traits (except BWT) was strong (0.79 to 0.86). These results indicate that

  20. Analysis of the genetic relationships and diversity among 11 populations of Xanthoceras sorbifolia using phenotypic and microsatellite marker data

    Directory of Open Access Journals (Sweden)

    Zhan Shen

    2017-03-01

    Conclusions: Microsatellite markers can be used to efficiently distinguish X. sorbifolia populations and assess their genetic diversity. The information we have provided will contribute to the conservation and management of this important plant genetic resource.

  1. Mild folate deficiency induces genetic and epigenetic instability and phenotype changes in prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Matsui Sei-Ichi

    2010-01-01

    Full Text Available Abstract Background Folate (vitamin B9 is essential for cellular proliferation as it is involved in the biosynthesis of deoxythymidine monophosphate (dTMP and s-adenosylmethionine (AdoMet. The link between folate depletion and the genesis and progression of cancers of epithelial origin is of high clinical relevance, but still unclear. We recently demonstrated that sensitivity to low folate availability is affected by the rate of polyamine biosynthesis, which is prominent in prostate cells. We, therefore, hypothesized that prostate cells might be highly susceptible to genetic, epigenetic and phenotypic changes consequent to folate restriction. Results We studied the consequences of long-term, mild folate depletion in a model comprised of three syngenic cell lines derived from the transgenic adenoma of the mouse prostate (TRAMP model, recapitulating different stages of prostate cancer; benign, transformed and metastatic. High-performance liquid chromatography analysis demonstrated that mild folate depletion (100 nM sufficed to induce imbalance in both the nucleotide and AdoMet pools in all prostate cell lines. Random oligonucleotide-primed synthesis (ROPS revealed a significant increase in uracil misincorporation and DNA single strand breaks, while spectral karyotype analysis (SKY identified five novel chromosomal rearrangements in cells grown with mild folate depletion. Using global approaches, we identified an increase in CpG island and histone methylation upon folate depletion despite unchanged levels of total 5-methylcytosine, indicating a broad effect of folate depletion on epigenetic regulation. These genomic changes coincided with phenotype changes in the prostate cells including increased anchorage-independent growth and reduced sensitivity to folate depletion. Conclusions This study demonstrates that prostate cells are highly susceptible to genetic and epigenetic changes consequent to mild folate depletion as compared to cells grown with

  2. Mild folate deficiency induces genetic and epigenetic instability and phenotype changes in prostate cancer cells

    Science.gov (United States)

    2010-01-01

    Background Folate (vitamin B9) is essential for cellular proliferation as it is involved in the biosynthesis of deoxythymidine monophosphate (dTMP) and s-adenosylmethionine (AdoMet). The link between folate depletion and the genesis and progression of cancers of epithelial origin is of high clinical relevance, but still unclear. We recently demonstrated that sensitivity to low folate availability is affected by the rate of polyamine biosynthesis, which is prominent in prostate cells. We, therefore, hypothesized that prostate cells might be highly susceptible to genetic, epigenetic and phenotypic changes consequent to folate restriction. Results We studied the consequences of long-term, mild folate depletion in a model comprised of three syngenic cell lines derived from the transgenic adenoma of the mouse prostate (TRAMP) model, recapitulating different stages of prostate cancer; benign, transformed and metastatic. High-performance liquid chromatography analysis demonstrated that mild folate depletion (100 nM) sufficed to induce imbalance in both the nucleotide and AdoMet pools in all prostate cell lines. Random oligonucleotide-primed synthesis (ROPS) revealed a significant increase in uracil misincorporation and DNA single strand breaks, while spectral karyotype analysis (SKY) identified five novel chromosomal rearrangements in cells grown with mild folate depletion. Using global approaches, we identified an increase in CpG island and histone methylation upon folate depletion despite unchanged levels of total 5-methylcytosine, indicating a broad effect of folate depletion on epigenetic regulation. These genomic changes coincided with phenotype changes in the prostate cells including increased anchorage-independent growth and reduced sensitivity to folate depletion. Conclusions This study demonstrates that prostate cells are highly susceptible to genetic and epigenetic changes consequent to mild folate depletion as compared to cells grown with supraphysiological

  3. A comparative study on genetic and environmental influences on metabolic phenotypes in Eastern (Chinese) and Western (Danish) populations

    DEFF Research Database (Denmark)

    Li, Shuxia

    2015-01-01

    the risk of clinic diseases e.g. diabetes, atherosclerosis, stroke and cardiovascular disease. Metabolic phenotypes, similar to most complex traits, can be influenced by both genetic and environmental factors as well as their interplay. Many family and twin studies have demonstrated both genetic...... and environmental factors play important role in the variation of metabolic phenotypes and intra-individual change over time. Although both genetic and environmental factors are involved the development of metabolic disorders, the role of environment should be emphasized as the expression or function of gene can...... be regulated to adapt to existing environmental circumstance. In other words, adaptive evolution in populations under distinct environmental and cultural circumstances could have resulted in varying genetic basis of metabolic factors and development of metabolic disorders or diseases. Thus, it can...

  4. Information transmission in genetic regulatory networks: a review

    Science.gov (United States)

    Tkačik, Gašper; Walczak, Aleksandra M.

    2011-04-01

    Genetic regulatory networks enable cells to respond to changes in internal and external conditions by dynamically coordinating their gene expression profiles. Our ability to make quantitative measurements in these biochemical circuits has deepened our understanding of what kinds of computations genetic regulatory networks can perform, and with what reliability. These advances have motivated researchers to look for connections between the architecture and function of genetic regulatory networks. Transmitting information between a network's inputs and outputs has been proposed as one such possible measure of function, relevant in certain biological contexts. Here we summarize recent developments in the application of information theory to gene regulatory networks. We first review basic concepts in information theory necessary for understanding recent work. We then discuss the functional complexity of gene regulation, which arises from the molecular nature of the regulatory interactions. We end by reviewing some experiments that support the view that genetic networks responsible for early development of multicellular organisms might be maximizing transmitted 'positional information'.

  5. Information transmission in genetic regulatory networks: a review.

    Science.gov (United States)

    Tkačik, Gašper; Walczak, Aleksandra M

    2011-04-20

    Genetic regulatory networks enable cells to respond to changes in internal and external conditions by dynamically coordinating their gene expression profiles. Our ability to make quantitative measurements in these biochemical circuits has deepened our understanding of what kinds of computations genetic regulatory networks can perform, and with what reliability. These advances have motivated researchers to look for connections between the architecture and function of genetic regulatory networks. Transmitting information between a network's inputs and outputs has been proposed as one such possible measure of function, relevant in certain biological contexts. Here we summarize recent developments in the application of information theory to gene regulatory networks. We first review basic concepts in information theory necessary for understanding recent work. We then discuss the functional complexity of gene regulation, which arises from the molecular nature of the regulatory interactions. We end by reviewing some experiments that support the view that genetic networks responsible for early development of multicellular organisms might be maximizing transmitted 'positional information'.

  6. Breed-specific hematological phenotypes in the dog: a natural resource for the genetic dissection of hematological parameters in a mammalian species.

    Directory of Open Access Journals (Sweden)

    Jennifer Lawrence

    Full Text Available Remarkably little has been published on hematological phenotypes of the domestic dog, the most polymorphic species on the planet. Information on the signalment and complete blood cell count of all dogs with normal red and white blood cell parameters judged by existing reference intervals was extracted from a veterinary database. Normal hematological profiles were available for 6046 dogs, 5447 of which also had machine platelet concentrations within the reference interval. Seventy-five pure breeds plus a mixed breed control group were represented by 10 or more dogs. All measured parameters except mean corpuscular hemoglobin concentration (MCHC varied with age. Concentrations of white blood cells (WBCs, neutrophils, monocytes, lymphocytes, eosinophils and platelets, but not red blood cell parameters, all varied with sex. Neutering status had an impact on hemoglobin concentration, mean corpuscular hemoglobin (MCH, MCHC, and concentrations of WBCs, neutrophils, monocytes, lymphocytes and platelets. Principal component analysis of hematological data revealed 37 pure breeds with distinctive phenotypes. Furthermore, all hematological parameters except MCHC showed significant differences between specific individual breeds and the mixed breed group. Twenty-nine breeds had distinctive phenotypes when assessed in this way, of which 19 had already been identified by principal component analysis. Tentative breed-specific reference intervals were generated for breeds with a distinctive phenotype identified by comparative analysis. This study represents the first large-scale analysis of hematological phenotypes in the dog and underlines the important potential of this species in the elucidation of genetic determinants of hematological traits, triangulating phenotype, breed and genetic predisposition.

  7. Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework.

    Science.gov (United States)

    Fanous, A H; Kendler, K S

    2005-01-01

    Schizophrenia has long been thought to be clinically heterogeneous. A range of studies suggests that this is due to genetic heterogeneity. Some clinical features, such as negative symptoms, are associated with a greater risk of illness in relatives. Affected sibling pairs are correlated for clinical and course features as well as subforms of illness, and twin studies suggest that this is due to genetic factors. This is further supported by findings that subjects from families linked to some chromosomal regions may differ clinically from those from unlinked families. Moreover, some genes may affect clinical features without altering susceptibility (ie are modifier genes). High-risk genotypes may have quantitative, rather than categorical effects, and may influence milder or subclinical phenotypes. Another recent finding is that nonpsychotic relatives may have personality features that resemble those of their affected relatives. These findings taken together suggest that there may be several classes of gene action in schizophrenia: some genes may influence susceptibility only, others may influence clinical features only, and still others may have a mixed effect. Furthermore, subsets of these classes may affect personality and other traits in nonpsychotic relatives. Understanding these classes of gene action may help guide the design of linkage and association studies that have increased power. We describe five classes of genes and their predictions of the outcomes of family, twin, and several types of linkage studies. We go on to explore how these predictions can in turn be used to aid in the design of linkage studies.

  8. Phenotypic effects of genetic variability in human clock genes on circadian and sleep parameters

    Indian Academy of Sciences (India)

    Malcolm Von Schantz

    2008-12-01

    Circadian rhythms and sleep are two separate but intimately related processes. Circadian rhythms are generated through the precisely controlled, cyclic expression of a number of genes designated clock genes. Genetic variability in these genes has been associated with a number of phenotypic differences in circadian as well as sleep parameters, both in mouse models and in humans. Diurnal preferences as determined by the selfreported Horne–Östberg (HÖ) questionnaire, has been associated with polymorphisms in the human genes CLOCK, PER1, PER2 and PER3. Circadian rhythm-related sleep disorders have also been associated with mutations and polymorphisms in clock genes, with the advanced type cosegrating in an autosomal dominant inheritance pattern with mutations in the genes PER2 and CSNK1D, and the delayed type associating without discernible Mendelian inheritance with polymorphisms in CLOCK and PER3. Several mouse models of clock gene null alleles have been demonstrated to have affected sleep homeostasis. Recent findings have shown that the variable number tandem polymorphism in PER3, previously linked to diurnal preference, has profound effects on sleep homeostasis and cognitive performance following sleep loss, confirming the close association between the processes of circadian rhythms and sleep at the genetic level.

  9. Mouse models for pseudoxanthoma elasticum: genetic and dietary modulation of the ectopic mineralization phenotypes.

    Directory of Open Access Journals (Sweden)

    Qiaoli Li

    Full Text Available Pseudoxanthoma elasticum (PXE, a heritable ectopic mineralization disorder, is caused by mutations in the ABCC6 gene. Null mice (Abcc6(-/- recapitulate the genetic, histopathologic and ultrastructural features of PXE, and they demonstrate early and progressive mineralization of vibrissae dermal sheath, which serves as a biomarker of the overall mineralization process. Recently, as part of a mouse aging study at The Jackson Laboratory, 31 inbred mouse strains were necropsied, and two of them, KK/HlJ and 129S1/SvImJ, were noted to have vibrissae dermal mineralization similar to Abcc6(-/- mice. These two strains were shown to harbor a single nucleotide polymorphism (rs32756904 in the Abcc6 gene, which resulted in out-of-frame splicing and marked reduction in ABCC6 protein expression in the liver of these mice. The same polymorphism is present in two additional mouse strains, DBA/2J and C3H/HeJ, with similar reduction in Abcc6 protein levels, yet these mice did not demonstrate tissue mineralization when kept on standard rodent diet. However, all four mouse strains, when placed on experimental diet enriched in phosphate and low in magnesium, developed extensive ectopic mineralization. These results indicate that the genetic background of mice and the mineral composition of their diet can profoundly modulate the ectopic mineralization process predicated on mutations in the Abcc6 gene. These mice provide novel model systems to study the pathomechanisms and the reasons for strain background on phenotypic variability of PXE.

  10. Multivariate analysis of complex gene expression and clinical phenotypes with genetic marker data.

    Science.gov (United States)

    Beyene, Joseph; Tritchler, David; Bull, Shelley B; Cartier, Kevin C; Jonasdottir, Gudrun; Kraja, Aldi T; Li, Na; Nock, Nora L; Parkhomenko, Elena; Rao, J Sunil; Stein, Catherine M; Sutradhar, Rinku; Waaijenborg, Sandra; Wang, Ke-Sheng; Wang, Yuanjia; Wolkow, Pavel

    2007-01-01

    This paper summarizes contributions to group 12 of the 15th Genetic Analysis Workshop. The papers in this group focused on multivariate methods and applications for the analysis of molecular data including genotypic data as well as gene expression microarray measurements and clinical phenotypes. A range of multivariate techniques have been employed to extract signals from the multi-feature data sets that were provided by the workshop organizers. The methods included data reduction techniques such as principal component analysis and cluster analysis; latent variable models including structural equations and item response modeling; joint multivariate modeling techniques as well as multivariate visualization tools. This summary paper categorizes and discusses individual contributions with regard to multiple classifications of multivariate methods. Given the wide variety in the data considered, the objectives of the analysis and the methods applied, direct comparison of the results of the various papers is difficult. However, the group was able to make many interesting comparisons and parallels between the various approaches. In summary, there was a consensus among authors in group 12 that the genetic research community should continue to draw experiences from other fields such as statistics, econometrics, chemometrics, computer science and linear systems theory.

  11. A Validated Phenotyping Algorithm for Genetic Association Studies in Age-related Macular Degeneration

    Science.gov (United States)

    Simonett, Joseph M.; Sohrab, Mahsa A.; Pacheco, Jennifer; Armstrong, Loren L.; Rzhetskaya, Margarita; Smith, Maureen; Geoffrey Hayes, M.; Fawzi, Amani A.

    2015-01-01

    Age-related macular degeneration (AMD), a multifactorial, neurodegenerative disease, is a leading cause of vision loss. With the rapid advancement of DNA sequencing technologies, many AMD-associated genetic polymorphisms have been identified. Currently, the most time consuming steps of these studies are patient recruitment and phenotyping. In this study, we describe the development of an automated algorithm to identify neovascular (wet) AMD, non-neovascular (dry) AMD and control subjects using electronic medical record (EMR)-based criteria. Positive predictive value (91.7%) and negative predictive value (97.5%) were calculated using expert chart review as the gold standard to assess algorithm performance. We applied the algorithm to an EMR-linked DNA bio-repository to study previously identified AMD-associated single nucleotide polymorphisms (SNPs), using case/control status determined by the algorithm. Risk alleles of three SNPs, rs1061170 (CFH), rs1410996 (CFH), and rs10490924 (ARMS2) were found to be significantly associated with the AMD case/control status as defined by the algorithm. With the rapid growth of EMR-linked DNA biorepositories, patient selection algorithms can greatly increase the efficiency of genetic association study. We have found that stepwise validation of such an algorithm can result in reliable cohort selection and, when coupled within an EMR-linked DNA biorepository, replicates previously published AMD-associated SNPs. PMID:26255974

  12. Mutual Entropy in Quantum Information and Information Genetics

    CERN Document Server

    Ohya, M

    2004-01-01

    After Shannon, entropy becomes a fundamental quantity to describe not only uncertainity or chaos of a system but also information carried by the system. Shannon's important discovery is to give a mathematical expression of the mutual entropy (information), information transmitted from an input system to an output system, by which communication processes could be analyzed on the stage of mathematical science. In this paper, first we review the quantum mutual entropy and discuss its uses in quantum information theory, and secondly we show how the classical mutual entropy can be used to analyze genomes, in particular, those of HIV.

  13. Population-based resequencing of APOA1 in 10,330 individuals: spectrum of genetic variation, phenotype, and comparison with extreme phenotype approach.

    Science.gov (United States)

    Haase, Christiane L; Frikke-Schmidt, Ruth; Nordestgaard, Børge G; Tybjærg-Hansen, Anne

    2012-01-01

    Rare genetic variants, identified by in-detail resequencing of loci, may contribute to complex traits. We used the apolipoprotein A-I gene (APOA1), a major high-density lipoprotein (HDL) gene, and population-based resequencing to determine the spectrum of genetic variants, the phenotypic characteristics of these variants, and how these results compared with results based on resequencing only the extremes of the apolipoprotein A-I (apoA-I) distribution. First, we resequenced APOA1 in 10,330 population-based participants in the Copenhagen City Heart Study. The spectrum and distribution of genetic variants was determined as a function of the number of individuals resequenced. Second, apoA-I and HDL cholesterol phenotypes were determined for nonsynonymous (NS) and synonymous (S) variants and were validated in the Copenhagen General Population Study (n = 45,239). Third, observed phenotypes were compared with those predicted using an extreme phenotype approach based on the apoA-I distribution. Our results are as follows: First, population-based resequencing of APOA1 identified 40 variants of which only 7 (18%) had minor allele frequencies >1%, and most were exceedingly rare. Second, 0.27% of individuals in the general population were heterozygous for NS variants which were associated with substantial reductions in apoA-I (up to 39 mg/dL) and/or HDL cholesterol (up to 0.9 mmol/L) and, surprisingly, 0.41% were heterozygous for variants predisposing to amyloidosis. NS variants associated with a hazard ratio of 1.72 (1.09-2.70) for myocardial infarction (MI), largely driven by A164S, a variant not associated with apoA-I or HDL cholesterol levels. Third, using the extreme apoA-I phenotype approach, NS variants correctly predicted the apoA-I phenotype observed in the population-based resequencing. However, using the extreme approach, between 79% (screening 0-1(st) percentile) and 21% (screening 0-20(th) percentile) of all variants were not identified; among these were variants

  14. Admixture mapping of end stage kidney disease genetic susceptibility using estimated mutual information ancestry informative markers

    Directory of Open Access Journals (Sweden)

    Geiger Dan

    2010-10-01

    Full Text Available Abstract Background The question of a genetic contribution to the higher prevalence and incidence of end stage kidney disease (ESKD among African Americans (AA remained unresolved, until recent findings using admixture mapping pointed to the association of a genomic locus on chromosome 22 with this disease phenotype. In the current study we utilize this example to demonstrate the utility of applying a multi-step admixture mapping approach. Methods A multi-step case only admixture mapping study, consisted of the following steps was designed: 1 Assembly of the sample dataset (ESKD AA; 2 Design of the estimated mutual information ancestry informative markers (n = 2016 screening panel 3; Genotyping the sample set whose size was determined by a power analysis (n = 576 appropriate for the initial screening panel; 4 Inference of local ancestry for each individual and identification of regions with increased AA ancestry using two different ancestry inference statistical approaches; 5 Enrichment of the initial screening panel; 6 Power analysis of the enriched panel 7 Genotyping of additional samples. 8 Re-analysis of the genotyping results to identify a genetic risk locus. Results The initial screening phase yielded a significant peak using the ADMIXMAP ancestry inference program applying case only statistics. Subgroup analysis of 299 ESKD patients with no history of diabetes yielded peaks using both the ANCESTRYMAP and ADMIXMAP ancestry inference programs. The significant peak was found on chromosome 22. Genotyping of additional ancestry informative markers on chromosome 22 that took into account linkage disequilibrium in the ancestral populations, and the addition of samples increased the statistical significance of the finding. Conclusions A multi-step admixture mapping analysis of AA ESKD patients replicated the finding of a candidate risk locus on chromosome 22, contributing to the heightened susceptibility of African Americans to develop non

  15. Thermal phenotypic plasticity of body size in Drosophila melanogaster: sexual dimorphism and genetic correlations

    Indian Academy of Sciences (India)

    Jean R. David; Amir Yassin; Jean-Claude Moreteau; Helene Legout; Brigitte Moreteau

    2011-08-01

    Thirty isofemale lines collected in three different years from the same wild French population were grown at seven different temperatures (12–31°C). Two linear measures, wing and thorax length, were taken on 10 females and 10 males of each line at each temperature, also enabling the calculation of the wing/thorax (W/T) ratio, a shape index related to wing loading. Genetic correlations were calculated using family means. The W–T correlation was independent of temperature and on average, 0.75. For each line, characteristic values of the temperature reaction norm were calculated, i.e. maximum value, temperature of maximum value and curvature. Significant negative correlations were found between curvature and maximum value or temperature of maximum value. Sexual dimorphism was analysed by considering either the correlation between sexes or the female/male ratio. Female–male correlation was on average 0.75 at the within line, within temperature level but increased up to 0.90 when all temperatures were averaged for each line. The female/male ratio was genetically variable among lines but without any temperature effect. For the female/male ratio, heritability (intraclass correlation) was about 0.20 and evolvability (genetic coefficient of variation) close to 1. Although significant, these values are much less than for the traits themselves. Phenotypic plasticity of sexual dimorphism revealed very similar reaction norms for wing and thorax length, i.e. a monotonically increasing sigmoid curve from about 1.11 up to 1.17. This shows that the males are more sensitive to a thermal increase than females. In contrast, the W/T ratio was almost identical in both sexes, with only a very slight temperature effect.

  16. Genetics

    Science.gov (United States)

    ... Inheritance; Heterozygous; Inheritance patterns; Heredity and disease; Heritable; Genetic markers ... The chromosomes are made up of strands of genetic information called DNA. Each chromosome contains sections of ...

  17. Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection.

    NARCIS (Netherlands)

    Pearson, E.R.; Pruhova, S.; Tack, C.J.J.; Johansen, A.; Castleden, H.A.; Lumb, P.J.; Wierzbicki, A.S.; Clark, P.M.; Lebl, J.; Pedersen, O.; Ellard, S.; Hansen, T.; Hattersley, A.T.

    2005-01-01

    AIMS/HYPOTHESIS: Heterozygous mutations in the gene of the transcription factor hepatocyte nuclear factor 4alpha (HNF-4alpha) are considered a rare cause of MODY with only 14 mutations reported to date. The description of the phenotype is limited to single families. We investigated the genetics and

  18. Inference of tumor evolution during chemotherapy by computational modeling and in situ analysis of genetic and phenotypic cellular diversity

    NARCIS (Netherlands)

    Almendro, Vanessa; Cheng, Yu-Kang; Randles, Amanda; Itzkovitz, Shalev; Marusyk, Andriy; Ametller, Elisabet; Gonzalez-Farre, Xavier; Muñoz, Montse; Russnes, Hege G; Helland, Aslaug; Rye, Inga H; Borresen-Dale, Anne-Lise; Maruyama, Reo; van Oudenaarden, Alexander; Dowsett, Mitchell; Jones, Robin L; Reis-Filho, Jorge; Gascon, Pere; Gönen, Mithat; Michor, Franziska; Polyak, Kornelia

    2014-01-01

    Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-

  19. Factor analysis in the Genetics of Asthma International Network family study identifies five major quantitative asthma phenotypes

    NARCIS (Netherlands)

    Pillai, S. G.; Tang, Y.; van den Oord, E.; Klotsman, M.; Barnes, K.; Carlsen, K.; Gerritsen, J.; Lenney, W.; Silverman, M.; Sly, P.; Sundy, J.; Tsanakas, J.; von Berg, A.; Whyte, M.; Ortega, H. G.; Anderson, W. H.; Helms, P. J.

    2008-01-01

    Background Asthma is a clinically heterogeneous disease caused by a complex interaction between genetic susceptibility and diverse environmental factors. In common with other complex diseases the lack of a standardized scheme to evaluate the phenotypic variability poses challenges in identifying the

  20. Phenotypic and genetic evaluation of elbow dysplasia in Dutch Labrador Retrievers, Golden Retrievers, and Bernese Mountain dogs

    NARCIS (Netherlands)

    Lavrijsen, I.C.M.; Heuven, H.C.M.; Voorhout, G.; Meij, B.P.; Theyse, L.F.H.; Leegwater, P.A.J.; Hazewinkel, H.A.W.

    2012-01-01

    Vet J. 2012 Aug;193(2):486-92. doi: 10.1016/j.tvjl.2012.01.001. Epub 2012 Feb 14. Phenotypic and genetic evaluation of elbow dysplasia in Dutch Labrador Retrievers, Golden Retrievers, and Bernese Mountain dogs. Lavrijsen IC, Heuven HC, Voorhout G, Meij BP, Theyse LF, Leegwater PA, Hazewinkel HA.

  1. Non-CLL-like monoclonal B-Cell lymphocytosis in the general population: Prevalence and phenotypic/genetic characteristics

    NARCIS (Netherlands)

    W.G. Nieto (Wendy); C. Teodosio (Cristina); A. López (Antonio); A. Rodríguez-Caballero (Arancha); A. Romero (Alfonso); P. Bárcena (Paloma); M.L. Gutierrez; A.W. Langerak (Anton); P. Fernandez-Navarro (Paulino); A. Orfao; J. Almeida (Julia); A.O.M.C.C.S. Santa Marta de Tormes; B.H.P.C.S. Garrido Sur; C.L.M.T.C.S. Ledesma; C.R.J.M.C.S. Alba de Tormes; C.L.R.C.S.F. Villalobos; D.V.P.J.C.S. Peñaranda; F.E.E.C.S. Pizarrales-Vidal; G.R.B.L.C.S. La Alberca; G.S.F.C.S. Periurbana Norte; G.M.J.C.S. Guijuelo; G.M.J.M.C.S. Vitigudino; J.R.M.J.C.S. Garrido Norte; J.C.T.B.C.S. Elena Ginel Diez; M.P.M.C.S. Fuentes de Oñoro; M.L.J.C.S. San Juan; M.D.M.P.C.S. Miguel Armijo; S.A.B.C.S. Aldeadavila de La Ribera; S.P.R.C.S. San Jose

    2010-01-01

    textabstractBackground: Monoclonal B-cell lymphocytosis (MBL) indicates <5 × 109peripheral blood (PB) clonal B-cells/L in healthy individuals. In most cases, MBL cells show similar phenotypic/genetic features to chronic lymphocytic leukemia cells - CLL-like MBL - but little is known about

  2. Data from: Genetic variation in variability: phenotypic variability of fledging weight and its evolution in a songbird population

    NARCIS (Netherlands)

    Mulder, H.A.; Gienapp, P.; Visser, M.E.

    2016-01-01

    Variation in traits is essential for natural selection to operate and genetic and environmental effects can contribute to this phenotypic variation. From domesticated populations, we know that families can differ in their level of within-family variance, which leads to the intriguing situation that

  3. The influence of gene flow and drift on genetic and phenotypic divergence in two species of Zosterops in Vanuatu.

    Science.gov (United States)

    Clegg, Sonya M; Phillimore, Albert B

    2010-04-12

    Colonization of an archipelago sets the stage for adaptive radiation. However, some archipelagos are home to spectacular radiations, while others have much lower levels of diversification. The amount of gene flow among allopatric populations is one factor proposed to contribute to this variation. In island colonizing birds, selection for reduced dispersal ability is predicted to produce changing patterns of regional population genetic structure as gene flow-dominated systems give way to drift-mediated divergence. If this transition is important in facilitating phenotypic divergence, levels of genetic and phenotypic divergence should be associated. We consider population genetic structure and phenotypic divergence among two co-distributed, congeneric (Genus: Zosterops) bird species inhabiting the Vanuatu archipelago. The more recent colonist, Z. lateralis, exhibits genetic patterns consistent with a strong influence of distance-mediated gene flow. However, complex patterns of asymmetrical gene flow indicate variation in dispersal ability or inclination among populations. The endemic species, Z. flavifrons, shows only a partial transition towards a drift-mediated system, despite a long evolutionary history on the archipelago. We find no strong evidence that gene flow constrains phenotypic divergence in either species, suggesting that levels of inter-island gene flow do not explain the absence of a radiation across this archipelago.

  4. Non-CLL-like monoclonal B-Cell lymphocytosis in the general population: Prevalence and phenotypic/genetic characteristics

    NARCIS (Netherlands)

    W.G. Nieto (Wendy); C. Teodosio (Cristina); A. López (Antonio); A. Rodríguez-Caballero (Arancha); A. Romero (Alfonso); P. Bárcena (Paloma); M.L. Gutierrez; A.W. Langerak (Ton); P. Fernandez-Navarro (Paulino); A. Orfao; J. Almeida (Julia); A.O.M.C.C.S. Santa Marta de Tormes; B.H.P.C.S. Garrido Sur; C.L.M.T.C.S. Ledesma; C.R.J.M.C.S. Alba de Tormes; C.L.R.C.S.F. Villalobos; D.V.P.J.C.S. Peñaranda; F.E.E.C.S. Pizarrales-Vidal; G.R.B.L.C.S. La Alberca; G.S.F.C.S. Periurbana Norte; G.M.J.C.S. Guijuelo; G.M.J.M.C.S. Vitigudino; J.R.M.J.C.S. Garrido Norte; J.C.T.B.C.S. Elena Ginel Diez; M.P.M.C.S. Fuentes de Oñoro; M.L.J.C.S. San Juan; M.D.M.P.C.S. Miguel Armijo; S.A.B.C.S. Aldeadavila de La Ribera; S.P.R.C.S. San Jose

    2010-01-01

    textabstractBackground: Monoclonal B-cell lymphocytosis (MBL) indicates <5 × 109peripheral blood (PB) clonal B-cells/L in healthy individuals. In most cases, MBL cells show similar phenotypic/genetic features to chronic lymphocytic leukemia cells - CLL-like MBL - but little is known about non-CLL-li

  5. Genetic and phenotypic correlations between feather pecking behavior, stress response, immune reponse, and egg quality traits in laying hens

    NARCIS (Netherlands)

    Buitenhuis, A.J.; Rodenburg, T.B.; Wissink, P.H.; Visscher, J.; Koene, P.; Bovenhuis, H.; Ducro, B.J.; Poel, van der J.J.

    2004-01-01

    The objective of the current study was to estimate genetic and phenotypic correlations among feather pecking (FP) behavior and stress response, immune response, and egg quality parameters. These traits have been measured in an F-2 cross, coming from a cross between a high and a low FP line of laying

  6. Power and sample size calculations in the presence of phenotype errors for case/control genetic association studies

    Directory of Open Access Journals (Sweden)

    Finch Stephen J

    2005-04-01

    Full Text Available Abstract Background Phenotype error causes reduction in power to detect genetic association. We present a quantification of phenotype error, also known as diagnostic error, on power and sample size calculations for case-control genetic association studies between a marker locus and a disease phenotype. We consider the classic Pearson chi-square test for independence as our test of genetic association. To determine asymptotic power analytically, we compute the distribution's non-centrality parameter, which is a function of the case and control sample sizes, genotype frequencies, disease prevalence, and phenotype misclassification probabilities. We derive the non-centrality parameter in the presence of phenotype errors and equivalent formulas for misclassification cost (the percentage increase in minimum sample size needed to maintain constant asymptotic power at a fixed significance level for each percentage increase in a given misclassification parameter. We use a linear Taylor Series approximation for the cost of phenotype misclassification to determine lower bounds for the relative costs of misclassifying a true affected (respectively, unaffected as a control (respectively, case. Power is verified by computer simulation. Results Our major findings are that: (i the median absolute difference between analytic power with our method and simulation power was 0.001 and the absolute difference was no larger than 0.011; (ii as the disease prevalence approaches 0, the cost of misclassifying a unaffected as a case becomes infinitely large while the cost of misclassifying an affected as a control approaches 0. Conclusion Our work enables researchers to specifically quantify power loss and minimum sample size requirements in the presence of phenotype errors, thereby allowing for more realistic study design. For most diseases of current interest, verifying that cases are correctly classified is of paramount importance.

  7. Phenotypic and Genetic Characterization of a Cohort of Pediatric Wilson Disease Patients

    Directory of Open Access Journals (Sweden)

    Elnaghy Suzan

    2011-06-01

    Full Text Available Abstract Background In Egypt, Wilson disease seems to be under diagnosed and clinical data on large cohorts are limited. The aim of this study is to highlight the clinical, laboratory and genetic characteristics of this disease in our pediatric population as well as to report our experience with both treatment options and outcome. Methods The study included 77 patients from 50 unrelated families (62 were followed up for a mean period of 58.9 ± 6.4 months and 27 were asymptomatic siblings. Data were collected retrospectively by record analysis and patient interviews. Diagnosis was confirmed by sequencing of the ATP7B gene in 64 patients Results Our patients had unique characteristics compared to other populations. They had a younger age of onset (median: 10 years, higher prevalence of Kayser-Fleischer rings (97.6% in the symptomatic patients, low ceruloplasmin (93.5%, high rate of parental consanguinity (78.9% as well as a more severe course. 71.42% of those on long term D-penicillamine improved or were stable during the follow up with severe side effects occurring in only 11.5%. Preemptive treatment with zinc monotherapy was an effective non-toxic alternative to D-penicillamine. Homozygous mutations were found in 85.7%, yet limited by the large number of mutations detected, it was difficult to find genotype-phenotype correlations. Missense mutations were the most common while protein-truncating mutations resulted in a more severe course with higher incidence of acute liver failure and neurological symptoms. Conclusions Egyptian children with Wilson disease present with early Kayser-Fleischer rings and early onset of liver and neurological disease. The mutational spectrum identified differs from that observed in other countries. The high rate of homozygous mutations (reflecting the high rate of consanguinity may potentially offer further insights on genotype-phenotype correlation

  8. Differential phenotypic and genetic expression of defence compounds in a plant-herbivore interaction along elevation.

    Science.gov (United States)

    Salgado, Ana L; Suchan, Tomasz; Pellissier, Loïc; Rasmann, Sergio; Ducrest, Anne-Lyse; Alvarez, Nadir

    2016-09-01

    Elevation gradients impose large differences in abiotic and biotic conditions over short distances, in turn, likely driving differences in gene expression more than would genetic variation per se, as natural selection and drift are less likely to fix alleles at such a narrow spatial scale. As elevation increases, the pressure exerted on plants by herbivores and on arthropod herbivores by predators decreases, and organisms spanning the elevation gradient are thus expected to show lower levels of defence at high elevation. The alternative hypothesis, based on the optimal defence theory, is that defence allocation should be higher in low-resource habitats such as those at high elevation, due to higher costs associated with tissue replacement. In this study, we analyse variation with elevation in (i) defence compound content in the plant Lotus corniculatus and (ii) gene expression associated with defence against predators in the specific phytophagous moth, Zygaena filipendulae. Both species produce cyanogenic glycosides (CNglcs) such as lotaustralin and linamarin as defence mechanisms, with the moth, in addition, being able to sequester CNglcs from its host plant. Specifically, we tested the assumption that the defence-associated phenotype in plants and the gene expression in the insect herbivore should covary between low- and high-elevation environments. We found that L. corniculatus accumulated more CNglcs at high elevation, a result in agreement with the optimal defence theory. By contrast, we found that the levels of expression in the defence genes of Z. filipendulae larvae were not related to the CNglc content of their host plant. Overall, expression levels were not correlated with elevation either, with the exception of the UGT33A1 gene, which showed a marginally significant trend towards higher expression at high elevation when using a simple statistical framework. These results suggest that the defence phenotype of plants against herbivores, and subsequent

  9. Differential phenotypic and genetic expression of defence compounds in a plant–herbivore interaction along elevation

    Science.gov (United States)

    Salgado, Ana L.; Suchan, Tomasz; Pellissier, Loïc; Rasmann, Sergio; Ducrest, Anne-Lyse

    2016-01-01

    Elevation gradients impose large differences in abiotic and biotic conditions over short distances, in turn, likely driving differences in gene expression more than would genetic variation per se, as natural selection and drift are less likely to fix alleles at such a narrow spatial scale. As elevation increases, the pressure exerted on plants by herbivores and on arthropod herbivores by predators decreases, and organisms spanning the elevation gradient are thus expected to show lower levels of defence at high elevation. The alternative hypothesis, based on the optimal defence theory, is that defence allocation should be higher in low-resource habitats such as those at high elevation, due to higher costs associated with tissue replacement. In this study, we analyse variation with elevation in (i) defence compound content in the plant Lotus corniculatus and (ii) gene expression associated with defence against predators in the specific phytophagous moth, Zygaena filipendulae. Both species produce cyanogenic glycosides (CNglcs) such as lotaustralin and linamarin as defence mechanisms, with the moth, in addition, being able to sequester CNglcs from its host plant. Specifically, we tested the assumption that the defence-associated phenotype in plants and the gene expression in the insect herbivore should covary between low- and high-elevation environments. We found that L. corniculatus accumulated more CNglcs at high elevation, a result in agreement with the optimal defence theory. By contrast, we found that the levels of expression in the defence genes of Z. filipendulae larvae were not related to the CNglc content of their host plant. Overall, expression levels were not correlated with elevation either, with the exception of the UGT33A1 gene, which showed a marginally significant trend towards higher expression at high elevation when using a simple statistical framework. These results suggest that the defence phenotype of plants against herbivores, and subsequent

  10. [Phenotypic and genetic features of cultural-morphologic variants of Bacillus anthracis].

    Science.gov (United States)

    Tsygankova, O I; Eremenko, E I; Tsygankova, E A; Buravtseva, N P; Riazanova, A G

    2008-01-01

    Comparative analysis of MVLA-genotypes of 6 Bacillus anthracis strains and 40 their variants differing on capsule- and toxin synthesis, hemolytic, proteolytic and lecitinase activity, nutritional requirements, susceptibility to anthrax bacteriophages, virulence, immunogenicity, and presence of genes for capsule and toxin synthesis was performed. Results of phylogenetic analysis of 5 chromosome locuses and plasmid locus pXO1aat which are variable for this sample of B. anthracis cultures showed that all strains divided on 2 main clusters - A and B. Cluster A consisted of 5 genotypes whereas cluster B - of 1 genotype. All highly virulent original strains and variants with characteristic phenotype Cap(CO2)(+)(O2)(-)Tox(+)ProtA(+)Hly(+) Lec(-)Trp(+) had identical genotype in 4 groups and in 5th group differences were present only in vrrA locus. All original strains and variants with the most atypical complex of phenotypic characteristics Cap (CO2)(+)(O2)(+)Tox(-)ProtA(-)Hly(-)Lec(-)Trp(-) also had the same genotype belonging to cluster B and diverged on characteristic of 5 chromosomal VNTR locuses and pXO1aat locus from typical strains. Absence of toxin production in vitro was not related to loss of genetic determinants of toxin components. Cultures with typical characteristics, one of which was ability to produce toxin in vitro, had larger sizes of amplicons of pXO1aat locus (135 and 132 nbp), whereas atoxigenic original strains and variants with complex of atypical characteristics and identical chromosome genotype had the smallest sizes (123 bnp). All original cultures were isolated in Russia, their genotypes are described for the first time.

  11. Toward a genetically-informed model of borderline personality disorder.

    Science.gov (United States)

    Livesley, John

    2008-02-01

    This article describes a conceptual framework for describing borderline personality disorder (BPD) based on empirical studies of the phenotypic structure and genetic architecture of personality. The proposed phenotype has 2 components: (1) a description of core self and interpersonal pathology-the defining features of personality disorder-as these features are expressed in the disorder; and (2) a set of traits based on the anxious-dependent or emotional dysregulation factor of the four-factor model of PD. Four kinds of traits are described: emotional (anxiousness, emotional reactivity, emotional intensity, and pessimistic-anhedonia), interpersonal (submissiveness, insecure attachment, social apprehensiveness, and need for approval), cognitive (cognitive dysregulation), and self-harm (behaviors and ideas). Formulation of the phenotype was guided by the conceptualization of personality as a system of interrelated sub-systems. The psychopathology associated with BPD involves most components of the system. The trait structure of the disorder is assumed to reflect the genetic architecture of personality and individual traits are assumed to be based on adaptive mechanisms. It is suggested that borderline traits are organized around the trait of anxiousness and that an important feature of BPD is dysregulation of the threat management system leading to pervasive fearfulness and unstable emotions. The interpersonal traits are assumed to be heritable characteristics that evolved to deal with interpersonal threats that arose as a result of social living. The potential for unstable and conflicted interpersonal relationships that is inherent to the disorder is assumed to result from the interplay between the adaptive structure of personality and psychosocial adversity. The etiology of the disorder is discussed in terms of biological and environmental factors associated with each component of the phenotype.

  12. Genetic selection for context-dependent stochastic phenotypes: Sp1 and TATA mutations increase phenotypic noise in HIV-1 gene expression.

    Directory of Open Access Journals (Sweden)

    Kathryn Miller-Jensen

    Full Text Available The sequence of a promoter within a genome does not uniquely determine gene expression levels and their variability; rather, promoter sequence can additionally interact with its location in the genome, or genomic context, to shape eukaryotic gene expression. Retroviruses, such as human immunodeficiency virus-1 (HIV, integrate their genomes into those of their host and thereby provide a biomedically-relevant model system to quantitatively explore the relationship between promoter sequence, genomic context, and noise-driven variability on viral gene expression. Using an in vitro model of the HIV Tat-mediated positive-feedback loop, we previously demonstrated that fluctuations in viral Tat-transactivating protein levels generate integration-site-dependent, stochastically-driven phenotypes, in which infected cells randomly 'switch' between high and low expressing states in a manner that may be related to viral latency. Here we extended this model and designed a forward genetic screen to systematically identify genetic elements in the HIV LTR promoter that modulate the fraction of genomic integrations that specify 'Switching' phenotypes. Our screen identified mutations in core promoter regions, including Sp1 and TATA transcription factor binding sites, which increased the Switching fraction several fold. By integrating single-cell experiments with computational modeling, we further investigated the mechanism of Switching-fraction enhancement for a selected Sp1 mutation. Our experimental observations demonstrated that the Sp1 mutation both impaired Tat-transactivated expression and also altered basal expression in the absence of Tat. Computational analysis demonstrated that the observed change in basal expression could contribute significantly to the observed increase in viral integrations that specify a Switching phenotype, provided that the selected mutation affected Tat-mediated noise amplification differentially across genomic contexts. Our study

  13. Juglans regia L., phenotypic selection and assessment of genetic variation within a simulated seed orchard

    Directory of Open Access Journals (Sweden)

    Fulvio Ducci

    2010-12-01

    Full Text Available Normal 0 14 false false false MicrosoftInternetExplorer4 Noble hardwoods are very important for the Italian furniture industry. Since 1985, approximately 170,000 ha have been planted in Italy with noble hardwoods. Among them, about 50% of species are represented by walnuts. Walnut (Juglans regia L., not native in Italy, has been the focus of a substantial research effort for breeding and improvement programmes. The priority has been to preserve the in situ genetic resource still existing after intensive felling. Phenotypes suitable for timber production showing important traits such as straight stem, nice branch architecture, dominance and adaptation (phenology have needed to be developed and selected. In order to reach this goals, selection of valuable progenies and the evaluation of the interaction genotype x environment, methods based essentially on a multi-trait Selection Index, were developed. Studies have been undertaken also to measure the variation of phenological traits, more correlated to traits valuable for architecture; in addition, neutral markers were used to assess genetic variation among different intensities of the adopted selections. The individual genetic component was found to be higher than at the inter-population level. Results showed that a hypothetical seed orchard made with progenies selected by morphology, phenology and genetic traits could provide material with a good performance and supply a variability similar to larger populations as the total plantation or the pseudo-natural system chosen for comparison. st1\\:*{behavior:url(#ieooui } /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Tabella normale"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman"; mso-ansi-language:#0400; mso

  14. Dubowitz syndrome is a complex comprised of multiple, genetically distinct and phenotypically overlapping disorders.

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    Douglas R Stewart

    Full Text Available Dubowitz syndrome is a rare disorder characterized by multiple congenital anomalies, cognitive delay, growth failure, an immune defect, and an increased risk of blood dyscrasia and malignancy. There is considerable phenotypic variability, suggesting genetic heterogeneity. We clinically characterized and performed exome sequencing and high-density array SNP genotyping on three individuals with Dubowitz syndrome, including a pair of previously-described siblings (Patients 1 and 2, brother and sister and an unpublished patient (Patient 3. Given the siblings' history of bone marrow abnormalities, we also evaluated telomere length and performed radiosensitivity assays. In the siblings, exome sequencing identified compound heterozygosity for a known rare nonsense substitution in the nuclear ligase gene LIG4 (rs104894419, NM_002312.3:c.2440C>T that predicts p.Arg814X (MAF:0.0002 and an NM_002312.3:c.613delT variant that predicts a p.Ser205Leufs*29 frameshift. The frameshift mutation has not been reported in 1000 Genomes, ESP, or ClinSeq. These LIG4 mutations were previously reported in the sibling sister; her brother had not been previously tested. Western blotting showed an absence of a ligase IV band in both siblings. In the third patient, array SNP genotyping revealed a de novo ∼ 3.89 Mb interstitial deletion at chromosome 17q24.2 (chr 17:62,068,463-65,963,102, hg18, which spanned the known Carney complex gene PRKAR1A. In all three patients, a median lymphocyte telomere length of ≤ 1st centile was observed and radiosensitivity assays showed increased sensitivity to ionizing radiation. Our work suggests that, in addition to dyskeratosis congenita, LIG4 and 17q24.2 syndromes also feature shortened telomeres; to confirm this, telomere length testing should be considered in both disorders. Taken together, our work and other reports on Dubowitz syndrome, as currently recognized, suggest that it is not a unitary entity but instead a collection of

  15. Origins of biological information and the genetic code

    Science.gov (United States)

    Fox, S. W.

    1974-01-01

    Information, defined as the capacity of a molecule or system for selective interactions with other molecules or systems, is followed through its evolution from prebiological information to protoribosomes. Emphasis is on proteins and protein-like polymers, and later on ATP. The research will contribute more to the understanding of the essence of the genetic mechanism.

  16. Communicating genetic risk information within families: a review.

    Science.gov (United States)

    Wiseman, Mel; Dancyger, Caroline; Michie, Susan

    2010-12-01

    This review of family communication of genetic risk information addresses questions of what the functions and influences on communication are; what, who and how family members are told about genetic risk information; what the impact for counsellee, relative and relationships are; whether there are differences by gender and condition; and what theories and methodologies are used. A systematic search strategy identified peer-reviewed journal articles published 1985-2009 using a mixture of methodologies. A Narrative Synthesis was used to extract and summarise data relevant to the research questions. This review identified 33 articles which found a consistent pattern of findings that communication about genetic risk within families is influenced by individual beliefs about the desirability of communicating genetic risk and by closeness of relationships within the family. None of the studies directly investigated the impact of communication on counsellees or their families, differences according to gender of counsellee or by condition nor alternative methods of communication with relatives. The findings mainly apply to late onset conditions such as Hereditary Breast and Ovarian Cancer. The most frequently used theory was Family Systems Theory and methods were generally qualitative. This review points to multifactorial influences on who is communicated with in families and what they are told about genetic risk information. Further research is required to investigate the impact of genetic risk information on family systems and differences between genders and conditions.

  17. Incorporating privileged genetic information for fundus image based glaucoma detection.

    Science.gov (United States)

    Duan, Lixin; Xu, Yanwu; Li, Wen; Chen, Lin; Wing, Damon Wing Kee; Wong, Tien Yin; Liu, Jiang

    2014-01-01

    Visual features extracted from retinal fundus images have been increasingly used for glaucoma detection, as those images are generally easy to acquire. In recent years, genetic researchers have found that some single nucleic polymorphisms (SNPs) play important roles in the manifestation of glaucoma and also show superiority over fundus images for glaucoma detection. In this work, we propose to use the SNPs to form the so-called privileged information and deal with a practical problem where both fundus images and privileged genetic information exist for the training subjects, while the test objects only have fundus images. To solve this problem, we present an effective approach based on the learning using privileged information (LUPI) paradigm to train a predictive model for the image visual features. Extensive experiments demonstrate the usefulness of our approach in incorporating genetic information for fundus image based glaucoma detection.

  18. Low-Anxiety Rat Phenotypes Can Be Further Reduced through Genetic Intervention

    Science.gov (United States)

    Granzotto, Natalli; Ramos, André

    2013-01-01

    Background A previous study using an intercross between the inbred rat strains Lewis (LEW) and Spontaneously Hypertensive Rats (SHR) identified a locus on chromosome 4, named Anxrr16, influencing an experimental index of anxiety and showing a transgressive effect, with alleles from the LEW strain (more anxious) decreasing rather than increasing anxiety. Objective To confirm the location and isolate the effect of a rat genome region named Anxrr16 through a planned genomic recombination strategy, where the target locus in SHR rats was replaced with LEW genetic material. Methods A new congenic strain, named SHR.LEW-Anxrr16 (SLA16), was developed from a cross between LEW (donor) and SHR (receptor) rats and then evaluated in several anxiety-related tests. The activity and attention levels of the new strain were also evaluated, since hyperactivity was observed during its construction and because SHR is a model of attention deficit hyperactivity disorder. Results Significant effects of Anxrr16 were found for open field central locomotion, as well as for other indices of anxiety from the light/dark box, triple test and T-maze. In all cases, the low-anxiety levels of SHR rats were further reduced by the insertion of LEW alleles. Differences in locomotor activity were found only in unfamiliar (hence stressful) environments and no genetic effects were observed in indices of attention. Conclusion The SLA16 strain can help in the identification of the molecular pathways involved in experimental anxiety and it demonstrates how apparently extreme phenotypes sometimes hide major opposite-acting genes. PMID:24386249

  19. Genetic microheterogeneity and phenotypic variation of Helicobacter pylori arginase in clinical isolates

    Directory of Open Access Journals (Sweden)

    Spadafora Domenico

    2007-04-01

    Full Text Available Abstract Background Clinical isolates of the gastric pathogen Helicobacter pylori display a high level of genetic macro- and microheterogeneity, featuring a panmictic, rather than clonal structure. The ability of H. pylori to survive the stomach acid is due, in part, to the arginase-urease enzyme system. Arginase (RocF hydrolyzes L-arginine to L-ornithine and urea, and urease hydrolyzes urea to carbon dioxide and ammonium, which can neutralize acid. Results The degree of variation in arginase was explored at the DNA sequence, enzyme activity and protein expression levels. To this end, arginase activity was measured from 73 minimally-passaged clinical isolates and six laboratory-adapted strains of H. pylori. The rocF gene from 21 of the strains was cloned into genetically stable E. coli and the enzyme activities measured. Arginase activity was found to substantially vary (>100-fold in both different H. pylori strains and in the E. coli model. Western blot analysis revealed a positive correlation between activity and amount of protein expressed in most H. pylori strains. Several H. pylori strains featured altered arginase activity upon in vitro passage. Pairwise alignments of the 21 rocF genes plus strain J99 revealed extensive microheterogeneity in the promoter region and 3' end of the rocF coding region. Amino acid S232, which was I232 in the arginase-negative clinical strain A2, was critical for arginase activity. Conclusion These studies demonstrated that H. pylori arginase exhibits extensive genotypic and phenotypic variation which may be used to understand mechanisms of microheterogeneity in H. pylori.

  20. Genes Predisposing to Thoracic Aortic Aneurysms and Dissections: Associated Phenotypes, Gene-Specific Management, and Genetic Testing

    Science.gov (United States)

    Milewicz, Dianna M.; Carlson, Alicia A.; Regalado, Ellen S.

    2011-01-01

    Thoracic aortic aneurysms leading to type A dissections (TAAD) are the major diseases affecting the aorta. A genetic predisposition for TAAD can occur as part of a genetic syndrome, as is the case for Marfan syndrome, due to mutations in FBN1, and Loeys-Dietz syndrome, which results from mutations in either TGFBR1 or TGFBR2. A predisposition to TAAD in the absence of syndromic features can be inherited in an autosomal dominant manner with decreased penetrance and variable expression, termed familial TAAD. Familial TAAD exhibits clinical and genetic heterogeneity. Genetic heterogeneity for familial TAAD has been demonstrated by the identification of four genes leading to TAAD, including TGFBR2 and TGFBR1, MYH11, and ACTA2. The phenotype and management of patients harboring mutations in these genes, along with genetic testing, will be addressed in this review. PMID:20452526

  1. Law & psychiatry: Genetic discrimination in mental disorders: the impact of the genetic information nondiscrimination act.

    Science.gov (United States)

    Appelbaum, Paul S

    2010-04-01

    Genetics is one of the most active areas of research on mental disorders. As genetic tests related to psychiatric disorders and their treatments proliferate in research and clinical settings, the possibility becomes more troubling that such information will be used for purposes other than those for which it was collected. Because of this, the federal Genetic Information Nondiscrimination Act of 2008 is of substantial importance to persons with mental disorders, persons at risk for the conditions, and family members of both groups. This column discusses the process of passing the legislation, along with the implications of the act.

  2. Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies.

    Science.gov (United States)

    Zhu, Hao; Shah, Samar; Shyh-Chang, Ng; Shinoda, Gen; Einhorn, William S; Viswanathan, Srinivas R; Takeuchi, Ayumu; Grasemann, Corinna; Rinn, John L; Lopez, Mary F; Hirschhorn, Joel N; Palmert, Mark R; Daley, George Q

    2010-07-01

    Recently, genome-wide association studies have implicated the human LIN28B locus in regulating height and the timing of menarche. LIN28B and its homolog LIN28A are functionally redundant RNA-binding proteins that block biogenesis of let-7 microRNAs. lin-28 and let-7 were discovered in Caenorhabditis elegans as heterochronic regulators of larval and vulval development but have recently been implicated in cancer, stem cell aging and pluripotency. The let-7 targets Myc, Kras, Igf2bp1 and Hmga2 are known regulators of mammalian body size and metabolism. To explore the function of the Lin28-Let-7 pathway in vivo, we engineered transgenic mice to express Lin28a and observed in them increased body size, crown-rump length and delayed onset of puberty. Investigation of metabolic and endocrine mechanisms of overgrowth in these transgenic mice revealed increased glucose metabolism and insulin sensitivity. Here we report a mouse that models the human phenotypes associated with genetic variation in the Lin28-Let-7 pathway.

  3. Infections associated with chronic granulomatous disease: linking genetics to phenotypic expression.

    Science.gov (United States)

    Ben-Ari, Josef; Wolach, Ofir; Gavrieli, Ronit; Wolach, Baruch

    2012-08-01

    Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency characterized by the absence or malfunction of the NADPH oxidase in phagocytic cells. As a result, there is an impaired ability to generate superoxide anions and the subsequent reactive oxygen intermediates. Consequently, CGD patients suffer from two clinical manifestations: recurrent, life-threatening bacterial and fungal infections and excessive inflammatory reactions leading to granulomatous lesions. Although the genotype of CGD was linked to the phenotypic expression of the disease, this connection is still controversial and poorly understood. Certain correlations were reported, but the clinical expression of the disease is usually unpredictable, regardless of the pattern of inheritance. CGD mainly affects the lungs, lymph nodes, skin, GI tract and liver. Patients are particularly susceptible to catalase-positive microorganisms, including Staphyloccocus aureus, Nocardia spp. and Gram-negative bacteria, such as Serratia marcescens, Burkholderia cepacea and Salmonella spp. Unusually, catalase-negative microorganisms were reported as well. New antibacterial and antimycotic agents considerably improved the prognosis of CGD. Therapy with IFN-γ is still controversial. Bone marrow stem cell transplantation is currently the only curative treatment and gene therapy needs further development. In this article, the authors discuss the genetic, functional and molecular aspects of CGD and their impact on the clinical expression, infectious complications and the hyperinflammatory state.

  4. Genetic and phenotypic diversity of carbofuran-degrading bacteria isolated from agricultural soils.

    Science.gov (United States)

    Shin, Dong-Hyeon; Kim, Dong-Uk; Seong, Chi-Nam; Song, Hong-Gyu; Ka, Jong-Ok

    2012-04-01

    Thirty-seven carbofuran-degrading bacteria were isolated from agricultural soils, and their genetic and phenotypic characteristics were investigated. The isolates were able to utilize carbofuran as a sole source of carbon and energy. Analysis of the 16S rRNA gene sequence indicated that the isolates were related to members of the genera Rhodococcus, Sphingomonas, and Sphingobium, including new types of carbofuran-degrading bacteria, Bosea and Microbacterium. Among the 37 isolates, 15 different chromosomal DNA patterns were obtained by polymerase chain reaction (PCR) amplification of repetitive extragenic palindromic (REP) sequences. Five of the 15 representative isolates were able to degrade carbofuran phenol, fenoxycarb, and carbaryl, in addition to carbofuran. Ten of the 15 representative isolates had 1 to 8 plasmids. Among the 10 plasmid-containing isolates, plasmid-cured strains were obtained from 5 strains. The cured strains could not degrade carbofuran and other pesticides anymore, suggesting that the carbofuran degradative genes were on the plasmid DNAs in these strains. When analyzed with PCR amplification and dot-blot hybridization using the primers targeting for the previously reported carbofuran hydrolase gene (mcd), all of the isolates did not show any positive signals, suggesting that their carbofuran hydrolase genes had no significant sequence homology with the mcd gene.

  5. Evaluation of genetic and phenotypic consistency of Bacillus coagulans MTCC 5856: a commercial probiotic strain.

    Science.gov (United States)

    Majeed, Muhammed; Nagabhushanam, Kalyanam; Natarajan, Sankaran; Sivakumar, Arumugam; Eshuis-de Ruiter, Talitha; Booij-Veurink, Janine; de Vries, Ynte P; Ali, Furqan

    2016-04-01

    Commercial probiotics preparation containing Bacillus coagulans have been sold in the market for several decades. Due to its high intra-species genomic diversity, it is very likely that B. coagulans strain may alter in different ways over multiple years of production. Therefore, the present study focuses to evaluate the genetic consistency and probiotic potential of B. coagulans MTCC 5856. Phenotypic and genotypic techniques including biochemical profiling, 16S rRNA sequencing, GTG 5″, BOX PCR fingerprinting, and Multi-Locus-Sequence typing (MLST) were carried out to evaluate the identity and consistency of the B. coagulans MTCC 5856. Further, in vitro probiotic potential, safety and stability at ambient temperature conditions of B. coagulans MTCC 5856 were evaluated. All the samples were identified as B. coagulans by biochemical profiling and 16S rRNA sequencing. GTG 5″, BOX PCR fingerprints and MLST studies revealed that the same strain was present over 3 years of commercial production. B. coagulans MTCC 5856 showed resistance to gastric acid, bile salt and exhibited antimicrobial activity in in-vitro studies. Additionally, B. coagulans MTCC 5856 was found to be non-mutagenic, non-cytotoxic, negative for enterotoxin genes and stable at ambient temperature (25 ± 2 °C) for 36 months. The data of the study verified that the same strain of B. coagulans MTCC 5856 was present in commercial preparation over multiple years of production.

  6. Consistent and reproducible positioning in longitudinal imaging for phenotyping genetically modified swine

    Science.gov (United States)

    Hammond, Emily; Dilger, Samantha K. N.; Stoyles, Nicholas; Judisch, Alexandra; Morgan, John; Sieren, Jessica C.

    2015-03-01

    Recent growth of genetic disease models in swine has presented the opportunity to advance translation of developed imaging protocols, while characterizing the genotype to phenotype relationship. Repeated imaging with multiple clinical modalities provides non-invasive detection, diagnosis, and monitoring of disease to accomplish these goals; however, longitudinal scanning requires repeatable and reproducible positioning of the animals. A modular positioning unit was designed to provide a fixed, stable base for the anesthetized animal through transit and imaging. Post ventilation and sedation, animals were placed supine in the unit and monitored for consistent vitals. Comprehensive imaging was performed with a computed tomography (CT) chest-abdomen-pelvis scan at each screening time point. Longitudinal images were rigidly registered, accounting for rotation, translation, and anisotropic scaling, and the skeleton was isolated using a basic thresholding algorithm. Assessment of alignment was quantified via eleven pairs of corresponding points on the skeleton with the first time point as the reference. Results were obtained with five animals over five screening time points. The developed unit aided in skeletal alignment within an average of 13.13 +/- 6.7 mm for all five subjects providing a strong foundation for developing qualitative and quantitative methods of disease tracking.

  7. Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

    Science.gov (United States)

    Rietveld, Cornelius A.; Esko, Tõnu; Davies, Gail; Pers, Tune H.; Turley, Patrick; Benyamin, Beben; Chabris, Christopher F.; Emilsson, Valur; Johnson, Andrew D.; Lee, James J.; de Leeuw, Christiaan; Marioni, Riccardo E.; Medland, Sarah E.; Miller, Michael B.; Rostapshova, Olga; van der Lee, Sven J.; Vinkhuyzen, Anna A. E.; Amin, Najaf; Conley, Dalton; Derringer, Jaime; van Duijn, Cornelia M.; Fehrmann, Rudolf; Franke, Lude; Glaeser, Edward L.; Hansell, Narelle K.; Hayward, Caroline; Iacono, William G.; Ibrahim-Verbaas, Carla; Jaddoe, Vincent; Karjalainen, Juha; Laibson, David; Lichtenstein, Paul; Liewald, David C.; Magnusson, Patrik K. E.; Martin, Nicholas G.; McGue, Matt; McMahon, George; Pedersen, Nancy L.; Pinker, Steven; Porteous, David J.; Posthuma, Danielle; Rivadeneira, Fernando; Smith, Blair H.; Starr, John M.; Tiemeier, Henning; Timpson, Nicholas J.; Trzaskowski, Maciej; Uitterlinden, André G.; Verhulst, Frank C.; Ward, Mary E.; Wright, Margaret J.; Davey Smith, George; Deary, Ian J.; Johannesson, Magnus; Plomin, Robert; Visscher, Peter M.; Benjamin, Daniel J.; Koellinger, Philipp D.

    2014-01-01

    We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory. PMID:25201988

  8. DNA Phenotyping: The prediction of human pigmentation traits from genetic data

    NARCIS (Netherlands)

    S. Walsh (Susan)

    2013-01-01

    textabstractPhenotyping is the ability to assign characteristics to an organism based on certain measurable parameters. In the case of DNA phenotyping, it is limited to the sole use of DNA to determine a phenotype such as an externally visible characteristic. In a forensic setting, it encompasses

  9. Recommendations for standardization and phenotype definitions in genetic studies of osteoarthritis: The TREAT-OA consortium

    NARCIS (Netherlands)

    J.M. Kerkhof (Hanneke); I. Meulenbelt (Ingrid); T. Akune (Toru); N.K. Arden (Nigel); A. Aromaa (Arpo); S.M. Bierma-Zeinstra (Sita); C. Cooper (Charles); J. Dai; M. Doherty (Michael); S. Doherty (Sally); D. Felson; A. Gonzalez (Antonio); A. Gordon; A. Harilainen (Arsi); D.J. Hart; V.B. Hauksson (Valdimar); M. Heliovaara (Markku); A. Hofman (Albert); S. Ikegawa; T. Ingvarsson (Torvaldur); Q. Jiang; H. Jonsson; I. Jonsdottir (Ingileif); H. Kawaguchi; M. Kloppenburg (Margreet); U.M. Kujala (Urho); N.E. Lane; P. Leino-Arjas (Päivi I.); L.S. Lohmander (Stefan); F.P. Luyten (Frank); K.N. Malizos (Konstantinos); M. Nakajima; M.C. Nevitt (Michael); H.A.P. Pols (Huib); F. Rivadeneira Ramirez (Fernando); D. Shi; E. Slagboom (Eline); T.D. Spector (Timothy); K. Stefansson (Kari); A. Sudo (Akihiro); A. Tamm; A.E. Tamm (Aile); A. Tsezou (Aspasia); A. Uchida; A.G. Uitterlinden (André); J.M. Wilkinson (Mark); N. Yoshimura; A.M. Valdes (Ana Maria); J.B.J. van Meurs (Joyce); A.J. Carr (Andrew Jonathan)

    2011-01-01

    textabstractObjective: To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes. Methods: Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consor

  10. DNA Phenotyping: The prediction of human pigmentation traits from genetic data

    NARCIS (Netherlands)

    S. Walsh (Susan)

    2013-01-01

    textabstractPhenotyping is the ability to assign characteristics to an organism based on certain measurable parameters. In the case of DNA phenotyping, it is limited to the sole use of DNA to determine a phenotype such as an externally visible characteristic. In a forensic setting, it encompasses th

  11. Phenotype to genotype using forward-genetic Mu-seq for identification and functional classification of maize mutants

    Directory of Open Access Journals (Sweden)

    Charles T Hunter

    2014-01-01

    Full Text Available In pursuing our long-term goals of identifying causal genes for mutant phenotypes in maize, we have developed a new, phenotype-to-genotype approach for transposon-based resources, and used this to identify candidate genes that co-segregate with visible kernel mutants. The strategy incorporates a redesigned Mu-seq protocol (sequence-based, transposon mapping for high-throughput identification of individual plants carrying Mu insertions. Forward-genetic Mu-seq also involves a genetic pipeline for generating families that segregate for mutants of interest, and grid designs for concurrent analysis of genotypes in multiple families. Critically, this approach not only eliminates gene-specific PCR genotyping, but also profiles all Mu-insertions in hundreds of individuals simultaneously. Here, we employ this scalable approach to study 12 families that showed Mendelian segregation of visible seed mutants. These families were analyzed in parallel, and 7 showed clear co-segregation between the selected phenotype and a Mu insertion in a specific gene. Results were confirmed by PCR. Mutant genes that associated with kernel phenotypes include those encoding: a new allele of Whirly1 (a transcription factor with high affinity for organellar and single-stranded DNA, a predicted splicing factor with a KH domain, a small protein with unknown function, a putative mitochondrial transcription-termination factor, and three proteins with pentatricopeptide repeat domains (predicted mitochondrial. Identification of such associations allows mutants to be prioritized for subsequent research based on their functional annotations. Forward-genetic Mu-seq also allows a systematic dissection of mutant classes with similar phenotypes. In the present work, a high proportion of kernel phenotypes were associated with mutations affecting organellar gene transcription and processing, highlighting the importance and non-redundance of genes controlling these aspects of seed development.

  12. Effect of Genetics, Environment, and Phenotype on the Metabolome of Maize Hybrids Using GC/MS and LC/MS.

    Science.gov (United States)

    Tang, Weijuan; Hazebroek, Jan; Zhong, Cathy; Harp, Teresa; Vlahakis, Chris; Baumhover, Brian; Asiago, Vincent

    2017-06-28

    We evaluated the variability of metabolites in various maize hybrids due to the effect of environment, genotype, phenotype as well as the interaction of the first two factors. We analyzed 480 forage and the same number of grain samples from 21 genetically diverse non-GM Pioneer brand maize hybrids, including some with drought tolerance and viral resistance phenotypes, grown at eight North American locations. As complementary platforms, both GC/MS and LC/MS were utilized to detect a wide diversity of metabolites. GC/MS revealed 166 and 137 metabolites in forage and grain samples, respectively, while LC/MS captured 1341 and 635 metabolites in forage and grain samples, respectively. Univariate and multivariate analyses were utilized to investigate the response of the maize metabolome to the environment, genotype, phenotype, and their interaction. Based on combined percentages from GC/MS and LC/MS datasets, the environment affected 36% to 84% of forage metabolites, while less than 7% were affected by genotype. The environment affected 12% to 90% of grain metabolites, whereas less than 27% were affected by genotype. Less than 10% and 11% of the metabolites were affected by phenotype in forage and grain, respectively. Unsupervised PCA and HCA analyses revealed similar trends, i.e., environmental effect was much stronger than genotype or phenotype effects. On the basis of comparisons of disease tolerant and disease susceptible hybrids, neither forage nor grain samples originating from different locations showed obvious phenotype effects. Our findings demonstrate that the combination of GC/MS and LC/MS based metabolite profiling followed by broad statistical analysis is an effective approach to identify the relative impact of environmental, genetic and phenotypic effects on the forage and grain composition of maize hybrids.

  13. Information transmission in genetic regulatory networks: a review

    CERN Document Server

    Walczak, Aleksandra M

    2011-01-01

    Genetic regulatory networks enable cells to respond to the changes in internal and external conditions by dynamically coordinating their gene expression profiles. Our ability to make quantitative measurements in these biochemical circuits has deepened our understanding of what kinds of computations genetic regulatory networks can perform and with what reliability. These advances have motivated researchers to look for connections between the architecture and function of genetic regulatory networks. Transmitting information between network's inputs and its outputs has been proposed as one such possible measure of function, relevant in certain biological contexts. Here we summarize recent developments in the application of information theory to gene regulatory networks. We first review basic concepts in information theory necessary to understand recent work. We then discuss the functional complexity of gene regulation which arrises from the molecular nature of the regulatory interactions. We end by reviewing som...

  14. Short-range phenotypic divergence among genetically distinct parapatric populations of an Australian funnel-web spider.

    Science.gov (United States)

    Wong, Mark K L; Woodman, James D; Rowell, David M

    2017-07-01

    Speciation involves divergence at genetic and phenotypic levels. Where substantial genetic differentiation exists among populations, examining variation in multiple phenotypic characters may elucidate the mechanisms by which divergence and speciation unfold. Previous work on the Australian funnel-web spider Atrax sutherlandi Gray (2010; Records of the Australian Museum62, 285-392; Mygalomorphae: Hexathelidae: Atracinae) has revealed a marked genetic structure along a 110-kilometer transect, with six genetically distinct, parapatric populations attributable to past glacial cycles. In the present study, we explore variation in three classes of phenotypic characters (metabolic rate, water loss, and morphological traits) within the context of this phylogeographic structuring. Variation in metabolic and water loss rates shows no detectable association with genetic structure; the little variation observed in these rates may be due to the spiders' behavioral adaptations (i.e., burrowing), which buffer the effects of climatic gradients across the landscape. However, of 17 morphological traits measured, 10 show significant variation among genetic populations, in a disjunct manner that is clearly not latitudinal. Moreover, patterns of variation observed for morphological traits serving different organismic functions (e.g., prey capture, burrowing, and locomotion) are dissimilar. In contrast, a previous study of an ecologically similar sympatric spider with little genetic structure indicated a strong latitudinal response in 10 traits over the same range. The congruence of morphological variation with deep phylogeographic structure in Tallaganda's A. sutherlandi populations, as well as the inconsistent patterns of variation across separate functional traits, suggest that the spiders are likely in early stages of speciation, with parapatric populations independently responding to local selective forces.

  15. 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.

  16. Phenotypic and genetic associations between reading comprehension, decoding skills, and ADHD dimensions: evidence from two population-based studies.

    Science.gov (United States)

    Plourde, Vickie; Boivin, Michel; Forget-Dubois, Nadine; Brendgen, Mara; Vitaro, Frank; Marino, Cecilia; Tremblay, Richard T; Dionne, Ginette

    2015-10-01

    The phenotypic and genetic associations between decoding skills and ADHD dimensions have been documented but less is known about the association with reading comprehension. The aim of the study is to document the phenotypic and genetic associations between reading comprehension and ADHD dimensions of inattention and hyperactivity/impulsivity in early schooling and compare them to those with decoding skills. Data were collected in two population-based samples of twins (Quebec Newborn Twin Study - QNTS) and singletons (Quebec Longitudinal Study of Child Development - QLSCD) totaling ≈ 2300 children. Reading was assessed with normed measures in second or third grade. Teachers assessed ADHD dimensions in kindergarten and first grade. Both decoding and reading comprehension were correlated with ADHD dimensions in a similar way: associations with inattention remained after controlling for the other ADHD dimension, behavior disorder symptoms and nonverbal abilities, whereas associations with hyperactivity/impulsivity did not. Genetic modeling showed that decoding and comprehension largely shared the same genetic etiology at this age and that their associations with inattention were mostly explained by shared genetic influences. Both reading comprehension and decoding are uniquely associated with inattention through a shared genetic etiology. © 2015 Association for Child and Adolescent Mental Health.

  17. Phenotypic and Genetic Heterogeneity in Vibrio cholerae O139 Isolated from Cholera Cases in Delhi, India during 2001-2006

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    Raikamal Ghosh

    2016-08-01

    Full Text Available Incidence of epidemic Vibrio cholerae serogroup O139 has declined in cholera endemic countries. However, sporadic cholera caused by V. cholerae O139 with notable genetic changes is still reported from many regions. In the present study, 42 V. cholerae O139 strains isolated from 2001 to 2006 in Delhi, India, were retrospectively analyzed to understand their phenotype and molecular characteristics. The majority of isolates were resistant to ampicillin, furazolidone and nalidixic acid. Though the integrative conjugative element was detected in all the O139 isolates, the 2004-2006 isolates remained susceptible to co-trimoxazole, chloramphenicol, and streptomycin. Cholera toxin genotype 1 was present in the majority of the O139 isolates while few had type 3 or a novel type 4. In the cholera toxin encoding gene (ctx restriction fragment length polymorphism, the majority of the isolates harbored three copies of CTX element, of which one was truncated. In this study, the ctx was detected for the first time in the small chromosome of V. cholerae O139 and one isolate harbored 5 copies of CTX element, of which 3 were truncated. The ribotype BII pattern was found in most of the O139 isolates. Three V. cholerae O139 isolated in 2001 had a new ribotype BVIII. Pulsed-field gel electrophoresis analysis revealed clonal variation in 2001 isolates compared to the 2004-2006 isolates. Molecular changes in V. cholerae O139 have to be closely monitored as this information may help in understanding the changing genetic features of this pathogen in relation to the epidemiology of cholera.

  18. Phenotypic and Genetic Heterogeneity in Vibrio cholerae O139 Isolated from Cholera Cases in Delhi, India during 2001-2006.

    Science.gov (United States)

    Ghosh, Raikamal; Sharma, Naresh C; Halder, Kalpataru; Bhadra, Rupak K; Chowdhury, Goutam; Pazhani, Gururaja P; Shinoda, Sumio; Mukhopadhyay, Asish K; Nair, G Balakrish; Ramamurthy, Thadavarayan

    2016-01-01

    Incidence of epidemic Vibrio cholerae serogroup O139 has declined in cholera endemic countries. However, sporadic cholera caused by V. cholerae O139 with notable genetic changes is still reported from many regions. In the present study, 42 V. cholerae O139 strains isolated from 2001 to 2006 in Delhi, India, were retrospectively analyzed to understand their phenotype and molecular characteristics. The majority of isolates were resistant to ampicillin, furazolidone and nalidixic acid. Though the integrative conjugative element was detected in all the O139 isolates, the 2004-2006 isolates remained susceptible to co-trimoxazole, chloramphenicol, and streptomycin. Cholera toxin genotype 1 was present in the majority of the O139 isolates while few had type 3 or a novel type 4. In the cholera toxin encoding gene (ctx) restriction fragment length polymorphism, the majority of the isolates harbored three copies of CTX element, of which one was truncated. In this study, the ctx was detected for the first time in the small chromosome of V. cholerae O139 and one isolate harbored 5 copies of CTX element, of which 3 were truncated. The ribotype BII pattern was found in most of the O139 isolates. Three V. cholerae O139 isolated in 2001 had a new ribotype BVIII. Pulsed-field gel electrophoresis analysis revealed clonal variation in 2001 isolates compared to the 2004-2006 isolates. Molecular changes in V. cholerae O139 have to be closely monitored as this information may help in understanding the changing genetic features of this pathogen in relation to the epidemiology of cholera.

  19. Female guppies agree to differ: phenotypic and genetic variation in mate-choice behavior and the consequences for sexual selection.

    Science.gov (United States)

    Brooks, R; Endler, J A

    2001-08-01

    Variation among females in mate choice may influence evolution by sexual selection. The genetic basis of this variation is of interest because the elaboration of mating preferences requires additive genetic variation in these traits. Here we measure the repeatability and heritability of two components of female choosiness (responsiveness and discrimination) and of female preference functions for the multiple ornaments borne by male guppies (Poecilia reticulata). We show that there is significant repeatable variation in both components of choosiness and in some preference functions but not in others. There appear to be several male ornaments that females find uniformly attractive and others for which females differ in preference. One consequence is that there is no universally attractive male phenotype. Only responsiveness shows significant additive genetic variation. Variation in responsiveness appears to mask variation in discrimination and some preference functions and may be the most biologically relevant source of phenotypic and genetic variation in mate-choice behavior. To test the potential evolutionary importance of the phenotypic variation in mate choice that we report, we estimated the opportunity for and the intensity of sexual selection under models of mate choice that excluded and that incorporated individual female variation. We then compared these estimates with estimates based on measured mating success. Incorporating individual variation in mate choice generally did not predict the outcome of sexual selection any better than models that ignored such variation.

  20. From phenotyping towards breeding strategies: using in vivo indicator traits and genetic markers to improve meat quality in an endangered pig breed.

    Science.gov (United States)

    Biermann, A D M; Yin, T; König von Borstel, U U; Rübesam, K; Kuhn, B; König, S

    2015-06-01

    measurements (0.39 v. 0.25). The presence of the unfavorable n allele was associated with increased electric conductivity, paler meat and higher drip loss. The allele substitution effect on IMF was unfavorable, indicating lower IMF when the n allele is present. A breeding strategy including the phenotype (BFiv) combined with genetic marker information at the RYR1 locus from the selection candidate, resulted in a 20% increase in accuracy and selection response when compared with a breeding strategy without genetic marker information.

  1. Gene network analysis shows immune-signaling and ERK1/2 as novel genetic markers for multiple addiction phenotypes: alcohol, smoking and opioid addiction.

    Science.gov (United States)

    Reyes-Gibby, Cielito C; Yuan, Christine; Wang, Jian; Yeung, Sai-Ching J; Shete, Sanjay

    2015-06-05

    Addictions to alcohol and tobacco, known risk factors for cancer, are complex heritable disorders. Addictive behaviors have a bidirectional relationship with pain. We hypothesize that the associations between alcohol, smoking, and opioid addiction observed in cancer patients have a genetic basis. Therefore, using bioinformatics tools, we explored the underlying genetic basis and identified new candidate genes and common biological pathways for smoking, alcohol, and opioid addiction. Literature search showed 56 genes associated with alcohol, smoking and opioid addiction. Using Core Analysis function in Ingenuity Pathway Analysis software, we found that ERK1/2 was strongly interconnected across all three addiction networks. Genes involved in immune signaling pathways were shown across all three networks. Connect function from IPA My Pathway toolbox showed that DRD2 is the gene common to both the list of genetic variations associated with all three addiction phenotypes and the components of the brain neuronal signaling network involved in substance addiction. The top canonical pathways associated with the 56 genes were: 1) calcium signaling, 2) GPCR signaling, 3) cAMP-mediated signaling, 4) GABA receptor signaling, and 5) G-alpha i signaling. Cancer patients are often prescribed opioids for cancer pain thus increasing their risk for opioid abuse and addiction. Our findings provide candidate genes and biological pathways underlying addiction phenotypes, which may be future targets for treatment of addiction. Further study of the variations of the candidate genes could allow physicians to make more informed decisions when treating cancer pain with opioid analgesics.

  2. Cannabis controversies: how genetics can inform the study of comorbidity.

    Science.gov (United States)

    Agrawal, Arpana; Lynskey, Michael T

    2014-03-01

    To review three key and controversial comorbidities of cannabis use-other illicit drug use, psychosis and depression, as well as suicide, from a genetically informed perspective. Selective review. Genetic factors play a critical role in the association between cannabis use, particularly early-onset use and use of other illicit drugs, psychosis and depression, as well as suicide, albeit via differing mechanisms. For other illicit drugs, while there is strong evidence for shared genetic influences, residual association that is attributable to causal or person-specific environmental factors cannot be ruled out. For depression, common genetic influences are solely responsible for the association with cannabis use but for suicidal attempt, evidence for person-specific factors persists. Finally, even though rates of cannabis use are inordinately high in those with psychotic disorders, there is no evidence of shared genetic etiologies underlying this comorbidity. Instead, there is limited evidence that adolescent cannabis use might moderate the extent to which diathesis influences psychosis. Overlapping genetic influences underlie the association between early-onset cannabis use and other illicit drug use as well as depression and suicide. For psychosis, mechanisms other than shared genetic influences might be at play. © 2014 Society for the Study of Addiction.

  3. Cannabis Controversies: How genetics can inform the study of comorbidity

    Science.gov (United States)

    Agrawal, Arpana; Lynskey, Michael T.

    2014-01-01

    Aims To review three key and controversial comorbidities of cannabis use – other illicit drug use, psychosis and depression as well as suicide, from a genetically informed perspective. Design Selective review. Results Genetic factors play a critical role in the association between cannabis use, particularly early-onset use and use of other illicit drugs, psychosis and depression as well as suicide, albeit via differing mechanisms. For other illicit drugs, while there is strong evidence for shared genetic influences, residual association that is attributable to causal or person-specific environmental factors cannot be ruled out. For depression, common genetic influences are solely responsible for the association with cannabis use but for suicidal attempt, evidence for person-specific factors persists. Finally, even though rates of cannabis use are inordinately high in those with psychotic disorders, there is no evidence of shared genetic etiologies underlying this comorbidity. Instead, there is limited evidence that adolescent cannabis use might moderate the extent to which diathesis influences psychosis. Conclusions Overlapping genetic influences underlie the association between early-onset cannabis use and other illicit drug use as well as depression and suicide. For psychosis, mechanisms other than shared genetic influences might be at play. PMID:24438181

  4. Different types of secondary information in the genetic code.

    Science.gov (United States)

    Maraia, Richard J; Iben, James R

    2014-07-01

    Whole-genome and functional analyses suggest a wealth of secondary or auxiliary genetic information (AGI) within the redundancy component of the genetic code. Although there are multiple aspects of biased codon use, we focus on two types of auxiliary information: codon-specific translational pauses that can be used by particular proteins toward their unique folding and biased codon patterns shared by groups of functionally related mRNAs with coordinate regulation. AGI is important to genetics in general and to human disease; here, we consider influences of its three major components, biased codon use itself, variations in the tRNAome, and anticodon modifications that distinguish synonymous decoding. AGI is plastic and can be used by different species to different extents, with tissue-specificity and in stress responses. Because AGI is species-specific, it is important to consider codon-sensitive experiments when using heterologous systems; for this we focus on the tRNA anticodon loop modification enzyme, CDKAL1, and its link to type 2 diabetes. Newly uncovered tRNAome variability among humans suggests roles in penetrance and as a genetic modifier and disease modifier. Development of experimental and bioinformatics methods are needed to uncover additional means of auxiliary genetic information.

  5. Rapid Cellular Phenotyping of Human Pluripotent Stem Cell-Derived Cardiomyocytes using a Genetically Encoded Fluorescent Voltage Sensor

    Directory of Open Access Journals (Sweden)

    Jordan S. Leyton-Mange

    2014-02-01

    Full Text Available In addition to their promise in regenerative medicine, pluripotent stem cells have proved to be faithful models of many human diseases. In particular, patient-specific stem cell-derived cardiomyocytes recapitulate key features of several life-threatening cardiac arrhythmia syndromes. For both modeling and regenerative approaches, phenotyping of stem cell-derived tissues is critical. Cellular phenotyping has largely relied upon expression of lineage markers rather than physiologic attributes. This is especially true for cardiomyocytes, in part because electrophysiological recordings are labor intensive. Likewise, most optical voltage indicators suffer from phototoxicity, which damages cells and degrades signal quality. Here we present the use of a genetically encoded fluorescent voltage indicator, ArcLight, which we demonstrate can faithfully report transmembrane potentials in human stem cell-derived cardiomyocytes. We demonstrate the application of this fluorescent sensor in high-throughput, serial phenotyping of differentiating cardiomyocyte populations and in screening for drug-induced cardiotoxicity.

  6. Selection of genetic and phenotypic features associated with inflammatory status of patients on dialysis using relaxed linear separability method.

    Directory of Open Access Journals (Sweden)

    Leon Bobrowski

    Full Text Available Identification of risk factors in patients with a particular disease can be analyzed in clinical data sets by using feature selection procedures of pattern recognition and data mining methods. The applicability of the relaxed linear separability (RLS method of feature subset selection was checked for high-dimensional and mixed type (genetic and phenotypic clinical data of patients with end-stage renal disease. The RLS method allowed for substantial reduction of the dimensionality through omitting redundant features while maintaining the linear separability of data sets of patients with high and low levels of an inflammatory biomarker. The synergy between genetic and phenotypic features in differentiation between these two subgroups was demonstrated.

  7. The relative importance of genetic diversity and phenotypic plasticity in determining invasion success of a clonal weed in the USA and China

    Directory of Open Access Journals (Sweden)

    Yupeng eGeng

    2016-02-01

    Full Text Available Phenotypic plasticity has been proposed as an important adaptive strategy for clonal plants in heterogeneous habitats. Increased phenotypic plasticity can be especially beneficial for invasive clonal plants, allowing them to colonize new environments even when genetic diversity is low. However, the relative importance of genetic diversity and phenotypic plasticity for invasion success remains largely unknown. Here, we performed molecular marker analyses and a common garden experiment to investigate the genetic diversity and phenotypic plasticity of the globally important weed Alternanthera philoxeroides in response to different water availability (terrestrial versus aquatic habitats. This species relies predominantly on clonal propagation in introduced ranges. We therefore expected genetic diversity to be restricted in the two sampled introduced ranges (the USA and China when compared to the native range (Argentina, but that phenotypic plasticity may allow the species’ full niche range to nonetheless be exploited. We found clones from China had very low genetic diversity in terms of both marker diversity and quantitative variation when compared with those from the USA and Argentina, probably reflecting different introduction histories. In contrast, similar patterns of phenotypic plasticity were found for clones from all three regions. Furthermore, despite the different levels of genetic diversity, bioclimatic modeling suggested that the full potential bioclimatic distribution had been invaded in both China and USA. Phenotypic plasticity, not genetic diversity, was therefore critical in allowing A. philoxeroides to invade diverse habitats across broad geographic areas.

  8. Single-cell mass spectrometry reveals the importance of genetic diversity and plasticity for phenotypic variation in nitrogen-limited Chlamydomonas.

    Science.gov (United States)

    Krismer, Jasmin; Tamminen, Manu; Fontana, Simone; Zenobi, Renato; Narwani, Anita

    2016-12-09

    Phenotypic variation is vital for microbial populations to survive environmental perturbations. Both genetic and non-genetic factors contribute to an organism's phenotypic variation and therefore its fitness. To investigate the correlation between genetic diversity and phenotypic variation, we applied our recently developed mass spectrometry method that allows for the simultaneous measurement of more than 25 different lipids and pigments with high throughput in the unicellular microalga Chlamydomonas reinhardtii. We monitored the impact of nitrogen limitation on a genetically diverse wild-type strain CC-1690 and two isoclonal isolates from CC-1690 named ANC3 and ANC5. Measuring molecular composition of thousands of single cells at different time points of the experiment allowed us to capture a dynamic picture of the phenotypic composition and adaptation of the populations over time. Although the genetically diverse population maintained phenotypic variation over the whole time course of the experiment, the isoclonal cultures showed higher synchronicity in their phenotypic response. Furthermore, the genetically diverse population showed equal or greater phenotypic variation over the whole time range in multidimensional trait space compared with isoclonal populations. However, along individual trait axes non-genetic variance was higher in isoclonal populations.The ISME Journal advance online publication, 9 December 2016; doi:10.1038/ismej.2016.167.

  9. The Relative Importance of Genetic Diversity and Phenotypic Plasticity in Determining Invasion Success of a Clonal Weed in the USA and China.

    Science.gov (United States)

    Geng, Yupeng; van Klinken, Rieks D; Sosa, Alejandro; Li, Bo; Chen, Jiakuan; Xu, Cheng-Yuan

    2016-01-01

    Phenotypic plasticity has been proposed as an important adaptive strategy for clonal plants in heterogeneous habitats. Increased phenotypic plasticity can be especially beneficial for invasive clonal plants, allowing them to colonize new environments even when genetic diversity is low. However, the relative importance of genetic diversity and phenotypic plasticity for invasion success remains largely unknown. Here, we performed molecular marker analyses and a common garden experiment to investigate the genetic diversity and phenotypic plasticity of the globally important weed Alternanthera philoxeroides in response to different water availability (terrestrial vs. aquatic habitats). This species relies predominantly on clonal propagation in introduced ranges. We therefore expected genetic diversity to be restricted in the two sampled introduced ranges (the USA and China) when compared to the native range (Argentina), but that phenotypic plasticity may allow the species' full niche range to nonetheless be exploited. We found clones from China had very low genetic diversity in terms of both marker diversity and quantitative variation when compared with those from the USA and Argentina, probably reflecting different introduction histories. In contrast, similar patterns of phenotypic plasticity were found for clones from all three regions. Furthermore, despite the different levels of genetic diversity, bioclimatic modeling suggested that the full potential bioclimatic distribution had been invaded in both China and USA. Phenotypic plasticity, not genetic diversity, was therefore critical in allowing A. philoxeroides to invade diverse habitats across broad geographic areas.

  10. Phenotypic diversity in patients with multiple serrated polyps: a genetics clinic study.

    Science.gov (United States)

    Buchanan, Daniel D; Sweet, Kevin; Drini, Musa; Jenkins, Mark A; Win, Aung Ko; Gattas, Michael; Walsh, Michael D; Clendenning, Mark; McKeone, Diane; Walters, Rhiannon; Roberts, Aedan; Young, Alasdair; Hampel, Heather; Hopper, John L; Goldblatt, Jack; George, Jill; Suthers, Graeme K; Phillips, Kerry; Young, Graeme P; Chow, Elizabeth; Parry, Susan; Woodall, Sonja; Tucker, Kathy; Muir, Amanda; Field, Michael; Greening, Sian; Gallinger, Steven; Green, Jane; Woods, Michael O; Spaetgens, Renee; de la Chapelle, Albert; Macrae, Finlay; Walker, Neal I; Jass, Jeremy R; Young, Joanne P

    2010-06-01

    Hyperplastic polyposis is a colonic polyposis condition of unknown aetiology. The purpose of this study was to examine the spectrum of phenotypic variation in patients with multiple serrated polyps as a basis for gene discovery. One hundred and twenty-six patients with multiple (> or = 5) serrated polyps were recruited to the study. Polyp counts were extracted from histology and colonoscopy reports. Ethnicity was self-reported. Family history of cancer data were derived from pedigrees. Ascertainment status was classified as either index case or identified by screening. The average reported polyp count was 39. Patients with highest polyp numbers were more likely to be male (P = 0.02). Colorectal cancer (CRC) was identified in 49 of 119 patients (41%) and 28% of these patients had multiple CRC. Young onset patients had higher polyp numbers (P = 0.03) and were more likely to have their CRC in the distal colon (P = 0.02). CRC was significantly associated with the presence of adenomas (P = 0.03). Patients were divided into moderate polyposis (5-79 serrated polyps) and dense polyposis (80 or more) categories. The dense polyposis category was associated with a lack of family history for CRC (P = 0.034) and male gender (P = 0.014), independent of ascertainment status and recruitment site. Multiple serrated polyps were associated with an increased personal risk of CRC. A subset of patients with the highest polyp numbers was more likely to be male and to have no family history of CRC. This result suggests heterogeneous modes of inheritance and has implications for studies investigating the genetic basis of multiple serrated polyps.

  11. Electrical stimulation of cardiac adipose tissue-derived progenitor cells modulates cell phenotype and genetic machinery.

    Science.gov (United States)

    Llucià-Valldeperas, A; Sanchez, B; Soler-Botija, C; Gálvez-Montón, C; Prat-Vidal, C; Roura, S; Rosell-Ferrer, J; Bragos, R; Bayes-Genis, A

    2015-11-01

    A major challenge of cardiac tissue engineering is directing cells to establish the physiological structure and function of the myocardium being replaced. Our aim was to examine the effect of electrical stimulation on the cardiodifferentiation potential of cardiac adipose tissue-derived progenitor cells (cardiac ATDPCs). Three different electrical stimulation protocols were tested; the selected protocol consisted of 2 ms monophasic square-wave pulses of 50 mV/cm at 1 Hz over 14 days. Cardiac and subcutaneous ATDPCs were grown on biocompatible patterned surfaces. Cardiomyogenic differentiation was examined by real-time PCR and immunocytofluorescence. In cardiac ATDPCs, MEF2A and GATA-4 were significantly upregulated at day 14 after stimulation, while subcutaneous ATDPCs only exhibited increased Cx43 expression. In response to electrical stimulation, cardiac ATDPCs elongated, and both cardiac and subcutaneous ATDPCs became aligned following the linear surface pattern of the construct. Cardiac ATDPC length increased by 11.3%, while subcutaneous ATDPC length diminished by 11.2% (p = 0.013 and p = 0.030 vs unstimulated controls, respectively). Compared to controls, electrostimulated cells became aligned better to the patterned surfaces when the pattern was perpendicular to the electric field (89.71 ± 28.47º for cardiac ATDPCs and 92.15 ± 15.21º for subcutaneous ATDPCs). Electrical stimulation of cardiac ATDPCs caused changes in cell phenotype and genetic machinery, making them more suitable for cardiac regeneration approaches. Thus, it seems advisable to use electrical cell training before delivery as a cell suspension or within engineered tissue.

  12. 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.

  13. Are Genetically Informed Designs Genetically Informative?: Comment on McGue, Elkins, Walden, and Iacono (2005) and Quantitative Behavioral Genetics

    Science.gov (United States)

    Partridge, Ty

    2005-01-01

    M. McGue, I. Elkins, B. Walden, and W. G. Iacono (see record 2005-14938-011) presented the findings from a twin study examining the relative contributions of genetic and environmental factors to the developmental trajectories of parent-adolescent relationships. From a behavioral genetics perspective, this study is well conceptualized, is well…

  14. Genotype-phenotype correlations in a mountain population community with high prevalence of Wilson's disease: genetic and clinical homogeneity.

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    Relu Cocoş

    Full Text Available Wilson's disease is an autosomal recessive disorder caused by more than 500 mutations in ATP7B gene presenting considerably clinical manifestations heterogeneity even in patients with a particular mutation. Previous findings suggested a potential role of additional genetic modifiers and environment factors on phenotypic expression among the affected patients. We conducted clinical and genetic investigations to perform genotype-phenotype correlation in two large families living in a socio-culturally isolated community with the highest prevalence of Wilson's disease ever reported of 1 ∶ 1130. Sequencing of ATP7B gene in seven affected individuals and 43 family members identified a common compound heterozygous genotype, H1069Q/M769H-fs, in five symptomatic and two asymptomatic patients and detected the presence of two out of seven identified single nucleotide polymorphisms in all affected patients. Symptomatic patients had similar clinical phenotype and age at onset (18 ± 1 years showing dysarthria and dysphagia as common clinical features at the time of diagnosis. Moreover, all symptomatic patients presented Kayser-Fleischer rings and lack of dystonia accompanied by unfavourable clinical outcomes. Our findings add value for understanding of genotype-phenotype correlations in Wilson's disease based on a multifamily study in an isolated population with high extent of genetic and environmental homogeneity as opposed to majority of reports. We observed an equal influence of presumed other genetic modifiers and environmental factors on clinical presentation and age at onset of Wilson's disease in patients with a particular genotype. These data provide valuable inferences that could be applied for predicting clinical management in asymptomatic patients in such communities.

  15. Association of ADH4 genetic variants with alcohol dependence risk and related phenotypes: results from a larger multicenter association study.

    Science.gov (United States)

    Preuss, Ulrich W; Ridinger, Monika; Rujescu, Dan; Samochowiec, Jerzy; Fehr, Christoph; Wurst, Friedrich M; Koller, Gabriele; Bondy, Brigitta; Wodarz, Norbert; Debniak, Tadeusz; Grzywacz, Anna; Soyka, Michael; Zill, Peter

    2011-04-01

    Genetic variants of the alcohol-metabolizing enzyme ADH4, located on chromosome 4q22-4q23, have been related to alcohol dependence (AD) risk in previous research. The aim of this association study in a large multicenter sample of alcohol-dependent individuals and controls is to confirm ADH4 single nucleotide polymorphism (SNP) and haplotype association with AD and relevant related phenotypes. One thousand, six hundred and twenty-two (1622) inpatient subjects and 1469 control subjects with DSM-IV. AD from four addiction treatment centres were included. Characteristics of AD and related phenotypes including alcohol withdrawal, Cloninger's type I and II and first ages of drinking, regular drinking and AD onset were obtained using standardized structured interviews. After subjects were genotyped for 2 ADH4 polymorphisms, single SNP case-control and haplotype analyses were conducted. Both variants--rs1800759 and rs1042364--and the A-A and C-G haplotypes were significantly related to AD across samples. Furthermore, associations with AD-related phenotypes and subtypes revealed a potential protective influence of this haplotype. This study confirms the significant relationship of ADH4 variants with AD and related phenotypes. While the rs1800759 and rs1042364 A-A haplotype had a potential protective influence on the risk for several AD-related phenotypes, this effect is rather small compared to functional variants of other alcohol or acetaldehyde-metabolizing enzymes like ALDH2*2 or ADH1B*2.

  16. The Bone Dysplasia Ontology: integrating genotype and phenotype information in the skeletal dysplasia domain.

    Science.gov (United States)

    Groza, Tudor; Hunter, Jane; Zankl, Andreas

    2012-03-26

    Skeletal dysplasias are a rare and heterogeneous group of genetic disorders affecting skeletal development. Patients with skeletal dysplasias suffer from many complex medical issues including degenerative joint disease and neurological complications. Because the data and expertise associated with this field is both sparse and disparate, significant benefits will potentially accrue from the availability of an ontology that provides a shared conceptualisation of the domain knowledge and enables data integration, cross-referencing and advanced reasoning across the relevant but distributed data sources. We introduce the design considerations and implementation details of the Bone Dysplasia Ontology. We also describe the different components of the ontology, including a comprehensive and formal representation of the skeletal dysplasia domain as well as the related genotypes and phenotypes. We then briefly describe SKELETOME, a community-driven knowledge curation platform that is underpinned by the Bone Dysplasia Ontology. SKELETOME enables domain experts to use, refine and extend and apply the ontology without any prior ontology engineering experience--to advance the body of knowledge in the skeletal dysplasia field. The Bone Dysplasia Ontology represents the most comprehensive structured knowledge source for the skeletal dysplasias domain. It provides the means for integrating and annotating clinical and research data, not only at the generic domain knowledge level, but also at the level of individual patient case studies. It enables links between individual cases and publicly available genotype and phenotype resources based on a community-driven curation process that ensures a shared conceptualisation of the domain knowledge and its continuous incremental evolution.

  17. Cortical plasticity within and across lifetimes: How can development inform us about phenotypic transformations?

    Directory of Open Access Journals (Sweden)

    James C Dooley

    2013-10-01

    Full Text Available The neocortex is the part of the mammalian brain that is involved in perception, cognition, and volitional motor control. It is a highly dynamic structure that is dramatically altered within the lifetime of an animal and in different lineages throughout the course of evolution. These alterations account for the remarkable variations in behavior that species exhibit. Of particular interest is how these cortical phenotypes change within the lifetime of the individual and eventually evolve in species over time. Because we cannot study the evolution of the neocortex directly we use comparative analysis to appreciate the types of changes that have been made to the neocortex and the similarities that exist across taxa. Developmental studies inform us about how these phenotypic transitions may arise by alterations in developmental cascades or changes in the physical environment in which the brain develops. Both genes and the sensory environment contribute to aspects of the phenotype and similar features, such as the size of a cortical field, can be altered in a variety of ways. Although both genes and the laws of physics place constraints on the evolution of the neocortex, mammals have evolved a number of mechanisms that allow them to loosen these constraints and often alter the course of their own evolution.

  18. An integrated Korean biodiversity and genetic information retrieval system.

    Science.gov (United States)

    Lim, Jeongheui; Bhak, Jong; Oh, Hee-Mock; Kim, Chang-Bae; Park, Yong-Ha; Paek, Woon Kee

    2008-12-12

    On-line biodiversity information databases are growing quickly and being integrated into general bioinformatics systems due to the advances of fast gene sequencing technologies and the Internet. These can reduce the cost and effort of performing biodiversity surveys and genetic searches, which allows scientists to spend more time researching and less time collecting and maintaining data. This will cause an increased rate of knowledge build-up and improve conservations. The biodiversity databases in Korea have been scattered among several institutes and local natural history museums with incompatible data types. Therefore, a comprehensive database and a nation wide web portal for biodiversity information is necessary in order to integrate diverse information resources, including molecular and genomic databases. The Korean Natural History Research Information System (NARIS) was built and serviced as the central biodiversity information system to collect and integrate the biodiversity data of various institutes and natural history museums in Korea. This database aims to be an integrated resource that contains additional biological information, such as genome sequences and molecular level diversity. Currently, twelve institutes and museums in Korea are integrated by the DiGIR (Distributed Generic Information Retrieval) protocol, with Darwin Core2.0 format as its metadata standard for data exchange. Data quality control and statistical analysis functions have been implemented. In particular, integrating molecular and genetic information from the National Center for Biotechnology Information (NCBI) databases with NARIS was recently accomplished. NARIS can also be extended to accommodate other institutes abroad, and the whole system can be exported to establish local biodiversity management servers. A Korean data portal, NARIS, has been developed to efficiently manage and utilize biodiversity data, which includes genetic resources. NARIS aims to be integral in maximizing

  19. Reverse genetic screening reveals poor correlation between morpholino-induced and mutant phenotypes in zebrafish.

    Science.gov (United States)

    Kok, Fatma O; Shin, Masahiro; Ni, Chih-Wen; Gupta, Ankit; Grosse, Ann S; van Impel, Andreas; Kirchmaier, Bettina C; Peterson-Maduro, Josi; Kourkoulis, George; Male, Ira; DeSantis, Dana F; Sheppard-Tindell, Sarah; Ebarasi, Lwaki; Betsholtz, Christer; Schulte-Merker, Stefan; Wolfe, Scot A; Lawson, Nathan D

    2015-01-12

    The widespread availability of programmable site-specific nucleases now enables targeted gene disruption in the zebrafish. In this study, we applied site-specific nucleases to generate zebrafish lines bearing individual mutations in more than 20 genes. We found that mutations in only a small proportion of genes caused defects in embryogenesis. Moreover, mutants for ten different genes failed to recapitulate published Morpholino-induced phenotypes (morphants). The absence of phenotypes in mutant embryos was not likely due to maternal effects or failure to eliminate gene function. Consistently, a comparison of published morphant defects with the Sanger Zebrafish Mutation Project revealed that approximately 80% of morphant phenotypes were not observed in mutant embryos, similar to our mutant collection. Based on these results, we suggest that mutant phenotypes become the standard metric to define gene function in zebrafish, after which Morpholinos that recapitulate respective phenotypes could be reliably applied for ancillary analyses.

  20. Evolutionary history of human disease genes reveals phenotypic connections and comorbidity among genetic diseases.

    Science.gov (United States)

    Park, Solip; Yang, Jae-Seong; Kim, Jinho; Shin, Young-Eun; Hwang, Jihye; Park, Juyong; Jang, Sung Key; Kim, Sanguk

    2012-01-01

    The extent to which evolutionary changes have impacted the phenotypic relationships among human diseases remains unclear. In this work, we report that phenotypically similar diseases are connected by the evolutionary constraints on human disease genes. Human disease groups can be classified into slowly or rapidly evolving classes, where the diseases in the slowly evolving class are enriched with morphological phenotypes and those in the rapidly evolving class are enriched with physiological phenotypes. Our findings establish a clear evolutionary connection between disease classes and disease phenotypes for the first time. Furthermore, the high comorbidity found between diseases connected by similar evolutionary constraints enables us to improve the predictability of the relative risk of human diseases. We find the evolutionary constraints on disease genes are a new layer of molecular connection in the network-based exploration of human diseases.

  1. MGIS: managing banana (Musa spp.) genetic resources information and high-throughput genotyping data

    Science.gov (United States)

    Guignon, V.; Sempere, G.; Sardos, J.; Hueber, Y.; Duvergey, H.; Andrieu, A.; Chase, R.; Jenny, C.; Hazekamp, T.; Irish, B.; Jelali, K.; Adeka, J.; Ayala-Silva, T.; Chao, C.P.; Daniells, J.; Dowiya, B.; Effa effa, B.; Gueco, L.; Herradura, L.; Ibobondji, L.; Kempenaers, E.; Kilangi, J.; Muhangi, S.; Ngo Xuan, P.; Paofa, J.; Pavis, C.; Thiemele, D.; Tossou, C.; Sandoval, J.; Sutanto, A.; Vangu Paka, G.; Yi, G.; Van den houwe, I.; Roux, N.

    2017-01-01

    Abstract Unraveling the genetic diversity held in genebanks on a large scale is underway, due to advances in Next-generation sequence (NGS) based technologies that produce high-density genetic markers for a large number of samples at low cost. Genebank users should be in a position to identify and select germplasm from the global genepool based on a combination of passport, genotypic and phenotypic data. To facilitate this, a new generation of information systems is being designed to efficiently handle data and link it with other external resources such as genome or breeding databases. The Musa Germplasm Information System (MGIS), the database for global ex situ-held banana genetic resources, has been developed to address those needs in a user-friendly way. In developing MGIS, we selected a generic database schema (Chado), the robust content management system Drupal for the user interface, and Tripal, a set of Drupal modules which links the Chado schema to Drupal. MGIS allows germplasm collection examination, accession browsing, advanced search functions, and germplasm orders. Additionally, we developed unique graphical interfaces to compare accessions and to explore them based on their taxonomic information. Accession-based data has been enriched with publications, genotyping studies and associated genotyping datasets reporting on germplasm use. Finally, an interoperability layer has been implemented to facilitate the link with complementary databases like the Banana Genome Hub and the MusaBase breeding database. Database URL: https://www.crop-diversity.org/mgis/

  2. Phenotypic and genetic variation between two populations of the Chinese yellow pond turtle, Mauremys mutica (Cantor, 1842)

    Institute of Scientific and Technical Information of China (English)

    Zhu Xinping; Zhou Li; Chen Yongle; Du Hejun; Gui Jianfang

    2008-01-01

    Mauremys mutica (Cantor, 1842) is an endangered species in China. Main phenotypic variations in body color, body weight, body shape, clutch size, egg size, and hatchling size were revealed between the southern and northern populations. Both populations have the phenomenon of "larger male" sexual size dimorphism (SSD), especially in the southern population. Furthermore, genetic variations between the two populations were analyzed by RAPD band patterns of 30 random individuals in each population. The average genetic distance was 0.299±0.108 among the samples of two populations. The average genetic distance between southern and northern populations was 0.305±0.046. Cluster analysis indicated that all the individuals from the southern and northern populations were clustered among themselves to form two distinct clades. A total of 20 population-specific RAPD fragments were scored from 16 primers, and could be used as RAPD markers for distinguishing the southern and the northern population. Based on the nucleotide sequences of two RAPD markers, two pairs of SCAR primers (SC1-S and SC2-S) were designed, which could be used as SCAR markers for the southern population. According to the significant phenotypic and genetic variations, we suggested that the northern population and southern population might be considered as two separate taxa, the "northern taxon" and the "southern taxon", and the conservation should be respectively conducted on the two taxa.

  3. Genetic and pharmacogenomic data on smoking: the bigger sample size, the less reliable phenotype? A critical review.

    Science.gov (United States)

    Lazary, Judit; Dome, Peter; Faludi, Gabor

    2011-03-01

    Increasing amount of genetic data on nicotine dependence (ND) is available in the literature, sometimes extremely large population size is reported but the study design is not always consequent. Phenotypic measures can vary from a simple 6-item self-rating scale to breath CO or serum cotinine level test but in genetic investigations this is not sophisticated; moreover the population stratification is also usually ignored. In contrast, possibly because of the strict traditions of pharmacological investigations, pharmacogenomic studies on smoking cessation therapy use more reliable phenotypic measures with high quality design consequently involving fewer participants. In spite of the heavy epidemiological data on smoking in Hungary, genetic background of heavy smoking is still not studied in this population. In this review we sum up the most important, replicated results but we also provide some critical remarks about the methodological shortcomings of these studies. Keeping in mind the value of large scale population ND association studies we would also like to emphasize that the clinical implementation of studies with larger samples but with weaker methodology and statistical analyses is limited. Similar to many other psychiatric disorders, ND is a multifactorial condition, therefore the measure of genetic effects requires a more complex study design.

  4. Genetic modifiers of sickle cell anemia in the BABY HUG cohort: influence on laboratory and clinical phenotypes.

    Science.gov (United States)

    Sheehan, Vivien A; Luo, Zhaoyu; Flanagan, Jonathan M; Howard, Thad A; Thompson, Bruce W; Wang, Winfred C; Kutlar, Abdullah; Ware, Russell E

    2013-07-01

    The recently completed BABY HUG trial investigated the safety and efficacy of hydroxyurea in infants with sickle cell anemia (SCA). To investigate the effects of known genetic modifiers, genomic DNA on 190 randomized subjects were analyzed for alpha thalassemia, beta-globin haplotype, polymorphisms affecting endogenous fetal hemoglobin (HbF) levels (XmnI, BCL11A, and HBS1L-MYB), UGT1A1 promoter polymorphisms, and the common G6PD A(-) mutation. At study entry, infants with alpha thalassemia trait had significantly lower mean corpuscular volume, total bilirubin, and absolute reticulocyte count. Beta-globin haplotypes associated with milder disease had significantly higher hemoglobin and %HbF. BCL11A and XmnI polymorphisms had significant effects on baseline HbF, while UGT1A1 promoter polymorphisms significantly influenced baseline serum bilirubin. At study exit, subjects randomized to placebo still exhibited laboratory effects of alpha thalassemia and other modifiers, while those assigned hydroxyurea had treatment effects that exceeded most genetic influences. The pain phenotype was influenced by HbF modifiers in both treatment groups. These data document that genetic polymorphisms do modify laboratory and clinical phenotypes even in very young patients with SCA. The hydroxyurea effects are more potent, however, indicating that treatment criteria should not be limited to certain genetic subsets, and supporting the use of hydroxyurea for all young patients with SCA.

  5. An ontology for microbial phenotypes.

    Science.gov (United States)

    Chibucos, Marcus C; Zweifel, Adrienne E; Herrera, Jonathan C; Meza, William; Eslamfam, Shabnam; Uetz, Peter; Siegele, Deborah A; Hu, James C; Giglio, Michelle G

    2014-11-30

    Phenotypic data are routinely used to elucidate gene function in organisms amenable to genetic manipulation. However, previous to this work, there was no generalizable system in place for the structured storage and retrieval of phenotypic information for bacteria. The Ontology of Microbial Phenotypes (OMP) has been created to standardize the capture of such phenotypic information from microbes. OMP has been built on the foundations of the Basic Formal Ontology and the Phenotype and Trait Ontology. Terms have logical definitions that can facilitate computational searching of phenotypes and their associated genes. OMP can be accessed via a wiki page as well as downloaded from SourceForge. Initial annotations with OMP are being made for Escherichia coli using a wiki-based annotation capture system. New OMP terms are being concurrently developed as annotation proceeds. We anticipate that diverse groups studying microbial genetics and associated phenotypes will employ OMP for standardizing microbial phenotype annotation, much as the Gene Ontology has standardized gene product annotation. The resulting OMP resource and associated annotations will facilitate prediction of phenotypes for unknown genes and result in new experimental characterization of phenotypes and functions.

  6. Genetic polymorphism of human glutathione S-transferase A1 gene in mainland Chinese and its association with phenotype

    Institute of Scientific and Technical Information of China (English)

    JiePING; HuiWANG

    2005-01-01

    AIM Human glutathione S-transferase A1 (GSTA1) is an important phase Ⅱ metabolizing enzyme involved in the metabolism of many therapeutic drugs and is responsible for the metabolic detoxification of numerous promutagens and procarcinogens. The genetic polymorphism of GSTA1 has important implications for drug efficacy and cancer susceptibility. In this study, we determined the distribution of GSTA1 genetic polymorphism in Mainland Chinese. And we also investigated whether there exists the potential phenotype alterations caused by the genetic polymorphism in human. METHODS Genomic DNA was ex-tracted from peripheral blood of 140 Chinese people and 16 liver tissues obtained from non-liverish patients who underwent partial hepatectomy. And then the genotypes of human GSTA1 gene were analyzed by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP).

  7. Modeling the Transition from a Phenotypic to Genotypic Conceptualization of Genetics in a University-Level Introductory Biology Context

    Science.gov (United States)

    Todd, Amber; Romine, William L.; Correa-Menendez, Josefina

    2017-07-01

    Identifying contingencies between constructs in a multi-faceted learning progression (LP) is a challenging task. Often, there is not enough evidence in the literature to support connections, and once identified, they are difficult to empirically test. Here, we use causal model search to evaluate how connections between ideas in a genetics LP change over time in the context of an introductory biology course. We identify primary and secondary hub ideas and connections between concepts before and after instruction to illustrate how students moved from a phenotypic grounding of genetics knowledge to a more genotypic grounding of their genetics knowledge after instruction. We discuss our results in light of conceptual change and illustrate the importance of understanding students' idea structures within a domain.

  8. QTLs of factors of the metabolic syndrome and echocardiographic phenotypes: the hypertension genetic epidemiology network study

    Directory of Open Access Journals (Sweden)

    de Simone Giovanni

    2008-11-01

    Full Text Available Abstract Background In a previous study of the Hypertension Genetic Epidemiology Network (HyperGEN we have shown that metabolic syndrome (MetS risk factors were moderately and significantly associated with echocardiographic (ECHO left ventricular (LV phenotypes. Methods The study included 1,393 African Americans and 1,133 whites, stratified by type 2 diabetes mellitus (DM status. Heritabilities of seven factor scores based on the analysis of 15 traits were sufficiently high to pursue QTL discovery in this follow-up study. Results Three of the QTLs discovered relate to combined MetS-ECHO factors of "blood pressure (BP-LV wall thickness" on chromosome 3 at 225 cM with a 2.8 LOD score, on chromosome 20 at 2.1 cM with a 2.6 LOD score; and for "LV wall thickness" factor on chromosome 16 at 113.5 with a 2.6 LOD score in whites. The remaining QTLs include one for a "body mass index-insulin (BMI-INS" factor with a LOD score of 3.9 on chromosome 2 located at 64.8 cM; one for the same factor on chromosome 12 at 91.4 cM with a 3.3 LOD score; one for a "BP" factor on chromosome 19 located at 67.8 cM with a 3.0 LOD score. A suggestive linkage was also found for "Lipids-INS" with a 2.7 LOD score located on chromosome 11 at 113.1 cM in African Americans. Of the above QTLs, the one on chromosome 12 for "BMI-INS" is replicated in both ethnicities, (with highest LOD scores in African Americans. In addition, the QTL for "LV wall thickness" on chromosome 16q24.2-q24.3 reached its local maximum LOD score at marker D16S402, which is positioned within the 5th intron of the cadherin 13 gene, implicated in heart and vascular remodeling. Conclusion Our previous study and this follow-up suggest gene loci for some crucial MetS and cardiac geometry risk factors that contribute to the risk of developing heart disease.

  9. Ethical aspects of participation in the database of genotypes and phenotypes of the National Center for Biotechnology Information: the Cancer and Leukemia Group B Experience.

    Science.gov (United States)

    Peppercorn, Jeffrey; Shapira, Iuliana; Deshields, Teressa; Kroetz, Deanna; Friedman, Paula; Spears, Patricia; Collyar, Deborah E; Shulman, Lawrence N; Dressler, Lynn; Bertagnolli, Monica M

    2012-10-15

    The rapid pace of genetics research, coupled with evolving standards for informed consent, can create ethical challenges regarding future use of tissue or information from completed clinical trials. The Cancer and Leukemia Group B (CALGB) Oncology Cooperative Group was faced with an ethical dilemma regarding sharing genetic data from a completed genome-wide association study (GWAS) that was conducted as part of a large, multicenter breast cancer clinical trial with a national database: the Database of Genotypes and Phenotypes National Center for Biotechnology Information (dbGaP). The CALGB Ethics Committee conducted a series of multidisciplinary meetings and teleconferences involving patient advocates, bioethicists, clinical researchers, and clinical oncologists to evaluate the ethical issues raised by this case and to identify lessons for improving informed consent to future genetics research in oncology trials. The Ethics Committee recommended that GWAS data be provided to dbGaP consistent with documented consent for future use of tissue among trial participants. Ethical issues, including adequacy of informed consent to future research, limitations of privacy in modern genetics research, the potential impact of population-based genetics research on health disparities, and recontact of research participants for clinical care or further research, were identified as major ethical considerations in this area. Although modern standards for informed consent should not prohibit research or sharing of data consistent with participant's intent and the public interest, there is an urgent need for national consensus on the appropriate use of archived tissue and standardized informed consent for future research among cancer clinical trial participants. Copyright © 2012 American Cancer Society.

  10. The Benefits of Using Genetic Information to Design Prevention Trials

    Science.gov (United States)

    Hu, Youna; Li, Li; Ehm, Margaret G.; Bing, Nan; Song, Kijoung; Nelson, Matthew R.; Talmud, Philippa J.; Hingorani, Aroon D.; Kumari, Meena; Kivimäki, Mika; Xu, Chun-Fang; Waterworth, Dawn M.; Whittaker, John C.; Abecasis, Gonçalo R.; Spino, Cathie; Kang, Hyun Min

    2013-01-01

    Clinical trials for preventative therapies are complex and costly endeavors focused on individuals likely to develop disease in a short time frame, randomizing them to treatment groups, and following them over time. In such trials, statistical power is governed by the rate of disease events in each group and cost is determined by randomization, treatment, and follow-up. Strategies that increase the rate of disease events by enrolling individuals with high risk of disease can significantly reduce study size, duration, and cost. Comprehensive study of common, complex diseases has resulted in a growing list of robustly associated genetic markers. Here, we evaluate the utility—in terms of trial size, duration, and cost—of enriching prevention trial samples by combining clinical information with genetic risk scores to identify individuals at greater risk of disease. We also describe a framework for utilizing genetic risk scores in these trials and evaluating the associated cost and time savings. With type 1 diabetes (T1D), type 2 diabetes (T2D), myocardial infarction (MI), and advanced age-related macular degeneration (AMD) as examples, we illustrate the potential and limitations of using genetic data for prevention trial design. We illustrate settings where incorporating genetic information could reduce trial cost or duration considerably, as well as settings where potential savings are negligible. Results are strongly dependent on the genetic architecture of the disease, but we also show that these benefits should increase as the list of robustly associated markers for each disease grows and as large samples of genotyped individuals become available. PMID:23541341

  11. Neuropathic pain phenotyping by international consensus (NeuroPPIC) for genetic studies: a NeuPSIG systematic review, Delphi survey, and expert panel recommendations.

    Science.gov (United States)

    van Hecke, Oliver; Kamerman, Peter R; Attal, Nadine; Baron, Ralf; Bjornsdottir, Gyda; Bennett, David L H; Bennett, Michael I; Bouhassira, Didier; Diatchenko, Luda; Freeman, Roy; Freynhagen, Rainer; Haanpää, Maija; Jensen, Troels S; Raja, Srinivasa N; Rice, Andrew S C; Seltzer, Zeʼev; Thorgeirsson, Thorgeir E; Yarnitsky, David; Smith, Blair H

    2015-11-01

    For genetic research to contribute more fully to furthering our knowledge of neuropathic pain, we require an agreed, valid, and feasible approach to phenotyping, to allow collaboration and replication in samples of sufficient size. Results from genetic studies on neuropathic pain have been inconsistent and have met with replication difficulties, in part because of differences in phenotypes used for case ascertainment. Because there is no consensus on the nature of these phenotypes, nor on the methods of collecting them, this study aimed to provide guidelines on collecting and reporting phenotypes in cases and controls for genetic studies. Consensus was achieved through a staged approach: (1) systematic literature review to identify all neuropathic pain phenotypes used in previous genetic studies; (2) Delphi survey to identify the most useful neuropathic pain phenotypes and their validity and feasibility; and (3) meeting of experts to reach consensus on the optimal phenotype(s) to be collected from patients with neuropathic pain for genetic studies. A basic "entry level" set of phenotypes was identified for any genetic study of neuropathic pain. This set identifies cases of "possible" neuropathic pain, and controls, and includes: (1) a validated symptom-based questionnaire to determine whether any pain is likely to be neuropathic; (2) body chart or checklist to identify whether the area of pain distribution is neuroanatomically logical; and (3) details of pain history (intensity, duration, any formal diagnosis). This NeuroPPIC "entry level" set of phenotypes can be expanded by more extensive and specific measures, as determined by scientific requirements and resource availability.

  12. Neuropathic pain phenotyping by international consensus (NeuroPPIC) for genetic studies: a NeuPSIG systematic review, Delphi survey, and expert panel recommendations

    Science.gov (United States)

    van Hecke, Oliver; Kamerman, Peter R.; Attal, Nadine; Baron, Ralf; Bjornsdottir, Gyda; Bennett, David L.H.; Bennett, Michael I.; Bouhassira, Didier; Diatchenko, Luda; Freeman, Roy; Freynhagen, Rainer; Haanpää, Maija; Jensen, Troels S.; Raja, Srinivasa N.; Rice, Andrew S.C.; Seltzer, Ze'ev; Thorgeirsson, Thorgeir E.; Yarnitsky, David; Smith, Blair H.

    2015-01-01

    Abstract For genetic research to contribute more fully to furthering our knowledge of neuropathic pain, we require an agreed, valid, and feasible approach to phenotyping, to allow collaboration and replication in samples of sufficient size. Results from genetic studies on neuropathic pain have been inconsistent and have met with replication difficulties, in part because of differences in phenotypes used for case ascertainment. Because there is no consensus on the nature of these phenotypes, nor on the methods of collecting them, this study aimed to provide guidelines on collecting and reporting phenotypes in cases and controls for genetic studies. Consensus was achieved through a staged approach: (1) systematic literature review to identify all neuropathic pain phenotypes used in previous genetic studies; (2) Delphi survey to identify the most useful neuropathic pain phenotypes and their validity and feasibility; and (3) meeting of experts to reach consensus on the optimal phenotype(s) to be collected from patients with neuropathic pain for genetic studies. A basic “entry level” set of phenotypes was identified for any genetic study of neuropathic pain. This set identifies cases of “possible” neuropathic pain, and controls, and includes: (1) a validated symptom-based questionnaire to determine whether any pain is likely to be neuropathic; (2) body chart or checklist to identify whether the area of pain distribution is neuroanatomically logical; and (3) details of pain history (intensity, duration, any formal diagnosis). This NeuroPPIC “entry level” set of phenotypes can be expanded by more extensive and specific measures, as determined by scientific requirements and resource availability. PMID:26469320

  13. Characterizing environmental and phenotypic associations using information theory and electronic health records

    Science.gov (United States)

    Wang, Xiaoyan; Hripcsak, George; Friedman, Carol

    2009-01-01

    Background The availability of up-to-date, executable, evidence-based medical knowledge is essential for many clinical applications, such as pharmacovigilance, but executable knowledge is costly to obtain and update. Automated acquisition of environmental and phenotypic associations in biomedical and clinical documents using text mining has showed some success. The usefulness of the association knowledge is limited, however, due to the fact that the specific relationships between clinical entities remain unknown. In particular, some associations are indirect relations due to interdependencies among the data. Results In this work, we develop methods using mutual information (MI) and its property, the data processing inequality (DPI), to help characterize associations that were generated based on use of natural language processing to encode clinical information in narrative patient records followed by statistical methods. Evaluation based on a random sample consisting of two drugs and two diseases indicates an overall precision of 81%. Conclusion This preliminary study demonstrates that the proposed method is effective for helping to characterize phenotypic and environmental associations obtained from clinical reports. PMID:19761567

  14. Detailed, standardized and systematic phenotyping for the interpretation of genetic variation

    NARCIS (Netherlands)

    Vulto-van Silfhout, A.T.

    2014-01-01

    The identification of the underlying genetic causes for neurodevelopmental disorders and/or congenital anomalies is complicated due to the high genetic heterogeneity of these disorders and the large amount of genetic variation in each individual. Therefore, the aim of this thesis is to improve the i

  15. The pangenome concept: a unifying view of genetic information.

    Science.gov (United States)

    Tetz, Victor V

    2005-07-01

    A way of viewing the genetic information in all organisms on Earth as constituents of the Pangenome is proposed. According to this concept, the Pangenome is the common (collective) genetic system of all living organisms, the organic molecules and their complexes (DNA- and RNA-containing viruses, plasmids, transposons, insertion sequences) involved in the storage and transmission processes of genetic information. Pangenomic stability and variability are discussed. This concept alerts to the inherent fluidity and transmissibility of DNA among organisms of all types, including horizontal gene transfer between closely related and formally unrelated macro- and microorganisms. The roles of death and of all known food chains as universal ways of gene distribution among different organisms are discussed. The contribution of bacteria and viruses in maintaining the circulation of genes within the Pangenome is presented. This concept implies that newly emerging genes are not bound to disappear together with the death of an organism or the extinction of a species and microorganisms are the main pool of genes. Some negative aspects of the intervention of molecular genetics, biotechnology, and ecology, including the spread of transgenic plants and animals, are summarized. It is shown that this concept may be used in medicine for the prognosis of an epidemic situation, particularly newly spreading pathogens, and for the development of new methods for the prophylaxis and early diagnosis of oncologic diseases. This concept can also help to find promising approaches to the discovery of drugs with novel principles of action.

  16. Toward automatic phenotyping of retinal images from genetically determined mono- and dizygotic twins using amplitude modulation-frequency modulation methods

    Science.gov (United States)

    Soliz, P.; Davis, B.; Murray, V.; Pattichis, M.; Barriga, S.; Russell, S.

    2010-03-01

    This paper presents an image processing technique for automatically categorize age-related macular degeneration (AMD) phenotypes from retinal images. Ultimately, an automated approach will be much more precise and consistent in phenotyping of retinal diseases, such as AMD. We have applied the automated phenotyping to retina images from a cohort of mono- and dizygotic twins. The application of this technology will allow one to perform more quantitative studies that will lead to a better understanding of the genetic and environmental factors associated with diseases such as AMD. A method for classifying retinal images based on features derived from the application of amplitude-modulation frequency-modulation (AM-FM) methods is presented. Retinal images from identical and fraternal twins who presented with AMD were processed to determine whether AM-FM could be used to differentiate between the two types of twins. Results of the automatic classifier agreed with the findings of other researchers in explaining the variation of the disease between the related twins. AM-FM features classified 72% of the twins correctly. Visual grading found that genetics could explain between 46% and 71% of the variance.

  17. SM2PH-db: an interactive system for the integrated analysis of phenotypic consequences of missense mutations in proteins involved in human genetic diseases.

    Science.gov (United States)

    Friedrich, Anne; Garnier, Nicolas; Gagnière, Nicolas; Nguyen, Hoan; Albou, Laurent-Philippe; Biancalana, Valérie; Bettler, Emmanuel; Deléage, Gilbert; Lecompte, Odile; Muller, Jean; Moras, Dino; Mandel, Jean-Louis; Toursel, Thierry; Moulinier, Luc; Poch, Olivier

    2010-02-01

    Understanding how genetic alterations affect gene products at the molecular level represents a first step in the elucidation of the complex relationships between genotypic and phenotypic variations, and is thus a major challenge in the postgenomic era. Here, we present SM2PH-db (http://decrypthon.igbmc.fr/sm2ph), a new database designed to investigate structural and functional impacts of missense mutations and their phenotypic effects in the context of human genetic diseases. A wealth of up-to-date interconnected information is provided for each of the 2,249 disease-related entry proteins (August 2009), including data retrieved from biological databases and data generated from a Sequence-Structure-Evolution Inference in Systems-based approach, such as multiple alignments, three-dimensional structural models, and multidimensional (physicochemical, functional, structural, and evolutionary) characterizations of mutations. SM2PH-db provides a robust infrastructure associated with interactive analysis tools supporting in-depth study and interpretation of the molecular consequences of mutations, with the more long-term goal of elucidating the chain of events leading from a molecular defect to its pathology. The entire content of SM2PH-db is regularly and automatically updated thanks to a computational grid data federation facilities provided in the context of the Decrypthon program.

  18. Information theory, multivariate dependence, and genetic network inference

    CERN Document Server

    Nemenman, Ilya

    2007-01-01

    We define the concept of dependence among multiple variables using maximum entropy techniques and introduce a graphical notation to denote the dependencies. Direct inference of information theoretic quantities from data uncovers dependencies even in undersampled regimes when the joint probability distribution cannot be reliably estimated. The method is tested on synthetic data. We anticipate it to be useful for inference of genetic circuits and other biological signaling networks.

  19. 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.

  20. Phenotypic and genetic relationships of feed efficiency with growth performance, ultrasound, and carcass merit traits in Angus and Charolais steers.

    Science.gov (United States)

    Mao, F; Chen, L; Vinsky, M; Okine, E; Wang, Z; Basarab, J; Crews, D H; Li, C

    2013-05-01

    Feed efficiency is of particular importance to the beef industry, as feed costs represent the single largest variable cost in beef production systems. Selection for more efficient cattle will lead to reduction of feed related costs, but should not have adverse impacts on quality of the carcass. In this study, we evaluated phenotypic and genetic correlations of residual feed intake (RFI), RFI adjusted for end-of-test ultrasound backfat thickness (RFIf), and RFI adjusted for ultrasound backfat thickness and LM area (RFIfr) with growth, ultrasound, and carcass merit traits in an Angus population of 551 steers and in a Charolais population of 417 steers. In the Angus steer population, the phenotypic and genetic correlation of RFI with carcass merit traits including HCW, carcass backfat, carcass LM area, lean meat yield, and carcass marbling were not significant or weak with correlations coefficients ranging from -0.0007 ± 0.05 to 0.18 ± 0.21. In the Charolais steer population, the phenotypic and genetic correlations of RFI with the carcass merit traits were also weak, with correlation coefficients ranging from -0.07 ± 0.06 to 0.19 ± 0.18, except for the genetic correlation with carcass average backfat, which was moderate with a magnitude of 0.42 ± 0.29. Inclusion of ultrasound backfat thickness in the model to predict the expected daily DMI for maintenance explained on average an additional 0.5% variation of DMI in the Angus steers and 2.3% variation of DMI in the Charolais steer population. Inclusion of both the ultrasound backfat and LM area in the model explained only 0.7% additional variance in DMI in the Angus steer population and only 0.6% in the Charolais steer population on top of the RFIf model. We concluded that RFIf adjusted for ultrasound backfat at the end of the test will lead to decreases of both the phenotypic and genetic correlations with carcass backfat and marbling score to a greater extent for late-maturing beef breeds such as Charolais than

  1. Towards systems genetic analyses in barley: Integration of phenotypic, expression and genotype data into GeneNetwork

    Directory of Open Access Journals (Sweden)

    Druka Arnis

    2008-11-01

    Full Text Available Abstract Background A typical genetical genomics experiment results in four separate data sets; genotype, gene expression, higher-order phenotypic data and metadata that describe the protocols, processing and the array platform. Used in concert, these data sets provide the opportunity to perform genetic analysis at a systems level. Their predictive power is largely determined by the gene expression dataset where tens of millions of data points can be generated using currently available mRNA profiling technologies. Such large, multidimensional data sets often have value beyond that extracted during their initial analysis and interpretation, particularly if conducted on widely distributed reference genetic materials. Besides quality and scale, access to the data is of primary importance as accessibility potentially allows the extraction of considerable added value from the same primary dataset by the wider research community. Although the number of genetical genomics experiments in different plant species is rapidly increasing, none to date has been presented in a form that allows quick and efficient on-line testing for possible associations between genes, loci and traits of interest by an entire research community. Description Using a reference population of 150 recombinant doubled haploid barley lines we generated novel phenotypic, mRNA abundance and SNP-based genotyping data sets, added them to a considerable volume of legacy trait data and entered them into the GeneNetwork http://www.genenetwork.org. GeneNetwork is a unified on-line analytical environment that enables the user to test genetic hypotheses about how component traits, such as mRNA abundance, may interact to condition more complex biological phenotypes (higher-order traits. Here we describe these barley data sets and demonstrate some of the functionalities GeneNetwork provides as an easily accessible and integrated analytical environment for exploring them. Conclusion By

  2. Identifying rare variants for genetic risk through a combined pedigree and phenotype approach: application to suicide and asthma.

    Science.gov (United States)

    Darlington, T M; Pimentel, R; Smith, K; Bakian, A V; Jerominski, L; Cardon, J; Camp, N J; Callor, W B; Grey, T; Singleton, M; Yandell, M; Renshaw, P F; Yurgelun-Todd, D A; Gray, D; Coon, H

    2014-10-21

    Suicidal behavior is a complex disorder, with evidence for genetic risk independent of other genetic risk factors including psychiatric disorders. Since 1996, over 3000 DNA samples from Utah suicide decedents have been collected and banked for research use through the Utah Medical Examiner. In addition, over 12,000 Utah suicides were identified through examination of death certificates back to 1904. By linking this data with the Utah Population Database, we have identified multiple extended pedigrees with increased risk for suicide completion. A number of medical conditions co-occur with suicide, including asthma, and this study was undertaken to identify genetic risk common to asthma and suicide. This study tests the hypothesis that a particular comorbid condition may identify a more homogeneous genetic subgroup, facilitating the identification of specific genetic risk factors in that group. From pedigrees at increased risk for suicide, we identified three pedigrees also at significantly increased familial risk for asthma. Five suicide decedents from each of these pedigrees, plus an additional three decedents not from these pedigrees with diagnosed asthma, and 10 decedents with close relatives with asthma were genotyped. Results were compared with 183 publicly available unaffected control exomes from 1000 Genomes and CEPH (Centre d'etude du polymorphisme humain) samples genotyped on the same platform. A further 432 suicide decedents were also genotyped as non-asthma suicide controls. Genotyping was done using the Infinium HumanExome BeadChip. For analysis, we used the pedigree extension of Variant Annotation, Analysis and Search Tool (pVAAST) to calculate the disease burden of each gene. The Phenotype Driven Variant Ontological Re-ranking tool (Phevor) then re-ranked our pVAAST results in context of the phenotype. Using asthma as a seed phenotype, Phevor traversed biomedical ontologies and identified genes with similar biological properties to those known to

  3. The Bone Dysplasia Ontology: integrating genotype and phenotype information in the skeletal dysplasia domain

    Directory of Open Access Journals (Sweden)

    Groza Tudor

    2012-03-01

    Full Text Available Abstract Background Skeletal dysplasias are a rare and heterogeneous group of genetic disorders affecting skeletal development. Patients with skeletal dysplasias suffer from many complex medical issues including degenerative joint disease and neurological complications. Because the data and expertise associated with this field is both sparse and disparate, significant benefits will potentially accrue from the availability of an ontology that provides a shared conceptualisation of the domain knowledge and enables data integration, cross-referencing and advanced reasoning across the relevant but distributed data sources. Results We introduce the design considerations and implementation details of the Bone Dysplasia Ontology. We also describe the different components of the ontology, including a comprehensive and formal representation of the skeletal dysplasia domain as well as the related genotypes and phenotypes. We then briefly describe SKELETOME, a community-driven knowledge curation platform that is underpinned by the Bone Dysplasia Ontology. SKELETOME enables domain experts to use, refine and extend and apply the ontology without any prior ontology engineering experience--to advance the body of knowledge in the skeletal dysplasia field. Conclusions The Bone Dysplasia Ontology represents the most comprehensive structured knowledge source for the skeletal dysplasias domain. It provides the means for integrating and annotating clinical and research data, not only at the generic domain knowledge level, but also at the level of individual patient case studies. It enables links between individual cases and publicly available genotype and phenotype resources based on a community-driven curation process that ensures a shared conceptualisation of the domain knowledge and its continuous incremental evolution.

  4. Cooperation as a signal of genetic or phenotypic quality in female mate choice? Evidence from preferences across the menstrual cycle.

    Science.gov (United States)

    Farrelly, Daniel

    2011-08-01

    Previous research highlighting the role sexual selection may play in the evolution of human cooperation has yet to distinguish what qualities such behaviours actually signal. The aim here was to examine whether female preferences for male cooperative behaviours are because they signal genetic or indirect phenotypic quality. This was possible by taking into account female participants' stage of menstrual cycle, as much research has shown that females at the most fertile stage show greater preferences specifically for signals of genetic quality than any other stage, particularly for short-term relationships. Therefore, different examples of cooperation (personality, costly signals, heroism) and the mate preferences for altruistic traits self-report scale were used across a series of four experiments to examine females' attitudes towards cooperation in potential mates for different relationship lengths at different stages of the menstrual cycle. The results here consistently show that female fertility had no effect on perceptions of cooperative behaviour, and that such traits were considered more important for long-term relationships. Therefore, this provides strong evidence that cooperative behaviour is important in mate choice as predominantly a signal of phenotypic rather than genetic quality.

  5. 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

    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......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...... genotyped 1798 white subjects at increased type 2 diabetes mellitus risk for 9 TRPM5 single nucleotide polymorphisms (namely, rs2301696, rs800344, rs800345, rs800347, rs800348, rs2074234, rs2301698, rs886277, and rs2301699) and also performed correlational analyses with metabolic traits. An oral glucose...

  6. Information schema constructs for defining warehouse databases of genotypes and phenotypes of system manifestation features

    Institute of Scientific and Technical Information of China (English)

    Shahab POURTALEBI‡; Imre HORVÁTH

    2016-01-01

    Our long-term objective is to develop a software toolbox for pre-embodiment design of complex and heterogeneous systems, such as cyber-physical systems. The novelty of this toolbox is that it uses system manifestation features (SMFs) for transdisciplinary modeling of these systems. The main challenges of implementation of the toolbox are functional design- and language-independent computational realization of the warehouses, and systematic development and management of the various evolving implements of SMFs (genotypes, phenotypes, and instances). Therefore, an information schema construct (ISC) based approach is proposed to create the schemata of the associated warehouse databases and the above-mentioned SMF implements. ISCs logically arrange the data contents of SMFs in a set of relational tables of varying semantics. In this article we present the ISCs necessary for creation of genotypes and phenotypes. They increase the efficiency of the database development process and make the data relationships transparent. Our follow-up research focuses on the elaboration of the SMF instances based system modeling methodology.

  7. Bridging the phenotypic and genetic data useful for integrated breeding through a data annotation using the Crop Ontology developed by the crop communities of practice

    Directory of Open Access Journals (Sweden)

    Rosemary eShrestha

    2012-08-01

    Full Text Available The Crop Ontology (CO of the Generation Challenge Program (GCP (http://cropontology.org/ is developed for the Integrated Breeding Platform (https://www.integratedbreeding.net/ by several centers of The Consultative Group on International Agricultural Research (CGIAR: Bioversity, CIMMYT, CIP, ICRISAT, IITA, and IRRI. Integrated breeding necessitates that breeders access genotypic and phenotypic data related to a given trait. The Crop Ontology provides validated trait names used by the crop communities of practice for harmonizing the annotation of phenotypic and genotypic data and thus supporting data accessibility and discovery through web queries. The trait information is completed by the description of the measurement methods and scales, and images. The trait dictionaries used to produce the Integrated Breeding (IB fieldbooks are synchronized with the Crop Ontology terms for an automatic annotation of the phenotypic data measured in the field. The IB fieldbook provides breeders with direct access to the CO to get additional descriptive information on the traits. Ontologies and trait dictionaries are online for cassava, chickpea, common bean, groundnut, maize, Musa, potato, rice, sorghum and wheat. Online curation and annotation tools facilitate (http://cropontology.org direct maintenance of the trait information and production of trait dictionaries by the crop communities. An important feature is the cross referencing of CO terms with the Crop database trait ID and with their synonyms in Plant Ontology and Trait Ontology. Web links between cross referenced terms in CO provide online access to data annotated with similar ontological terms, particularly the genetic data in Gramene (University of Cornell or the evaluation and climatic data in the Global Repository of evaluation trials of the Climate Change, Agriculture and Food Security programme (CCAFS. Cross-referencing and annotation will be further applied in the Integrated Breeding Platform.

  8. Bridging the phenotypic and genetic data useful for integrated breeding through a data annotation using the Crop Ontology developed by the crop communities of practice

    Science.gov (United States)

    Shrestha, Rosemary; Matteis, Luca; Skofic, Milko; Portugal, Arllet; McLaren, Graham; Hyman, Glenn; Arnaud, Elizabeth

    2012-01-01

    The Crop Ontology (CO) of the Generation Challenge Program (GCP) (http://cropontology.org/) is developed for the Integrated Breeding Platform (IBP) (http://www.integratedbreeding.net/) by several centers of The Consultative Group on International Agricultural Research (CGIAR): bioversity, CIMMYT, CIP, ICRISAT, IITA, and IRRI. Integrated breeding necessitates that breeders access genotypic and phenotypic data related to a given trait. The CO provides validated trait names used by the crop communities of practice (CoP) for harmonizing the annotation of phenotypic and genotypic data and thus supporting data accessibility and discovery through web queries. The trait information is completed by the description of the measurement methods and scales, and images. The trait dictionaries used to produce the Integrated Breeding (IB) fieldbooks are synchronized with the CO terms for an automatic annotation of the phenotypic data measured in the field. The IB fieldbook provides breeders with direct access to the CO to get additional descriptive information on the traits. Ontologies and trait dictionaries are online for cassava, chickpea, common bean, groundnut, maize, Musa, potato, rice, sorghum, and wheat. Online curation and annotation tools facilitate (http://cropontology.org) direct maintenance of the trait information and production of trait dictionaries by the crop communities. An important feature is the cross referencing of CO terms with the Crop database trait ID and with their synonyms in Plant Ontology (PO) and Trait Ontology (TO). Web links between cross referenced terms in CO provide online access to data annotated with similar ontological terms, particularly the genetic data in Gramene (University of Cornell) or the evaluation and climatic data in the Global Repository of evaluation trials of the Climate Change, Agriculture and Food Security programme (CCAFS). Cross-referencing and annotation will be further applied in the IBP. PMID:22934074

  9. Genetics

    DEFF Research Database (Denmark)

    Christensen, Kaare; McGue, Matt

    2016-01-01

    The sequenced genomes of individuals aged ≥80 years, who were highly educated, self-referred volunteers and with no self-reported chronic diseases were compared to young controls. In these data, healthy ageing is a distinct phenotype from exceptional longevity and genetic factors that protect...

  10. A randomized trial of genetic information for personalized nutrition.

    Science.gov (United States)

    Nielsen, Daiva E; El-Sohemy, Ahmed

    2012-10-01

    Personal genetic information has become increasingly accessible to the public as a result of direct-to-consumer (DTC) genetic tests; however, concerns have been raised over their value and potential risks. We compared the effects of providing genotype-based dietary advice with general recommendations on behavioral outcomes using a randomized controlled study. Participants were men and women from the Toronto Nutrigenomics and Health Study between the ages of 20-35 years (n = 149) who completed a survey to assess their awareness of DTC genetic tests and nutrigenomics, as well as potential motivations for undergoing genetic testing. Participants were then randomized into an intervention (I) or control (C) group and were given either genotype-based personalized dietary advice or general dietary advice, respectively. A second survey was administered to assess the participants' opinions of the dietary reports they received. A greater proportion of participants in the intervention group agreed that they understood the dietary advice they were given (93% (I) vs. 78% (C); p = 0.009). Participants in the intervention group were more likely to agree that the dietary recommendations they received would be useful when considering their diet (88% (I) vs. 72% (C); p = 0.02) and wanted to know more about the recommendations (95% (I) vs. 76% (C); p personalized nutrition.

  11. Comparative genomics of Brachyspira pilosicoli strains: genome rearrangements, reductions and correlation of genetic compliment with phenotypic diversity

    Directory of Open Access Journals (Sweden)

    Mappley Luke J

    2012-09-01

    Full Text Available Abstract Background The anaerobic spirochaete Brachyspira pilosicoli causes enteric disease in avian, porcine and human hosts, amongst others. To date, the only available genome sequence of B. pilosicoli is that of strain 95/1000, a porcine isolate. In the first intra-species genome comparison within the Brachyspira genus, we report the whole genome sequence of B. pilosicoli B2904, an avian isolate, the incomplete genome sequence of B. pilosicoli WesB, a human isolate, and the comparisons with B. pilosicoli 95/1000. We also draw on incomplete genome sequences from three other Brachyspira species. Finally we report the first application of the high-throughput Biolog phenotype screening tool on the B. pilosicoli strains for detailed comparisons between genotype and phenotype. Results Feature and sequence genome comparisons revealed a high degree of similarity between the three B. pilosicoli strains, although the genomes of B2904 and WesB were larger than that of 95/1000 (~2,765, 2.890 and 2.596 Mb, respectively. Genome rearrangements were observed which correlated largely with the positions of mobile genetic elements. Through comparison of the B2904 and WesB genomes with the 95/1000 genome, features that we propose are non-essential due to their absence from 95/1000 include a peptidase, glycine reductase complex components and transposases. Novel bacteriophages were detected in the newly-sequenced genomes, which appeared to have involvement in intra- and inter-species horizontal gene transfer. Phenotypic differences predicted from genome analysis, such as the lack of genes for glucuronate catabolism in 95/1000, were confirmed by phenotyping. Conclusions The availability of multiple B. pilosicoli genome sequences has allowed us to demonstrate the substantial genomic variation that exists between these strains, and provides an insight into genetic events that are shaping the species. In addition, phenotype screening allowed determination of how

  12. A forward genetic screen with a thalamocortical axon reporter mouse yields novel neurodevelopment mutants and a distinct emx2 mutant phenotype

    Directory of Open Access Journals (Sweden)

    Vock Vita M

    2011-01-01

    Full Text Available Abstract Background The dorsal thalamus acts as a gateway and modulator for information going to and from the cerebral cortex. This activity requires the formation of reciprocal topographic axon connections between thalamus and cortex. The axons grow along a complex multistep pathway, making sharp turns, crossing expression boundaries, and encountering intermediate targets. However, the cellular and molecular components mediating these steps remain poorly understood. Results To further elucidate the development of the thalamocortical system, we first created a thalamocortical axon reporter line to use as a genetic tool for sensitive analysis of mutant mouse phenotypes. The TCA-tau-lacZ reporter mouse shows specific, robust, and reproducible labeling of thalamocortical axons (TCAs, but not the overlapping corticothalamic axons, during development. Moreover, it readily reveals TCA pathfinding abnormalities in known cortical mutants such as reeler. Next, we performed an unbiased screen for genes involved in thalamocortical development using random mutagenesis with the TCA reporter. Six independent mutant lines show aberrant TCA phenotypes at different steps of the pathway. These include ventral misrouting, overfasciculation, stalling at the corticostriatal boundary, and invasion of ectopic cortical cell clusters. An outcross breeding strategy coupled with a genomic panel of single nucleotide polymorphisms facilitated genetic mapping with small numbers of mutant mice. We mapped a ventral misrouting mutant to the Emx2 gene, and discovered that some TCAs extend to the olfactory bulbs in this mutant. Mapping data suggest that other lines carry mutations in genes not previously known for roles in thalamocortical development. Conclusions These data demonstrate the feasibility of a forward genetic approach to understanding mammalian brain morphogenesis and wiring. A robust axonal reporter enabled sensitive analysis of a specific axon tract inside the

  13. Phenotypic and genetic differentiation among yellow monkeyflower populations from thermal and non-thermal soils in Yellowstone National Park.

    Science.gov (United States)

    Lekberg, Ylva; Roskilly, Beth; Hendrick, Margaret F; Zabinski, Catherine A; Barr, Camille M; Fishman, Lila

    2012-09-01

    In flowering plants, soil heterogeneity can generate divergent natural selection over fine spatial scales, and thus promote local adaptation in the absence of geographic barriers to gene flow. Here, we investigate phenotypic and genetic differentiation in one of the few flowering plants that thrives in both geothermal and non-thermal soils in Yellowstone National Park (YNP). Yellow monkeyflowers (Mimulus guttatus) growing at two geothermal ("thermal") sites in YNP were distinct in growth form and phenology from paired populations growing nearby ( 0.34), which were only weakly differentiated from each other (all F (ST) Yellowstone.

  14. Genetic variation in the oxytocin receptor gene is associated with a social phenotype in autism spectrum disorders.

    Science.gov (United States)

    Harrison, Ashley J; Gamsiz, Ece D; Berkowitz, Isaac C; Nagpal, Shailender; Jerskey, Beth A

    2015-12-01

    Oxytocin regulates social behavior in animal models. Research supports an association between genetic variation in the oxytocin receptor gene (OXTR) and autism spectrum disorders (ASD). In this study, we examine the association between the OXTR gene and a specific social phenotype within ASD. This genotype-phenotype investigation may provide insight into how OXTR conveys risk for social impairment. The current study investigated 10 SNPS in the OXTR gene that have been previously shown to be associated with ASD. We examine the association of these SNPs with both a social phenotype and a repetitive behavior phenotype comprised of behaviors commonly impaired in ASD in the Simons simplex collection (SSC). Using a large sample to examine the association between OXTR and ASD (n = range: 485-1002), we find evidence to support a relation between two OXTR SNPs and the examined social phenotype among children diagnosed with ASD. Greater impairment on the social responsiveness scale standardized total score and on several subdomains was observed among individuals with one or more copies of the minor frequency allele in both rs7632287 and rs237884. Linkage disequilibrium (LD) mapping suggests that these two SNPs are in LD within and overlapping the 3' untranslated region (3'-UTR) of the OXTR gene. These two SNPs were also associated with greater impairment on the repetitive behavior scale. Results of this study indicate that social impairment and repetitive behaviors in ASD are associated with genomic variation in the 3'UTR of the OXTR gene. These variants may be linked to an allele that alters stability of the mRNA message although further work is necessary to test this hypothesis.

  15. Estimation of total genetic effects for survival time in crossbred laying hens showing cannibalism, using pedigree or genomic information.

    Science.gov (United States)

    Brinker, T; Raymond, B; Bijma, P; Vereijken, A; Ellen, E D

    2017-02-01

    Mortality of laying hens due to cannibalism is a major problem in the egg-laying industry. Survival depends on two genetic effects: the direct genetic effect of the individual itself (DGE) and the indirect genetic effects of its group mates (IGE). For hens housed in sire-family groups, DGE and IGE cannot be estimated using pedigree information, but the combined effect of DGE and IGE is estimated in the total breeding value (TBV). Genomic information provides information on actual genetic relationships between individuals and might be a tool to improve TBV accuracy. We investigated whether genomic information of the sire increased TBV accuracy compared with pedigree information, and we estimated genetic parameters for survival time. A sire model with pedigree information (BLUP) and a sire model with genomic information (ssGBLUP) were used. We used survival time records of 7290 crossbred offspring with intact beaks from four crosses. Cross-validation was used to compare the models. Using ssGBLUP did not improve TBV accuracy compared with BLUP which is probably due to the limited number of sires available per cross (~50). Genetic parameter estimates were similar for BLUP and ssGBLUP. For both BLUP and ssGBLUP, total heritable variance (T(2) ), expressed as a proportion of phenotypic variance, ranged from 0.03 ± 0.04 to 0.25 ± 0.09. Further research is needed on breeding value estimation for socially affected traits measured on individuals kept in single-family groups. © 2016 The Authors. Journal of Animal Breeding and Genetics Published by Blackwell Verlag GmbH.

  16. Phenotype-Environment Interactions in Genetic Syndromes Associated with Severe or Profound Intellectual Disability

    Science.gov (United States)

    Tunnicliffe, Penny; Oliver, Chris

    2011-01-01

    The research literature notes both biological and operant theories of behavior disorder in individuals with intellectual disabilities. These two theories of genetic predisposition and operant reinforcement remain quite distinct; neither theory on its own is sufficient to explain challenging behavior in genetic syndromes and an integrated approach…

  17. From risk genes to psychiatric phenotypes - Studies of fibroblast growth factor-related and genome-wide genetic variants in humans and mice

    NARCIS (Netherlands)

    Terwisscha van Scheltinga, A.F.

    2013-01-01

    Schizophrenia is a severe mental disorder with a high heritability. This thesis describes studies on the association between genetic variants and phenotypes related to schizophrenia, such as brain volume and IQ, in order to learn about which processes are affected by schizophrenia-associated genetic

  18. Beyond Punnett Squares: Student Word Association and Explanations of Phenotypic Variation through an Integrative Quantitative Genetics Unit Investigating Anthocyanin Inheritance and Expression in "Brassica rapa" Fast Plants

    Science.gov (United States)

    Batzli, Janet M.; Smith, Amber R.; Williams, Paul H.; McGee, Seth A.; Dosa, Katalin; Pfammatter, Jesse

    2014-01-01

    Genetics instruction in introductory biology is often confined to Mendelian genetics and avoids the complexities of variation in quantitative traits. Given the driving question "What determines variation in phenotype (Pv)? (Pv=Genotypic variation Gv + environmental variation Ev)," we developed a 4-wk unit for an inquiry-based laboratory…

  19. Beyond Punnett Squares: Student Word Association and Explanations of Phenotypic Variation through an Integrative Quantitative Genetics Unit Investigating Anthocyanin Inheritance and Expression in "Brassica rapa" Fast Plants

    Science.gov (United States)

    Batzli, Janet M.; Smith, Amber R.; Williams, Paul H.; McGee, Seth A.; Dosa, Katalin; Pfammatter, Jesse

    2014-01-01

    Genetics instruction in introductory biology is often confined to Mendelian genetics and avoids the complexities of variation in quantitative traits. Given the driving question "What determines variation in phenotype (Pv)? (Pv=Genotypic variation Gv + environmental variation Ev)," we developed a 4-wk unit for an inquiry-based laboratory…

  20. From integrative genomics to systems genetics in the rat to link genotypes to phenotypes

    Science.gov (United States)

    Moreno-Moral, Aida

    2016-01-01

    ABSTRACT Complementary to traditional gene mapping approaches used to identify the hereditary components of complex diseases, integrative genomics and systems genetics have emerged as powerful strategies to decipher the key genetic drivers of molecular pathways that underlie disease. Broadly speaking, integrative genomics aims to link cellular-level traits (such as mRNA expression) to the genome to identify their genetic determinants. With the characterization of several cellular-level traits within the same system, the integrative genomics approach evolved into a more comprehensive study design, called systems genetics, which aims to unravel the complex biological networks and pathways involved in disease, and in turn map their genetic control points. The first fully integrated systems genetics study was carried out in rats, and the results, which revealed conserved trans-acting genetic regulation of a pro-inflammatory network relevant to type 1 diabetes, were translated to humans. Many studies using different organisms subsequently stemmed from this example. The aim of this Review is to describe the most recent advances in the fields of integrative genomics and systems genetics applied in the rat, with a focus on studies of complex diseases ranging from inflammatory to cardiometabolic disorders. We aim to provide the genetics community with a comprehensive insight into how the systems genetics approach came to life, starting from the first integrative genomics strategies [such as expression quantitative trait loci (eQTLs) mapping] and concluding with the most sophisticated gene network-based analyses in multiple systems and disease states. Although not limited to studies that have been directly translated to humans, we will focus particularly on the successful investigations in the rat that have led to primary discoveries of genes and pathways relevant to human disease. PMID:27736746

  1. Genetic Redundancies Enhance Information Transfer in Noisy Regulatory Circuits

    Science.gov (United States)

    Rodrigo, Guillermo; Poyatos, Juan F.

    2016-01-01

    Cellular decision making is based on regulatory circuits that associate signal thresholds to specific physiological actions. This transmission of information is subjected to molecular noise what can decrease its fidelity. Here, we show instead how such intrinsic noise enhances information transfer in the presence of multiple circuit copies. The result is due to the contribution of noise to the generation of autonomous responses by each copy, which are altogether associated with a common decision. Moreover, factors that correlate the responses of the redundant units (extrinsic noise or regulatory cross-talk) contribute to reduce fidelity, while those that further uncouple them (heterogeneity within the copies) can lead to stronger information gain. Overall, our study emphasizes how the interplay of signal thresholding, redundancy, and noise influences the accuracy of cellular decision making. Understanding this interplay provides a basis to explain collective cell signaling mechanisms, and to engineer robust decisions with noisy genetic circuits. PMID:27741249

  2. Clinical and genetic analysis of 29 Brazilian patients with Huntington's disease-like phenotype

    Directory of Open Access Journals (Sweden)

    Guilherme Riccioppo Rodrigues

    2011-06-01

    Full Text Available Huntington's disease (HD is a neurodegenerative disorder characterized by chorea, behavioral disturbances and dementia, caused by a pathological expansion of the CAG trinucleotide in the HTT gene. Several patients have been recognized with the typical HD phenotype without the expected mutation. The objective of this study was to assess the occurrence of diseases such as Huntington's disease-like 2 (HDL2, spinocerebellar ataxia (SCA 1, SCA2, SCA3, SCA7, dentatorubral-pallidoluysian atrophy (DRPLA and chorea-acanthocytosis (ChAc among 29 Brazilian patients with a HD-like phenotype. In the group analyzed, we found 3 patients with HDL2 and 2 patients with ChAc. The diagnosis was not reached in 79.3% of the patients. HDL2 was the main cause of the HD-like phenotype in the group analyzed, and is attributable to the African ancestry of this population. However, the etiology of the disease remains undetermined in the majority of the HD negative patients with HD-like phenotype.

  3. Is Sensory Over-Responsivity Distinguishable from Childhood Behavior Problems? A Phenotypic and Genetic Analysis

    Science.gov (United States)

    Van Hulle, Carol A.; Schmidt, Nicole L.; Goldsmith, H. Hill

    2012-01-01

    Background: Although impaired sensory processing accompanies various clinical conditions, the question of its status as an independent disorder remains open. Our goal was to delineate the comorbidity (or lack thereof) between childhood psychopathology and sensory over-responsivity (SOR) in middle childhood using phenotypic and behavior-genetic…

  4. Phenotypic convergence in genetically distinct lineages of a Rhinolophus species complex (Mammalia, Chiroptera.

    Directory of Open Access Journals (Sweden)

    David S Jacobs

    Full Text Available Phenotypes of distantly related species may converge through adaptation to similar habitats and/or because they share biological constraints that limit the phenotypic variants produced. A common theme in bats is the sympatric occurrence of cryptic species that are convergent in morphology but divergent in echolocation frequency, suggesting that echolocation may facilitate niche partitioning, reducing competition. If so, allopatric populations freed from competition, could converge in both morphology and echolocation provided they occupy similar niches or share biological constraints. We investigated the evolutionary history of a widely distributed African horseshoe bat, Rhinolophus darlingi, in the context of phenotypic convergence. We used phylogenetic inference to identify and date lineage divergence together with phenotypic comparisons and ecological niche modelling to identify morphological and geographical correlates of those lineages. Our results indicate that R. darlingi is paraphyletic, the eastern and western parts of its distribution forming two distinct non-sister lineages that diverged ~9.7 Mya. We retain R. darlingi for the eastern lineage and argue that the western lineage, currently the sub-species R. d. damarensis, should be elevated to full species status. R. damarensis comprises two lineages that diverged ~5 Mya. Our findings concur with patterns of divergence of other co-distributed taxa which are associated with increased regional aridification between 7-5 Mya suggesting possible vicariant evolution. The morphology and echolocation calls of R. darlingi and R. damarensis are convergent despite occupying different biomes. This suggests that adaptation to similar habitats is not responsible for the convergence. Furthermore, R. darlingi forms part of a clade comprising species that are bigger and echolocate at lower frequencies than R. darlingi, suggesting that biological constraints are unlikely to have influenced the

  5. Phenotypic convergence in genetically distinct lineages of a Rhinolophus species complex (Mammalia, Chiroptera).

    Science.gov (United States)

    Jacobs, David S; Babiker, Hassan; Bastian, Anna; Kearney, Teresa; van Eeden, Rowen; Bishop, Jacqueline M

    2013-01-01

    Phenotypes of distantly related species may converge through adaptation to similar habitats and/or because they share biological constraints that limit the phenotypic variants produced. A common theme in bats is the sympatric occurrence of cryptic species that are convergent in morphology but divergent in echolocation frequency, suggesting that echolocation may facilitate niche partitioning, reducing competition. If so, allopatric populations freed from competition, could converge in both morphology and echolocation provided they occupy similar niches or share biological constraints. We investigated the evolutionary history of a widely distributed African horseshoe bat, Rhinolophus darlingi, in the context of phenotypic convergence. We used phylogenetic inference to identify and date lineage divergence together with phenotypic comparisons and ecological niche modelling to identify morphological and geographical correlates of those lineages. Our results indicate that R. darlingi is paraphyletic, the eastern and western parts of its distribution forming two distinct non-sister lineages that diverged ~9.7 Mya. We retain R. darlingi for the eastern lineage and argue that the western lineage, currently the sub-species R. d. damarensis, should be elevated to full species status. R. damarensis comprises two lineages that diverged ~5 Mya. Our findings concur with patterns of divergence of other co-distributed taxa which are associated with increased regional aridification between 7-5 Mya suggesting possible vicariant evolution. The morphology and echolocation calls of R. darlingi and R. damarensis are convergent despite occupying different biomes. This suggests that adaptation to similar habitats is not responsible for the convergence. Furthermore, R. darlingi forms part of a clade comprising species that are bigger and echolocate at lower frequencies than R. darlingi, suggesting that biological constraints are unlikely to have influenced the convergence. Instead, the

  6. Shannon information entropy in the canonical genetic code.

    Science.gov (United States)

    Nemzer, Louis R

    2017-02-21

    The Shannon entropy measures the expected information value of messages. As with thermodynamic entropy, the Shannon entropy is only defined within a system that identifies at the outset the collections of possible messages, analogous to microstates, that will be considered indistinguishable macrostates. This fundamental insight is applied here for the first time to amino acid alphabets, which group the twenty common amino acids into families based on chemical and physical similarities. To evaluate these schemas objectively, a novel quantitative method is introduced based the inherent redundancy in the canonical genetic code. Each alphabet is taken as a separate system that partitions the 64 possible RNA codons, the microstates, into families, the macrostates. By calculating the normalized mutual information, which measures the reduction in Shannon entropy, conveyed by single nucleotide messages, groupings that best leverage this aspect of fault tolerance in the code are identified. The relative importance of properties related to protein folding - like hydropathy and size - and function, including side-chain acidity, can also be estimated. This approach allows the quantification of the average information value of nucleotide positions, which can shed light on the coevolution of the canonical genetic code with the tRNA-protein translation mechanism. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Comparative analysis of phenotypes features in two common genetic variants of limb-girdle muscular dystrophy

    Directory of Open Access Journals (Sweden)

    I. V. Sharkova

    2015-01-01

    Full Text Available The algorithm of differential diagnosis of the two most common genetic variants the limb-girdle muscular dystrophy (LGMD2A and DMD, developed on the basis of a comprehensive survey of 85 patients with a diagnosis specification using techniques of DNA analysis. It is shown that the accurate diagnosis of LGMD genetic types should be based on the results of the clinical and genealogical, biochemical and molecular genetic analysis. The proposed algorithm will significantly reduces the economic and time costs with expensive DNA testing.

  8. Social Cognition, Social Skill, and the Broad Autism Phenotype

    Science.gov (United States)

    Sasson, Noah J.; Nowlin, Rachel B.; Pinkham, Amy E.

    2013-01-01

    Social-cognitive deficits differentiate parents with the "broad autism phenotype" from non-broad autism phenotype parents more robustly than other neuropsychological features of autism, suggesting that this domain may be particularly informative for identifying genetic and brain processes associated with the phenotype. The current study…

  9. Genetic and phenotypic variation in central and northern European populations of Aedes (Aedimorphus) vexans (Meigen, 1830) (Diptera, Culicidae).

    Science.gov (United States)

    Francuski, Ljubinka; Milankov, Vesna; Ludoški, Jasmina; Krtinić, Bosiljka; Lundström, Jan O; Kemenesi, Gábor; Ferenc, Jakab

    2016-06-01

    The floodwater mosquito Aedes vexans can be a massive nuisance in the flood plain areas of mainland Europe, and is the vector of Tahyna virus and a potential vector of Dirofilaria immitis. This epidemiologically important species forms three subspecies worldwide, of which Aedes vexans arabiensis has a wide distribution in Europe and Africa. We quantified the genetic and phenotypic variation in Ae. vexans arabiensis in populations from Sweden (northern Europe), Hungary, and Serbia (central Europe). A landscape genetics approach (FST , STRUCTURE, BAPS, GENELAND) revealed significant differentiation between northern and southern populations. Similar to genetic data, wing geometric morphometrics revealed two different clusters, one made by Swedish populations, while another included Hungarian and Serbian populations. Moreover, integrated genetic and morphometric data from the spatial analysis suggested groupings of populations into three clusters, one of which was from Swedish and Hungarian populations. Data on spatial analysis regarding an intermediate status of the Hungarian population was supported by observed Isolation-by-Distance patterns. Furthermore, a low proportion of interpopulation vs intrapopulation variance revealed by AMOVA and low-to-moderate FST values on a broader geographical scale indicate a continuous between-population exchange of individuals, including considerable gene flow on the regional scale, are likely to be responsible for the maintenance of the observed population similarity in Aе. vexans. We discussed data considering population structure in the light of vector control strategies of the mosquito from public health importance.

  10. Novel frem1-related mouse phenotypes and evidence of genetic interactions with gata4 and slit3.

    Directory of Open Access Journals (Sweden)

    Tyler F Beck

    Full Text Available The FRAS1-related extracellular matrix 1 (FREM1 gene encodes an extracellular matrix protein that plays a critical role in the development of multiple organ systems. In humans, recessive mutations in FREM1 cause eye defects, congenital diaphragmatic hernia, renal anomalies and anorectal malformations including anteriorly placed anus. A similar constellation of findings-microphthalmia, cryptophthalmos, congenital diaphragmatic hernia, renal agenesis and rectal prolapse-have been described in FREM1-deficient mice. In this paper, we identify a homozygous Frem1 missense mutation (c.1687A>T, p.Ile563Phe in an N-ethyl-N-nitrosourea (ENU-derived mouse strain, crf11, with microphthalmia, cryptophthalmos, renal agenesis and rectal prolapse. This mutation affects a highly conserved residue in FREM1's third CSPG domain. The p.Ile563Phe change is predicted to be deleterious and to cause decreased FREM1 protein stability. The crf11 allele also fails to complement the previously described eyes2 allele of Frem1 (p.Lys826* providing further evidence that the crf11 phenotype is due to changes affecting Frem1 function. We then use mice bearing the crf11 and eyes2 alleles to identify lung lobulation defects and decreased anogenital distance in males as novel phenotypes associated with FREM1 deficiency in mice. Due to phenotypic overlaps between FREM1-deficient mice and mice that are deficient for the retinoic acid-responsive transcription factor GATA4 and the extracellular matrix protein SLIT3, we also perform experiments to look for in vivo genetic interactions between the genes that encode these proteins. These experiments reveal that Frem1 interacts genetically with Gata4 in the development of lung lobulation defects and with Slit3 in the development of renal agenesis. These results demonstrate that FREM1-deficient mice faithfully recapitulate many of the phenotypes seen in individuals with FREM1 deficiency and that variations in GATA4 and SLIT3 expression

  11. Negative phenotypic and genetic correlation between natal dispersal propensity and nest-defence behaviour in a wild bird.

    Science.gov (United States)

    Bize, Pierre; Daniel, Grégory; Viblanc, Vincent A; Martin, Julien G A; Doligez, Blandine

    2017-07-01

    Natural selection is expected to favour the integration of dispersal and phenotypic traits allowing individuals to reduce dispersal costs. Accordingly, associations have been found between dispersal and personality traits such as aggressiveness and exploration, which may facilitate settlement in a novel environment. However, the determinism of these associations has only rarely been explored. Here, we highlight the functional integration of individual personality in nest-defence behaviour and natal dispersal propensity in a long-lived colonial bird, the Alpine swift (Apus melba), providing insights into genetic constraints shaping the coevolution of these two traits. We report a negative association between natal dispersal and nest-defence (i.e. risk taking) behaviour at both the phenotypic and genetic level. This negative association may result from direct selection if risk-averseness benefits natal dispersers by reducing the costs of settlement in an unfamiliar environment, or from indirect selection if individuals with lower levels of nest defence also show lower levels of aggressiveness, reducing costs of settlement among unfamiliar neighbours in a colony. In both cases, these results highlight that risk taking is an important behavioural trait to consider in the study of dispersal evolution. © 2017 The Author(s).

  12. Population prevalence of hereditary breast cancer phenotypes and implementation of a genetic cancer risk assessment program in southern Brazil

    Science.gov (United States)

    2009-01-01

    In 2004, a population-based cohort (the Núcleo Mama Porto Alegre - NMPOA Cohort) was started in Porto Alegre, southern Brazil and within that cohort, a hereditary breast cancer study was initiated, aiming to determine the prevalence of hereditary breast cancer phenotypes and evaluate acceptance of a genetic cancer risk assessment (GCRA) program. Women from that cohort who reported a positive family history of cancer were referred to GCRA. Of the 9218 women enrolled, 1286 (13.9%) reported a family history of cancer. Of the 902 women who attended GCRA, 55 (8%) had an estimated lifetime risk of breast cancer ≥ 20% and 214 (23.7%) had pedigrees suggestive of a breast cancer predisposition syndrome; an unexpectedly high number of these fulfilled criteria for Li-Fraumeni-like syndrome (122 families, 66.7%). The overall prevalence of a hereditary breast cancer phenotype was 6.2% (95%CI: 5.67-6.65). These findings identified a problem of significant magnitude in the region and indicate that genetic cancer risk evaluation should be undertaken in a considerable proportion of the women from this community. The large proportion of women who attended GCRA (72.3%) indicates that the program was well-accepted by the community, regardless of the potential cultural, economic and social barriers. PMID:21637504

  13. Modeling of multivariate longitudinal phenotypes in family genetic studies with Bayesian multiplicity adjustment

    OpenAIRE

    Ding, Lili; Kurowski, Brad G; He, Hua; Alexander, Eileen S.; Mersha, Tesfaye B.; Fardo, David W.; Zhang, Xue; Pilipenko, Valentina V; Kottyan, Leah; Martin, Lisa J.

    2014-01-01

    Genetic studies often collect data on multiple traits. Most genetic association analyses, however, consider traits separately and ignore potential correlation among traits, partially because of difficulties in statistical modeling of multivariate outcomes. When multiple traits are measured in a pedigree longitudinally, additional challenges arise because in addition to correlation between traits, a trait is often correlated with its own measures over time and with measurements of other family...

  14. Charting the genotype-phenotype map: lessons from the Drosophila melanogaster Genetic Reference Panel.

    Science.gov (United States)

    Mackay, Trudy F C; Huang, Wen

    2017-08-22

    Understanding the genetic architecture (causal molecular variants, their effects, and frequencies) of quantitative traits is important for precision agriculture and medicine and predicting adaptive evolution, but is challenging in most species. The Drosophila melanogaster Genetic Reference Panel (DGRP) is a collection of 205 inbred strains with whole genome sequences derived from a single wild population in Raleigh, NC, USA. The large amount of quantitative genetic variation, lack of population structure, and rapid local decay of linkage disequilibrium in the DGRP and outbred populations derived from DGRP lines present a favorable scenario for performing genome-wide association (GWA) mapping analyses to identify candidate causal genes, polymorphisms, and pathways affecting quantitative traits. The many GWA studies utilizing the DGRP have revealed substantial natural genetic variation for all reported traits, little evidence for variants with large effects but enrichment for variants with low P-values, and a tendency for lower frequency variants to have larger effects than more common variants. The variants detected in the GWA analyses rarely overlap those discovered using mutagenesis, and often are the first functional annotations of computationally predicted genes. Variants implicated in GWA analyses typically have sex-specific and genetic background-specific (epistatic) effects, as well as pleiotropic effects on other quantitative traits. Studies in the DGRP reveal substantial genetic control of environmental variation. Taking account of genetic architecture can greatly improve genomic prediction in the DGRP. These features of the genetic architecture of quantitative traits are likely to apply to other species, including humans. For further resources related to this article, please visit the WIREs website. © 2017 Wiley Periodicals, Inc.

  15. Duodenal Neoplasms of Gastric Phenotype: An Immunohistochemical and Genetic Study With a Practical Approach to the Classification.

    Science.gov (United States)

    Hida, Risa; Yamamoto, Hidetaka; Hirahashi, Minako; Kumagai, Reiko; Nishiyama, Kenichi; Gi, Toshihiro; Esaki, Motohiro; Kitazono, Takanari; Oda, Yoshinao

    2017-03-01

    Duodenal neoplasm of gastric phenotype (DNGP) is very rare, and details of its histopathologic, genetic, and biological features are still unclear. Frequent gene mutations in GNAS, KRAS, and APC have been reported in pyloric gland adenomas and fundic gland-type neoplasms (initially reported as low-grade adenocarcinomas) of the stomach. Here we retrospectively analyzed 16 cases of extra-ampullary DNGP (benign to malignant), and we examined the mucin immunoprofile and oncogene mutations (GNAS, KRAS, APC, BRAF, and CTNNB1). The 16 DNGPs were histologically classified into adenomas (5 pyloric gland adenomas and 2 foveolar-type adenomas), neoplasms of uncertain malignant potential (NUMPs, n=6), and invasive adenocarcinomas (n=3). NUMPs consisted of slightly atypical epithelial cells with pale, eosinophilic, or basophilic cytoplasm growing in an anastomosing or branching glandular pattern, often with expansive submucosal extension. In contrast to invasive adenocarcinomas, NUMPs lacked significant nuclear irregularity, desmoplastic stromal reaction, lymphovascular invasion, and metastasis; their features were reminiscent of fundic gland-type neoplasms of the stomach. Immunophenotypically, most of NUMPs were predominantly positive for MUC6 with variable expressions of pepsinogen-I, HKATPase, human gastric mucin, and MUC5AC. Molecular analyses revealed the gene mutations of GNAS in 6 (38%) of 16 DNGPs (4 [57%] adenomas, 1 [16%] NUMP, and 1 [33%] invasive adenocarcinoma) and APC in 4 of 15 (27%) DNGPs: no adenomas, 2 (33%) NUMPs, and 2 (67%) invasive adenocarcinomas. BRAF mutation was present in only 1 (16%) NUMP, and KRAS and CTNNB1 mutations were absent. In conclusion, gastric-phenotype adenomas and NUMPs of the duodenum are similar to their counterparts of the stomach, in terms of histologic, genetic, and clinicopathologic features. We propose the term "NUMP" as an intermediate category between adenoma and definitely invasive adenocarcinoma. Our findings may provide novel

  16. Genetic suppressors of the Lotus japonicus har1-1 hypernodulation phenotype

    DEFF Research Database (Denmark)

    Murray, Jeremy; Karas, Bogumil; Ross, Loretta

    2006-01-01

    symbiosis (RNS), a screen for suppressors of the L. japonicus har1-1 hypernodulation phenotype was performed. Of 150,000 M2 plants analyzed, 61 stable L. japonicus double-mutant lines were isolated. In the context of the har1-1 mutation, 26 mutant lines were unable to form RNS, whereas the remaining 35...... mutant lines carried more subtle symbiotic phenotypes, either forming white ineffective nodules or showing reduced nodulation capacity. When challenged with Glomus intraradices, 18 of the 61 suppressor lines were unable to establish a symbiosis with this arbuscular mycorrhiza fungus. Using a combined...... because some of them may specify novel plant functions that regulate nodule development in L. japonicus. To facilitate mapping of the latter class of mutants, an introgression line, in which the har1-1 allele was introduced into a polymorphic background of L. japonicus ecotype MG20, was constructed...

  17. Genetic modification of glaucoma associated phenotypes between AKXD-28/Ty and DBA/2J mice

    Directory of Open Access Journals (Sweden)

    Zabaleta Adriana

    2001-01-01

    Full Text Available Abstract Background Glaucoma is a common disease but its molecular etiology is poorly understood. It involves retinal ganglion cell death and optic nerve damage that is often associated with elevated intraocular pressure. Identifying genes that modify glaucoma associated phenotypes is likely to provide insights to mechanisms of glaucoma. We previously reported glaucoma in DBA/2J mice caused by recessive alleles at two loci, isa and ipd, that cause iris stromal atrophy and iris pigment dispersion, respectively. A approach for identifying modifier genes is to study the effects of specific mutations in different mouse strains. When the phenotypic effect of a mutation is modified upon its introduction into a new strain, crosses between the parental strains can be used to identify modifier genes. The purpose of this study was to determine if the effects of the DBA/2J derived isa and ipd loci are modified in strain AKXD-28/Ty. Results AKXD-28/Ty mice develop glaucoma characterized by intraocular pressure elevation, retinal ganglion loss, and optic nerve excavation. In AKXD-28/Ty, isa causes an iris stromal atrophy phenotype as in DBA/2J. However, the iris pigment dispersion phenotype associated with ipd in DBA/2J does not occur in AKXD-28/Ty. Additionally, a greater severity and speed of retinal and optic nerve damage following intraocular pressure elevation in AKXD-28/Ty compared to DBA/2J mice suggests that AKXD-28/Ty is more susceptible to pressure-induced cell death. Conclusions The consequences of the ipd and isa mutations are modified in the AKXD-28/Ty background. These strains provide a resource for the identification of modifier genes that modulate pigment dispersion and susceptibility to pressure-induced cell death.

  18. HLA associations reveal genetic heterogeneity in psoriatic arthritis and in the psoriasis phenotype.

    LENUS (Irish Health Repository)

    Winchester, Robert

    2012-04-01

    Rigorously ascertained cases of psoriatic arthritis in subjects presenting to a rheumatology unit were compared with cases of psoriasis in subjects presenting to a dermatology unit, where subjects with musculoskeletal features were excluded, to address 1) the extent to which the contribution of the major histocompatibility complex (MHC) to psoriatic arthritis susceptibility resembles that in psoriasis, and 2) whether MHC genes determine quantitative traits within the psoriatic arthritis phenotype.

  19. ApiNATOMY: a novel toolkit for visualizing multiscale anatomy schematics with phenotype-related information.

    Science.gov (United States)

    de Bono, Bernard; Grenon, Pierre; Sammut, Stephen John

    2012-05-01

    A significant proportion of biomedical resources carries information that cross references to anatomical structures across multiple scales. To improve the visualization of such resources in their anatomical context, we developed an automated methodology that produces anatomy schematics in a consistent manner,and provides for the overlay of anatomy-related resource information onto the same diagram. This methodology, called ApiNATOMY, draws upon the topology of ontology graphs to automatically lay out treemaps representing body parts as well as semantic metadata linking to such ontologies. More generally, ApiNATOMY treemaps provide an efficient and manageable way to visualize large biomedical ontologies in a meaningful and consistent manner. In the anatomy domain, such treemaps will allow epidemiologists, clinicians, and biomedical scientists to review, and interact with, anatomically aggregated heterogeneous data and model resources. Such an approach supports the visual identification of functional relations between anatomically colocalized resources that may not be immediately amenable to automation by ontology-based inferencing. We also describe the application of ApiNATOMY schematics to integrate, and add value to, human phenotype-related information—results are found at http://apinatomy.org. The long-term goal for the ApiNATOMY toolkit is to support clinical and scientific graphical user interfaces and dashboards for biomedical resource management and data analytics.

  20. Analysis of phenotypic and genetic parameters for growthrelated traits in the half smooth tongue sole, Cynoglossus semilaevis

    Science.gov (United States)

    Liu, Feng; Li, Yangzhen; Du, Min; Shao, Changwei; Chen, Songlin

    2016-01-01

    Phenotypic and genetic parameters for growth-related traits in the half-smooth tongue sole, Cynoglossus semilaevis, were estimated in 22 full-sib families produced by normal and neo-male breeding stocks. As phenotypic males with female genotypes, neo-males are harmful in C. semilaevis aquaculture because they reduce overall production. The present study evaluated the difference in the growth-related traits: total length (TL), body weight (BW) and square root of body weight (SQ_BW) at the age of 570 days between normal and neo-male offspring (neo-males used as male parents). The difference in the proportion of females between normal and neo-male offspring was also assessed. Based on the linear mixed model, restricted maximum likelihood (REML) and best linear unbiased prediction (BLUP) were used to estimate various (co)variance components and estimated breeding values (EBVs) of growth-related traits. As a result, all the mean values of the three studied traits were significantly larger in normal offspring than in neo-male offspring. Additionally, the female proportion was significantly larger in normal offspring than in neo-male offspring. Heritability was 0.128±0.066 2 for TL, 0.128±0.065 5 for BW and 0.132±0.062 9 for SQ_BW, all of which were low level heritabilities. The correlation coefficients of EBVs and phenotypic values of the target traits were 0.516 for TL, 0.524 for BW and 0.506 for SQ_BW, all of which were highly significant ( P standard errors (0.063-0.123 for genotype, and 0.010-0.018 for phenotype). Compared with normal offspring, neo-male offspring have lower breeding values for each studied trait through EBVs comparison. Therefore, neo-male offspring should not be used as broodstock in a C. semilaevis breeding programs.

  1. Joint analysis of phenotypic and molecular diversity provides new insights on the genetic variability of the Brazilian physic nut germplasm bank.

    Science.gov (United States)

    Alves, Alexandre Alonso; Bhering, Leonardo Lopes; Rosado, Tatiana Barbosa; Laviola, Bruno Galvêas; Formighieri, Eduardo Fernandes; Cruz, Cosme Damião

    2013-09-01

    The genetic variability of the Brazilian physic nut (Jatropha curcas) germplasm bank (117 accessions) was assessed using a combination of phenotypic and molecular data. The joint dissimilarity matrix showed moderate correlation with the original matrices of phenotypic and molecular data. However, the correlation between the phenotypic dissimilarity matrix and the genotypic dissimilarity matrix was low. This finding indicated that molecular markers (RAPD and SSR) did not adequately sample the genomic regions that were relevant for phenotypic differentiation of the accessions. The dissimilarity values of the joint dissimilarity matrix were used to measure phenotypic + molecular diversity. This diversity varied from 0 to 1.29 among the 117 accessions, with an average dissimilarity among genotypes of 0.51. Joint analysis of phenotypic and molecular diversity indicated that the genetic diversity of the physic nut germplasm was 156% and 64% higher than the diversity estimated from phenotypic and molecular data, respectively. These results show that Jatropha genetic variability in Brazil is not as limited as previously thought.

  2. Phenotypic and genetic diversity in Sinorhizobium meliloti and S. medicae from drought and salt affected regions of Morocco

    Directory of Open Access Journals (Sweden)

    Udupa Sripada M

    2010-01-01

    Full Text Available Abstract Background Sinorhizobium meliloti and S. medicae are symbiotic nitrogen fixing bacteria in root nodules of forage legume alfalfa (Medicago sativa L.. In Morocco, alfalfa is usually grown in marginal soils of arid and semi-arid regions frequently affected by drought, extremes of temperature and soil pH, soil salinity and heavy metals, which affect biological nitrogen fixing ability of rhizobia and productivity of the host. This study examines phenotypic diversity for tolerance to the above stresses and genotypic diversity at Repetitive Extragenic Pallindromic DNA regions of Sinorhizobium nodulating alfalfa, sampled from marginal soils of arid and semi-arid regions of Morocco. Results RsaI digestion of PCR amplified 16S rDNA of the 157 sampled isolates, assigned 136 isolates as S. meliloti and the rest as S. medicae. Further phenotyping of these alfalfa rhizobia for tolerance to the environmental stresses revealed a large degree of variation: 55.41%, 82.16%, 57.96% and 3.18% of the total isolates were tolerant to NaCl (>513 mM, water stress (-1.5 MPa, high temperature (40°C and low pH (3.5, respectively. Sixty-seven isolates of S. meliloti and thirteen isolates of S. medicae that were tolerant to salinity were also tolerant to water stress. Most of the isolates of the two species showed tolerance to heavy metals (Cd, Mn and Zn and antibiotics (chloramphenicol, spectinomycin, streptomycin and tetracycline. The phenotypic clusters observed by the cluster analysis clearly showed adaptations of the S. meliloti and S. medicae strains to the multiple stresses. Genotyping with rep-PCR revealed higher genetic diversity within these phenotypic clusters and classified all the 157 isolates into 148 genotypes. No relationship between genotypic profiles and the phenotypes was observed. The Analysis of Molecular Variance revealed that largest proportion of significant (P Conclusion High degree of phenotypic and genotypic diversity is present in S

  3. Engagement with Genetic Information and Uptake of Genetic Testing: the Role of Trust and Personal Cancer History.

    Science.gov (United States)

    Roberts, Megan C; Taber, Jennifer M; Klein, William M

    2017-01-20

    We used national survey data to (1) determine the extent to which individuals trust the sources from which they are most likely to receive information about cancer-related genetic tests (BRCA1/2, Lynch syndrome), (2) examine how level of trust for sources of genetic information might be related to cancer-related genetic testing uptake, and (3) determine whether key factors, such as cancer history and numeracy, moderate the latter association. We used cross-sectional data from the Health Information National Trends Survey. Our study sample included individuals who responded that they had heard or read about genetic tests (n = 1117). All analyses accounted for complex survey design. Although respondents trusted information from health professionals the most, they were significantly less likely to report hearing about genetic testing from such professionals than via television (p information source from which participants heard about genetic tests were associated with increased odds of genetic testing uptake, particularly among those with a personal cancer history. Numeracy was not associated with genetic testing uptake. Because health professionals were among the most trusted health information sources, they may serve as important brokers of genetic testing information for those with a personal cancer history.

  4. Identification of genetic modifiers of behavioral phenotypes in serotonin transporter knockout rats

    Directory of Open Access Journals (Sweden)

    Nijman Isaäc J

    2010-05-01

    Full Text Available Abstract Background Genetic variation in the regulatory region of the human serotonin transporter gene (SLC6A4 has been shown to affect brain functionality and personality. However, large heterogeneity in its biological effects is observed, which is at least partially due to genetic modifiers. To gain insight into serotonin transporter (SERT-specific genetic modifiers, we studied an intercross between the Wistar SERT-/- rat and the behaviorally and genetically divergent Brown Norway rat, and performed a QTL analysis. Results In a cohort of >150 intercross SERT-/- and control (SERT+/+ rats we characterized 12 traits that were previously associated with SERT deficiency, including activity, exploratory pattern, cocaine-induced locomotor activity, and abdominal and subcutaneous fat. Using 325 genetic markers, 10 SERT-/--specific quantitative trait loci (QTLs for parameters related to activity and exploratory pattern (Chr.1,9,11,14, and cocaine-induced anxiety and locomotor activity (Chr.5,8 were identified. No significant QTLs were found for fat parameters. Using in silico approaches we explored potential causal genes within modifier QTL regions and found interesting candidates, amongst others, the 5-HT1D receptor (Chr. 5, dopamine D2 receptor (Chr. 8, cannabinoid receptor 2 (Chr. 5, and genes involved in fetal development and plasticity (across chromosomes. Conclusions We anticipate that the SERT-/--specific QTLs may lead to the identification of new modulators of serotonergic signaling, which may be targets for pharmacogenetic and therapeutic approaches.

  5. Heterogeneous Phenotype of Long QT Syndrome Caused by the KCNH2-H562R Mutation: Importance of Familial Genetic Testing.

    Science.gov (United States)

    Muñoz-Esparza, Carmen; García-Molina, Esperanza; Salar-Alcaraz, Mariela; Peñafiel-Verdú, Pablo; Sánchez-Muñoz, Juan J; Martínez Sánchez, Juan; Cabañas-Perianes, Valentín; Valdés Chávarri, Mariano; García Alberola, Arcadio; Gimeno-Blanes, Juan R

    2015-10-01

    Long QT syndrome is an inherited ion channelopathy that leads to syncope and sudden death. Because of the heterogeneous phenotype of this disease, genetic testing is fundamental to detect individuals with concealed long QT syndrome. In this study, we determined the features of a family with 13 carriers of the KCNH2-H562R missense mutation, which affects the pore region of the HERG channel. We identified the KCNH2-H562R mutation in a 65-year-old man with a prolonged QTc interval who had experienced an episode of torsade de pointes. Subsequently, a total of 13 mutation carriers were identified in the family. Carriers (age 48 [26] years; 46% males) underwent clinical evaluation, electrocardiography and echocardiography. The mean (standard deviation) QTc in carriers was 493 (42) ms (3 [23%] showed normal QTc); 6 (46%) had symptoms (4, syncope; 1, sudden death; 1, aborted sudden death [proband]). While under treatment with beta-blockers, 11 of 12 carriers (92%) remained asymptomatic at 5 years of follow-up (1 patient required left cardiac sympathectomy). The QTc shortening with beta-blockers was 50 (37) ms. There was 1 sudden death in a patient who refused treatment. Family study is essential in the interpretation of a genetic testing result. This article describes the heterogeneous and variable phenotype of a large family with the KCNH2-H562R mutation and highlights the role of genetic study for the appropriate identification of at-risk individuals who would benefit from treatment. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  6. Genetic and Environmental Basis in Phenotype Correlation Between Physical Function and Cognition in Aging Chinese Twins

    DEFF Research Database (Denmark)

    Xu, Chunsheng; Zhang, Dongfeng; Tian, Xiaocao

    2017-01-01

    Although the correlation between cognition and physical function has been well studied in the general population, the genetic and environmental nature of the correlation has been rarely investigated. We conducted a classical twin analysis on cognitive and physical function, including forced...... expiratory volume in one second (FEV1), forced vital capacity (FVC), handgrip strength, five-times-sit-to-stand test (FTSST), near visual acuity, and number of teeth lost in 379 complete twin pairs. Bivariate twin models were fitted to estimate the genetic and environmental correlation between physical...... and cognitive function. Bivariate analysis showed mildly positively genetic correlations between cognition and FEV1, r G = 0.23 [95% CI: 0.03, 0.62], as well as FVC, r G = 0.35 [95% CI: 0.06, 1.00]. We found that FTSST and cognition presented very high common environmental correlation, r C = -1.00 [95% CI: -1...

  7. Genetic, environmental and phenotypic relationships among gestation length, birth weight, growth traits and age at first calving in beef cattle.

    Science.gov (United States)

    Bourdon, R M; Brinks, J S

    1982-09-01

    Data on the Red Angus, Angus and Hereford herds of Pioneer Hi-Bred International, Inc., Des Moines, Iowa, collected from 1968 to 1976, were analyzed for relationships among gestation length, birth weight, prenatal gain (birth weight adjusted for gestation length), growth traits and age at first calving. A total of 5,691 calf records, 1,783 listing gestation length, were included in the study. Paternal half-sib analyses and least-squares procedures were used to compute heritability estimates and genetic, environmental and phenotypic correlations among traits. Genetic correlations among growth traits, including prenatal gain, were high in all cases. Heritability estimates for gestation length and birth weight were .36 and .43, respectively, for bull calves and .37 and .35 for heifer calves. Genetic correlations between these traits were .25 and .22 for bull and heifer calves, respectively. Gestation length was negatively correlated (genetically) with all growth traits except birth weight. This result suggests that faster growing fetuses may trigger parturition earlier than average. Age at first calving was negatively correlated (genetically) with growth traits, indicating a favorable relationship between growth and early reproduction. Analysis of several selection indexes combining either birth weight and yearling weight or gestation length and yearling weight indicated that continued response to selection for growth without excessive increase in birth weight is feasible. Selection for growth and moderate birth weight would be more effective than selection for growth and shorter gestation, suggesting that the former method would both shorten gestation and alter the growth curve. Repeatability estimates for gestation length and birth weight were .20 and .22, respectively. Maternal effects accounted for approximately 10% of the variation in each trait.

  8. Genetic and Environmental Basis in Phenotype Correlation Between Physical Function and Cognition in Aging Chinese Twins

    DEFF Research Database (Denmark)

    Xu, Chunsheng; Zhang, Dongfeng; Tian, Xiaocao

    2017-01-01

    expiratory volume in one second (FEV1), forced vital capacity (FVC), handgrip strength, five-times-sit-to-stand test (FTSST), near visual acuity, and number of teeth lost in 379 complete twin pairs. Bivariate twin models were fitted to estimate the genetic and environmental correlation between physical......Although the correlation between cognition and physical function has been well studied in the general population, the genetic and environmental nature of the correlation has been rarely investigated. We conducted a classical twin analysis on cognitive and physical function, including forced...

  9. Pheno2Geno : High-throughput generation of genetic markers and maps from molecular phenotypes for crosses between inbred strains

    NARCIS (Netherlands)

    Zych, Konrad; Li, Yang; van der Velde, Joeri K.; Joosen, Ronny V. L.; Ligterink, Wilco; Jansen, Ritsert C.; Arends, Danny

    2015-01-01

    Background: Genetic markers and maps are instrumental in quantitative trait locus (QTL) mapping in segregating populations. The resolution of QTL localization depends on the number of informative recombinations in the population and how well they are tagged by markers. Larger populations and denser

  10. Pheno2Geno - High-throughput generation of genetic markers and maps from molecular phenotypes for crosses between inbred strains

    NARCIS (Netherlands)

    Zych, K.; Li, Y.; Velde, van der K.J.; Joosen, R.V.L.; Ligterink, W.; Jansen, R.C.; Arends, D.

    2015-01-01

    Background Genetic markers and maps are instrumental in quantitative trait locus (QTL) mapping in segregating populations. The resolution of QTL localization depends on the number of informative recombinations in the population and how well they are tagged by markers. Larger populations and denser m

  11. Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides.

    Science.gov (United States)

    Sztainberg, Yehezkel; Chen, Hong-mei; Swann, John W; Hao, Shuang; Tang, Bin; Wu, Zhenyu; Tang, Jianrong; Wan, Ying-Wooi; Liu, Zhandong; Rigo, Frank; Zoghbi, Huda Y

    2015-12-03

    Copy number variations have been frequently associated with developmental delay, intellectual disability and autism spectrum disorders. MECP2 duplication syndrome is one of the most common genomic rearrangements in males and is characterized by autism, intellectual disability, motor dysfunction, anxiety, epilepsy, recurrent respiratory tract infections and early death. The broad range of deficits caused by methyl-CpG-binding protein 2 (MeCP2) overexpression poses a daunting challenge to traditional biochemical-pathway-based therapeutic approaches. Accordingly, we sought strategies that directly target MeCP2 and are amenable to translation into clinical therapy. The first question that we addressed was whether the neurological dysfunction is reversible after symptoms set in. Reversal of phenotypes in adult symptomatic mice has been demonstrated in some models of monogenic loss-of-function neurological disorders, including loss of MeCP2 in Rett syndrome, indicating that, at least in some cases, the neuroanatomy may remain sufficiently intact so that correction of the molecular dysfunction underlying these disorders can restore healthy physiology. Given the absence of neurodegeneration in MECP2 duplication syndrome, we propose that restoration of normal MeCP2 levels in MECP2 duplication adult mice would rescue their phenotype. By generating and characterizing a conditional Mecp2-overexpressing mouse model, here we show that correction of MeCP2 levels largely reverses the behavioural, molecular and electrophysiological deficits. We also reduced MeCP2 using an antisense oligonucleotide strategy, which has greater translational potential. Antisense oligonucleotides are small, modified nucleic acids that can selectively hybridize with messenger RNA transcribed from a target gene and silence it, and have been successfully used to correct deficits in different mouse models. We find that antisense oligonucleotide treatment induces a broad phenotypic rescue in adult

  12. Selection in a fluctuating environment leads to decreased genetic variation and facilitates the evolution of phenotypic plasticity.

    Science.gov (United States)

    Hallsson, L R; Björklund, M

    2012-07-01

    Changes in the environment are expected to induce changes in the quantitative genetic variation, which influences the ability of a population to adapt to environmental change. Furthermore, environmental changes are not constant in time, but fluctuate. Here, we investigate the effect of rapid, continuous and/or fluctuating temperature changes in the seed beetle Callosobruchus maculatus, using an evolution experiment followed by a split-brood experiment. In line with expectations, individuals responded in a plastic way and had an overall higher potential to respond to selection after a rapid change in the environment. After selection in an environment with increasing temperature, plasticity remained unchanged (or decreased) and environmental variation decreased, especially when fluctuations were added; these results were unexpected. As expected, the genetic variation decreased after fluctuating selection. Our results suggest that fluctuations in the environment have major impact on the response of a population to environmental change; in a highly variable environment with low predictability, a plastic response might not be beneficial and the response is genetically and environmentally canalized resulting in a low potential to respond to selection and low environmental sensitivity. Interestingly, we found greater variation for phenotypic plasticity after selection, suggesting that the potential for plasticity to evolve is facilitated after exposure to environmental fluctuations. Our study highlights that environmental fluctuations should be considered when investigating the response of a population to environmental change.

  13. Phenotypic and genetic diversity of rice seed-associated bacteria and their role in pathogenicity and biological control.

    Science.gov (United States)

    Cottyn, B; Debode, J; Regalado, E; Mew, T W; Swings, J

    2009-09-01

    To study the phenotypic and genetic diversity of culturable bacteria associated with rice seed and to asses the antagonistic and pathogenic potential of the isolated bacteria. Seed of rice cultivar PSBRc14 was collected from farmers' fields of irrigated lowland in southern Luzon, Philippines. Isolations of distinct colonies yielded 498 isolates. Classification of the isolates according to similarities in cellular characteristics, whole-cell fatty acid composition, and colony appearance differentiated 101 morphotype groups. Predominant bacteria were Coryneform spp., Pantoea spp. and Pseudomonas spp. Other bacteria regularly present were Actinomycetes spp., Bacillus pumilus, B. subtilis, Burkholderia glumae, Enterobacter cloacae, Paenibacillus polymyxa, Staphylococcus spp. and Xanthomonas spp. The genetic diversity among isolates was assessed by BOX-PCR fingerprinting of genomic DNA and represented 284 fingerprint types (FPTs). Most FPTs (78%) were not shared among samples, while eight FPTs occurred frequently in the samples. Seven of these FPTs also occurred frequently in a previous collection made from rainfed lowlands of Iloilo island, Philippines. Sixteen per cent of the isolates inhibited in vitro the mycelial growth of the rice pathogens Rhizoctonia solani and Pyricularia grisea, whereas 4% were pathogens identified as Burkholderia glumae, Burkholderia gladioli and Acidovorax avenae ssp. avenae. This study reveals a broad morphological and genetic diversity of bacteria present on seed of a single rice cultivar. This line of work contributes to a better understanding of the microbial diversity present on rice seed and stresses its importance as a carrier of antagonists and pathogens.

  14. Patient autonomy and relatives' right to know genetic information.

    Science.gov (United States)

    Gilbar, Roy

    2007-12-01

    One of the most difficult issues doctors face is a conflict between their professional duties. Such a conflict may arise when doctors know that information has implications not only for patients but also for family members but their duty of confidentiality prevents them from disclosing it. A comparative analysis of English and Israeli medical law reveals that the doctors' duty is based on two principles: a liberal perception of patient autonomy and an overriding utilitarian principle of prevention of harm. However, socio-medical research indicates that these principles do not entirely reflect the views of patients and doctors and are too narrow to deal with the complex situations in practice. Thus, it is argued that the doctor's legal duty of confidentiality should be reconsidered and qualified when it concerns the family. It is suggested that if medical law seeks to recognize the various interests family members have in genetic information then we should consider a different approach, founded on a relational interpretation of autonomy and communitarian notions of solidarity and moral responsibility. This approach perceives confidentiality and privacy as embracing the family unit, based on the view that close relatives are not entirely outside the private sphere of the individual but rather are integral to his or her identity. Thus, to the utilitarian mechanism available in medical law this approach adds a social criterion: The effect any decision (to disclose or not to disclose) will have on the familial relationship and on the dynamics of the particular family. This will provide a more flexible and workable alternative for doctors to resolve familial tensions over access to genetic information.

  15. Intervention of genetic flow of the foreign cattle toward diversity of phenotype expressions of local cattle in the District of Banyuwangi

    Directory of Open Access Journals (Sweden)

    MOHAMAD AMIN

    2010-04-01

    Full Text Available Amin M (2010 Intervention of genetic flow of the foreign cattle toward diversity of phenotype expressions of local cattle in the District of Banyuwangi. Biodiversitas 10: 69-74. The aims of the present research are two folds: to know the phenotypic diversity and to reconstruct the cross-breeding pattern of local cattle in Banyuwangi. Based on three sampling areas, it was found that there were 32 phenotypic cattle (10 in the sub districts of Rogojampi, 16 in Tegaldlimo and 6 in Glagah areas. The phenotypic varieties were caused by two factors, namely the flow of genetic intervention of the other local cattle (Bali, Ongole, and Brahman cattle and the artificial insemination program using the semen of Limousine, Simmental, Aberdeen Angus and Santa Gertrudis cattle.

  16. Delineation of Behavioral Phenotypes in Genetic Syndromes: Characteristics of Autism Spectrum Disorder, Affect and Hyperactivity

    Science.gov (United States)

    Oliver, Chris; Berg, Katy; Moss, Jo; Arron, Kate; Burbidge, Cheryl

    2011-01-01

    We investigated autism spectrum disorder (ASD) symptomatology, hyperactivity and affect in seven genetic syndromes; Angelman (AS; n = 104), Cri du Chat (CdCS; 58), Cornelia de Lange (CdLS; 101), Fragile X (FXS; 191), Prader-Willi (PWS; 189), Smith-Magenis (SMS; 42) and Lowe (LS; 56) syndromes (age range 4-51). ASD symptomatology was heightened in…

  17. Delineation of Behavioral Phenotypes in Genetic Syndromes: Characteristics of Autism Spectrum Disorder, Affect and Hyperactivity

    Science.gov (United States)

    Oliver, Chris; Berg, Katy; Moss, Jo; Arron, Kate; Burbidge, Cheryl

    2011-01-01

    We investigated autism spectrum disorder (ASD) symptomatology, hyperactivity and affect in seven genetic syndromes; Angelman (AS; n = 104), Cri du Chat (CdCS; 58), Cornelia de Lange (CdLS; 101), Fragile X (FXS; 191), Prader-Willi (PWS; 189), Smith-Magenis (SMS; 42) and Lowe (LS; 56) syndromes (age range 4-51). ASD symptomatology was heightened in…

  18. Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

    NARCIS (Netherlands)

    C.A. Rietveld (Niels); T. Esko (Tõnu); G. Davies (Gail); T.H. Pers (Tune); P. Turley (Patrick); B. Benyamin (Beben); C.F. Chabris (Christopher F.); V. Emilsson (Valur); A.D. Johnson (Andrew); J.J. Lee (James J.); C. de Leeuw (Christiaan); R.E. Marioni (Riccardo); S.E. Medland (Sarah Elizabeth); M. Miller (Mike); O. Rostapshova (Olga); S. van der Lee (Sven); A.A.E. Vinkhuyzen (Anna A.); N. Amin (Najaf); D. Conley (Dalton); J. Derringer; C.M. van Duijn (Cock); R.S.N. Fehrmann (Rudolf); L. Franke (Lude); E.L. Glaeser (Edward L.); N.K. Hansell (Narelle); C. Hayward (Caroline); W.G. Iacono (William); C.A. Ibrahim-Verbaas (Carla); V.W.V. Jaddoe (Vincent); J. Karjalainen (Juha); D. Laibson (David); P. Lichtenstein (Paul); D.C. Liewald (David C.); P.K. Magnusson (Patrik); N.G. Martin (Nicholas); M. McGue (Matt); G. Mcmahon (George); N.L. Pedersen (Nancy); S. Pinker (Steven); D.J. Porteous (David J.); D. Posthuma (Danielle); F. Rivadeneira Ramirez (Fernando); B.H. Smithk (Blair H.); J.M. Starr (John); H.W. Tiemeier (Henning); N.J. Timpsonm (Nicholas J.); M. Trzaskowskin (Maciej); A.G. Uitterlinden (André); F.C. Verhulst (Frank); M.E. Ward (Mary); M.J. Wright (Margaret); G.D. Smith; I.J. Deary (Ian J.); M. Johannesson (Magnus); R. Plomin (Robert); P.M. Visscher (Peter); D.J. Benjamin (Daniel J.); D. Cesarini (David); Ph.D. Koellinger (Philipp)

    2014-01-01

    textabstractWe identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxyphenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education

  19. Mouse-human experimental epigenetic analysis unmasks dietary targets and genetic liability for diabetic phenotypes

    Science.gov (United States)

    Multhaup, Michael L.; Seldin, Marcus; Jaffe, Andrew E.; Lei, Xia; Kirchner, Henriette; Mondal, Prosenjit; Li, Yuanyuan; Rodriguez, Varenka; Drong, Alexander; Hussain, Mehboob; Lindgren, Cecilia; McCarthy, Mark; Näslund, Erik; Zierath, Juleen R.; Wong, G. William; Feinberg, Andrew P.

    2015-01-01

    SUMMARY Using a functional approach to investigate the epigenetics of Type 2 Diabetes (T2D), we combine three lines of evidence – diet-induced epigenetic dysregulation in mouse, epigenetic conservation in humans, and T2D clinical risk evidence – to identify genes implicated in T2D pathogenesis through epigenetic mechanisms related to obesity. Beginning with dietary manipulation of genetically homogeneous mice, we identify differentially DNA-methylated genomic regions. We then replicate these results in adipose samples from lean and obese patients pre- and post-Roux-en-Y gastric bypass, identifying regions where both the location and direction of methylation change is conserved. These regions overlap with 27 genetic T2D risk loci, only one of which was deemed significant by GWAS alone. Functional analysis of genes associated with these regions revealed four genes with roles in insulin resistance, demonstrating the potential general utility of this approach for complementing conventional human genetic studies by integrating cross-species epigenomics and clinical genetic risk. PMID:25565211

  20. Genetic differentiation between resistance phenotypes in the phytophagous flea beetle, Phyllotreta nemorum

    NARCIS (Netherlands)

    Jong, de P.W.; Breuker, C.J.; Vos, de H.; Vermeer, K.M.C.A.; Oku, K.; Verbaarschot, P.G.H.; Nielsen, J.K.; Brakefield, P.M.

    2009-01-01

    The flea beetle Phyllotreta nemorum L. (Coleoptera: Chrysomelidae) is genetically polymorphic for resistance against the defences of one of its host plants, Barbarea vulgaris R.Br. (Brassicales: Brassicaceae). Whereas resistant flea beetles are able to use B. vulgaris as well as other cruciferous pl

  1. Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort

    DEFF Research Database (Denmark)

    Lindquist, S G; Schwartz, M; Batbayli, M

    2009-01-01

    Autosomal dominantly transmitted Alzheimer's disease (AD) and frontotemporal dementia (FTD) are genetically heterogeneous disorders. To date, three genes have been identified in which mutations cause early-onset autosomal dominant inherited AD: APP, PSEN1, and PSEN2. Mutations in two genes...

  2. Altered distribution of susceptibility phenotypes implies environmental modulation of genetic resistance

    Science.gov (United States)

    Thomas R. Gordon; Neil McRoberts

    2012-01-01

    Resistance to disease is determined by the genetic capacit