Genetic structure and invasion history of the house mouse (Mus musculus domesticus) in Senegal, West Africa: a legacy of colonial and contemporary times.

Science.gov (United States)

Lippens, C; Estoup, A; Hima, M K; Loiseau, A; Tatard, C; Dalecky, A; Bâ, K; Kane, M; Diallo, M; Sow, A; Niang, Y; Piry, S; Berthier, K; Leblois, R; Duplantier, J-M; Brouat, C

2017-08-01

Knowledge of the genetic make-up and demographic history of invasive populations is critical to understand invasion mechanisms. Commensal rodents are ideal models to study whether complex invasion histories are typical of introductions involving human activities. The house mouse Mus musculus domesticus is a major invasive synanthropic rodent originating from South-West Asia. It has been largely studied in Europe and on several remote islands, but the genetic structure and invasion history of this taxon have been little investigated in several continental areas, including West Africa. In this study, we focussed on invasive populations of M. m. domesticus in Senegal. In this focal area for European settlers, the distribution area and invasion spread of the house mouse is documented by decades of data on commensal rodent communities. Genetic variation at one mitochondrial locus and 16 nuclear microsatellite markers was analysed from individuals sampled in 36 sites distributed across the country. A combination of phylogeographic and population genetics methods showed that there was a single introduction event on the northern coast of Senegal, from an exogenous (probably West European) source, followed by a secondary introduction from northern Senegal into a coastal site further south. The geographic locations of these introduction sites were consistent with the colonial history of Senegal. Overall, the marked microsatellite genetic structure observed in Senegal, even between sites located close together, revealed a complex interplay of different demographic processes occurring during house mouse spatial expansion, including sequential founder effects and stratified dispersal due to human transport along major roads.

Identifying novel genes for atherosclerosis through mouse-human comparative genetics

NARCIS (Netherlands)

Wang, XS; Ishimori, N; Korstanje, R; Rollins, J; Paigen, B

Susceptibility to atherosclerosis is determined by both environmental and genetic factors. Its genetic determinants have been studied by use of quantitative- trait - locus ( QTL) analysis. So far, 21 atherosclerosis QTLs have been identified in the mouse: 7 in a high- fat - diet model only, 9 in a

Genetic traces of east-to-west human expansion waves in Eurasia.

Science.gov (United States)

Chaix, Raphaëlle; Austerlitz, Frédéric; Hegay, Tatyana; Quintana-Murci, Lluís; Heyer, Evelyne

2008-07-01

In this study, we describe the landscape of human demographic expansions in Eurasia using a large continental Y chromosome and mitochondrial DNA dataset. Variation at these two uniparentally-inherited genetic systems retraces expansions that occurred in the past 60 ky, and shows a clear decrease of expansion ages from east to west Eurasia. To investigate the demographic events at the origin of this westward decrease of expansion ages, the estimated divergence ages between Eurasian populations are compared with the estimated expansion ages within each population. Both markers suggest that the demographic expansion diffused from east to west in Eurasia in a demic way, i.e., through migrations of individuals (and not just through diffusion of new technologies), highlighting the prominent role of eastern regions within Eurasia during Palaeolithic times. (c) 2008 Wiley-Liss, Inc.

Mouse Genome Informatics (MGI) Resource: Genetic, Genomic, and Biological Knowledgebase for the Laboratory Mouse.

Science.gov (United States)

Eppig, Janan T

2017-07-01

The Mouse Genome Informatics (MGI) Resource supports basic, translational, and computational research by providing high-quality, integrated data on the genetics, genomics, and biology of the laboratory mouse. MGI serves a strategic role for the scientific community in facilitating biomedical, experimental, and computational studies investigating the genetics and processes of diseases and enabling the development and testing of new disease models and therapeutic interventions. This review describes the nexus of the body of growing genetic and biological data and the advances in computer technology in the late 1980s, including the World Wide Web, that together launched the beginnings of MGI. MGI develops and maintains a gold-standard resource that reflects the current state of knowledge, provides semantic and contextual data integration that fosters hypothesis testing, continually develops new and improved tools for searching and analysis, and partners with the scientific community to assure research data needs are met. Here we describe one slice of MGI relating to the development of community-wide large-scale mutagenesis and phenotyping projects and introduce ways to access and use these MGI data. References and links to additional MGI aspects are provided. © The Author 2017. Published by Oxford University Press.

Genetic mouse models of brain ageing and Alzheimer's disease.

Science.gov (United States)

Bilkei-Gorzo, Andras

2014-05-01

Progression of brain ageing is influenced by a complex interaction of genetic and environmental factors. Analysis of genetically modified animals with uniform genetic backgrounds in a standardised, controlled environment enables the dissection of critical determinants of brain ageing on a molecular level. Human and animal studies suggest that increased load of damaged macromolecules, efficacy of DNA maintenance, mitochondrial activity, and cellular stress defences are critical determinants of brain ageing. Surprisingly, mouse lines with genetic impairment of anti-oxidative capacity generally did not show enhanced cognitive ageing but rather an increased sensitivity to oxidative challenge. Mouse lines with impaired mitochondrial activity had critically short life spans or severe and rapidly progressing neurodegeneration. Strains with impaired clearance in damaged macromolecules or defects in the regulation of cellular stress defences showed alterations in the onset and progression of cognitive decline. Importantly, reduced insulin/insulin-like growth factor signalling generally increased life span but impaired cognitive functions revealing a complex interaction between ageing of the brain and of the body. Brain ageing is accompanied by an increased risk of developing Alzheimer's disease. Transgenic mouse models expressing high levels of mutant human amyloid precursor protein showed a number of symptoms and pathophysiological processes typical for early phase of Alzheimer's disease. Generally, therapeutic strategies effective against Alzheimer's disease in humans were also active in the Tg2576, APP23, APP/PS1 and 5xFAD lines, but a large number of false positive findings were also reported. The 3xtg AD model likely has the highest face and construct validity but further studies are needed. Copyright © 2013 Elsevier Inc. All rights reserved.

Olfaction in three genetic and two MPTP-induced Parkinson's disease mouse models.

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Stefan Kurtenbach

Full Text Available Various genetic or toxin-induced mouse models are frequently used for investigation of early PD pathology. Although olfactory impairment is known to precede motor symptoms by years, it is not known whether it is caused by impairments in the brain, the olfactory epithelium, or both. In this study, we investigated the olfactory function in three genetic Parkinson's disease (PD mouse models and mice treated with MPTP intraperitoneally and intranasally. To investigate olfactory function, we performed electro-olfactogram recordings (EOGs and an olfactory behavior test (cookie-finding test. We show that neither a parkin knockout mouse strain, nor intraperitoneal MPTP treated animals display any olfactory impairment in EOG recordings and the applied behavior test. We also found no difference in the responses of the olfactory epithelium to odorants in a mouse strain over-expressing doubly mutated α-synuclein, while this mouse strain was not suitable to test olfaction in a cookie-finding test as it displays a mobility impairment. A transgenic mouse expressing mutated α-synuclein in dopaminergic neurons performed equal to control animals in the cookie-finding test. Further we show that intranasal MPTP application can cause functional damage of the olfactory epithelium.

Mouse forward genetics in the study of the peripheral nervous system and human peripheral neuropathy

Science.gov (United States)

Douglas, Darlene S.; Popko, Brian

2009-01-01

Forward genetics, the phenotype-driven approach to investigating gene identity and function, has a long history in mouse genetics. Random mutations in the mouse transcend bias about gene function and provide avenues towards unique discoveries. The study of the peripheral nervous system is no exception; from historical strains such as the trembler mouse, which led to the identification of PMP22 as a human disease gene causing multiple forms of peripheral neuropathy, to the more recent identification of the claw paw and sprawling mutations, forward genetics has long been a tool for probing the physiology, pathogenesis, and genetics of the PNS. Even as spontaneous and mutagenized mice continue to enable the identification of novel genes, provide allelic series for detailed functional studies, and generate models useful for clinical research, new methods, such as the piggyBac transposon, are being developed to further harness the power of forward genetics. PMID:18481175

LASP-01: Distribution of Mouse Embryonic Stem Cells Expressing MicroRNAs | Frederick National Laboratory for Cancer Research

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The Laboratory Animal Sciences Program manages the expansion, processing, and distribution of1,501 genetically engineered mouse embryonic stem cell (mESC) linesharboring conditional microRNA transgenes. The Laboratory Animal Sciences Prog

DGCR8 Promotes Neural Progenitor Expansion and Represses Neurogenesis in the Mouse Embryonic Neocortex

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Nadin Hoffmann

2018-04-01

Full Text Available DGCR8 and DROSHA are the minimal functional core of the Microprocessor complex essential for biogenesis of canonical microRNAs and for the processing of other RNAs. Conditional deletion of Dgcr8 and Drosha in the murine telencephalon indicated that these proteins exert crucial functions in corticogenesis. The identification of mechanisms of DGCR8- or DROSHA-dependent regulation of gene expression in conditional knockout mice are often complicated by massive apoptosis. Here, to investigate DGCR8 functions on amplification/differentiation of neural progenitors cells (NPCs in corticogenesis, we overexpress Dgcr8 in the mouse telencephalon, by in utero electroporation (IUEp. We find that DGCR8 promotes the expansion of NPC pools and represses neurogenesis, in absence of apoptosis, thus overcoming the usual limitations of Dgcr8 knockout-based approach. Interestingly, DGCR8 selectively promotes basal progenitor amplification at later developmental stages, entailing intriguing implications for neocortical expansion in evolution. Finally, despite a 3- to 5-fold increase of DGCR8 level in the mouse telencephalon, the composition, target preference and function of the DROSHA-dependent Microprocessor complex remain unaltered. Thus, we propose that DGCR8-dependent modulation of gene expression in corticogenesis is more complex than previously known, and possibly DROSHA-independent.

Towards Transgenic Primates: What can we learn from mouse genetics?

OpenAIRE

KUANG, Hui; WANG, Phillip L.; TSIEN, Joe Z.

2009-01-01

Considering the great physiological and behavioral similarities with humans, monkeys represent the ideal models not only for the study of complex cognitive behavior but also for the preclinical research and development of novel therapeutics for treating human diseases. Various powerful genetic technologies initially developed for making mouse models are being explored for generating transgenic primate models. We review the latest genetic engineering technologies and discuss the potentials and...

Influence of early life exposure, host genetics and diet on the mouse gut microbiome and metabolome

Energy Technology Data Exchange (ETDEWEB)

Snijders, Antoine M.; Langley, Sasha A.; Kim, Young-Mo; Brislawn, Colin J.; Noecker, Cecilia; Zink, Erika M.; Fansler, Sarah J.; Casey, Cameron P.; Miller, Darla R.; Huang, Yurong; Karpen, Gary H.; Celniker, Susan E.; Brown, James B.; Borenstein, Elhanan; Jansson, Janet K.; Metz, Thomas O.; Mao, Jian-Hua

2016-11-28

Although the gut microbiome plays important roles in host physiology, health and disease1, we lack understanding of the complex interplay between host genetics and early life environment on the microbial and metabolic composition of the gut.We used the genetically diverse Collaborative Cross mouse system2 to discover that early life history impacts themicrobiome composition, whereas dietary changes have only a moderate effect. By contrast, the gut metabolome was shaped mostly by diet, with specific non-dietary metabolites explained by microbial metabolism. Quantitative trait analysis identified mouse genetic trait loci (QTL) that impact the abundances of specific microbes. Human orthologues of genes in the mouse QTL are implicated in gastrointestinal cancer. Additionally, genes located in mouse QTL for Lactobacillales abundance are implicated in arthritis, rheumatic disease and diabetes. Furthermore, Lactobacillales abundance was predictive of higher host T-helper cell counts, suggesting an important link between Lactobacillales and host adaptive immunity.

Towards Transgenic Primates: What can we learn from mouse genetics?

Institute of Scientific and Technical Information of China (English)

KUANG Hui; WANG Phillip L.; TSIEN Joe Z.

2009-01-01

Considering the great physiological and behavioral similarities with humans, monkeys represent the ideal models not only for the study of complex cognitive behavior but also for the precUnical research and development of novel therapeutics for treating human diseases. Various powerful genetic tech-nologies initially developed for making mouse models are being explored for generating transgenic primate models. We review the latest genetic engineering technologies and discuss the potentials and limitations for systematic production of transgenic primates.

Towards Transgenic Primates:What can we learn from mouse genetics?

Institute of Scientific and Technical Information of China (English)

WANG; Phillip; L.; TSIEN; Joe; Z.

2009-01-01

Considering the great physiological and behavioral similarities with humans,monkeys represent the ideal models not only for the study of complex cognitive behavior but also for the preclinical research and development of novel therapeutics for treating human diseases.Various powerful genetic tech-nologies initially developed for making mouse models are being explored for generating transgenic primate models.We review the latest genetic engineering technologies and discuss the potentials and limitations for systematic production of transgenic primates.

Ternary alloy material prediction using genetic algorithm and cluster expansion

Energy Technology Data Exchange (ETDEWEB)

Chen, Chong [Iowa State Univ., Ames, IA (United States)

2015-12-01

This thesis summarizes our study on the crystal structures prediction of Fe-V-Si system using genetic algorithm and cluster expansion. Our goal is to explore and look for new stable compounds. We started from the current ten known experimental phases, and calculated formation energies of those compounds using density functional theory (DFT) package, namely, VASP. The convex hull was generated based on the DFT calculations of the experimental known phases. Then we did random search on some metal rich (Fe and V) compositions and found that the lowest energy structures were body centered cube (bcc) underlying lattice, under which we did our computational systematic searches using genetic algorithm and cluster expansion. Among hundreds of the searched compositions, thirteen were selected and DFT formation energies were obtained by VASP. The stability checking of those thirteen compounds was done in reference to the experimental convex hull. We found that the composition, 24-8-16, i.e., Fe₃VSi₂ is a new stable phase and it can be very inspiring to the future experiments.

Genetic diversity and structure related to expansion history and habitat isolation: stone marten populating rural-urban habitats.

Science.gov (United States)

Wereszczuk, Anna; Leblois, Raphaël; Zalewski, Andrzej

2017-12-22

Population genetic diversity and structure are determined by past and current evolutionary processes, among which spatially limited dispersal, genetic drift, and shifts in species distribution boundaries have major effects. In most wildlife species, environmental modifications by humans often lead to contraction of species' ranges and/or limit their dispersal by acting as environmental barriers. However, in species well adapted to anthropogenic habitat or open landscapes, human induced environmental changes may facilitate dispersal and range expansions. In this study, we analysed whether isolation by distance and deforestation, among other environmental features, promotes or restricts dispersal and expansion in stone marten (Martes foina) populations. We genotyped 298 martens from eight sites at twenty-two microsatellite loci to characterize the genetic variability, population structure and demographic history of stone martens in Poland. At the landscape scale, limited genetic differentiation between sites in a mosaic of urban, rural and forest habitats was mostly influenced by isolation by distance. Statistical clustering and multivariate analyses showed weak genetic structuring with two to four clusters and a high rate of gene flow between them. Stronger genetic differentiation was detected for one stone marten population (NE1) located inside a large forest complex. Genetic differentiation between this site and all others was 20% higher than between other sites separated by similar distances. The genetic uniqueness index of NE1 was also twofold higher than in other sites. Past demographic history analyses showed recent expansion of this species in north-eastern Poland. A decrease in genetic diversity from south to north, and MIGRAINE analyses indicated the direction of expansion of stone marten. Our results showed that two processes, changes in species distribution boundaries and limited dispersal associated with landscape barriers, affect genetic diversity and

Genetic characterization and improved genotyping of the dysferlin-deficient mouse strain Dysf (tm1Kcam).

Science.gov (United States)

Wiktorowicz, Tatiana; Kinter, Jochen; Kobuke, Kazuhiro; Campbell, Kevin P; Sinnreich, Michael

2015-01-01

Mouse models of dysferlinopathies are valuable tools with which to investigate the pathomechanisms underlying these diseases and to test novel therapeutic strategies. One such mouse model is the Dysf (tm1Kcam) strain, which was generated using a targeting vector to replace a 12-kb region of the dysferlin gene and which features a progressive muscular dystrophy. A prerequisite for successful animal studies using genetic mouse models is an accurate genotyping protocol. Unfortunately, the lack of robustness of currently available genotyping protocols for the Dysf (tm1Kcam) mouse has prevented efficient colony management. Initial attempts to improve the genotyping protocol based on the published genomic structure failed. These difficulties led us to analyze the targeted locus of the dysferlin gene of the Dysf (tm1Kcam) mouse in greater detail. In this study we resequenced and analyzed the targeted locus of the Dysf (tm1Kcam) mouse and developed a novel PCR protocol for genotyping. We found that instead of a deletion, the dysferlin locus in the Dysf (tm1Kcam) mouse carries a targeted insertion. This genetic characterization enabled us to establish a reliable method for genotyping of the Dysf (tm1Kcam) mouse, and thus has made efficient colony management possible. Our work will make the Dysf (tm1Kcam) mouse model more attractive for animal studies of dysferlinopathies.

Analysis of Copy Number Variation in the Abp Gene Regions of Two House Mouse Subspecies Suggests Divergence during the Gene Family Expansions.

Science.gov (United States)

Pezer, Željka; Chung, Amanda G; Karn, Robert C; Laukaitis, Christina M

2017-06-01

The Androgen-binding protein ( Abp ) gene region of the mouse genome contains 64 genes, some encoding pheromones that influence assortative mating between mice from different subspecies. Using CNVnator and quantitative PCR, we explored copy number variation in this gene family in natural populations of Mus musculus domesticus ( Mmd ) and Mus musculus musculus ( Mmm ), two subspecies of house mice that form a narrow hybrid zone in Central Europe. We found that copy number variation in the center of the Abp gene region is very common in wild Mmd , primarily representing the presence/absence of the final duplications described for the mouse genome. Clustering of Mmd individuals based on this variation did not reflect their geographical origin, suggesting no population divergence in the Abp gene cluster. However, copy number variation patterns differ substantially between Mmd and other mouse taxa. Large blocks of Abp genes are absent in Mmm , Mus musculus castaneus and an outgroup, Mus spretus , although with differences in variation and breakpoint locations. Our analysis calls into question the reliance on a reference genome for interpreting the detailed organization of genes in taxa more distant from the Mmd reference genome. The polymorphic nature of the gene family expansion in all four taxa suggests that the number of Abp genes, especially in the central gene region, is not critical to the survival and reproduction of the mouse. However, Abp haplotypes of variable length may serve as a source of raw genetic material for new signals influencing reproductive communication and thus speciation of mice. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Genetic Pattern and Demographic History of Salminus brasiliensis: Population Expansion in the Pantanal Region during the Pleistocene

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Lívia A. de Carvalho Mondin

2018-01-01

Full Text Available Pleistocene climate changes were major historical events that impacted South American biodiversity. Although the effects of such changes are well-documented for several biomes, it is poorly known how these climate shifts affected the biodiversity of the Pantanal floodplain. Fish are one of the most diverse groups in the Pantanal floodplains and can be taken as a suitable biological model for reconstructing paleoenvironmental scenarios. To identify the effects of Pleistocene climate changes on Pantanal’s ichthyofauna, we used genetic data from multiple populations of a top-predator long-distance migratory fish, Salminus brasiliensis. We specifically investigated whether Pleistocene climate changes affected the demography of this species. If this was the case, we expected to find changes in population size over time. Thus, we assessed the genetic diversity of S. brasiliensis to trace the demographic history of nine populations from the Upper Paraguay basin, which includes the Pantanal floodplain, that form a single genetic group, employing approximate Bayesian computation (ABC to test five scenarios: constant population, old expansion, old decline, old bottleneck following by recent expansion, and old expansion following by recent decline. Based on two mitochondrial DNA markers, our inferences from ABC analysis, the results of Bayesian skyline plot, the implications of star-like networks, and the patterns of genetic diversity (high haplotype diversity and low-to-moderate nucleotide diversity indicated a sudden population expansion. ABC allowed us to make strong quantitative inferences about the demographic history of S. brasiliensis. We estimated a small ancestral population size that underwent a drastic fivefold expansion, probably associated with the colonization of newly formed habitats. The estimated time of this expansion was consistent with a humid and warm phase as inferred by speleothem growth phases and travertine records during

Comparative genetics: synergizing human and NOD mouse studies for identifying genetic causation of type 1 diabetes.

Science.gov (United States)

Driver, John P; Chen, Yi-Guang; Mathews, Clayton E

2012-01-01

Although once widely anticipated to unlock how human type 1 diabetes (T1D) develops, extensive study of the nonobese diabetic (NOD) mouse has failed to yield effective treatments for patients with the disease. This has led many to question the usefulness of this animal model. While criticism about the differences between NOD and human T1D is legitimate, in many cases disease in both species results from perturbations modulated by the same genes or different genes that function within the same biological pathways. Like in humans, unusual polymorphisms within an MHC class II molecule contributes the most T1D risk in NOD mice. This insight supports the validity of this model and suggests the NOD has been improperly utilized to study how to cure or prevent disease in patients. Indeed, clinical trials are far from administering T1D therapeutics to humans at the same concentration ranges and pathological states that inhibit disease in NOD mice. Until these obstacles are overcome it is premature to label the NOD mouse a poor surrogate to test agents that cure or prevent T1D. An additional criticism of the NOD mouse is the past difficulty in identifying genes underlying T1D using conventional mapping studies. However, most of the few diabetogenic alleles identified to date appear relevant to the human disorder. This suggests that rather than abandoning genetic studies in NOD mice, future efforts should focus on improving the efficiency with which diabetes susceptibility genes are detected. The current review highlights why the NOD mouse remains a relevant and valuable tool to understand the genes and their interactions that promote autoimmune diabetes and therapeutics that inhibit this disease. It also describes a new range of technologies that will likely transform how the NOD mouse is used to uncover the genetic causes of T1D for years to come.

Network statistics of genetically-driven gene co-expression modules in mouse crosses

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Marie-Pier eScott-Boyer

2013-12-01

Full Text Available In biology, networks are used in different contexts as ways to represent relationships between entities, such as for instance interactions between genes, proteins or metabolites. Despite progress in the analysis of such networks and their potential to better understand the collective impact of genes on complex traits, one remaining challenge is to establish the biologic validity of gene co-expression networks and to determine what governs their organization. We used WGCNA to construct and analyze seven gene expression datasets from several tissues of mouse recombinant inbred strains (RIS. For six out of the 7 networks, we found that linkage to module QTLs (mQTLs could be established for 29.3% of gene co-expression modules detected in the several mouse RIS. For about 74.6% of such genetically-linked modules, the mQTL was on the same chromosome as the one contributing most genes to the module, with genes originating from that chromosome showing higher connectivity than other genes in the modules. Such modules (that we considered as genetically-driven had network statistic properties (density, centralization and heterogeneity that set them apart from other modules in the network. Altogether, a sizeable portion of gene co-expression modules detected in mouse RIS panels had genetic determinants as their main organizing principle. In addition to providing a biologic interpretation validation for these modules, these genetic determinants imparted on them particular properties that set them apart from other modules in the network, to the point that they can be predicted to a large extent on the basis of their network statistics.

Genetic diversity in India and the inference of Eurasian population expansion.

Science.gov (United States)

Xing, Jinchuan; Watkins, W Scott; Hu, Ya; Huff, Chad D; Sabo, Aniko; Muzny, Donna M; Bamshad, Michael J; Gibbs, Richard A; Jorde, Lynn B; Yu, Fuli

2010-01-01

Genetic studies of populations from the Indian subcontinent are of great interest because of India's large population size, complex demographic history, and unique social structure. Despite recent large-scale efforts in discovering human genetic variation, India's vast reservoir of genetic diversity remains largely unexplored. To analyze an unbiased sample of genetic diversity in India and to investigate human migration history in Eurasia, we resequenced one 100-kb ENCODE region in 92 samples collected from three castes and one tribal group from the state of Andhra Pradesh in south India. Analyses of the four Indian populations, along with eight HapMap populations (692 samples), showed that 30% of all SNPs in the south Indian populations are not seen in HapMap populations. Several Indian populations, such as the Yadava, Mala/Madiga, and Irula, have nucleotide diversity levels as high as those of HapMap African populations. Using unbiased allele-frequency spectra, we investigated the expansion of human populations into Eurasia. The divergence time estimates among the major population groups suggest that Eurasian populations in this study diverged from Africans during the same time frame (approximately 90 to 110 thousand years ago). The divergence among different Eurasian populations occurred more than 40,000 years after their divergence with Africans. Our results show that Indian populations harbor large amounts of genetic variation that have not been surveyed adequately by public SNP discovery efforts. Our data also support a delayed expansion hypothesis in which an ancestral Eurasian founding population remained isolated long after the out-of-Africa diaspora, before expanding throughout Eurasia. © 2010 Xing et al.; licensee BioMed Central Ltd.

Mouse genetic approaches applied to the normal tissue radiation response

International Nuclear Information System (INIS)

Haston, Christina K.

2012-01-01

The varying responses of inbred mouse models to radiation exposure present a unique opportunity to dissect the genetic basis of radiation sensitivity and tissue injury. Such studies are complementary to human association studies as they permit both the analysis of clinical features of disease, and of specific variants associated with its presentation, in a controlled environment. Herein I review how animal models are studied to identify specific genetic variants influencing predisposition to radiation-induced traits. Among these radiation-induced responses are documented strain differences in repair of DNA damage and in extent of tissue injury (in the lung, skin, and intestine) which form the base for genetic investigations. For example, radiation-induced DNA damage is consistently greater in tissues from BALB/cJ mice, than the levels in C57BL/6J mice, suggesting there may be an inherent DNA damage level per strain. Regarding tissue injury, strain specific inflammatory and fibrotic phenotypes have been documented for principally, C57BL/6 C3H and A/J mice but a correlation among responses such that knowledge of the radiation injury in one tissue informs of the response in another is not evident. Strategies to identify genetic differences contributing to a trait based on inbred strain differences, which include linkage analysis and the evaluation of recombinant congenic (RC) strains, are presented, with a focus on the lung response to irradiation which is the only radiation-induced tissue injury mapped to date. Such approaches are needed to reveal genetic differences in susceptibility to radiation injury, and also to provide a context for the effects of specific genetic variation uncovered in anticipated clinical association studies. In summary, mouse models can be studied to uncover heritable variation predisposing to specific radiation responses, and such variations may point to pathways of importance to phenotype development in the clinic.

Invited review: Genetic and genomic mouse models for livestock research

Directory of Open Access Journals (Sweden)

D. Arends

2018-02-01

Full Text Available Knowledge about the function and functioning of single or multiple interacting genes is of the utmost significance for understanding the organism as a whole and for accurate livestock improvement through genomic selection. This includes, but is not limited to, understanding the ontogenetic and environmentally driven regulation of gene action contributing to simple and complex traits. Genetically modified mice, in which the functions of single genes are annotated; mice with reduced genetic complexity; and simplified structured populations are tools to gain fundamental knowledge of inheritance patterns and whole system genetics and genomics. In this review, we briefly describe existing mouse resources and discuss their value for fundamental and applied research in livestock.

A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder

Directory of Open Access Journals (Sweden)

David G Ashbrook

2015-07-01

Full Text Available Bipolar disorder (BD is a significant neuropsychiatric disorder with a lifetime prevalence of ~1%. To identify genetic variants underlying BD genome-wide association studies (GWAS have been carried out. While many variants of small effect associated with BD have been identified few have yet been confirmed, partly because of the low power of GWAS due to multiple comparisons being made. Complementary mapping studies using murine models have identified genetic variants for behavioral traits linked to BD, often with high power, but these identified regions often contain too many genes for clear identification of candidate genes. In the current study we have aligned human BD GWAS results and mouse linkage studies to help define and evaluate candidate genes linked to BD, seeking to use the power of the mouse mapping with the precision of GWAS. We use quantitative trait mapping for open field test and elevated zero maze data in the largest mammalian model system, the BXD recombinant inbred mouse population, to identify genomic regions associated with these BD-like phenotypes. We then investigate these regions in whole genome data from the Psychiatric Genomics Consortium’s bipolar disorder GWAS to identify candidate genes associated with BD. Finally we establish the biological relevance and pathways of these genes in a comprehensive systems genetics analysis.We identify four genes associated with both mouse anxiety and human BD. While TNR is a novel candidate for BD, we can confirm previously suggested associations with CMYA5, MCTP1 and RXRG. A cross-species, systems genetics analysis shows that MCTP1, RXRG and TNR coexpress with genes linked to psychiatric disorders and identify the striatum as a potential site of action. CMYA5, MCTP1, RXRG and TNR are associated with mouse anxiety and human BD. We hypothesize that MCTP1, RXRG and TNR influence intercellular signaling in the striatum.

High-precision genetic mapping of behavioral traits in the diversity outbred mouse population

Science.gov (United States)

Logan, R W; Robledo, R F; Recla, J M; Philip, V M; Bubier, J A; Jay, J J; Harwood, C; Wilcox, T; Gatti, D M; Bult, C J; Churchill, G A; Chesler, E J

2013-01-01

Historically our ability to identify genetic variants underlying complex behavioral traits in mice has been limited by low mapping resolution of conventional mouse crosses. The newly developed Diversity Outbred (DO) population promises to deliver improved resolution that will circumvent costly fine-mapping studies. The DO is derived from the same founder strains as the Collaborative Cross (CC), including three wild-derived strains. Thus the DO provides more allelic diversity and greater potential for discovery compared to crosses involving standard mouse strains. We have characterized 283 male and female DO mice using open-field, light–dark box, tail-suspension and visual-cliff avoidance tests to generate 38 behavioral measures. We identified several quantitative trait loci (QTL) for these traits with support intervals ranging from 1 to 3 Mb in size. These intervals contain relatively few genes (ranging from 5 to 96). For a majority of QTL, using the founder allelic effects together with whole genome sequence data, we could further narrow the positional candidates. Several QTL replicate previously published loci. Novel loci were also identified for anxiety- and activity-related traits. Half of the QTLs are associated with wild-derived alleles, confirming the value to behavioral genetics of added genetic diversity in the DO. In the presence of wild-alleles we sometimes observe behaviors that are qualitatively different from the expected response. Our results demonstrate that high-precision mapping of behavioral traits can be achieved with moderate numbers of DO animals, representing a significant advance in our ability to leverage the mouse as a tool for behavioral genetics PMID:23433259

Genetic Contributors to Intergenerational CAG Repeat Instability in Huntington's Disease Knock-In Mice.

Science.gov (United States)

Neto, João Luís; Lee, Jong-Min; Afridi, Ali; Gillis, Tammy; Guide, Jolene R; Dempsey, Stephani; Lager, Brenda; Alonso, Isabel; Wheeler, Vanessa C; Pinto, Ricardo Mouro

2017-02-01

Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in exon 1 of the HTT gene. Longer repeat sizes are associated with increased disease penetrance and earlier ages of onset. Intergenerationally unstable transmissions are common in HD families, partly underlying the genetic anticipation seen in this disorder. HD CAG knock-in mouse models also exhibit a propensity for intergenerational repeat size changes. In this work, we examine intergenerational instability of the CAG repeat in over 20,000 transmissions in the largest HD knock-in mouse model breeding datasets reported to date. We confirmed previous observations that parental sex drives the relative ratio of expansions and contractions. The large datasets further allowed us to distinguish effects of paternal CAG repeat length on the magnitude and frequency of expansions and contractions, as well as the identification of large repeat size jumps in the knock-in models. Distinct degrees of intergenerational instability were observed between knock-in mice of six background strains, indicating the occurrence of trans-acting genetic modifiers. We also found that lines harboring a neomycin resistance cassette upstream of Htt showed reduced expansion frequency, indicative of a contributing role for sequences in cis, with the expanded repeat as modifiers of intergenerational instability. These results provide a basis for further understanding of the mechanisms underlying intergenerational repeat instability. Copyright © 2017 by the Genetics Society of America.

Nras Overexpression Results in Granulocytosis, T-Cell Expansion and Early Lethality in Mice

DEFF Research Database (Denmark)

Lassen, Louise Berkhoudt; Gonzalez, Borja Ballarin; Schmitz, Alexander

2012-01-01

NRAS is a proto-oncogene involved in numerous myeloid malignancies. Here, we report on a mouse line bearing a single retroviral long terminal repeat inserted into Nras. This genetic modification resulted in an increased level of wild type Nras mRNA giving the possibility of studying the function ...... the increment in immature myeloid cells detected in these mice. The short latency period indicates that Nras overexpression alone is sufficient to cause dose-dependent granulocytosis and T-cell expansion....

Development of Genetic Testing for Fragile X Syndrome and Associated Disorders, and Estimates of the Prevalence of FMR1 Expansion Mutations

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James N. Macpherson

2016-11-01

Full Text Available The identification of a trinucleotide (CGG expansion as the chief mechanism of mutation in Fragile X syndrome in 1991 heralded a new chapter in molecular diagnostic genetics and generated a new perspective on mutational mechanisms in human genetic disease, which rapidly became a central paradigm (“dynamic mutation” as more and more of the common hereditary neurodevelopmental disorders were ascribed to this novel class of mutation. The progressive expansion of a CGG repeat in the FMR1 gene from “premutation” to “full mutation” provided an explanation for the “Sherman paradox,” just as similar expansion mechanisms in other genes explained the phenomenon of “anticipation” in their pathogenesis. Later, FMR1 premutations were unexpectedly found associated with two other distinct phenotypes: primary ovarian insufficiency and tremor-ataxia syndrome. This review will provide a historical perspective on procedures for testing and reporting of Fragile X syndrome and associated disorders, and the population genetics of FMR1 expansions, including estimates of prevalence and the influence of AGG interspersions on the rate and probability of expansion.

Urban park characteristics, genetic variation, and historical demography of white-footed mouse (Peromyscus leucopus populations in New York City

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Jason Munshi-South

2014-03-01

Full Text Available Severe fragmentation is a typical fate of native remnant habitats in cities, and urban wildlife with limited dispersal ability are predicted to lose genetic variation in isolated urban patches. However, little information exists on the characteristics of urban green spaces required to conserve genetic variation. In this study, we examine whether isolation in New York City (NYC parks results in genetic bottlenecks in white-footed mice (Peromyscus leucopus, and test the hypotheses that park size and time since isolation are associated with genetic variability using nonlinear regression and information-theoretic model selection. White-footed mice have previously been documented to exhibit male-biased dispersal, which may create disparities in genetic variation between males and females in urban parks. We use genotypes of 18 neutral microsatellite data and four different statistical tests to assess this prediction. Given that sex-biased dispersal may create disparities between population genetic patterns inferred from bi- vs. uni-parentally inherited markers, we also sequenced a 324 bp segment of the mitochondrial D-loop for independent inferences of historical demography in urban P. leucopus. We report that isolation in urban parks does not necessarily result in genetic bottlenecks; only three out of 14 populations in NYC parks exhibited a signature of a recent bottleneck at 18 neutral microsatellite loci. Mouse populations in larger urban parks, or parks that have been isolated for shorter periods of time, also do not generally contain greater genetic variation than populations in smaller parks. These results suggest that even small networks of green spaces may be sufficient to maintain the evolutionary potential of native species with certain characteristics. We also found that isolation in urban parks results in weak to nonexistent sex-biased dispersal in a species known to exhibit male-biased dispersal in less fragmented environments. In

Genetic mouse models relevant to schizophrenia: taking stock and looking forward.

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Harrison, Paul J; Pritchett, David; Stumpenhorst, Katharina; Betts, Jill F; Nissen, Wiebke; Schweimer, Judith; Lane, Tracy; Burnet, Philip W J; Lamsa, Karri P; Sharp, Trevor; Bannerman, David M; Tunbridge, Elizabeth M

2012-03-01

Genetic mouse models relevant to schizophrenia complement, and have to a large extent supplanted, pharmacological and lesion-based rat models. The main attraction is that they potentially have greater construct validity; however, they share the fundamental limitations of all animal models of psychiatric disorder, and must also be viewed in the context of the uncertain and complex genetic architecture of psychosis. Some of the key issues, including the choice of gene to target, the manner of its manipulation, gene-gene and gene-environment interactions, and phenotypic characterization, are briefly considered in this commentary, illustrated by the relevant papers reported in this special issue. Copyright © 2011 Elsevier Ltd. All rights reserved.

Population genetic analysis of Bromus tectorum (Poaceae) indicates recent range expansion may be facilitated by specialist genotypes

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Keith R. Merrill; Susan E. Meyer; Craig E. Coleman

2012-01-01

The mechanisms for range expansion in invasive species depend on how genetic variation is structured in the introduced range. This study examined neutral genetic variation in the invasive annual grass Bromus tectorum in the Intermountain Western United States. Patterns of microsatellite (SSR) genotype distribution in this highly inbreeding species were used to make...

The genetic legacy of the expansion of Turkic-speaking nomads across Eurasia.

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Yunusbayev, Bayazit; Metspalu, Mait; Metspalu, Ene; Valeev, Albert; Litvinov, Sergei; Valiev, Ruslan; Akhmetova, Vita; Balanovska, Elena; Balanovsky, Oleg; Turdikulova, Shahlo; Dalimova, Dilbar; Nymadawa, Pagbajabyn; Bahmanimehr, Ardeshir; Sahakyan, Hovhannes; Tambets, Kristiina; Fedorova, Sardana; Barashkov, Nikolay; Khidiyatova, Irina; Mihailov, Evelin; Khusainova, Rita; Damba, Larisa; Derenko, Miroslava; Malyarchuk, Boris; Osipova, Ludmila; Voevoda, Mikhail; Yepiskoposyan, Levon; Kivisild, Toomas; Khusnutdinova, Elza; Villems, Richard

2015-04-01

The Turkic peoples represent a diverse collection of ethnic groups defined by the Turkic languages. These groups have dispersed across a vast area, including Siberia, Northwest China, Central Asia, East Europe, the Caucasus, Anatolia, the Middle East, and Afghanistan. The origin and early dispersal history of the Turkic peoples is disputed, with candidates for their ancient homeland ranging from the Transcaspian steppe to Manchuria in Northeast Asia. Previous genetic studies have not identified a clear-cut unifying genetic signal for the Turkic peoples, which lends support for language replacement rather than demic diffusion as the model for the Turkic language's expansion. We addressed the genetic origin of 373 individuals from 22 Turkic-speaking populations, representing their current geographic range, by analyzing genome-wide high-density genotype data. In agreement with the elite dominance model of language expansion most of the Turkic peoples studied genetically resemble their geographic neighbors. However, western Turkic peoples sampled across West Eurasia shared an excess of long chromosomal tracts that are identical by descent (IBD) with populations from present-day South Siberia and Mongolia (SSM), an area where historians center a series of early Turkic and non-Turkic steppe polities. While SSM matching IBD tracts (> 1cM) are also observed in non-Turkic populations, Turkic peoples demonstrate a higher percentage of such tracts (p-values ≤ 0.01) compared to their non-Turkic neighbors. Finally, we used the ALDER method and inferred admixture dates (~9th-17th centuries) that overlap with the Turkic migrations of the 5th-16th centuries. Thus, our results indicate historical admixture among Turkic peoples, and the recent shared ancestry with modern populations in SSM supports one of the hypothesized homelands for their nomadic Turkic and related Mongolic ancestors.

The genetic legacy of the expansion of Turkic-speaking nomads across Eurasia.

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Bayazit Yunusbayev

2015-04-01

Full Text Available The Turkic peoples represent a diverse collection of ethnic groups defined by the Turkic languages. These groups have dispersed across a vast area, including Siberia, Northwest China, Central Asia, East Europe, the Caucasus, Anatolia, the Middle East, and Afghanistan. The origin and early dispersal history of the Turkic peoples is disputed, with candidates for their ancient homeland ranging from the Transcaspian steppe to Manchuria in Northeast Asia. Previous genetic studies have not identified a clear-cut unifying genetic signal for the Turkic peoples, which lends support for language replacement rather than demic diffusion as the model for the Turkic language's expansion. We addressed the genetic origin of 373 individuals from 22 Turkic-speaking populations, representing their current geographic range, by analyzing genome-wide high-density genotype data. In agreement with the elite dominance model of language expansion most of the Turkic peoples studied genetically resemble their geographic neighbors. However, western Turkic peoples sampled across West Eurasia shared an excess of long chromosomal tracts that are identical by descent (IBD with populations from present-day South Siberia and Mongolia (SSM, an area where historians center a series of early Turkic and non-Turkic steppe polities. While SSM matching IBD tracts (> 1cM are also observed in non-Turkic populations, Turkic peoples demonstrate a higher percentage of such tracts (p-values ≤ 0.01 compared to their non-Turkic neighbors. Finally, we used the ALDER method and inferred admixture dates (~9th-17th centuries that overlap with the Turkic migrations of the 5th-16th centuries. Thus, our results indicate historical admixture among Turkic peoples, and the recent shared ancestry with modern populations in SSM supports one of the hypothesized homelands for their nomadic Turkic and related Mongolic ancestors.

Rangewide genetic analysis of Lesser Prairie-Chicken reveals population structure, range expansion, and possible introgression

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Oyler-McCance, Sara J.; DeYoung, Randall W; Fike, Jennifer; Hagen, Christian A.; Johnson, Jeff A.; Larsson, Lena C.; Patten, Michael

2016-01-01

The distribution of the Lesser Prairie-Chicken (Tympanuchus pallidicinctus) has been markedly reduced due to loss and fragmentation of habitat. Portions of the historical range, however, have been recolonized and even expanded due to planting of conservation reserve program (CRP) fields that provide favorable vegetation structure for Lesser Prairie-Chickens. The source population(s) feeding the range expansion is unknown, yet has resulted in overlap between Lesser and Greater Prairie-Chickens (T. cupido) increasing the potential for hybridization. Our objectives were to characterize connectivity and genetic diversity among populations, identify source population(s) of recent range expansion, and examine hybridization with the Greater Prairie-Chicken. We analyzed 640 samples from across the range using 13 microsatellites. We identified three to four populations corresponding largely to ecoregions. The Shinnery Oak Prairie and Sand Sagebrush Prairie represented genetically distinct populations (F ST > 0.034 and F ST > 0.023 respectively). The Shortgrass/CRP Mosaic and Mixed Grass ecoregions appeared admixed (F ST = 0.009). Genetic diversity was similar among ecoregions and N e ranged from 142 (95 % CI 99–236) for the Shortgrass/CRP Mosaic to 296 (95 % CI 233–396) in the Mixed Grass Prairie. No recent migration was detected among ecoregions, except asymmetric dispersal from both the Mixed Grass Prairie and to a lesser extent the Sand Sagebrush Prairie north into adjacent Shortgrass/CRP Mosaic (m = 0.207, 95 % CI 0.116–0.298, m = 0.097, 95 % CI 0.010–0.183, respectively). Indices investigating potential hybridization in the Shortgrass/CRP Mosaic revealed that six of the 13 individuals with hybrid phenotypes were significantly admixed suggesting hybridization. Continued monitoring of diversity within and among ecoregions is warranted as are actions promoting genetic connectivity and range expansion.

Genetic screening of Greek patients with Huntington’s disease phenocopies identifies an SCA8 expansion.

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Koutsis, G; Karadima, G; Pandraud, A; Sweeney, M G; Paudel, R; Houlden, H; Wood, N W; Panas, M

2012-09-01

Huntington’s disease (HD) is an autosomal dominant disorder characterized by a triad of chorea, psychiatric disturbance and cognitive decline. Around 1% of patients with HD-like symptoms lack the causative HD expansion and are considered HD phenocopies. Genetic diseases that can present as HD phenocopies include HD-like syndromes such as HDL1, HDL2 and HDL4 (SCA17), some spinocerebellar ataxias (SCAs) and dentatorubral-pallidoluysian atrophy (DRPLA). In this study we screened a cohort of 21 Greek patients with HD phenocopy syndromes formutations causing HDL2, SCA17, SCA1, SCA2, SCA3,SCA8, SCA12 and DRPLA. Fifteen patients (71%) had a positive family history. We identified one patient (4.8% of the total cohort) with an expansion of 81 combined CTA/CTG repeats at the SCA8 locus. This falls within what is believed to be the high-penetrance allele range. In addition to the classic HD triad, the patient had features of dystonia and oculomotor apraxia. There were no cases of HDL2, SCA17, SCA1, SCA2, SCA3, SCA12 or DRPLA. Given the controversy surrounding the SCA8 expansion, the present finding may be incidental. However, if pathogenic, it broadens the phenotype that may be associated with SCA8 expansions. The absence of any other mutations in our cohort is not surprising, given the low probability of reaching a genetic diagnosis in HD phenocopy patients.

[Genetic variation and differentiation in striped field mouse Apodemus agrarius inferred from RAPD-PCR analysis].

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Atopkin, D M; Bogdanov, A S; Chelomina, G N

2007-06-01

Genetic variation and differentiation of the trans-Palearctic species Apodemus agrarius (striped field mouse), whose range consists of two large isolates-European-Siberian and Far Eastern-Chinese, were examined using RAPD-PCR analysis. The material from the both parts of the range was examined (41 individual of A. agrarius from 18 localities of Russia, Ukraine, Moldova, and Kazakhstan); the Far-Eastern part was represented by samples from the Amur region, Khabarovsk krai, and Primorye (Russia). Differences in frequencies of polymorphic RAPD loci were found between the European-Siberian and the Far Eastern population groups of striped field mouse. No "fixed" differences between them in RAPD spectra were found, and none of the used statistical methods permitted to distinguish with absolute certainty animals from the two range parts. Thus, genetic isolation of the European-Siberian and the Far Eastern population groups of A. agrarius is not strict. These results support the hypothesis on recent dispersal of striped field mouse from East to West Palearctics (during the Holocene climatic optimum, 7000 to 4500 years ago) and subsequent disjunction of the species range (not earlier than 4000-4500 years ago). The Far Eastern population group is more polymorphic than the European-Siberian one, while genetic heterogeneity is more uniformly distributed within it. This is probably explained by both historical events that happened during the species dispersal in the past, and different environmental conditions for the species in different parts of its range. The Far Eastern population group inhabits the area close to the distribution center of A. agrarius. It is likely that this group preserved genetic variation of the formerly integral ancestral form, while some amount of genetic polymorphism could be lost during the species colonization of the Siberian and European areas. To date, the settlement density and population number in general are higher than within the European

USING OF MOUSE MODEL TO ANALYZE IMMUNE RESPONSE TO INFECTIOUS PATHOGENS BY THE METHODS OF CLASSICAL GENETICS

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A. Poltorak

2011-01-01

Full Text Available Abstract. Identification and studying of numerous functions of all genes of the human beings is one of the main objects of modern biological science. Due to high level of homology between mouse and human genomes the important role to reach above mentioned goal belongs to the mouse model which using in the classical genetics increase in connection with appearance of different inbred mouse lines. For instance, the differences in immune response to infectious pathogens in various mouse lines were used many times to determine immunologically competent genes. That is why the contribution of mouse model in understanding of the mechanisms of immune response to infectious pathogens is difficult to overestimate. In the current review some of the most successful and well known examples of mouse using in studies of anti-infectious response are described.

Fork stalling and template switching as a mechanism for polyalanine tract expansion affecting the DYC mutant of HOXD13, a new murine model of synpolydactyly.

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Cocquempot, Olivier; Brault, Véronique; Babinet, Charles; Herault, Yann

2009-09-01

Polyalanine expansion diseases are proposed to result from unequal crossover of sister chromatids that increases the number of repeats. In this report we suggest an alternative mechanism we put forward while we investigated a new spontaneous mutant that we named "Dyc" for "Digit in Y and Carpe" phenotype. Phenotypic analysis revealed an abnormal limb patterning similar to that of the human inherited congenital disease synpolydactyly (SPD) and to the mouse mutant model Spdh. Both human SPD and mouse Spdh mutations affect the Hoxd13 gene within a 15-residue polyalanine-encoding repeat in the first exon of the gene, leading to a dominant negative HOXD13. Genetic analysis of the Dyc mutant revealed a trinucleotide expansion in the polyalanine-encoding region of the Hoxd13 gene resulting in a 7-alanine expansion. However, unlike the Spdh mutation, this expansion cannot result from a simple duplication of a short segment. Instead, we propose the fork stalling and template switching (FosTeS) described for generation of nonrecurrent genomic rearrangements as a possible mechanism for the Dyc polyalanine extension, as well as for other polyalanine expansions described in the literature and that could not be explained by unequal crossing over.

Range expansion, genetic differentiation, and phenotypic adaption of Hippophae neurocarpa (Elaeagnaceae) on the Qinghai- Tibet Plateau

Czech Academy of Sciences Publication Activity Database

Kou, Y.-X.; Wu, Y.-X.; Jia, Dong-Rui; Li, Z.-H.; Wang, Y.-J.

2014-01-01

Roč. 52, č. 3 (2014), s. 303-312 ISSN 1674-4918 Institutional support: RVO:67985939 Keywords : genetic differentiation * phenotyp adaptation * range expansion Subject RIV: EF - Botanics OBOR OECD: Plant sciences, botany Impact factor: 1.488, year: 2014

Genetic variations in two seahorse species (Hippocampus mohnikei and Hippocampus trimaculatus): evidence for middle Pleistocene population expansion.

Science.gov (United States)

Zhang, Yanhong; Pham, Nancy Kim; Zhang, Huixian; Lin, Junda; Lin, Qiang

2014-01-01

Population genetic of seahorses is confidently influenced by their species-specific ecological requirements and life-history traits. In the present study, partial sequences of mitochondrial cytochrome b (cytb) and control region (CR) were obtained from 50 Hippocampus mohnikei and 92 H. trimaculatus from four zoogeographical zones. A total of 780 base pairs of cytb gene were sequenced to characterize mitochondrial DNA (mtDNA) diversity. The mtDNA marker revealed high haplotype diversity, low nucleotide diversity, and a lack of population structure across both populations of H. mohnikei and H. trimaculatus. A neighbour-joining (NJ) tree of cytb gene sequences showed that H. mohnikei haplotypes formed one cluster. A maximum likelihood (ML) tree of cytb gene sequences showed that H. trimaculatus belonged to one lineage. The star-like pattern median-joining network of cytb and CR markers indicated a previous demographic expansion of H. mohnikei and H. trimaculatus. The cytb and CR data sets exhibited a unimodal mismatch distribution, which may have resulted from population expansion. Mismatch analysis suggested that the expansion was initiated about 276,000 years ago for H. mohnikei and about 230,000 years ago for H. trimaculatus during the middle Pleistocene period. This study indicates a possible signature of genetic variation and population expansion in two seahorses under complex marine environments.

Mouse Models of C9orf72 Hexanucleotide Repeat Expansion in Amyotrophic Lateral Sclerosis/ Frontotemporal Dementia

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Ranjan Batra

2017-07-01

Full Text Available The presence of hexanucleotide repeat expansion (HRE in the first intron of the human C9orf72 gene is the most common genetic cause underlying both familial amyotrophic lateral sclerosis (ALS and frontotemporal dementia (FTD. Studies aimed at elucidating the pathogenic mechanisms associated of C9orf72 FTD and ALS (C9FTD/ALS have focused on the hypothesis of RNA and protein toxic gain-of-function models, including formation of nuclear RNA foci containing GGGGCC (G4C2 HRE, inclusions containing dipeptide repeat proteins through a non-canonical repeat associated non-ATG (RAN translation mechanism, and on loss-of-function of the C9orf72 protein. Immense effort to elucidate these mechanisms has been put forth and toxic gain-of-function models have especially gained attention. Various mouse models that recapitulate distinct disease-related pathological, functional, and behavioral phenotypes have been generated and characterized. Although these models express the C9orf72 HRE mutation, there are numerous differences among them, including the transgenesis approach to introduce G4C2-repeat DNA, genomic coverage of C9orf72 features in the transgene, G4C2-repeat length after genomic stabilization, spatiotemporal expression profiles of RNA foci and RAN protein aggregates, neuropathological features, and neurodegeneration-related clinical symptoms. This review aims to (1 provide an overview of the key characteristics; (2 provide insights into potential pathological factors contributing to neurotoxicity and clinical phenotypes through systematic comparison of these models.

Spatiotemporal patterns of non-genetically modified crops in the era of expansion of genetically modified food.

Science.gov (United States)

Sun, Jing; Wu, Wenbin; Tang, Huajun; Liu, Jianguo

2015-09-18

Despite heated debates over the safety of genetically modified (GM) food, GM crops have been expanding rapidly. Much research has focused on the expansion of GM crops. However, the spatiotemporal dynamics of non-genetically modified (non-GM) crops are not clear, although they may have significant environmental and agronomic impacts and important policy implications. To understand the dynamics of non-GM crops and to inform the debates among relevant stakeholders, we conducted spatiotemporal analyses of China's major non-GM soybean production region, the Heilongjiang Province. Even though the total soybean planting area decreased from 2005 to 2010, surprisingly, there were hotspots of increase. The results also showed hotspots of loss as well as a large decline in the number and continuity of soybean plots. Since China is the largest non-GM soybean producer in the world, the decline of its major production region may signal the continual decline of global non-GM soybeans.

Genetic effects of combined chemical-X-ray treatments in male mouse germ cells

International Nuclear Information System (INIS)

Cattanach, B.M.; Rasberry, C.

1987-01-01

Several studies have shown that the yield of genetic damage induced by radiation in male mouse germ cells can be modified by chemical treatments. Pre-treatments with radio-protecting agents have given contradictory results but this appears to be largely attributable to the different germ cell stages tested and dependent upon the level of radiation damage induced. Pre-treatments which enhance the yield of genetic damage have been reported although, as yet, no tests have been conducted with radio-sensitizers. Another form of interaction between chemicals and radiation is specifically found with spermatogonial stem cells. Chemicals that kill cells can, by population depletion, substantially and predictably modify the genetic response to subsequent radiation exposure over a period of several days, or even weeks. Enhancement and reduction in the genetic yield can be attained, dependent upon the interval between treatments, with the modification also varying with the type of genetic damage scored. Post-treatment with one chemical (TEM) has been shown to reduce the genetic response to radiation exposure. (author)

Genetic variations in two seahorse species (Hippocampus mohnikei and Hippocampus trimaculatus: evidence for middle Pleistocene population expansion.

Directory of Open Access Journals (Sweden)

Yanhong Zhang

Full Text Available Population genetic of seahorses is confidently influenced by their species-specific ecological requirements and life-history traits. In the present study, partial sequences of mitochondrial cytochrome b (cytb and control region (CR were obtained from 50 Hippocampus mohnikei and 92 H. trimaculatus from four zoogeographical zones. A total of 780 base pairs of cytb gene were sequenced to characterize mitochondrial DNA (mtDNA diversity. The mtDNA marker revealed high haplotype diversity, low nucleotide diversity, and a lack of population structure across both populations of H. mohnikei and H. trimaculatus. A neighbour-joining (NJ tree of cytb gene sequences showed that H. mohnikei haplotypes formed one cluster. A maximum likelihood (ML tree of cytb gene sequences showed that H. trimaculatus belonged to one lineage. The star-like pattern median-joining network of cytb and CR markers indicated a previous demographic expansion of H. mohnikei and H. trimaculatus. The cytb and CR data sets exhibited a unimodal mismatch distribution, which may have resulted from population expansion. Mismatch analysis suggested that the expansion was initiated about 276,000 years ago for H. mohnikei and about 230,000 years ago for H. trimaculatus during the middle Pleistocene period. This study indicates a possible signature of genetic variation and population expansion in two seahorses under complex marine environments.

Mouse to human comparative genetics reveals a novel immunoglobulin E-controlling locus on Hsa8q12

Czech Academy of Sciences Publication Activity Database

Gusareva, Elena; Havelková, Helena; Blažková, Hana; Kosařová, Marcela; Kučera, P.; Král, V.; Salyakina, D.; Mulller-Myhsok, b.; Lipoldová, Marie

2009-01-01

Roč. 61, č. 1 (2009), s. 15-25 ISSN 0093-7711 R&D Projects: GA ČR GA310/06/1745; GA MŠk(CZ) LC06009 Institutional research plan: CEZ:AV0Z50520514 Keywords : atopy * specific IgE * genetic loci * mouse-human homology * Czech population * 8q12 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.988, year: 2009

The Mouse Tumor Biology Database: A Comprehensive Resource for Mouse Models of Human Cancer.

Science.gov (United States)

Krupke, Debra M; Begley, Dale A; Sundberg, John P; Richardson, Joel E; Neuhauser, Steven B; Bult, Carol J

2017-11-01

Research using laboratory mice has led to fundamental insights into the molecular genetic processes that govern cancer initiation, progression, and treatment response. Although thousands of scientific articles have been published about mouse models of human cancer, collating information and data for a specific model is hampered by the fact that many authors do not adhere to existing annotation standards when describing models. The interpretation of experimental results in mouse models can also be confounded when researchers do not factor in the effect of genetic background on tumor biology. The Mouse Tumor Biology (MTB) database is an expertly curated, comprehensive compendium of mouse models of human cancer. Through the enforcement of nomenclature and related annotation standards, MTB supports aggregation of data about a cancer model from diverse sources and assessment of how genetic background of a mouse strain influences the biological properties of a specific tumor type and model utility. Cancer Res; 77(21); e67-70. ©2017 AACR . ©2017 American Association for Cancer Research.

Low genetic diversity and recent demographic expansion in the red starfish Echinaster sepositus (Retzius 1816).

Science.gov (United States)

Garcia-Cisneros, Alex; Palacín, Creu; Ben Khadra, Yousra; Pérez-Portela, Rocío

2016-09-15

Understanding the phylogeography and genetic structure of populations and the processes responsible of patterns therein is crucial for evaluating the vulnerability of marine species and developing management strategies. In this study, we explore how past climatic events and ongoing oceanographic and demographic processes have shaped the genetic structure and diversity of the Atlanto-Mediterranean red starfish Echinaster sepositus. The species is relatively abundant in some areas of the Mediterranean Sea, but some populations have dramatically decreased over recent years due to direct extraction for ornamental aquariums and souvenir industries. Analyses across most of the distribution range of the species based on the mitochondrial cytochrome c oxidase subunit I gene and eight microsatellite loci revealed very low intraspecific genetic diversity. The species showed a weak genetic structure within marine basins despite the a priori low dispersal potential of its lecithotrophic larva. Our results also revealed a very recent demographic expansion across the distribution range of the species. The genetic data presented here indicate that the species might be highly vulnerable, due to its low intraspecific genetic diversity.

Genetic organization of the agouti region of the mouse

International Nuclear Information System (INIS)

Siracusa, L.D.; Russell, L.B.; Eicher, E.M.; Corrow, D.J.; Copeland, N.G.; Jenkins, N.A.

1987-01-01

The agouti locus on mouse chromosome 2 acts via the hair follicle to control the melanic type and distribution of hair pigments. The diverse phenotypes associated with various agouti mutations have led to speculation about the organization of the agouti locus. Earlier studies indicated that two presumed agouti alleles, lethal yellow (A/sup y/) and lethal light-bellied nonagouti (a/sup x/), are pseudoallelic. The authors present genetic data showing probable recombination between A/sup y/ and three agouti mutations (a/sup t/, a, and a/sup x/), which suggest that A/sup y/ is a pseudoallele of the agouti locus. The close linkage of an endogenous ecotropic murine leukemia provirus, Emv-15, to A/sup y/ provides a molecular access to genes at or near the agouti locus. However, previous studies suggested that the Emv-15 locus can recombine with some agouti alleles and therefore they analyzed mice from recombinant inbred strains and backcrosses to measure the genetic distance between various agouti alleles and the Emv-15 locus. The data indicate that the Emv-15 locus is less the 0.3 cM from the agouti locus. These experiments provide a conceptual framework for initiating chromosome walking experiments designed to retrieve sequences from the agouti locus and give new insight into the genetic organization of the agouti region

Genetically engineered mouse models of craniopharyngioma: an opportunity for therapy development and understanding of tumor biology.

Science.gov (United States)

Apps, John Richard; Martinez-Barbera, Juan Pedro

2017-05-01

Adamantinomatous craniopharyngioma (ACP) is the commonest tumor of the sellar region in childhood. Two genetically engineered mouse models have been developed and are giving valuable insights into ACP biology. These models have identified novel pathways activated in tumors, revealed an important function of paracrine signalling and extended conventional theories about the role of organ-specific stem cells in tumorigenesis. In this review, we summarize these mouse models, what has been learnt, their limitations and open questions for future research. We then discussed how these mouse models may be used to test novel therapeutics against potentially targetable pathways recently identified in human ACP. © 2017 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.

Refugial isolation and range expansions drive the genetic structure of Oxyria sinensis (Polygonaceae) in the Himalaya-Hengduan Mountains

Science.gov (United States)

Meng, Lihua; Chen, Gang; Li, Zhonghu; Yang, Yongping; Wang, Zhengkun; Wang, Liuyang

2015-01-01

The formation of the Mekong-Salween Divide and climatic oscillations in Pleistocene were the main drivers for the contemporary diversity and genetic structure of plants in the Himalaya-Hengduan Mountains (HHM). To identify the relative roles of the two historical events in shaping population history of plants in HHM, we investigated the phylogeographic pattern of Oxyria sinensis, a perennial plant endemic to the HHM. Sixteen chloroplast haplotypes were identified and were clustered into three phylogenetic clades. The age of the major clades was estimated to be in the Pleistocene, falling into several Pleistocene glacial stages and postdating the formation of the Mekong-Salween Divide. Range expansions occurred at least twice in the early and middle Pleistocene, but the spatial genetic distribution rarely changed since the Last Glacial Maximum. Our results suggest that temporary mountain glaciers may act as barriers in promoting the lineage divergence in O. sinensis and that subsequential range expansions and secondary contacts might reshape the genetic distribution in geography and blur the boundary of population differentiation created in the earlier glacial stages. This study demonstrates that Pleistocene climatic change and mountain glaciers, rather than the Mekong-Salween Divide, play the primary role in shaping the spatial genetic structure of O. sinensis. PMID:26013161

System network planning expansion using mathematical programming, genetic algorithms and tabu search

International Nuclear Information System (INIS)

Sadegheih, A.; Drake, P.R.

2008-01-01

In this paper, system network planning expansion is formulated for mixed integer programming, a genetic algorithm (GA) and tabu search (TS). Compared with other optimization methods, GAs are suitable for traversing large search spaces, since they can do this relatively rapidly and because the use of mutation diverts the method away from local minima, which will tend to become more common as the search space increases in size. GA's give an excellent trade off between solution quality and computing time and flexibility for taking into account specific constraints in real situations. TS has emerged as a new, highly efficient, search paradigm for finding quality solutions to combinatorial problems. It is characterized by gathering knowledge during the search and subsequently profiting from this knowledge. The attractiveness of the technique comes from its ability to escape local optimality. The cost function of this problem consists of the capital investment cost in discrete form, the cost of transmission losses and the power generation costs. The DC load flow equations for the network are embedded in the constraints of the mathematical model to avoid sub-optimal solutions that can arise if the enforcement of such constraints is done in an indirect way. The solution of the model gives the best line additions and also provides information regarding the optimal generation at each generation point. This method of solution is demonstrated on the expansion of a 10 bus bar system to 18 bus bars. Finally, a steady-state genetic algorithm is employed rather than generational replacement, also uniform crossover is used

Genetic Dissection of Cardiac Remodeling in an Isoproterenol-Induced Heart Failure Mouse Model.

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Jessica Jen-Chu Wang

2016-07-01

Full Text Available We aimed to understand the genetic control of cardiac remodeling using an isoproterenol-induced heart failure model in mice, which allowed control of confounding factors in an experimental setting. We characterized the changes in cardiac structure and function in response to chronic isoproterenol infusion using echocardiography in a panel of 104 inbred mouse strains. We showed that cardiac structure and function, whether under normal or stress conditions, has a strong genetic component, with heritability estimates of left ventricular mass between 61% and 81%. Association analyses of cardiac remodeling traits, corrected for population structure, body size and heart rate, revealed 17 genome-wide significant loci, including several loci containing previously implicated genes. Cardiac tissue gene expression profiling, expression quantitative trait loci, expression-phenotype correlation, and coding sequence variation analyses were performed to prioritize candidate genes and to generate hypotheses for downstream mechanistic studies. Using this approach, we have validated a novel gene, Myh14, as a negative regulator of ISO-induced left ventricular mass hypertrophy in an in vivo mouse model and demonstrated the up-regulation of immediate early gene Myc, fetal gene Nppb, and fibrosis gene Lgals3 in ISO-treated Myh14 deficient hearts compared to controls.

The generation expansion planning of the Brazilian electric sector employing genetic algorithms; O planejamento da expansao da geracao do setor eletrico brasileiro utilizando os algoritmos geneticos

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Kazay, Heloisa Firmo

2001-07-01

The generation expansion-planning problem is a non-linear large-scale optimisation problem, which is even larger when it refers to the Brazilian system, and when one considers the multiple intervening uncertainty sources. To handle the complexity of the problem, decomposition schemes have been used. Usually, such schemes divide the expansion problem into two sub-problems: one related to the construction of new plants (investment sub-problem) and another dealing with the task of operating the system (operation sub-problem). This thesis proposes a genetic algorithm to solve the investment sub-problem. Initially, an analysis of the state of the art on the generation expansion planning and the field of the genetic algorithms are presented. Then follows a practical application of the proposed algorithm in a model of generation expansion planning under uncertainty. Finally, the results obtained in two case studies are presented and analysed. These results indicate that the proposed genetic algorithm is an effective alternative to the solution of the investment sub-problem. (author)

Northern range expansion of European populations of the wasp spider Argiope bruennichi is associated with global warming-correlated genetic admixture and population-specific temperature adaptations.

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Krehenwinkel, Henrik; Tautz, Diethard

2013-04-01

Poleward range expansions are observed for an increasing number of species, which may be an effect of global warming during the past decades. However, it is still not clear in how far these expansions reflect simple geographical shifts of species ranges, or whether new genetic adaptations play a role as well. Here, we analyse the expansion of the wasp spider Argiope bruennichi into Northern Europe during the last century. We have used a range-wide sampling of contemporary populations and historical specimens from museums to trace the phylogeography and genetic changes associated with the range shift. Based on the analysis of mitochondrial, microsatellite and SNP markers, we observe a higher level of genetic diversity in the expanding populations, apparently due to admixture of formerly isolated lineages. Using reciprocal transplant experiments for testing overwintering tolerance, as well as temperature preference and tolerance tests in the laboratory, we find that the invading spiders have possibly shifted their temperature niche. This may be a key adaptation for survival in Northern latitudes. The museum samples allow a reconstruction of the invasion's genetic history. A first, small-scale range shift started around 1930, in parallel with the onset of global warming. A more massive invasion of Northern Europe associated with genetic admixture and morphological changes occurred in later decades. We suggest that the latter range expansion into far Northern latitudes may be a consequence of the admixture that provided the genetic material for adaptations to new environmental regimes. Hence, global warming could have facilitated the initial admixture of populations and this resulted in genetic lineages with new habitat preferences. © 2013 Blackwell Publishing Ltd.

Rapid genetic algorithm optimization of a mouse computational model: Benefits for anthropomorphization of neonatal mouse cardiomyocytes

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Corina Teodora Bot

2012-11-01

Full Text Available While the mouse presents an invaluable experimental model organism in biology, its usefulness in cardiac arrhythmia research is limited in some aspects due to major electrophysiological differences between murine and human action potentials (APs. As previously described, these species-specific traits can be partly overcome by application of a cell-type transforming clamp (CTC to anthropomorphize the murine cardiac AP. CTC is a hybrid experimental-computational dynamic clamp technique, in which a computationally calculated time-dependent current is inserted into a cell in real time, to compensate for the differences between sarcolemmal currents of that cell (e.g., murine and the desired species (e.g., human. For effective CTC performance, mismatch between the measured cell and a mathematical model used to mimic the measured AP must be minimal. We have developed a genetic algorithm (GA approach that rapidly tunes a mathematical model to reproduce the AP of the murine cardiac myocyte under study. Compared to a prior implementation that used a template-based model selection approach, we show that GA optimization to a cell-specific model results in a much better recapitulation of the desired AP morphology with CTC. This improvement was more pronounced when anthropomorphizing neonatal mouse cardiomyocytes to human-like APs than to guinea pig APs. CTC may be useful for a wide range of applications, from screening effects of pharmaceutical compounds on ion channel activity, to exploring variations in the mouse or human genome. Rapid GA optimization of a cell-specific mathematical model improves CTC performance and may therefore expand the applicability and usage of the CTC technique.

Mouse-human experimental epigenetic analysis unmasks dietary targets and genetic liability for diabetic phenotypes

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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

Genetic Targeting of Arginase-II in Mouse Prevents Renal Oxidative Stress and Inflammation in Diet-Induced Obesity.

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Huang, Ji; Rajapakse, Angana; Xiong, Yuyan; Montani, Jean-Pierre; Verrey, François; Ming, Xiu-Fen; Yang, Zhihong

2016-01-01

Obesity is associated with development and progression of chronic kidney disease (CKD). Recent evidence demonstrates that enhanced levels of the L-arginine:ureahydrolase, including the two isoenzymes arginase-I (Arg-I) and arginase-II (Arg-II) in vascular endothelial cells promote uncoupling of endothelial nitric oxide synthase (eNOS), leading to increased superoxide radical anion and decreased NO production thereby endothelial dysfunction. Arg-II but not Arg-I is abundantly expressed in kidney and the role of Arg-II in CKD is uncertain and controversial. We aimed to investigate the role of Arg-II in renal damage associated with diet-induced obesity mouse model. Wild type (WT) C57BL/6 mice and mice deficient in Arg-II gene (Arg-II -/- ) were fed with either a normal chow (NC) or a high-fat-diet (HFD) for 14 weeks (starting at the age of 7 weeks) to induce obesity. In WT mice, HFD feeding caused frequent renal lipid accumulation, enhancement of renal reactive oxygen species (ROS) levels which could be attenuated by a NOS inhibitor, suggesting uncoupling of NOS in kidney. HFD feeding also significantly augmented renal Arg-II expression and activity. All the alterations in the kidney under HFD feeding were reduced in Arg-II -/- mice. Moreover, mesangial expansion as analyzed by Periodic Acid Schiff (PAS) staining and renal expression of vascular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in HFD-fed WT mouse assessed by immunoblotting were reduced in the HFD-fed Arg-II -/- mice, although there was no significant difference in body weight and renal weight/body weight ratio between the WT and Arg-II -/- mice. Thus, Arg-II expression/activity is enhanced in kidney of diet-induced obesity mice. Genetic targeting of Arg-II prevents renal damage associated with obesity, suggesting an important role of Arg-II in obesity-associated renal disease development.

Genetic Targeting of Arginase-II in Mouse Prevents Renal Oxidative Stress and Inflammation in Diet-Induced Obesity

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Ji Huang

2016-11-01

Full Text Available Obesity is associated with development and progression of chronic kidney disease (CKD. Recent evidence demonstrates that enhanced levels of the L-arginine:ureahydrolase, including the two isoenzymes arginase-I (Arg-I and arginase-II (Arg-II in vascular endothelial cells promote uncoupling of endothelial nitric oxide synthase (eNOS, leading to increased superoxide radical anion and decreased NO production thereby endothelial dysfunction. Arg-II but not Arg-I is abundantly expressed in kidney and the role of Arg-II in CKD is uncertain and controversial. We aimed to investigate the role of Arg-II in renal damage associated with diet-induced obesity mouse model. Wild type (WT C57BL/6 mice and mice deficient in Arg-II gene (Arg-II-/- were fed with either a normal chow (NC or a high-fat-diet (HFD for 14 weeks (starting at the age of 7 weeks to induce obesity. In WT mice, HFD feeding caused frequent renal lipid accumulation, enhancement of renal ROS levels which could be attenuated by a NOS inhibitor, suggesting uncoupling of NOS in kidney. HFD feeding also significantly augmented renal Arg-II expression and activity. All the alterations in the kidney under HFD feeding were reduced in Arg-II-/- mice. Moreover, mesangial expansion as analysed by Periodic Acid Schiff (PAS staining and renal expression of vascular adhesion molecule-1 (VCAM-1 and intercellular adhesion molecule-1 (ICAM-1 in HFD-fed WT mouse assessed by immunoblotting were reduced in the HFD-fed Arg-II-/- mice, although there was no significant difference in body weight and renal weight/body weight ratio between the WT and Arg-II-/- mice. Thus, Arg-II expression/activity is enhanced in kidney of diet-induced obesity mice. Genetic targeting of Arg-II prevents renal damage associated with obesity, suggesting an important role of Arg-II in obesity-associated renal disease development.

Mutation studies upon spermatogonial stem cells of mammals and genetic tests for non-disjunction in the mouse

International Nuclear Information System (INIS)

Cattanach, B.M.

1993-01-01

Studies upon strain differences in genetic response to radiation may facilitate extrapolation of mouse data to man. The objective of the project is to investigate the basis of the genetic responses obtained with different treatment regimes. Two systems of genetic (complementation) tests were developed using Robertsonian translocations in tester animals to detect non-disjunction and chromosome loss events in normal mice. The aim is to evaluate the two methods for detecting chromosome 11 loss, and compare the frequency of chromosomes 11 and 13 loss following X-irradiation of males and females. (R.P.) 6 refs., 3 tabs

Physiology of SLC12 transporters: lessons from inherited human genetic mutations and genetically engineered mouse knockouts.

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Gagnon, Kenneth B; Delpire, Eric

2013-04-15

Among the over 300 members of the solute carrier (SLC) group of integral plasma membrane transport proteins are the nine electroneutral cation-chloride cotransporters belonging to the SLC12 gene family. Seven of these transporters have been functionally described as coupling the electrically silent movement of chloride with sodium and/or potassium. Although in silico analysis has identified two additional SLC12 family members, no physiological role has been ascribed to the proteins encoded by either the SLC12A8 or the SLC12A9 genes. Evolutionary conservation of this gene family from protists to humans confirms their importance. A wealth of physiological, immunohistochemical, and biochemical studies have revealed a great deal of information regarding the importance of this gene family to human health and disease. The sequencing of the human genome has provided investigators with the capability to link several human diseases with mutations in the genes encoding these plasma membrane proteins. The availability of bacterial artificial chromosomes, recombination engineering techniques, and the mouse genome sequence has simplified the creation of targeting constructs to manipulate the expression/function of these cation-chloride cotransporters in the mouse in an attempt to recapitulate some of these human pathologies. This review will summarize the three human disorders that have been linked to the mutation/dysfunction of the Na-Cl, Na-K-2Cl, and K-Cl cotransporters (i.e., Bartter's, Gitleman's, and Andermann's syndromes), examine some additional pathologies arising from genetically modified mouse models of these cotransporters including deafness, blood pressure, hyperexcitability, and epithelial transport deficit phenotypes.

Mutation types and aging differently affect revertant fiber expansion in dystrophic mdx and mdx52 mice.

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Yusuke Echigoya

Full Text Available Duchenne muscular dystrophy (DMD, one of the most common and lethal genetic disorders, and the mdx mouse myopathies are caused by a lack of dystrophin protein. These dystrophic muscles contain sporadic clusters of dystrophin-expressing revertant fibers (RFs, as detected by immunohistochemistry. RFs are known to arise from muscle precursor cells with spontaneous exon skipping (alternative splicing and clonally expand in size with increasing age through the process of muscle degeneration/regeneration. The expansion of revertant clusters is thought to represent the cumulative history of muscle regeneration and proliferation of such precursor cells. However, the precise mechanisms by which RFs arise and expand are poorly understood. Here, to test the effects of mutation types and aging on RF expansion and muscle regeneration, we examined the number of RFs in mdx mice (containing a nonsense mutation in exon 23 and mdx52 mice (containing deletion mutation of exon 52 with the same C57BL/6 background at 2, 6, 12, and 18months of age. Mdx mice displayed a significantly higher number of RFs compared to mdx52 mice in all age groups, suggesting that revertant fiber expansion largely depends on the type of mutation and/or location in the gene. A significant increase in the expression and clustering levels of RFs was found beginning at 6months of age in mdx mice compared with mdx52 mice. In contrast to the significant expansion of RFs with increasing age, the number of centrally nucleated fibers and embryonic myosin heavy chain-positive fibers (indicative of cumulative and current muscle regeneration, respectively decreased with age in both mouse strains. These results suggest that mutation types and aging differently affect revertant fiber expansion in mdx and mdx52 mice.

Fatal Prion Disease in a Mouse Model of Genetic E200K Creutzfeldt-Jakob Disease

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Friedman-Levi, Yael; Meiner, Zeev; Canello, Tamar; Frid, Kati; Kovacs, Gabor G.; Budka, Herbert; Avrahami, Dana; Gabizon, Ruth

2011-01-01

Genetic prion diseases are late onset fatal neurodegenerative disorders linked to pathogenic mutations in the prion protein-encoding gene, PRNP. The most prevalent of these is the substitution of Glutamate for Lysine at codon 200 (E200K), causing genetic Creutzfeldt-Jakob disease (gCJD) in several clusters, including Jews of Libyan origin. Investigating the pathogenesis of genetic CJD, as well as developing prophylactic treatments for young asymptomatic carriers of this and other PrP mutations, may well depend upon the availability of appropriate animal models in which long term treatments can be evaluated for efficacy and toxicity. Here we present the first effective mouse model for E200KCJD, which expresses chimeric mouse/human (TgMHu2M) E199KPrP on both a null and a wt PrP background, as is the case for heterozygous patients and carriers. Mice from both lines suffered from distinct neurological symptoms as early as 5–6 month of age and deteriorated to death several months thereafter. Histopathological examination of the brain and spinal cord revealed early gliosis and age-related intraneuronal deposition of disease-associated PrP similarly to human E200K gCJD. Concomitantly we detected aggregated, proteinase K resistant, truncated and oxidized PrP forms on immunoblots. Inoculation of brain extracts from TgMHu2ME199K mice readily induced, the first time for any mutant prion transgenic model, a distinct fatal prion disease in wt mice. We believe that these mice may serve as an ideal platform for the investigation of the pathogenesis of genetic prion disease and thus for the monitoring of anti-prion treatments. PMID:22072968

Fatal prion disease in a mouse model of genetic E200K Creutzfeldt-Jakob disease.

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Yael Friedman-Levi

2011-11-01

Full Text Available Genetic prion diseases are late onset fatal neurodegenerative disorders linked to pathogenic mutations in the prion protein-encoding gene, PRNP. The most prevalent of these is the substitution of Glutamate for Lysine at codon 200 (E200K, causing genetic Creutzfeldt-Jakob disease (gCJD in several clusters, including Jews of Libyan origin. Investigating the pathogenesis of genetic CJD, as well as developing prophylactic treatments for young asymptomatic carriers of this and other PrP mutations, may well depend upon the availability of appropriate animal models in which long term treatments can be evaluated for efficacy and toxicity. Here we present the first effective mouse model for E200KCJD, which expresses chimeric mouse/human (TgMHu2M E199KPrP on both a null and a wt PrP background, as is the case for heterozygous patients and carriers. Mice from both lines suffered from distinct neurological symptoms as early as 5-6 month of age and deteriorated to death several months thereafter. Histopathological examination of the brain and spinal cord revealed early gliosis and age-related intraneuronal deposition of disease-associated PrP similarly to human E200K gCJD. Concomitantly we detected aggregated, proteinase K resistant, truncated and oxidized PrP forms on immunoblots. Inoculation of brain extracts from TgMHu2ME199K mice readily induced, the first time for any mutant prion transgenic model, a distinct fatal prion disease in wt mice. We believe that these mice may serve as an ideal platform for the investigation of the pathogenesis of genetic prion disease and thus for the monitoring of anti-prion treatments.

Meis1 Is Required for Adult Mouse Erythropoiesis, Megakaryopoiesis and Hematopoietic Stem Cell Expansion.

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Michelle Erin Miller

Full Text Available Meis1 is recognized as an important transcriptional regulator in hematopoietic development and is strongly implicated in the pathogenesis of leukemia, both as a Hox transcription factor co-factor and independently. Despite the emerging recognition of Meis1's importance in the context of both normal and leukemic hematopoiesis, there is not yet a full understanding of Meis1's functions and the relevant pathways and genes mediating its functions. Recently, several conditional mouse models for Meis1 have been established. These models highlight a critical role for Meis1 in adult mouse hematopoietic stem cells (HSCs and implicate reactive oxygen species (ROS as a mediator of Meis1 function in this compartment. There are, however, several reported differences between these studies in terms of downstream progenitor populations impacted and effectors of function. In this study, we describe further characterization of a conditional knockout model based on mice carrying a loxP-flanked exon 8 of Meis1 which we crossed onto the inducible Cre localization/expression strains, B6;129-Gt(ROSA26Sor(tm1(Cre/ERTNat/J or B6.Cg-Tg(Mx1-Cre1Cgn/J. Findings obtained from these two inducible Meis1 knockout models confirm and extend previous reports of the essential role of Meis1 in adult HSC maintenance and expansion and provide new evidence that highlights key roles of Meis1 in both megakaryopoiesis and erythropoiesis. Gene expression analyses point to a number of candidate genes involved in Meis1's role in hematopoiesis. Our data additionally support recent evidence of a role of Meis1 in ROS regulation.

Characterization of a genetically engineered mouse model of hemophilia A with complete deletion of the F8 gene.

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Chao, B N; Baldwin, W H; Healey, J F; Parker, E T; Shafer-Weaver, K; Cox, C; Jiang, P; Kanellopoulou, C; Lollar, P; Meeks, S L; Lenardo, M J

2016-02-01

ESSENTIALS: Anti-factor VIII (FVIII) inhibitory antibody formation is a severe complication in hemophilia A therapy. We genetically engineered and characterized a mouse model with complete deletion of the F8 coding region. F8(TKO) mice exhibit severe hemophilia, express no detectable F8 mRNA, and produce FVIII inhibitors. The defined background and lack of FVIII in F8(TKO) mice will aid in studying FVIII inhibitor formation. The most important complication in hemophilia A treatment is the development of inhibitory anti-Factor VIII (FVIII) antibodies in patients after FVIII therapy. Patients with severe hemophilia who express no endogenous FVIII (i.e. cross-reacting material, CRM) have the greatest incidence of inhibitor formation. However, current mouse models of severe hemophilia A produce low levels of truncated FVIII. The lack of a corresponding mouse model hampers the study of inhibitor formation in the complete absence of FVIII protein. We aimed to generate and characterize a novel mouse model of severe hemophilia A (designated the F8(TKO) strain) lacking the complete coding sequence of F8 and any FVIII CRM. Mice were created on a C57BL/6 background using Cre-Lox recombination and characterized using in vivo bleeding assays, measurement of FVIII activity by coagulation and chromogenic assays, and anti-FVIII antibody production using ELISA. All F8 exonic coding regions were deleted from the genome and no F8 mRNA was detected in F8(TKO) mice. The bleeding phenotype of F8(TKO) mice was comparable to E16 mice by measurements of factor activity and tail snip assay. Similar levels of anti-FVIII antibody titers after recombinant FVIII injections were observed between F8(TKO) and E16 mice. We describe a new C57BL/6 mouse model for severe hemophilia A patients lacking CRM. These mice can be directly bred to the many C57BL/6 strains of genetically engineered mice, which is valuable for studying the impact of a wide variety of genes on FVIII inhibitor formation on a

Population expansion and genetic structure in Carcharhinus brevipinna in the southern Indo-Pacific.

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Pascal T Geraghty

Full Text Available Quantifying genetic diversity and metapopulation structure provides insights into the evolutionary history of a species and helps develop appropriate management strategies. We provide the first assessment of genetic structure in spinner sharks (Carcharhinus brevipinna, a large cosmopolitan carcharhinid, sampled from eastern and northern Australia and South Africa.Sequencing of the mitochondrial DNA NADH dehydrogenase subunit 4 gene for 430 individuals revealed 37 haplotypes and moderately high haplotype diversity (h = 0.6770 ±0.025. While two metrics of genetic divergence (ΦST and F ST revealed somewhat different results, subdivision was detected between South Africa and all Australian locations (pairwise ΦST, range 0.02717-0.03508, p values ≤ 0.0013; pairwise F ST South Africa vs New South Wales = 0.04056, p = 0.0008. Evidence for fine-scale genetic structuring was also detected along Australia's east coast (pairwise ΦST = 0.01328, p < 0.015, and between south-eastern and northern locations (pairwise ΦST = 0.00669, p < 0.04.The Indian Ocean represents a robust barrier to contemporary gene flow in C. brevipinna between Australia and South Africa. Gene flow also appears restricted along a continuous continental margin in this species, with data tentatively suggesting the delineation of two management units within Australian waters. Further sampling, however, is required for a more robust evaluation of the latter finding. Evidence indicates that all sampled populations were shaped by a substantial demographic expansion event, with the resultant high genetic diversity being cause for optimism when considering conservation of this commercially-targeted species in the southern Indo-Pacific.

Phylogeographic patterns of Lygus pratensis (Hemiptera: Miridae): Evidence for weak genetic structure and recent expansion in northwest China.

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Zhang, Li-Juan; Cai, Wan-Zhi; Luo, Jun-Yu; Zhang, Shuai; Wang, Chun-Yi; Lv, Li-Min; Zhu, Xiang-Zhen; Wang, Li; Cui, Jin-Jie

2017-01-01

Lygus pratensis (L.) is an important cotton pest in China, especially in the northwest region. Nymphs and adults cause serious quality and yield losses. However, the genetic structure and geographic distribution of L. pratensis is not well known. We analyzed genetic diversity, geographical structure, gene flow, and population dynamics of L. pratensis in northwest China using mitochondrial and nuclear sequence datasets to study phylogeographical patterns and demographic history. L. pratensis (n = 286) were collected at sites across an area spanning 2,180,000 km2, including the Xinjiang and Gansu-Ningxia regions. Populations in the two regions could be distinguished based on mitochondrial criteria but the overall genetic structure was weak. The nuclear dataset revealed a lack of diagnostic genetic structure across sample areas. Phylogenetic analysis indicated a lack of population level monophyly that may have been caused by incomplete lineage sorting. The Mantel test showed a significant correlation between genetic and geographic distances among the populations based on the mtDNA data. However the nuclear dataset did not show significant correlation. A high level of gene flow among populations was indicated by migration analysis; human activities may have also facilitated insect movement. The availability of irrigation water and ample cotton hosts makes the Xinjiang region well suited for L. pratensis reproduction. Bayesian skyline plot analysis, star-shaped network, and neutrality tests all indicated that L. pratensis has experienced recent population expansion. Climatic changes and extensive areas occupied by host plants have led to population expansion of L. pratensis. In conclusion, the present distribution and phylogeographic pattern of L. pratensis was influenced by climate, human activities, and availability of plant hosts.

IL-10 Production Is Critical for Sustaining the Expansion of CD5+ B and NKT Cells and Restraining Autoantibody Production in Congenic Lupus-Prone Mice.

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Yuriy Baglaenko

Full Text Available The development and progression of systemic lupus erythematosus is mediated by the complex interaction of genetic and environmental factors. To decipher the genetics that contribute to pathogenesis and the production of pathogenic autoantibodies, our lab has focused on the generation of congenic lupus-prone mice derived from the New Zealand Black (NZB strain. Previous work has shown that an NZB-derived chromosome 4 interval spanning 32 to 151 Mb led to expansion of CD5+ B and Natural Killer T (NKT cells, and could suppress autoimmunity when crossed with a lupus-prone mouse strain. Subsequently, it was shown that CD5+ B cells but not NKT cells derived from these mice could suppress the development of pro-inflammatory T cells. In this paper, we aimed to further resolve the genetics that leads to expansion of these two innate-like populations through the creation of additional sub-congenic mice and to characterize the role of IL-10 in the suppression of autoimmunity through the generation of IL-10 knockout mice. We show that expansion of CD5+ B cells and NKT cells localizes to a chromosome 4 interval spanning 91 to 123 Mb, which is distinct from the region that mediates the majority of the suppressive phenotype. We also demonstrate that IL-10 is critical to restraining autoantibody production and surprisingly plays a vital role in supporting the expansion of innate-like populations.

IL-10 Production Is Critical for Sustaining the Expansion of CD5+ B and NKT Cells and Restraining Autoantibody Production in Congenic Lupus-Prone Mice.

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Baglaenko, Yuriy; Manion, Kieran P; Chang, Nan-Hua; Gracey, Eric; Loh, Christina; Wither, Joan E

2016-01-01

The development and progression of systemic lupus erythematosus is mediated by the complex interaction of genetic and environmental factors. To decipher the genetics that contribute to pathogenesis and the production of pathogenic autoantibodies, our lab has focused on the generation of congenic lupus-prone mice derived from the New Zealand Black (NZB) strain. Previous work has shown that an NZB-derived chromosome 4 interval spanning 32 to 151 Mb led to expansion of CD5+ B and Natural Killer T (NKT) cells, and could suppress autoimmunity when crossed with a lupus-prone mouse strain. Subsequently, it was shown that CD5+ B cells but not NKT cells derived from these mice could suppress the development of pro-inflammatory T cells. In this paper, we aimed to further resolve the genetics that leads to expansion of these two innate-like populations through the creation of additional sub-congenic mice and to characterize the role of IL-10 in the suppression of autoimmunity through the generation of IL-10 knockout mice. We show that expansion of CD5+ B cells and NKT cells localizes to a chromosome 4 interval spanning 91 to 123 Mb, which is distinct from the region that mediates the majority of the suppressive phenotype. We also demonstrate that IL-10 is critical to restraining autoantibody production and surprisingly plays a vital role in supporting the expansion of innate-like populations.

Isolation, culture and adenoviral transduction of parietal cells from mouse gastric mucosa

International Nuclear Information System (INIS)

Gliddon, Briony L; Nguyen, Nhung V; Gunn, Priscilla A; Gleeson, Paul A; Driel, Ian R van

2008-01-01

Here we describe a method for the isolation of intact gastric glands from mice and primary culture and transfection of mouse gastric epithelial cells. Collagenase digestion of PBS-perfused mouse stomachs released large intact gastric glands that were plated on a basement membrane matrix. The heterogeneous gland cell cultures typically contain ∼60% parietal cells. Isolated mouse parietal cells remain viable in culture for up to 5 days and react strongly with an antibody specific to the gastric H + /K + ATPase. Isolated intact mouse gastric glands and primary cultures of mouse parietal cells respond to the secretagogue, histamine. Typical morphological changes from a resting to an acid-secreting active parietal cell were observed. In resting cultures of mouse parietal cells, the H + /K + ATPase displayed a cytoplasmic punctate staining pattern consistent with tubulovesicle element structures. Following histamine stimulation, an expansion of internal apical vacuole structures was observed together with a pronounced redistribution of the H + /K + ATPase from the cytoplasm to the apical vacuoles. A reproducible procedure to express genes of interest exogenously in these cultures of mouse parietal cells was also established. This method combines recombinant adenoviral transduction with magnetic field-assisted transfection resulting in ∼30% transduced parietal cells. Adenoviral-transduced parietal cells maintain their ability to undergo agonist-induced activation. This protocol will be useful for the isolation, culture and expression of genes in parietal cells from genetically modified mice and as such will be an invaluable tool for studying the complex exocytic and endocytic trafficking events of the H + /K + ATPase which underpin the regulation of acid secretion

A report from the Sixth International Mouse Genome Conference

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Brown, S. [Saint Mary`s Hospital Medical School, London (United Kingdom). Dept. of Biochemistry and Molecular Genetics

1992-12-31

The Sixth Annual Mouse Genome Conference was held in October, 1992 at Buffalo, USA. The mouse is one of the primary model organisms in the Human Genome Project. Through the use of gene targeting studies the mouse has become a powerful biological model for the study of gene function and, in addition, the comparison of the many homologous mutations identified in human and mouse have widened our understanding of the biology of these two organisms. A primary goal in the mouse genome program has been to create a genetic map of STSs of high resolution (<1cM) that would form the basis for the physical mapping of the whole mouse genome. Buffalo saw substantial new progress towards the goal of a very high density genetic map and the beginnings of substantive efforts towards physical mapping in chromosome regions with a high density of genetic markers.

Decreased Bone Formation Explains Osteoporosis in a Genetic Mouse Model of Hemochromatosiss.

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Mathilde Doyard

Full Text Available Osteoporosis may complicate iron overload diseases such as genetic hemochromatosis. However, molecular mechanisms involved in the iron-related osteoporosis remains poorly understood. Recent in vitro studies support a role of osteoblast impairment in iron-related osteoporosis. Our aim was to analyse the impact of excess iron in Hfe-/- mice on osteoblast activity and on bone microarchitecture. We studied the bone formation rate, a dynamic parameter reflecting osteoblast activity, and the bone phenotype of Hfe-/- male mice, a mouse model of human hemochromatosis, by using histomorphometry. Hfe-/- animals were sacrificed at 6 months and compared to controls. We found that bone contains excess iron associated with increased hepatic iron concentration in Hfe-/- mice. We have shown that animals with iron overload have decreased bone formation rate, suggesting a direct impact of iron excess on active osteoblasts number. For bone mass parameters, we showed that iron deposition was associated with bone loss by producing microarchitectural impairment with a decreased tendency in bone trabecular volume and trabecular number. A disorganization of trabecular network was found with marrow spaces increased, which was confirmed by enhanced trabecular separation and star volume of marrow spaces. These microarchitectural changes led to a loss of connectivity and complexity in the trabecular network, which was confirmed by decreased interconnectivity index and increased Minkowski's fractal dimension. Our results suggest for the first time in a genetic hemochromatosis mouse model, that iron overload decreases bone formation and leads to alterations in bone mass and microarchitecture. These observations support a negative effect of iron on osteoblast recruitment and/or function, which may contribute to iron-related osteoporosis.

Early peroxisome proliferator-activated receptor gamma regulated genes involved in expansion of pancreatic beta cell mass

Directory of Open Access Journals (Sweden)

Vivas Yurena

2011-12-01

Full Text Available Abstract Background The progression towards type 2 diabetes depends on the allostatic response of pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. The endocrine pancreas is a plastic tissue able to expand or regress in response to the requirements imposed by physiological and pathophysiological states associated to insulin resistance such as pregnancy, obesity or ageing, but the mechanisms mediating beta cell mass expansion in these scenarios are not well defined. We have recently shown that ob/ob mice with genetic ablation of PPARγ2, a mouse model known as the POKO mouse failed to expand its beta cell mass. This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Thus, comparison of these models islets particularly at early ages could provide some new insights on early PPARγ dependent transcriptional responses involved in the process of beta cell mass expansion Results Here we have investigated PPARγ dependent transcriptional responses occurring during the early stages of beta cell adaptation to insulin resistance in wild type, ob/ob, PPARγ2 KO and POKO mice. We have identified genes known to regulate both the rate of proliferation and the survival signals of beta cells. Moreover we have also identified new pathways induced in ob/ob islets that remained unchanged in POKO islets, suggesting an important role for PPARγ in maintenance/activation of mechanisms essential for the continued function of the beta cell. Conclusions Our data suggest that the expansion of beta cell mass observed in ob/ob islets is associated with the activation of an immune response that fails to occur in POKO islets. We have also indentified other PPARγ dependent differentially regulated pathways including cholesterol biosynthesis, apoptosis through TGF-β signaling and decreased oxidative phosphorylation.

The Mouse Genome Database (MGD): facilitating mouse as a model for human biology and disease.

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Eppig, Janan T; Blake, Judith A; Bult, Carol J; Kadin, James A; Richardson, Joel E

2015-01-01

The Mouse Genome Database (MGD, http://www.informatics.jax.org) serves the international biomedical research community as the central resource for integrated genomic, genetic and biological data on the laboratory mouse. To facilitate use of mouse as a model in translational studies, MGD maintains a core of high-quality curated data and integrates experimentally and computationally generated data sets. MGD maintains a unified catalog of genes and genome features, including functional RNAs, QTL and phenotypic loci. MGD curates and provides functional and phenotype annotations for mouse genes using the Gene Ontology and Mammalian Phenotype Ontology. MGD integrates phenotype data and associates mouse genotypes to human diseases, providing critical mouse-human relationships and access to repositories holding mouse models. MGD is the authoritative source of nomenclature for genes, genome features, alleles and strains following guidelines of the International Committee on Standardized Genetic Nomenclature for Mice. A new addition to MGD, the Human-Mouse: Disease Connection, allows users to explore gene-phenotype-disease relationships between human and mouse. MGD has also updated search paradigms for phenotypic allele attributes, incorporated incidental mutation data, added a module for display and exploration of genes and microRNA interactions and adopted the JBrowse genome browser. MGD resources are freely available to the scientific community. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

The genetic structure of Turnip mosaic virus population reveals the rapid expansion of a new emergent lineage in China.

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Li, Xiangdong; Zhu, Tiansheng; Yin, Xiao; Zhang, Chengling; Chen, Jia; Tian, Yanping; Liu, Jinliang

2017-08-29

Turnip mosaic virus (TuMV) is one of the most widespread and economically important virus infecting both crop and ornamental species of the family Brassicaceae. TuMV isolates can be classified to five phylogenetic lineages, basal-B, basal-BR, Asian-BR, world-B and Orchis. To understand the genetic structure of TuMV from radish in China, the 3'-terminal genome of 90 TuMV isolates were determined and analyzed with other available Chinese isolates. The results showed that the Chinese TuMV isolates from radish formed three groups: Asian-BR, basal-BR and world-B. More than half of these isolates (52.54%) were clustered to basal-BR group, and could be further divided into three sub-groups. The TuMV basal-BR isolates in the sub-groups I and II were genetically homologous with Japanese ones, while those in sub-group III formed a distinct lineage. Sub-populations of TuMV basal-BR II and III were new emergent and in a state of expansion. The Chinese TuMV radish populations were under negative selection. Gene flow between TuMV populations from Tai'an, Weifang and Changchun was frequent. The genetic structure of Turnip mosaic virus population reveals the rapid expansion of a new emergent lineage in China.

Genetic structure and contrasting selection pattern at two major histocompatibility complex genes in wild house mouse populations

Czech Academy of Sciences Publication Activity Database

Čížková, Dagmar; Goüy de Bellocq, J.; Baird, S. J. E.; Piálek, Jaroslav; Bryja, Josef

2011-01-01

Roč. 106, č. 5 (2011), s. 727-740 ISSN 0018-067X R&D Projects: GA AV ČR IAA600930608; GA ČR GA206/08/0640 Institutional research plan: CEZ:AV0Z60930519 Keywords : MHC * house mouse * selection * population structure * trans-species polymorphism Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.597, year: 2011

A CRISPR Path to Engineering New Genetic Mouse Models for Cardiovascular Research.

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Miano, Joseph M; Zhu, Qiuyu Martin; Lowenstein, Charles J

2016-06-01

Previous efforts to target the mouse genome for the addition, subtraction, or substitution of biologically informative sequences required complex vector design and a series of arduous steps only a handful of laboratories could master. The facile and inexpensive clustered regularly interspaced short palindromic repeats (CRISPR) method has now superseded traditional means of genome modification such that virtually any laboratory can quickly assemble reagents for developing new mouse models for cardiovascular research. Here, we briefly review the history of CRISPR in prokaryotes, highlighting major discoveries leading to its formulation for genome modification in the animal kingdom. Core components of CRISPR technology are reviewed and updated. Practical pointers for 2-component and 3-component CRISPR editing are summarized with many applications in mice including frameshift mutations, deletion of enhancers and noncoding genes, nucleotide substitution of protein-coding and gene regulatory sequences, incorporation of loxP sites for conditional gene inactivation, and epitope tag integration. Genotyping strategies are presented and topics of genetic mosaicism and inadvertent targeting discussed. Finally, clinical applications and ethical considerations are addressed as the biomedical community eagerly embraces this astonishing innovation in genome editing to tackle previously intractable questions. © 2016 American Heart Association, Inc.

A CRISPR Path to Engineering New Genetic Mouse Models for Cardiovascular Research

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Miano, Joseph M.; Zhu, Qiuyu Martin; Lowenstein, Charles J.

2016-01-01

Previous efforts to target the mouse genome for the addition, subtraction, or substitution of biologically informative sequences required complex vector design and a series of arduous steps only a handful of labs could master. The facile and inexpensive clustered regularly interspaced short palindromic repeats (CRISPR) method has now superseded traditional means of genome modification such that virtually any lab can quickly assemble reagents for developing new mouse models for cardiovascular research. Here we briefly review the history of CRISPR in prokaryotes, highlighting major discoveries leading to its formulation for genome modification in the animal kingdom. Core components of CRISPR technology are reviewed and updated. Practical pointers for two-component and three-component CRISPR editing are summarized with a number of applications in mice including frameshift mutations, deletion of enhancers and non-coding genes, nucleotide substitution of protein-coding and gene regulatory sequences, incorporation of loxP sites for conditional gene inactivation, and epitope tag integration. Genotyping strategies are presented and topics of genetic mosaicism and inadvertent targeting discussed. Finally, clinical applications and ethical considerations are addressed as the biomedical community eagerly embraces this astonishing innovation in genome editing to tackle previously intractable questions. PMID:27102963

Identification of Treatment Targets in a Genetic Mouse Model of Voluntary Methamphetamine Drinking.

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Phillips, T J; Mootz, J R K; Reed, C

2016-01-01

Methamphetamine has powerful stimulant and euphoric effects that are experienced as rewarding and encourage use. Methamphetamine addiction is associated with debilitating illnesses, destroyed relationships, child neglect, violence, and crime; but after many years of research, broadly effective medications have not been identified. Individual differences that may impact not only risk for developing a methamphetamine use disorder but also affect treatment response have not been fully considered. Human studies have identified candidate genes that may be relevant, but lack of control over drug history, the common use or coabuse of multiple addictive drugs, and restrictions on the types of data that can be collected in humans are barriers to progress. To overcome some of these issues, a genetic animal model comprised of lines of mice selectively bred for high and low voluntary methamphetamine intake was developed to identify risk and protective alleles for methamphetamine consumption, and identify therapeutic targets. The mu opioid receptor gene was supported as a target for genes within a top-ranked transcription factor network associated with level of methamphetamine intake. In addition, mice that consume high levels of methamphetamine were found to possess a nonfunctional form of the trace amine-associated receptor 1 (TAAR1). The Taar1 gene is within a mouse chromosome 10 quantitative trait locus for methamphetamine consumption, and TAAR1 function determines sensitivity to aversive effects of methamphetamine that may curb intake. The genes, gene interaction partners, and protein products identified in this genetic mouse model represent treatment target candidates for methamphetamine addiction. © 2016 Elsevier Inc. All rights reserved.

CAG Expansions Are Genetically Stable and Form Nontoxic Aggregates in Cells Lacking Endogenous Polyglutamine Proteins

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Ashley A. Zurawel

2016-09-01

Full Text Available Proteins containing polyglutamine (polyQ regions are found in almost all eukaryotes, albeit with various frequencies. In humans, proteins such as huntingtin (Htt with abnormally expanded polyQ regions cause neurodegenerative diseases such as Huntington’s disease (HD. To study how the presence of endogenous polyQ aggregation modulates polyQ aggregation and toxicity, we expressed polyQ expanded Htt fragments (polyQ Htt in Schizosaccharomyces pombe. In stark contrast to other unicellular fungi, such as Saccharomyces cerevisiae, S. pombe is uniquely devoid of proteins with more than 10 Q repeats. We found that polyQ Htt forms aggregates within S. pombe cells only with exceedingly long polyQ expansions. Surprisingly, despite the presence of polyQ Htt aggregates in both the cytoplasm and nucleus, no significant growth defect was observed in S. pombe cells. Further, PCR analysis showed that the repetitive polyQ-encoding DNA region remained constant following transformation and after multiple divisions in S. pombe, in contrast to the genetic instability of polyQ DNA sequences in other organisms. These results demonstrate that cells with a low content of polyQ or other aggregation-prone proteins can show a striking resilience with respect to polyQ toxicity and that genetic instability of repetitive DNA sequences may have played an important role in the evolutionary emergence and exclusion of polyQ expansion proteins in different organisms.

Homogenous Population Genetic Structure of the Non-Native Raccoon Dog (Nyctereutes procyonoides) in Europe as a Result of Rapid Population Expansion

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Drygala, Frank; Korablev, Nikolay; Ansorge, Hermann; Fickel, Joerns; Isomursu, Marja; Elmeros, Morten; Kowalczyk, Rafał; Baltrunaite, Laima; Balciauskas, Linas; Saarma, Urmas; Schulze, Christoph; Borkenhagen, Peter; Frantz, Alain C.

2016-01-01

The extent of gene flow during the range expansion of non-native species influences the amount of genetic diversity retained in expanding populations. Here, we analyse the population genetic structure of the raccoon dog (Nyctereutes procyonoides) in north-eastern and central Europe. This invasive species is of management concern because it is highly susceptible to fox rabies and an important secondary host of the virus. We hypothesized that the large number of introduced animals and the species’ dispersal capabilities led to high population connectivity and maintenance of genetic diversity throughout the invaded range. We genotyped 332 tissue samples from seven European countries using 16 microsatellite loci. Different algorithms identified three genetic clusters corresponding to Finland, Denmark and a large ‘central’ population that reached from introduction areas in western Russia to northern Germany. Cluster assignments provided evidence of long-distance dispersal. The results of an Approximate Bayesian Computation analysis supported a scenario of equal effective population sizes among different pre-defined populations in the large central cluster. Our results are in line with strong gene flow and secondary admixture between neighbouring demes leading to reduced genetic structuring, probably a result of its fairly rapid population expansion after introduction. The results presented here are remarkable in the sense that we identified a homogenous genetic cluster inhabiting an area stretching over more than 1500km. They are also relevant for disease management, as in the event of a significant rabies outbreak, there is a great risk of a rapid virus spread among raccoon dog populations. PMID:27064784

Genetic and immunohistochemical analysis of HSPA5 in mouse and human retinas.

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Chintalapudi, Sumana R; Wang, XiaoFei; Li, Huiling; Lau, Yin H Chan; Williams, Robert W; Jablonski, Monica M

2016-01-01

Photoreceptor degenerative diseases are among the leading causes of vision loss. Although the causative genetic mutations are often known, mechanisms leading to photoreceptor degeneration remain poorly defined. We have previously demonstrated that the photoreceptor membrane-associated protein XAP-1 antigen is a product of the HSPA5 gene. In this study, we used systems genetic methods, statistical modeling, and immunostaining to identify and analyze candidate genes that modulate Hspa5 expression in the retina. Quantitative trait locus (QTL) mapping was used to map the genomic region that regulates Hspa5 in the cross between C57BL/6J X DBA/2J mice (BXD) genetic reference panel. The stepwise refinement of candidate genes was based on expression QTL mapping, gene expression correlation analyses (direct and partial), and analysis of regional sequence variants. The subcellular localization of candidate proteins and HSPA5 in mouse and human retinas was evaluated by immunohistochemistry. Differences in the localization of extracellular HSPA5 were assessed between healthy human donor and atrophic age-related macular degeneration (AMD) donor eyes. In the eyes of healthy mice, extracellular HSPA5 was confined to the area around the cone photoreceptor outer segments. Mapping variation in Hspa5 mRNA expression levels in the retina revealed a statistically significant trans -acting expression QTL (eQTL) on Chromosome 2 (Chr 2) and a suggestive locus on Chr 15. Sulf2 on Chr 2 was the strongest candidate gene based on partial correlation analysis, Pearson correlation with Hspa5 , expression levels in the retina, a missense variant in exon 14, and its reported function in the extracellular matrix and interphotoreceptor matrix. SULF2 is localized to the rod and cone photoreceptors in both human and mouse retinas. In human retinas with no pathology, extracellular HSPA5 was localized around many cones within the macular area. In contrast, fewer HSPA5-immunopositive cones were

Strain screen and haplotype association mapping of wheel running in inbred mouse strains.

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Lightfoot, J Timothy; Leamy, Larry; Pomp, Daniel; Turner, Michael J; Fodor, Anthony A; Knab, Amy; Bowen, Robert S; Ferguson, David; Moore-Harrison, Trudy; Hamilton, Alicia

2010-09-01

Previous genetic association studies of physical activity, in both animal and human models, have been limited in number of subjects and genetically homozygous strains used as well as number of genomic markers available for analysis. Expansion of the available mouse physical activity strain screens and the recently published dense single-nucleotide polymorphism (SNP) map of the mouse genome (approximately 8.3 million SNPs) and associated statistical methods allowed us to construct a more generalizable map of the quantitative trait loci (QTL) associated with physical activity. Specifically, we measured wheel running activity in male and female mice (average age 9 wk) in 41 inbred strains and used activity data from 38 of these strains in a haplotype association mapping analysis to determine QTL associated with activity. As seen previously, there was a large range of activity patterns among the strains, with the highest and lowest strains differing significantly in daily distance run (27.4-fold), duration of activity (23.6-fold), and speed (2.9-fold). On a daily basis, female mice ran further (24%), longer (13%), and faster (11%). Twelve QTL were identified, with three (on Chr. 12, 18, and 19) in both male and female mice, five specific to males, and four specific to females. Eight of the 12 QTL, including the 3 general QTL found for both sexes, fell into intergenic areas. The results of this study further support the findings of a moderate to high heritability of physical activity and add general genomic areas applicable to a large number of mouse strains that can be further mined for candidate genes associated with regulation of physical activity. Additionally, results suggest that potential genetic mechanisms arising from traditional noncoding regions of the genome may be involved in regulation of physical activity.

Genetic Ablation of Type III Adenylyl Cyclase Exerts Region-Specific Effects on Cilia Architecture in the Mouse Nose.

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Rosemary C Challis

Full Text Available We recently reported that olfactory sensory neurons in the dorsal zone of the mouse olfactory epithelium exhibit drastic location-dependent differences in cilia length. Furthermore, genetic ablation of type III adenylyl cyclase (ACIII, a key olfactory signaling protein and ubiquitous marker for primary cilia, disrupts the cilia length pattern and results in considerably shorter cilia, independent of odor-induced activity. Given the significant impact of ACIII on cilia length in the dorsal zone, we sought to further investigate the relationship between cilia length and ACIII level in various regions throughout the mouse olfactory epithelium. We employed whole-mount immunohistochemical staining to examine olfactory cilia morphology in phosphodiesterase (PDE 1C-/-;PDE4A-/- (simplified as PDEs-/- hereafter and ACIII-/- mice in which ACIII levels are reduced and ablated, respectively. As expected, PDEs-/- animals exhibit dramatically shorter cilia in the dorsal zone (i.e., where the cilia pattern is found, similar to our previous observation in ACIII-/- mice. Remarkably, in a region not included in our previous study, ACIII-/- animals (but not PDEs-/- mice have dramatically elongated, comet-shaped cilia, as opposed to characteristic star-shaped olfactory cilia. Here, we reveal that genetic ablation of ACIII has drastic, location-dependent effects on cilia architecture in the mouse nose. These results add a new dimension to our current understanding of olfactory cilia structure and regional organization of the olfactory epithelium. Together, these findings have significant implications for both cilia and sensory biology.

Towards a defined ECM and small molecule based monolayer culture system for the expansion of mouse and human intestinal stem cells.

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Tong, Zhixiang; Martyn, Keir; Yang, Andy; Yin, Xiaolei; Mead, Benjamin E; Joshi, Nitin; Sherman, Nicholas E; Langer, Robert S; Karp, Jeffrey M

2018-02-01

Current ISC culture systems face significant challenges such as animal-derived or undefined matrix compositions, batch-to-batch variability (e.g. Matrigel-based organoid culture), and complexity of assaying cell aggregates such as organoids which renders the research and clinical translation of ISCs challenging. Here, through screening for suitable ECM components, we report a defined, collagen based monolayer culture system that supports the growth of mouse and human intestinal epithelial cells (IECs) enriched for an Lgr5 + population comparable or higher to the levels found in a standard Matrigel-based organoid culture. The system, referred to as the Bolstering Lgr5 Transformational (BLT) Sandwich culture, comprises a collagen IV-coated porous substrate and a collagen I gel overlay which sandwich an IEC monolayer in between. The distinct collagen cues synergistically regulate IEC attachment, proliferation, and Lgr5 expression through maximizing the engagement of distinct cell surface adhesion receptors (i.e. integrin α2β1, integrin β4) and cell polarity. Further, we apply our BLT Sandwich system to identify that the addition of a bone morphogenetic protein (BMP) receptor inhibitor (LDN-193189) improves the expansion of Lgr5-GFP + cells from mouse small intestinal crypts by nearly 2.5-fold. Notably, the BLT Sandwich culture is capable of expanding human-derived IECs with higher LGR5 mRNA levels than conventional Matrigel culture, providing superior expansion of human LGR5 + ISCs. Considering the key roles Lgr5 + ISCs play in intestinal epithelial homeostasis and regeneration, we envision that our BLT Sandwich culture system holds great potential for understanding and manipulating ISC biology in vitro (e.g. for modeling ISC-mediated gut diseases) or for expanding a large number of ISCs for clinical utility (e.g. for stem cell therapy). Copyright © 2017 Elsevier Ltd. All rights reserved.

Glutamate Oxaloacetate Transaminase (Got) Genetics in the Mouse: Polymorphism of Got-1

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Chapman, Verne M.; Ruddle, Frank H.

1972-01-01

We have examined a polymorphism for the soluble glutamate oxaloacetate (GOT-1) isozyme system which was found in the Asian mouse Mus castaneus. Variants of GOT-1 segregate as though they are controlled by codominant alleles for a single autosomal locus which we have designated Got-1. No close linkage of genes for soluble and mitochondrial forms of the enzyme, GOT-1 and GOT-2 respectively, was observed. Furthermore, no close linkage of Got-1 and the loci c, Gpi-1, Mod-2, Mod-1, Ld-1, Gpd-1, Pgm-1 or Gpo-1 was observed. Our results demonstrate the utility of sampling Mus from diverse populations to extend the repertoire of polymorphic loci and the genetic linkage map. PMID:17248564

Growth promotion of genetically modified hematopoietic progenitors using an antibody/c-Mpl chimera.

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Kawahara, Masahiro; Chen, Jianhong; Sogo, Takahiro; Teng, Jinying; Otsu, Makoto; Onodera, Masafumi; Nakauchi, Hiromitsu; Ueda, Hiroshi; Nagamune, Teruyuki

2011-09-01

Thrombopoietin is a potent cytokine that exerts proliferation of hematopoietic stem cells (HSCs) through its cognate receptor, c-Mpl. Therefore, mimicry of c-Mpl signaling by a receptor recognizing an artificial ligand would be attractive to attain specific expansion of genetically modified HSCs. Here we propose a system enabling selective expansion of genetically modified cells using an antibody/receptor chimera that can be activated by a specific antigen. We constructed an antibody/c-Mpl chimera, in which single-chain Fv (ScFv) of an anti-fluorescein antibody was tethered to the extracellular D2 domain of the erythropoietin receptor and transmembrane/cytoplasmic domains of c-Mpl. When the chimera was expressed in interleukin (IL)-3-dependent pro-B cell line Ba/F3, genetically modified cells were selectively expanded in the presence of fluorescein-conjugated BSA (BSA-FL) as a specific antigen. Furthermore, highly purified mouse HSCs transduced with the retrovirus carrying antibody/c-Mpl chimera gene proliferated in vitro in response to BSA-FL, and the cells retained in vivo long-term repopulating abilities. These results demonstrate that the antibody/c-Mpl chimera is capable of signal transduction that mimics wild-type c-Mpl signaling. Copyright © 2011 Elsevier Ltd. All rights reserved.

Generation of Mouse Haploid Somatic Cells by Small Molecules for Genome-wide Genetic Screening

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Zheng-Quan He

2017-08-01

Full Text Available The recent success of derivation of mammalian haploid embryonic stem cells (haESCs has provided a powerful tool for large-scale functional analysis of the mammalian genome. However, haESCs rapidly become diploidized after differentiation, posing challenges for genetic analysis. Here, we show that the spontaneous diploidization of haESCs happens in metaphase due to mitotic slippage. Diploidization can be suppressed by small-molecule-mediated inhibition of CDK1 and ROCK. Through ROCK inhibition, we can generate haploid somatic cells of all three germ layers from haESCs, including terminally differentiated neurons. Using piggyBac transposon-based insertional mutagenesis, we generated a haploid neural cell library harboring genome-wide mutations for genetic screening. As a proof of concept, we screened for Mn2+-mediated toxicity and identified the Park2 gene. Our findings expand the applications of mouse haploid cell technology to somatic cell types and may also shed light on the mechanisms of ploidy maintenance.

Genetic and immunohistochemical analysis of HSPA5 in mouse and human retinas

Science.gov (United States)

Chintalapudi, Sumana R.; Wang, XiaoFei; Li, Huiling; Lau, Yin H. Chan; Williams, Robert W.; Jablonski, Monica M.

2016-01-01

Purpose Photoreceptor degenerative diseases are among the leading causes of vision loss. Although the causative genetic mutations are often known, mechanisms leading to photoreceptor degeneration remain poorly defined. We have previously demonstrated that the photoreceptor membrane-associated protein XAP-1 antigen is a product of the HSPA5 gene. In this study, we used systems genetic methods, statistical modeling, and immunostaining to identify and analyze candidate genes that modulate Hspa5 expression in the retina. Methods Quantitative trait locus (QTL) mapping was used to map the genomic region that regulates Hspa5 in the cross between C57BL/6J X DBA/2J mice (BXD) genetic reference panel. The stepwise refinement of candidate genes was based on expression QTL mapping, gene expression correlation analyses (direct and partial), and analysis of regional sequence variants. The subcellular localization of candidate proteins and HSPA5 in mouse and human retinas was evaluated by immunohistochemistry. Differences in the localization of extracellular HSPA5 were assessed between healthy human donor and atrophic age-related macular degeneration (AMD) donor eyes. Results In the eyes of healthy mice, extracellular HSPA5 was confined to the area around the cone photoreceptor outer segments. Mapping variation in Hspa5 mRNA expression levels in the retina revealed a statistically significant trans-acting expression QTL (eQTL) on Chromosome 2 (Chr 2) and a suggestive locus on Chr 15. Sulf2 on Chr 2 was the strongest candidate gene based on partial correlation analysis, Pearson correlation with Hspa5, expression levels in the retina, a missense variant in exon 14, and its reported function in the extracellular matrix and interphotoreceptor matrix. SULF2 is localized to the rod and cone photoreceptors in both human and mouse retinas. In human retinas with no pathology, extracellular HSPA5 was localized around many cones within the macular area. In contrast, fewer HSPA5

The Pleiotropic Phenotype of Apc Mutations in the Mouse: Allele Specificity and Effects of the Genetic Background

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Halberg, Richard B.; Chen, Xiaodi; Amos-Landgraf, James M.; White, Alanna; Rasmussen, Kristin; Clipson, Linda; Pasch, Cheri; Sullivan, Ruth; Pitot, Henry C.; Dove, William F.

2008-01-01

Familial adenomatous polyposis (FAP) is a human cancer syndrome characterized by the development of hundreds to thousands of colonic polyps and extracolonic lesions including desmoid fibromas, osteomas, epidermoid cysts, and congenital hypertrophy of the pigmented retinal epithelium. Afflicted individuals are heterozygous for mutations in the APC gene. Detailed investigations of mice heterozygous for mutations in the ortholog Apc have shown that other genetic factors strongly influence the phenotype. Here we report qualitative and quantitative modifications of the phenotype of Apc mutants as a function of three genetic variables: Apc allele, p53 allele, and genetic background. We have found major differences between the Apc alleles Min and 1638N in multiplicity and regionality of intestinal tumors, as well as in incidence of extracolonic lesions. By contrast, Min mice homozygous for either of two different knockout alleles of p53 show similar phenotypic effects. These studies illustrate the classic principle that functional genetics is enriched by assessing penetrance and expressivity with allelic series. The mouse permits study of an allelic gene series on multiple genetic backgrounds, thereby leading to a better understanding of gene action in a range of biological processes. PMID:18723878

Induction, by thymidylate stress, of genetic recombination as evidenced by deletion of a transferred genetic marker in mouse FM3A cells

International Nuclear Information System (INIS)

Ayusawa, D.; Koyama, H.; Shimizu, K.; Kaneda, S.; Takeishi, K.; Seno, T.

1986-01-01

Studies were made on the genetic consequences of methotrexate-directed thymidylate stress, focusing attention on a human thymidylate synthase gene that was introduced as a heterologous genetic marker into mouse thymidylate synthase-negative mutant cells. Thymidylate stress induced thymidylate synthase-negative segregants with concomitant loss of human thymidylate synthase activity with frequencies 1 to 2 orders of magnitude higher than the uninduced spontaneous level in some but not all transformant lines. Induction of the segregants was suppressed almost completely by cycloheximide and partially by caffeine. Thymidylate stress did not, however, induce mutations, as determined by measuring resistance to ouabain or 6-thioguanine. Thymidylate synthase-negative segregants were also induced by other means such as bromodeoxyuridine treatment and X-ray irradiation. In each of the synthase-negative segregants induced by thymidylate stress, a DNA segment including almost the whole coding region of the transferred human thymidylate synthase gene was deleted in a very specific manner, as shown by Southern blot analysis with a human Alu sequence and a human thymidylate synthase cDNA as probes. In the segregants that emerged spontaneously at low frequency, the entire transferred genetic marker was lost. In the segregants induced by X-ray irradiation, structural alterations of the genetic marker were random. These results show that thymidylate stress is a physiological factor that provokes the instability of this exogenously incorporated DNA in some specific manner and produces nonrandom genetic recombination in mammalian cells

Landscape resistance and habitat combine to provide an optimal model of genetic structure and connectivity at the range margin of a small mammal.

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Marrotte, R R; Gonzalez, A; Millien, V

2014-08-01

We evaluated the effect of habitat and landscape characteristics on the population genetic structure of the white-footed mouse. We develop a new approach that uses numerical optimization to define a model that combines site differences and landscape resistance to explain the genetic differentiation between mouse populations inhabiting forest patches in southern Québec. We used ecological distance computed from resistance surfaces with Circuitscape to infer the effect of the landscape matrix on gene flow. We calculated site differences using a site index of habitat characteristics. A model that combined site differences and resistance distances explained a high proportion of the variance in genetic differentiation and outperformed models that used geographical distance alone. Urban and agriculture-related land uses were, respectively, the most and the least resistant landscape features influencing gene flow. Our method detected the effect of rivers and highways as highly resistant linear barriers. The density of grass and shrubs on the ground best explained the variation in the site index of habitat characteristics. Our model indicates that movement of white-footed mouse in this region is constrained along routes of low resistance. Our approach can generate models that may improve predictions of future northward range expansion of this small mammal. © 2014 John Wiley & Sons Ltd.

Range expansion of heterogeneous populations.

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Reiter, Matthias; Rulands, Steffen; Frey, Erwin

2014-04-11

Risk spreading in bacterial populations is generally regarded as a strategy to maximize survival. Here, we study its role during range expansion of a genetically diverse population where growth and motility are two alternative traits. We find that during the initial expansion phase fast-growing cells do have a selective advantage. By contrast, asymptotically, generalists balancing motility and reproduction are evolutionarily most successful. These findings are rationalized by a set of coupled Fisher equations complemented by stochastic simulations.

Transplantation of mouse HSCs genetically modified to express a CD4-restricted TCR results in long-term immunity that destroys tumors and initiates spontaneous autoimmunity.

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Ha, Sung P; Klemen, Nicholas D; Kinnebrew, Garrett H; Brandmaier, Andrew G; Marsh, Jon; Hangoc, Giao; Palmer, Douglas C; Restifo, Nicholas P; Cornetta, Kenneth; Broxmeyer, Hal E; Touloukian, Christopher E

2010-12-01

The development of effective cancer immunotherapies has been consistently hampered by several factors, including an inability to instigate long-term effective functional antitumor immunity. This is particularly true for immunotherapies that focus on the adoptive transfer of activated or genetically modified mature CD8+ T cells. In this study, we sought to alter and enhance long-term host immunity by genetically modifying, then transplanting, mouse HSCs. We first cloned a previously identified tumor-reactive HLA-DR4-restricted CD4+ TCR specific for the melanocyte differentiation antigen tyrosinase-related protein 1 (Tyrp1), then constructed both a high-expression lentivirus vector and a TCR-transgenic mouse expressing the genes encoding this TCR. Using these tools, we demonstrated that both mouse and human HSCs established durable, high-efficiency TCR gene transfer following long-term transplantation into lethally irradiated mice transgenic for HLA-DR4. Recipients of genetically modified mouse HSCs developed spontaneous autoimmune vitiligo that was associated with the presence of a Th1-polarized memory effector CD4+ T cell population that expressed the Tyrp1-specific TCR. Most importantly, large numbers of CD4+ T cells expressing the Tyrp1-specific TCR were detected in secondary HLA-DR4-transgenic transplant recipients, and these mice were able to destroy subcutaneously administered melanoma cells without the aid of vaccination, immune modulation, or cytokine administration. These results demonstrate the creation of what we believe to be a novel translational model of durable lentiviral gene transfer that results in long-term effective immunity.

Inherited effects from mouse immature oocytes following low-dose irradiation

International Nuclear Information System (INIS)

Straume, T.; Khan, R.; Raabe, O.G.; Walsh, K.J.; Wiley, L.M.

1992-07-01

Immature oocytes represent the genetic pool in female mice as well as in women and therefore are principal cells of concern for genetic studies. Previous studies have demonstrated that genetic effects in female mice can be masked by the hypersensitive plasma membrane lethality target of immature oocytes. Studies have also shown that genetic effects can be detected when the plasma mambrane is sufficiently spared. Here, new data obtained using the mouse preimplantation embryo chimera assay are presented and discussed in light of previous findings for irradiated mouse oocytes

Effect of Co-segregating Markers on High-Density Genetic Maps and Prediction of Map Expansion Using Machine Learning Algorithms.

Science.gov (United States)

N'Diaye, Amidou; Haile, Jemanesh K; Fowler, D Brian; Ammar, Karim; Pozniak, Curtis J

2017-01-01

Advances in sequencing and genotyping methods have enable cost-effective production of high throughput single nucleotide polymorphism (SNP) markers, making them the choice for linkage mapping. As a result, many laboratories have developed high-throughput SNP assays and built high-density genetic maps. However, the number of markers may, by orders of magnitude, exceed the resolution of recombination for a given population size so that only a minority of markers can accurately be ordered. Another issue attached to the so-called 'large p, small n' problem is that high-density genetic maps inevitably result in many markers clustering at the same position (co-segregating markers). While there are a number of related papers, none have addressed the impact of co-segregating markers on genetic maps. In the present study, we investigated the effects of co-segregating markers on high-density genetic map length and marker order using empirical data from two populations of wheat, Mohawk × Cocorit (durum wheat) and Norstar × Cappelle Desprez (bread wheat). The maps of both populations consisted of 85% co-segregating markers. Our study clearly showed that excess of co-segregating markers can lead to map expansion, but has little effect on markers order. To estimate the inflation factor (IF), we generated a total of 24,473 linkage maps (8,203 maps for Mohawk × Cocorit and 16,270 maps for Norstar × Cappelle Desprez). Using seven machine learning algorithms, we were able to predict with an accuracy of 0.7 the map expansion due to the proportion of co-segregating markers. For example in Mohawk × Cocorit, with 10 and 80% co-segregating markers the length of the map inflated by 4.5 and 16.6%, respectively. Similarly, the map of Norstar × Cappelle Desprez expanded by 3.8 and 11.7% with 10 and 80% co-segregating markers. With the increasing number of markers on SNP-chips, the proportion of co-segregating markers in high-density maps will continue to increase making map expansion

Effect of Co-segregating Markers on High-Density Genetic Maps and Prediction of Map Expansion Using Machine Learning Algorithms

Directory of Open Access Journals (Sweden)

Amidou N’Diaye

2017-08-01

Full Text Available Advances in sequencing and genotyping methods have enable cost-effective production of high throughput single nucleotide polymorphism (SNP markers, making them the choice for linkage mapping. As a result, many laboratories have developed high-throughput SNP assays and built high-density genetic maps. However, the number of markers may, by orders of magnitude, exceed the resolution of recombination for a given population size so that only a minority of markers can accurately be ordered. Another issue attached to the so-called ‘large p, small n’ problem is that high-density genetic maps inevitably result in many markers clustering at the same position (co-segregating markers. While there are a number of related papers, none have addressed the impact of co-segregating markers on genetic maps. In the present study, we investigated the effects of co-segregating markers on high-density genetic map length and marker order using empirical data from two populations of wheat, Mohawk × Cocorit (durum wheat and Norstar × Cappelle Desprez (bread wheat. The maps of both populations consisted of 85% co-segregating markers. Our study clearly showed that excess of co-segregating markers can lead to map expansion, but has little effect on markers order. To estimate the inflation factor (IF, we generated a total of 24,473 linkage maps (8,203 maps for Mohawk × Cocorit and 16,270 maps for Norstar × Cappelle Desprez. Using seven machine learning algorithms, we were able to predict with an accuracy of 0.7 the map expansion due to the proportion of co-segregating markers. For example in Mohawk × Cocorit, with 10 and 80% co-segregating markers the length of the map inflated by 4.5 and 16.6%, respectively. Similarly, the map of Norstar × Cappelle Desprez expanded by 3.8 and 11.7% with 10 and 80% co-segregating markers. With the increasing number of markers on SNP-chips, the proportion of co-segregating markers in high-density maps will continue to increase

On the edge of Bantu expansions: mtDNA, Y chromosome and lactase persistence genetic variation in southwestern Angola

Directory of Open Access Journals (Sweden)

Beleza Sandra

2009-04-01

Full Text Available Abstract Background Current information about the expansion of Bantu-speaking peoples is hampered by the scarcity of genetic data from well identified populations from southern Africa. Here, we fill an important gap in the analysis of the western edge of the Bantu migrations by studying for the first time the patterns of Y-chromosome, mtDNA and lactase persistence genetic variation in four representative groups living around the Namib Desert in southwestern Angola (Ovimbundu, Ganguela, Nyaneka-Nkumbi and Kuvale. We assessed the differentiation between these populations and their levels of admixture with Khoe-San groups, and examined their relationship with other sub-Saharan populations. We further combined our dataset with previously published data on Y-chromosome and mtDNA variation to explore a general isolation with migration model and infer the demographic parameters underlying current genetic diversity in Bantu populations. Results Correspondence analysis, lineage sharing patterns and admixture estimates indicate that the gene pool from southwestern Angola is predominantly derived from West-Central Africa. The pastoralist Herero-speaking Kuvale people were additionally characterized by relatively high frequencies of Y-chromosome (12% and mtDNA (22% Khoe-San lineages, as well as by the presence of the -14010C lactase persistence mutation (6%, which likely originated in non-Bantu pastoralists from East Africa. Inferred demographic parameters show that both male and female populations underwent significant size growth after the split between the western and eastern branches of Bantu expansions occurring 4000 years ago. However, males had lower population sizes and migration rates than females throughout the Bantu dispersals. Conclusion Genetic variation in southwestern Angola essentially results from the encounter of an offshoot of West-Central Africa with autochthonous Khoisan-speaking peoples from the south. Interactions between the Bantus

Mouse Genome Informatics (MGI)

Data.gov (United States)

U.S. Department of Health & Human Services — MGI is the international database resource for the laboratory mouse, providing integrated genetic, genomic, and biological data to facilitate the study of human...

Identification of the UBP1 locus as a critical blood pressure determinant using a combination of mouse and human genetics

DEFF Research Database (Denmark)

Koutnikova, Hana; Laakso, Markku; Lu, Lu

2009-01-01

complementarities of mouse and human genetic approaches, identifies the UBP1 locus as a critical blood pressure determinant. UBP1 plays a role in cholesterol and steroid metabolism via the transcriptional activation of CYP11A, the rate-limiting enzyme in pregnenolone and aldosterone biosynthesis. We suggest......Hypertension is a major health problem of largely unknown genetic origins. To identify new genes responsible for hypertension, genetic analysis of recombinant inbred strains of mice followed by human association studies might prove powerful and was exploited in our current study. Using a set of 27...... recombinant BXD strains of mice we identified a quantitative trait locus (QTL) for blood pressure (BP) on distal chromosome 9. The association analysis of markers encompassing the syntenic region on human chromosome 3 gave in an additive genetic model the strongest association for rs17030583 C/T and rs2291897...

Strains and Stressors: An Analysis of Touchscreen Learning in Genetically Diverse Mouse Strains

Science.gov (United States)

Graybeal, Carolyn; Bachu, Munisa; Mozhui, Khyobeni; Saksida, Lisa M.; Bussey, Timothy J.; Sagalyn, Erica; Williams, Robert W.; Holmes, Andrew

2014-01-01

Touchscreen-based systems are growing in popularity as a tractable, translational approach for studying learning and cognition in rodents. However, while mouse strains are well known to differ in learning across various settings, performance variation between strains in touchscreen learning has not been well described. The selection of appropriate genetic strains and backgrounds is critical to the design of touchscreen-based studies and provides a basis for elucidating genetic factors moderating behavior. Here we provide a quantitative foundation for visual discrimination and reversal learning using touchscreen assays across a total of 35 genotypes. We found significant differences in operant performance and learning, including faster reversal learning in DBA/2J compared to C57BL/6J mice. We then assessed DBA/2J and C57BL/6J for differential sensitivity to an environmental insult by testing for alterations in reversal learning following exposure to repeated swim stress. Stress facilitated reversal learning (selectively during the late stage of reversal) in C57BL/6J, but did not affect learning in DBA/2J. To dissect genetic factors underlying these differences, we phenotyped a family of 27 BXD strains generated by crossing C57BL/6J and DBA/2J. There was marked variation in discrimination, reversal and extinction learning across the BXD strains, suggesting this task may be useful for identifying underlying genetic differences. Moreover, different measures of touchscreen learning were only modestly correlated in the BXD strains, indicating that these processes are comparatively independent at both genetic and phenotypic levels. Finally, we examined the behavioral structure of learning via principal component analysis of the current data, plus an archival dataset, totaling 765 mice. This revealed 5 independent factors suggestive of “reversal learning,” “motivation-related late reversal learning,” “discrimination learning,” “speed to respond,” and �

The immune receptor Trem1 cooperates with diminished DNA damage response to induce preleukemic stem cell expansion.

Science.gov (United States)

Du, W; Amarachintha, S; Wilson, A; Pang, Q

2017-02-01

Fanconi anemia (FA) is an inherited bone marrow failure syndrome with extremely high risk of leukemic transformation. Here we investigate the relationship between DNA damage response (DDR) and leukemogenesis using the Fanca knockout mouse model. We found that chronic exposure of the Fanca -/- hematopoietic stem cells to DNA crosslinking agent mitomycin C in vivo leads to diminished DDR, and the emergence/expansion of pre-leukemia stem cells (pre-LSCs). Surprisingly, although genetic correction of Fanca deficiency in the pre-LSCs restores DDR and reduces genomic instability, but fails to prevent pre-LSC expansion or delay leukemia development in irradiated recipients. Furthermore, we identified transcription program underlying dysregulated DDR and cell migration, myeloid proliferation, and immune response in the Fanca -/- pre-LSCs. Forced expression of the downregulated DNA repair genes, Rad51c or Trp53i13, in the Fanca -/- pre-LSCs partially rescues DDR but has no effect on leukemia, whereas shRNA knockdown of the upregulated immune receptor genes Trem1 or Pilrb improves leukemia-related survival, but not DDR or genomic instability. Furthermore, Trem1 cooperates with diminished DDR in vivo to promote Fanca -/- pre-LSC expansion and leukemia development. Our study implicates diminishing DDR as a root cause of FA leukemogenesis, which subsequently collaborates with other signaling pathways for leukemogenic transformation.

Identification of genes important for cutaneous function revealed by a large scale reverse genetic screen in the mouse.

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Tia DiTommaso

2014-10-01

Full Text Available The skin is a highly regenerative organ which plays critical roles in protecting the body and sensing its environment. Consequently, morbidity and mortality associated with skin defects represent a significant health issue. To identify genes important in skin development and homeostasis, we have applied a high throughput, multi-parameter phenotype screen to the conditional targeted mutant mice generated by the Wellcome Trust Sanger Institute's Mouse Genetics Project (Sanger-MGP. A total of 562 different mouse lines were subjected to a variety of tests assessing cutaneous expression, macroscopic clinical disease, histological change, hair follicle cycling, and aberrant marker expression. Cutaneous lesions were associated with mutations in 23 different genes. Many of these were not previously associated with skin disease in the organ (Mysm1, Vangl1, Trpc4ap, Nom1, Sparc, Farp2, and Prkab1, while others were ascribed new cutaneous functions on the basis of the screening approach (Krt76, Lrig1, Myo5a, Nsun2, and Nf1. The integration of these skin specific screening protocols into the Sanger-MGP primary phenotyping pipelines marks the largest reported reverse genetic screen undertaken in any organ and defines approaches to maximise the productivity of future projects of this nature, while flagging genes for further characterisation.

10. international mouse genome conference

Energy Technology Data Exchange (ETDEWEB)

Meisler, M.H.

1996-12-31

Ten years after hosting the First International Mammalian Genome Conference in Paris in 1986, Dr. Jean-Louis Guenet presided over the Tenth Conference at the Pasteur Institute, October 7--10, 1996. The 1986 conference was a satellite to the Human Gene Mapping Workshop and had approximately 50 attendees. The 1996 meeting was attended by 300 scientists from around the world. In the interim, the number of mapped loci in the mouse increased from 1,000 to over 20,000. This report contains a listing of the program and its participants, and two articles that review the meeting and the role of the laboratory mouse in the Human Genome project. More than 200 papers were presented at the conference covering the following topics: International mouse chromosome committee meetings; Mutant generation and identification; Physical and genetic maps; New technology and resources; Chromatin structure and gene regulation; Rate and hamster genetic maps; Informatics and databases; and Quantitative trait analysis.

Evidence for coral range expansion accompanied by reduced diversity of Symbiodinium genotypes

KAUST Repository

Grupstra, Carsten G. B.

2017-05-15

Zooxanthellate corals are threatened by climate change but may be able to escape increasing temperatures by colonizing higher latitudes. To determine the effect of host range expansion on symbiont genetic diversity, we examined genetic variation among populations of Symbiodinium psygmophilum associated with Oculina patagonica, a range-expanding coral that acquires its symbionts through horizontal transmission. We optimized five microsatellite primer pairs for S. psygmophilum and tested them on Oculina spp. samples from the western North Atlantic and the Mediterranean. We then used them to compare symbiont genotype diversity between an Iberian core and an expansion front population of O. patagonica. Only one multilocus S. psygmophilum genotype was identified at the expansion front, and it was shared with the core population, which harbored seven multilocus genotypes. This pattern suggests that O. patagonica range expansion is accompanied by reduced symbiont genetic diversity, possibly due to limited dispersal of symbionts or local selection.

Mammalian developmental genetics in the twentieth century.

Science.gov (United States)

Artzt, Karen

2012-12-01

This Perspectives is a review of the breathtaking history of mammalian genetics in the past century and, in particular, of the ways in which genetic thinking has illuminated aspects of mouse development. To illustrate the power of that thinking, selected hypothesis-driven experiments and technical advances are discussed. Also included in this account are the beginnings of mouse genetics at the Bussey Institute, Columbia University, and The Jackson Laboratory and a retrospective discussion of one of the classic problems in developmental genetics, the T/t complex and its genetic enigmas.

Histochemical studies on genetical control of hormonal enzyme inducibility in the mouse. I. Non-specific esterase activity and regional histology of the epididymis

DEFF Research Database (Denmark)

Blecher, S R; Kirkeby, S

1978-01-01

As a base line for future cell genetical studies the authors record the distribution of non-specific esterase reaction in the various histologically distinguishable cell types of the mouse epididymis. The findings are correlated with previous descriptions of the lobar structure of the organ...

Utrophin Compensates dystrophin Loss during Mouse Spermatogenesis

OpenAIRE

Chen, Hung-Chih; Chin, Yu-Feng; Lundy, David J.; Liang, Chung-Tiang; Chi, Ya-Hui; Kuo, Paolin; Hsieh, Patrick C. H.

2017-01-01

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder resulting from mutations in the dystrophin gene. The mdx/utrn ?/? mouse, lacking in both dystrophin and its autosomal homologue utrophin, is commonly used to model the clinical symptoms of DMD. Interestingly, these mice are infertile but the mechanisms underlying this phenomenon remain unclear. Using dystrophin deficient mdx mouse and utrophin haplodeficient mdx/utrn +/? mouse models, we demonstrate the contribution of Dp427 (f...

The Genetics of PTPN1 and Obesity: Insights from Mouse Models of Tissue-Specific PTP1B Deficiency

Directory of Open Access Journals (Sweden)

Ryan C. Tsou

2012-01-01

Full Text Available The protein tyrosine phosphatase PTP1B is a negative regulator of both insulin and leptin signaling and is involved in the control of glucose homeostasis and energy expenditure. Due to its prominent role in regulating metabolism, PTP1B is a promising therapeutic target for the treatment of human obesity and type 2 diabetes. The PTP1B protein is encoded by the PTPN1 gene on human chromosome 20q13, a region that shows linkage with insulin resistance, type 2 diabetes, and obesity in human populations. In this paper, we summarize the genetics of the PTPN1 locus and associations with metabolic disease. In addition, we discuss the tissue-specific functions of PTP1B as gleaned from genetic mouse models.

Genetic enrichment of cardiomyocytes derived from mouse ...

African Journals Online (AJOL)

Jane

2011-06-22

Jun 22, 2011 ... Pluripotent embryonic stem cells (ESC) have the ability to differentiate into a ... We describe a simple method to generate relatively pure cardiomyocytes from mouse ... In this study, we described the generation of transgenic.

Two disjunct Pleistocene populations and anisotropic postglacial expansion shaped the current genetic structure of the relict plant Amborella trichopoda.

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Rémi Tournebize

Full Text Available Past climate fluctuations shaped the population dynamics of organisms in space and time, and have impacted their present intra-specific genetic structure. Demo-genetic modelling allows inferring the way past demographic and migration dynamics have determined this structure. Amborella trichopoda is an emblematic relict plant endemic to New Caledonia, widely distributed in the understory of non-ultramafic rainforests. We assessed the influence of the last glacial climates on the demographic history and the paleo-distribution of 12 Amborella populations covering the whole current distribution. We performed coalescent genetic modelling of these dynamics, based on both whole-genome resequencing and microsatellite genotyping data. We found that the two main genetic groups of Amborella were shaped by the divergence of two ancestral populations during the last glacial maximum. From 12,800 years BP, the South ancestral population has expanded 6.3-fold while the size of the North population has remained stable. Recent asymmetric gene flow between the groups further contributed to the phylogeographical pattern. Spatially explicit coalescent modelling allowed us to estimate the location of ancestral populations with good accuracy (< 22 km and provided indications regarding the mid-elevation pathways that facilitated post-glacial expansion.

Rational Design of Mouse Models for Cancer Research

NARCIS (Netherlands)

Landgraf, M.; McGovern, J.A.; Friedl, P.; Hutmacher, D.W.

2018-01-01

The laboratory mouse is widely considered as a valid and affordable model organism to study human disease. Attempts to improve the relevance of murine models for the investigation of human pathologies led to the development of various genetically engineered, xenograft and humanized mouse models.

Stereotactic Body Radiation Therapy Delivery in a Genetically Engineered Mouse Model of Lung Cancer

Energy Technology Data Exchange (ETDEWEB)

Du, Shisuo; Lockamy, Virginia [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Zhou, Lin [Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan (China); Xue, Christine; LeBlanc, Justin [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Glenn, Shonna [Xstrahl, Inc, Suwanee, Georgia (United States); Shukla, Gaurav; Yu, Yan; Dicker, Adam P.; Leeper, Dennis B. [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Lu, You [Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan (China); Lu, Bo, E-mail: bo.lu@jefferson.edu [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States)

2016-11-01

Purpose: To implement clinical stereotactic body radiation therapy (SBRT) using a small animal radiation research platform (SARRP) in a genetically engineered mouse model of lung cancer. Methods and Materials: A murine model of multinodular Kras-driven spontaneous lung tumors was used for this study. High-resolution cone beam computed tomography (CBCT) imaging was used to identify and target peripheral tumor nodules, whereas off-target lung nodules in the contralateral lung were used as a nonirradiated control. CBCT imaging helps localize tumors, facilitate high-precision irradiation, and monitor tumor growth. SBRT planning, prescription dose, and dose limits to normal tissue followed the guidelines set by RTOG protocols. Pathologic changes in the irradiated tumors were investigated using immunohistochemistry. Results: The image guided radiation delivery using the SARRP system effectively localized and treated lung cancer with precision in a genetically engineered mouse model of lung cancer. Immunohistochemical data confirmed the precise delivery of SBRT to the targeted lung nodules. The 60 Gy delivered in 3 weekly fractions markedly reduced the proliferation index, Ki-67, and increased apoptosis per staining for cleaved caspase-3 in irradiated lung nodules. Conclusions: It is feasible to use the SARRP platform to perform dosimetric planning and delivery of SBRT in mice with lung cancer. This allows for preclinical studies that provide a rationale for clinical trials involving SBRT, especially when combined with immunotherapeutics.

Growth control of genetically modified cells using an antibody/c-Kit chimera.

Science.gov (United States)

Kaneko, Etsuji; Kawahara, Masahiro; Ueda, Hiroshi; Nagamune, Teruyuki

2012-05-01

Gene therapy has been regarded as an innovative potential treatment against serious congenital diseases. However, applications of gene therapy remain limited, partly because its clinical success depends on therapeutic gene-transduced cells acquiring a proliferative advantage. To address this problem, we have developed the antigen-mediated genetically modified cell amplification (AMEGA) system, which uses chimeric receptors to enable the selective proliferation of gene-transduced cells. In this report, we describe mimicry of c-Kit signaling and its application to the AMEGA system. We created an antibody/c-Kit chimera in which the extracellular domain of c-Kit is replaced with an anti-fluorescein single-chain Fv antibody fragment and the extracellular D2 domain of the erythropoietin receptor. A genetically modified mouse pro-B cell line carrying this chimera showed selective expansion in the presence of fluorescein-conjugated BSA (BSA-FL) as a growth inducer. By further engineering the transmembrane domain of the chimera to reduce interchain interaction we attained stricter ligand-dependency. Since c-Kit is an important molecule in the expansion of hematopoietic stem cells (HSCs), this antibody/c-Kit chimera could be a promising tool for gene therapy targeting HSCs. Copyright © 2011 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Understanding the Basis of Auriculocondylar Syndrome: Insights From Human and Mouse Genetic Studies

Science.gov (United States)

Clouthier, David E.; Passos Bueno, Maria Rita; Tavares, Andre L.P.; Lyonnet, Stanislas; Amiel, Jeanne; Gordon, Christopher T.

2014-01-01

Among human birth defect syndromes, malformations affecting the face are perhaps the most striking due to cultural and psychological expectations of facial shape. One such syndrome is auriculocondylar syndrome (ACS), in which patients present with defects in ear and mandible development. Affected structures arise from cranial neural crest cells, a population of cells in the embryo that reside in the pharyngeal arches and give rise to most of the bone, cartilage and connective tissue of the face. Recent studies have found that most cases of ACS arise from defects in signaling molecules associated with the endothelin signaling pathway. Disruption of this signaling pathway in both mouse and zebrafish results in loss of identity of neural crest cells of the mandibular portion of the first pharyngeal arch and the subsequent repatterning of these cells, leading to homeosis of lower jaw structures into more maxillary-like structures. These findings illustrate the importance of endothelin signaling in normal human craniofacial development and illustrate how clinical and basic science approaches can coalesce to improve our understanding of the genetic basis of human birth syndromes. Further, understanding the genetic basis for ACS that lies outside of known endothelin signaling components may help elucidate unknown aspects critical to the establishment of neural crest cell patterning during facial morphogenesis. PMID:24123988

Murine adipose tissue-derived stromal cell apoptosis and susceptibility to oxidative stress in vitro are regulated by genetic background.

Directory of Open Access Journals (Sweden)

Robert Pazdro

Full Text Available Adipose tissue-derived stromal cells (ADSCs are of interest for regenerative medicine as they are isolated easily and can differentiate into multiple cell lineages. Studies of their in vitro proliferation, survival, and differentiation are common; however, genetic effects on these phenotypes remain unknown. To test if these phenotypes are genetically regulated, ADSCs were isolated from three genetically diverse inbred mouse strains--C57BL/6J (B6, BALB/cByJ (BALB, and DBA/2J (D2--in which genetic regulation of hematopoietic stem function is well known. ADSCs from all three strains differentiated into osteogenic and chondrogenic lineages in vitro. ADSCs from BALB grew least well in vitro, probably due to apoptotic cell death after several days in culture. BALB ADSCs were also the most susceptible to the free radical inducers menadione and H2O2. ADSCs from the three possible F1 hybrids were employed to further define genetic regulation of ADSC phenotypes. D2, but not B6, alleles stimulated ADSC expansion in BALB cells. In contrast, B6, but not D2, alleles rescued BALB H2O2 resistance. We conclude that low oxidative stress resistance does not limit BALB ADSC growth in vitro, as these phenotypes are genetically regulated independently. In addition, ADSCs from these strains are an appropriate model system to investigate genetic regulation of ADSC apoptosis and stress resistance in future studies. Such investigations are essential to optimize cell expansion and differentiation and thus, potential for regenerative medicine.

Selective rescue of heightened anxiety but not gait ataxia in a premutation 90CGG mouse model of Fragile X-associated tremor/ataxia syndrome.

Science.gov (United States)

Castro, Hoanna; Kul, Emre; Buijsen, Ronald A M; Severijnen, Lies-Anne W F M; Willemsen, Rob; Hukema, Renate K; Stork, Oliver; Santos, Mónica

2017-06-01

A CGG-repeat expansion in the premutation range in the Fragile X mental retardation 1 gene (FMR1) has been identified as the genetic cause of Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder that manifests with action tremor, gait ataxia and cognitive impairments. In this study, we used a bigenic mouse model, in which expression of a 90CGG premutation tract is activated in neural cells upon doxycycline administration-P90CGG mouse model. We, here, demonstrate the behavioural manifestation of clinically relevant features of FXTAS patients and premutation carrier individuals in this inducible mouse model. P90CGG mice display heightened anxiety, deficits in motor coordination and impaired gait and represent the first FXTAS model that exhibits an ataxia phenotype as observed in patients. The behavioural phenotype is accompanied by the formation of ubiquitin/FMRpolyglycine-positive intranuclear inclusions, as another hallmark of FXTAS, in the cerebellum, hippocampus and amygdala. Strikingly, upon cessation of transgene induction the anxiety phenotype of mice recovers along with a reduction of intranuclear inclusions in dentate gyrus and amygdala. In contrast, motor function deteriorates further and no reduction in intranuclear inclusions can be observed in the cerebellum. Our data thus demonstrate that expression of a 90CGG premutation expansion outside of the FMR1 context is sufficient to evoke an FXTAS-like behavioural phenotype. Brain region-specific neuropathology and (partial) behavioural reversibility make the inducible P90CGG a valuable mouse model for testing pathogenic mechanisms and therapeutic intervention methods. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Spatial Impairment and Memory in Genetic Disorders: Insights from Mouse Models

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Sang Ah Lee

2017-02-01

Full Text Available Research across the cognitive and brain sciences has begun to elucidate some of the processes that guide navigation and spatial memory. Boundary geometry and featural landmarks are two distinct classes of environmental cues that have dissociable neural correlates in spatial representation and follow different patterns of learning. Consequently, spatial navigation depends both on the type of cue available and on the type of learning provided. We investigated this interaction between spatial representation and memory by administering two different tasks (working memory, reference memory using two different environmental cues (rectangular geometry, striped landmark in mouse models of human genetic disorders: Prader-Willi syndrome (PWScrm+/p− mice, n = 12 and Beta-catenin mutation (Thr653Lys-substituted mice, n = 12. This exploratory study provides suggestive evidence that these models exhibit different abilities and impairments in navigating by boundary geometry and featural landmarks, depending on the type of memory task administered. We discuss these data in light of the specific deficits in cognitive and brain function in these human syndromes and their animal model counterparts.

40 CFR 798.5195 - Mouse biochemical specific locus test.

Science.gov (United States)

2010-07-01

...-induced variants are bred to determine the genetic nature of the change. (f) Data and reports—(1... SUBSTANCES CONTROL ACT (CONTINUED) HEALTH EFFECTS TESTING GUIDELINES Genetic Toxicity § 798.5195 Mouse...) A biochemical specific locus mutation is a genetic change resulting from a DNA lesion causing...

Cross-packaging of genetically distinct mouse and primate retroviral RNAs

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Jaballah Soumeya

2009-07-01

Full Text Available Abstract Background The mouse mammary tumor virus (MMTV is unique from other retroviruses in having multiple viral promoters, which can be regulated by hormones in a tissue specific manner. This unique property has lead to increased interest in studying MMTV replication with the hope of developing MMTV based vectors for human gene therapy. However, it has recently been reported that related as well as unrelated retroviruses can cross-package each other's genome raising safety concerns towards the use of candidate retroviral vectors for human gene therapy. Therefore, using a trans complementation assay, we looked at the ability of MMTV RNA to be cross-packaged and propagated by an unrelated primate Mason-Pfizer monkey virus (MPMV that has intracellular assembly process similar to that of MMTV. Results Our results revealed that MMTV and MPMV RNAs could be cross-packaged by the heterologous virus particles reciprocally suggesting that pseudotyping between two genetically distinct retroviruses can take place at the RNA level. However, the cross-packaged RNAs could not be propagated further indicating a block at post-packaging events in the retroviral life cycle. To further confirm that the specificity of cross-packaging was conferred by the packaging sequences (ψ, we cloned the packaging sequences of these viruses on expression plasmids that generated non-viral RNAs. Test of these non-viral RNAs confirmed that the reciprocal cross-packaging was primarily due to the recognition of ψ by the heterologous virus proteins. Conclusion The results presented in this study strongly argue that MPMV and MMTV are promiscuous in their ability to cross-package each other's genome suggesting potential RNA-protein interactions among divergent retroviral RNAs proposing that these interactions are more complicated than originally thought. Furthermore, these observations raise the possibility that MMTV and MPMV genomes could also co-package providing substrates for

Defining the role of polyamines in colon carcinogenesis using mouse models

Directory of Open Access Journals (Sweden)

Natalia A Ignatenko

2011-01-01

Full Text Available Genetics and diet are both considered important risk determinants for colorectal cancer, a leading cause of death in the US and worldwide. Genetically engineered mouse (GEM models have made a significant contribution to the characterization of colorectal cancer risk factors. Reliable, reproducible, and clinically relevant animal models help in the identification of the molecular events associated with disease progression and in the development of effictive treatment strategies. This review is focused on the use of mouse models for studying the role of polyamines in colon carcinogenesis. We describe how the available mouse models of colon cancer such as the multiple intestinal neoplasia (Min mice and knockout genetic models facilitate understanding of the role of polyamines in colon carcinogenesis and help in the development of a rational strategy for colon cancer chemoprevention.

Number and location of mouse mammary tumor virus proviral DNA in mouse DNA of normal tissue and of mammary tumors.

Science.gov (United States)

Groner, B; Hynes, N E

1980-01-01

The Southern DNA filter transfer technique was used to characterize the genomic location of the mouse mammary tumor proviral DNA in different inbred strains of mice. Two of the strains (C3H and CBA) arose from a cross of a Bagg albino (BALB/c) mouse and a DBA mouse. The mouse mammary tumor virus-containing restriction enzyme DNA fragments of these strains had similar patterns, suggesting that the proviruses of these mice are in similar genomic locations. Conversely, the pattern arising from the DNA of the GR mouse, a strain genetically unrelated to the others, appeared different, suggesting that its mouse mammary tumor proviruses are located in different genomic sites. The structure of another gene, that coding for beta-globin, was also compared. The mice strains which we studied can be categorized into two classes, expressing either one or two beta-globin proteins. The macroenvironment of the beta-globin gene appeared similar among the mice strains belonging to one genetic class. Female mice of the C3H strain exogenously transmit mouse mammary tumor virus via the milk, and their offspring have a high incidence of mammary tumor occurrence. DNA isolated from individual mammary tumors taken from C3H mice or from BALB/c mice foster nursed on C3H mothers was analyzed by the DNA filter transfer technique. Additional mouse mammary tumor virus-containing fragments were found in the DNA isolated from each mammary tumor. These proviral sequences were integrated into different genomic sites in each tumor. Images PMID:6245257

Nrl-Cre transgenic mouse mediates loxP recombination in developing rod photoreceptors.

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Brightman, Diana S; Razafsky, David; Potter, Chloe; Hodzic, Didier; Chen, Shiming

2016-03-01

The developing mouse retina is a tractable model for studying neurogenesis and differentiation. Although transgenic Cre mouse lines exist to mediate conditional genetic manipulations in developing mouse retinas, none of them act specifically in early developing rods. For conditional genetic manipulations of developing retinas, a Nrl-Cre mouse line in which the Nrl promoter drives expression of Cre in rod precursors was created. The results showed that Nrl-Cre expression was specific to the retina where it drives rod-specific recombination with a temporal pattern similar to endogenous Nrl expression during retinal development. This Nrl-Cre transgene does not negatively impact retinal structure and function. Taken together, the data suggested that the Nrl-Cre mouse line was a valuable tool to drive Cre-mediated recombination specifically in developing rods. © 2016 Wiley Periodicals, Inc.

Unnatural base pair systems toward the expansion of the genetic alphabet in the central dogma.

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Hirao, Ichiro; Kimoto, Michiko

2012-01-01

Toward the expansion of the genetic alphabet of DNA, several artificial third base pairs (unnatural base pairs) have been created. Synthetic DNAs containing the unnatural base pairs can be amplified faithfully by PCR, along with the natural A-T and G-C pairs, and transcribed into RNA. The unnatural base pair systems now have high potential to open the door to next generation biotechnology. The creation of unnatural base pairs is a consequence of repeating "proof of concept" experiments. In the process, initially designed base pairs were modified to address their weak points. Some of them were artificially evolved to ones with higher efficiency and selectivity in polymerase reactions, while others were eliminated from the analysis. Here, we describe the process of unnatural base pair development, as well as the tests of their applications.

Evaluating population expansion of black bears using spatial capture-recapture

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Sun, Catherine C.; Fuller, Angela K.; Hare, Matthew P.; Hurst, Jeremy E.

2017-01-01

The population of American black bears (Ursus americanus) in southern New York, USA has been growing and expanding in range since the 1990s. This has motivated a need to anticipate future patterns of range expansion. We conducted a non-invasive, genetic, spatial capture-recapture (SCR) study to estimate black bear density and identify spatial patterns of population density that are potentially associated with range expansion. We collected hair samples in a 2,519-km2 study area in southern New York with barbed-wire hair snares and identified individuals and measured genetic diversity using 7 microsatellite loci and 1 sex-linked marker. We estimated a mean density of black bears in the region of 13.7 bears/100 km2, and detected a slight latitudinal gradient in density consistent with the documented range expansion. However, elevation and the amounts of forest, crop, and developed landcover types did not influence density, suggesting that bears are using a diversity of resources in this heterogeneous landscape outside their previously described distribution. These results provide the first robust baseline estimates for population density and distribution associated with different landcover types in the expanded bear range. Further, genetic diversity was comparable to that of non-expanding black bear populations in the eastern United States, and in combination with the latitudinal density gradient, suggest that the study area is not at the colonizing front of the range expansion. In addition, the diversity of landcover types used by bears in the study area implies a possible lack of constraints for further northern expansion of the black bear range. Our non-invasive, genetic, spatial capture-recapture approach has utility for studying populations of other species that may be expanding in range because SCR allows for the testing of explicit, spatial ecological hypotheses. 

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

International Nuclear Information System (INIS)

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

2000-01-01

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

Mouse Genome Informatics (MGI) Is the International Resource for Information on the Laboratory Mouse.

Science.gov (United States)

Law, MeiYee; Shaw, David R

2018-01-01

Mouse Genome Informatics (MGI, http://www.informatics.jax.org/ ) web resources provide free access to meticulously curated information about the laboratory mouse. MGI's primary goal is to help researchers investigate the genetic foundations of human diseases by translating information from mouse phenotypes and disease models studies to human systems. MGI provides comprehensive phenotypes for over 50,000 mutant alleles in mice and provides experimental model descriptions for over 1500 human diseases. Curated data from scientific publications are integrated with those from high-throughput phenotyping and gene expression centers. Data are standardized using defined, hierarchical vocabularies such as the Mammalian Phenotype (MP) Ontology, Mouse Developmental Anatomy and the Gene Ontologies (GO). This chapter introduces you to Gene and Allele Detail pages and provides step-by-step instructions for simple searches and those that take advantage of the breadth of MGI data integration.

Population Genetic Structure and Evidence of Demographic Expansion of the Ayu (Plecoglossus altivelis in East Asia

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Ye-Seul Kwan

2012-10-01

Full Text Available Plecoglossus altivelis (ayu is an amphidromous fish widely distributed in Northeastern Asia from the East China Sea to the northern Japanese coastal waters, encompassing the Korean Peninsula within its range. The shore lines of northeastern region in Asia have severely fluctuated following glaciations in the Quaternary. In the present study, we investigate the population genetic structure and historical demographic change of P. altivelis at a population level in East Asia. Analysis of molecular variance (AMOVA based on 244 mitochondrial control region DNA sequences clearly showed that as the sampling scope extended to a larger geographic area, genetic differentiation began to become significant, particularly among Northeastern populations. A series of hierarchical AMOVA could detect the genetic relationship of three closely located islands between Korea and Japan that might have been tightly connected by the regional Tsushima current. Neutrality and mismatch distribution analyses revealed a strong signature of a recent population expansion of P. altivelis in East Asia, estimated at 126 to 391 thousand years ago during the late Pleistocene. Therefore it suggests that the present population of P. altivelis traces back to its approximate demographic change long before the last glacial maximum. This contrasts our a priori expectation that the most recent glacial event might have the most crucial effect on the present day demography of marine organisms through bottleneck and subsequent increase of effective population size in this region.

Comparative population genetics of two invading ticks: Evidence of the ecological mechanisms underlying tick range expansions.

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Nadolny, Robyn; Gaff, Holly; Carlsson, Jens; Gauthier, David

2015-10-01

Two species of ixodid tick, Ixodes affinis Neumann and Amblyomma maculatum Koch, are simultaneously expanding their ranges throughout the mid-Atlantic region of the US. Although we have some understanding of the ecology and life history of these species, the ecological mechanisms governing where and how new populations establish and persist are unclear. To assess population connectivity and ancestry, we sequenced a fragment of the 16S mitochondrial rRNA gene from a representative sample of individuals of both species from populations throughout the eastern US. We found that despite overlapping host preferences throughout ontogeny, each species exhibited very different genetic and geographic patterns of population establishment and connectivity. I. affinis was of two distinct mitochondrial clades, with a clear geographic break separating northern and southern populations. Both I. affinis populations showed evidence of recent expansion, although the southern population was more genetically diverse, indicating a longer history of establishment. A. maculatum exhibited diverse haplotypes that showed no significant relationship with geographic patterns and little apparent connectivity between sites. Heteroplasmy was also observed in the 16S mitochondrial rRNA gene in 3.5% of A. maculatum individuals. Genetic evidence suggests that these species rely on different key life stages to successfully disperse into novel environments, and that host vagility, habitat stability and habitat connectivity all play critical roles in the establishment of new tick populations. Copyright © 2015 Elsevier B.V. All rights reserved.

Genetic context determines susceptibility to intraocular pressure elevation in a mouse pigmentary glaucoma

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Cosma Ioan M

2006-07-01

Full Text Available Abstract Background DBA/2J (D2 mice develop an age-related form of glaucoma. Their eyes progressively develop iris pigment dispersion and iris atrophy followed by increased intraocular pressure (IOP and glaucomatous optic nerve damage. Mutant alleles of the Gpnmb and Tyrp1 genes are necessary for the iris disease, but it is unknown whether alleles of other D2 gene(s are necessary for the distinct later stages of disease. We initiated a study of congenic strains to further define the genetic requirements and disease mechanisms of the D2 glaucoma. Results To further understand D2 glaucoma, we created congenic strains of mice on the C57BL/6J (B6 genetic background. B6 double-congenic mice carrying D2-derived Gpnmb and Tyrp1 mutations develop a D2-like iris disease. B6 single-congenics with only the Gpnmb and Tyrp1 mutations develop milder forms of iris disease. Genetic epistasis experiments introducing a B6 tyrosinase mutation into the congenic strains demonstrated that both the single and double-congenic iris diseases are rescued by interruption of melanin synthesis. Importantly, our experiments analyzing mice at ages up to 27 months indicate that the B6 double-congenic mice are much less prone to IOP elevation and glaucoma than are D2 mice. Conclusion As demonstrated here, the Gpnmb and Tyrp1 iris phenotypes are both individually dependent on tyrosinase function. These results support involvement of abnormal melanosomal events in the diseases caused by each gene. In the context of the inbred D2 mouse strain, the glaucoma phenotype is clearly influenced by more genes than just Gpnmb and Tyrp1. Despite the outward similarity of pigment-dispersing iris disease between D2 and the B6 double-congenic mice, the congenic mice are much less susceptible to developing high IOP and glaucoma. These new congenic strains provide a valuable new resource for further studying the genetic and mechanistic complexity of this form of glaucoma.

The Mouse SAGE Site: database of public mouse SAGE libraries

Czech Academy of Sciences Publication Activity Database

Divina, Petr; Forejt, Jiří

2004-01-01

Roč. 32, - (2004), s. D482-D483 ISSN 0305-1048 R&D Projects: GA MŠk LN00A079; GA ČR GV204/98/K015 Grant - others:HHMI(US) 555000306 Institutional research plan: CEZ:AV0Z5052915 Keywords : mouse SAGE libraries * web -based database Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.260, year: 2004

EuroPhenome and EMPReSS: online mouse phenotyping resource.

Science.gov (United States)

Mallon, Ann-Marie; Blake, Andrew; Hancock, John M

2008-01-01

EuroPhenome (http://www.europhenome.org) and EMPReSS (http://empress.har.mrc.ac.uk/) form an integrated resource to provide access to data and procedures for mouse phenotyping. EMPReSS describes 96 Standard Operating Procedures for mouse phenotyping. EuroPhenome contains data resulting from carrying out EMPReSS protocols on four inbred laboratory mouse strains. As well as web interfaces, both resources support web services to enable integration with other mouse phenotyping and functional genetics resources, and are committed to initiatives to improve integration of mouse phenotype databases. EuroPhenome will be the repository for a recently initiated effort to carry out large-scale phenotyping on a large number of knockout mouse lines (EUMODIC).

Noncanonical Wnt signaling promotes obesity-induced adipose tissue inflammation and metabolic dysfunction independent of adipose tissue expansion.

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Fuster, José J; Zuriaga, María A; Ngo, Doan Thi-Minh; Farb, Melissa G; Aprahamian, Tamar; Yamaguchi, Terry P; Gokce, Noyan; Walsh, Kenneth

2015-04-01

Adipose tissue dysfunction plays a pivotal role in the development of insulin resistance in obese individuals. Cell culture studies and gain-of-function mouse models suggest that canonical Wnt proteins modulate adipose tissue expansion. However, no genetic evidence supports a role for endogenous Wnt proteins in adipose tissue dysfunction, and the role of noncanonical Wnt signaling remains largely unexplored. Here we provide evidence from human, mouse, and cell culture studies showing that Wnt5a-mediated, noncanonical Wnt signaling contributes to obesity-associated metabolic dysfunction by increasing adipose tissue inflammation. Wnt5a expression is significantly upregulated in human visceral fat compared with subcutaneous fat in obese individuals. In obese mice, Wnt5a ablation ameliorates insulin resistance, in parallel with reductions in adipose tissue inflammation. Conversely, Wnt5a overexpression in myeloid cells augments adipose tissue inflammation and leads to greater impairments in glucose homeostasis. Wnt5a ablation or overexpression did not affect fat mass or adipocyte size. Mechanistically, Wnt5a promotes the expression of proinflammatory cytokines by macrophages in a Jun NH2-terminal kinase-dependent manner, leading to defective insulin signaling in adipocytes. Exogenous interleukin-6 administration restores insulin resistance in obese Wnt5a-deficient mice, suggesting a central role for this cytokine in Wnt5a-mediated metabolic dysfunction. Taken together, these results demonstrate that noncanonical Wnt signaling contributes to obesity-induced insulin resistance independent of adipose tissue expansion. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

High-Resolution Maps of Mouse Reference Populations

Czech Academy of Sciences Publication Activity Database

Šimeček, Petr; Forejt, Jiří; Williams, R. W.; Shiroishi, T.; Takada, T.; Lu, L.; Johnson, T. E.; Bennett, B.; Deschepper, C. F.; Scott-Boyer, M.P.; de Villena, F.P.M.; Churchill, G. A.

2017-01-01

Roč. 7, č. 10 (2017), s. 3427-3434 ISSN 2160-1836 R&D Projects: GA ČR GA16-01969S; GA MŠk(CZ) LM2015040; GA MŠk(CZ) LQ1604 Institutional support: RVO:68378050 Keywords : chromosome substitution strains * recombinant inbred strains * mouse diversity genotyping array * gene conversions Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Genetics and heredity (medical genetics to be 3) Impact factor: 2.861, year: 2016

Complex Genetics of Behavior: BXDs in the Automated Home-Cage.

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Loos, Maarten; Verhage, Matthijs; Spijker, Sabine; Smit, August B

2017-01-01

This chapter describes a use case for the genetic dissection and automated analysis of complex behavioral traits using the genetically diverse panel of BXD mouse recombinant inbred strains. Strains of the BXD resource differ widely in terms of gene and protein expression in the brain, as well as in their behavioral repertoire. A large mouse resource opens the possibility for gene finding studies underlying distinct behavioral phenotypes, however, such a resource poses a challenge in behavioral phenotyping. To address the specifics of large-scale screening we describe how to investigate: (1) how to assess mouse behavior systematically in addressing a large genetic cohort, (2) how to dissect automation-derived longitudinal mouse behavior into quantitative parameters, and (3) how to map these quantitative traits to the genome, deriving loci underlying aspects of behavior.

Multilayered Genetic and Omics Dissection of Mitochondrial Activity in a Mouse Reference Population

Science.gov (United States)

Wu, Yibo; Williams, Evan G.; Dubuis, Sébastien; Mottis, Adrienne; Jovaisaite, Virginija; Houten, Sander M.; Argmann, Carmen A.; Faridi, Pouya; Wolski, Witold; Kutalik, Zoltán; Zamboni, Nicola; Auwerx, Johan; Aebersold, Ruedi

2014-01-01

SUMMARY The manner by which genotype and environment affect complex phenotypes is one of the fundamental questions in biology. In this study, we quantified the transcriptome—a subset of the metabolome—and, using targeted proteomics, quantified a subset of the liver proteome from 40 strains of the BXD mouse genetic reference population on two diverse diets. We discovered dozens of transcript, protein, and metabolite QTLs, several of which linked to metabolic phenotypes. Most prominently, Dhtkd1 was identified as a primary regulator of 2-aminoadipate, explaining variance in fasted glucose and diabetes status in both mice and humans. These integrated molecular profiles also allowed further characterization of complex pathways, particularly the mitochondrial unfolded protein response (UPRmt). UPRmt shows strikingly variant responses at the transcript and protein level that are remarkably conserved among C. elegans, mice, and humans. Overall, these examples demonstrate the value of an integrated multilayered omics approach to characterize complex metabolic phenotypes. PMID:25215496

Mouse Models for Drug Discovery. Can New Tools and Technology Improve Translational Power?

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Zuberi, Aamir; Lutz, Cathleen

2016-01-01

Abstract The use of mouse models in biomedical research and preclinical drug evaluation is on the rise. The advent of new molecular genome-altering technologies such as CRISPR/Cas9 allows for genetic mutations to be introduced into the germ line of a mouse faster and less expensively than previous methods. In addition, the rapid progress in the development and use of somatic transgenesis using viral vectors, as well as manipulations of gene expression with siRNAs and antisense oligonucleotides, allow for even greater exploration into genomics and systems biology. These technological advances come at a time when cost reductions in genome sequencing have led to the identification of pathogenic mutations in patient populations, providing unprecedented opportunities in the use of mice to model human disease. The ease of genetic engineering in mice also offers a potential paradigm shift in resource sharing and the speed by which models are made available in the public domain. Predictively, the knowledge alone that a model can be quickly remade will provide relief to resources encumbered by licensing and Material Transfer Agreements. For decades, mouse strains have provided an exquisite experimental tool to study the pathophysiology of the disease and assess therapeutic options in a genetically defined system. However, a major limitation of the mouse has been the limited genetic diversity associated with common laboratory mice. This has been overcome with the recent development of the Collaborative Cross and Diversity Outbred mice. These strains provide new tools capable of replicating genetic diversity to that approaching the diversity found in human populations. The Collaborative Cross and Diversity Outbred strains thus provide a means to observe and characterize toxicity or efficacy of new therapeutic drugs for a given population. The combination of traditional and contemporary mouse genome editing tools, along with the addition of genetic diversity in new modeling

Mouse Models for Drug Discovery. Can New Tools and Technology Improve Translational Power?

Science.gov (United States)

Zuberi, Aamir; Lutz, Cathleen

2016-12-01

The use of mouse models in biomedical research and preclinical drug evaluation is on the rise. The advent of new molecular genome-altering technologies such as CRISPR/Cas9 allows for genetic mutations to be introduced into the germ line of a mouse faster and less expensively than previous methods. In addition, the rapid progress in the development and use of somatic transgenesis using viral vectors, as well as manipulations of gene expression with siRNAs and antisense oligonucleotides, allow for even greater exploration into genomics and systems biology. These technological advances come at a time when cost reductions in genome sequencing have led to the identification of pathogenic mutations in patient populations, providing unprecedented opportunities in the use of mice to model human disease. The ease of genetic engineering in mice also offers a potential paradigm shift in resource sharing and the speed by which models are made available in the public domain. Predictively, the knowledge alone that a model can be quickly remade will provide relief to resources encumbered by licensing and Material Transfer Agreements. For decades, mouse strains have provided an exquisite experimental tool to study the pathophysiology of the disease and assess therapeutic options in a genetically defined system. However, a major limitation of the mouse has been the limited genetic diversity associated with common laboratory mice. This has been overcome with the recent development of the Collaborative Cross and Diversity Outbred mice. These strains provide new tools capable of replicating genetic diversity to that approaching the diversity found in human populations. The Collaborative Cross and Diversity Outbred strains thus provide a means to observe and characterize toxicity or efficacy of new therapeutic drugs for a given population. The combination of traditional and contemporary mouse genome editing tools, along with the addition of genetic diversity in new modeling systems

Assessment of genetic risk for human exposure to radiation. State of the art

International Nuclear Information System (INIS)

Shevchenko, V.A.

2000-01-01

Historical aspects of the conception of genetic risk of human irradiation for recent 40 years. Methodology of assessing the genetic risk of radiation exposure is based on the concept of hitting the target. To predict genetic risk of irradiation, the direct and indirect methods of assessment, extrapolation, integral and populational criteria of risk analysis is widely used. Combination of these methods permits to calculate the risk from human exposure on the basis of data obtained for mice. Method of doubling dose based on determination of the dose doubling the level of natural mutational process in humans is the main one used to predict the genetic risk. Till 1972 the main model for assessing the genetic risk was the human/mouse model (the use of data on the spontaneous human variability and data on the frequency of induced mutations in mice). In the period from 1972 till 1994 the mouse/mouse model was intensively elaborated in many laboratories. This model was also used in this period to analyse the genetic risk of human irradiation. Recent achievements associated with the study of molecular nature of many hereditary human diseases as well as the criticism of a fundamental principles of the mouse/mouse model for estimating the genetic risk on a new basis. Estimates of risk for the different classes of genetic diseases have been obtained using the doubling-dose method [ru

FMR1 CGG repeat expansion mutation detection and linked haplotype analysis for reliable and accurate preimplantation genetic diagnosis of fragile X syndrome.

Science.gov (United States)

Rajan-Babu, Indhu-Shree; Lian, Mulias; Cheah, Felicia S H; Chen, Min; Tan, Arnold S C; Prasath, Ethiraj B; Loh, Seong Feei; Chong, Samuel S

2017-07-19

Fragile X mental retardation 1 (FMR1) full-mutation expansion causes fragile X syndrome. Trans-generational fragile X syndrome transmission can be avoided by preimplantation genetic diagnosis (PGD). We describe a robust PGD strategy that can be applied to virtually any couple at risk of transmitting fragile X syndrome. This novel strategy utilises whole-genome amplification, followed by triplet-primed polymerase chain reaction (TP-PCR) for robust detection of expanded FMR1 alleles, in parallel with linked multi-marker haplotype analysis of 13 highly polymorphic microsatellite markers located within 1 Mb of the FMR1 CGG repeat, and the AMELX/Y dimorphism for gender identification. The assay was optimised and validated on single lymphoblasts isolated from fragile X reference cell lines, and applied to a simulated PGD case and a clinical in vitro fertilisation (IVF)-PGD case. In the simulated PGD case, definitive diagnosis of the expected results was achieved for all 'embryos'. In the clinical IVF-PGD case, delivery of a healthy baby girl was achieved after transfer of an expansion-negative blastocyst. FMR1 TP-PCR reliably detects presence of expansion mutations and obviates reliance on informative normal alleles for determining expansion status in female embryos. Together with multi-marker haplotyping and gender determination, misdiagnosis and diagnostic ambiguity due to allele dropout is minimised, and couple-specific assay customisation can be avoided.

Generation Expansion Planning in pool market: A hybrid modified game theory and improved genetic algorithm

International Nuclear Information System (INIS)

Shayanfar, H.A.; Lahiji, A. Saliminia; Aghaei, J.; Rabiee, A.

2009-01-01

Unlike the traditional policy, Generation Expansion Planning (GEP) problem in competitive framework is complicated. In the new policy, each Generation Company (GENCO) decides to invest in such a way that obtains as much profit as possible. This paper presents a new hybrid algorithm to determine GEP in a Pool market. The proposed algorithm is divided in two programming levels: master and slave. In the master level a Modified Game Theory (MGT) is proposed to evaluate the contrast of GENCOs by the Independent System Operator (ISO). In the slave level, an Improved Genetic Algorithm (IGA) method is used to find the best solution of each GENCO for decision-making of investment. The validity of the proposed method is examined in the case study including three GENCOs with multi-type of power plants. The results show that the presented method is both satisfactory and consistent with expectation. (author)

Characterization of a male reproductive transcriptome for Peromyscus eremicus (Cactus mouse

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Lauren L. Kordonowy

2016-10-01

Full Text Available Rodents of the genus Peromyscus have become increasingly utilized models for investigations into adaptive biology. This genus is particularly powerful for research linking genetics with adaptive physiology or behaviors, and recent research has capitalized on the unique opportunities afforded by the ecological diversity of these rodents. Well characterized genomic and transcriptomic data is intrinsic to explorations of the genetic architecture responsible for ecological adaptations. Therefore, this study characterizes the transcriptome of three male reproductive tissues (testes, epididymis and vas deferens of Peromyscus eremicus (Cactus mouse, a desert specialist. The transcriptome assembly process was optimized in order to produce a high quality and substantially complete annotated transcriptome. This composite transcriptome was generated to characterize the expressed transcripts in the male reproductive tract of P. eremicus, which will serve as a crucial resource for future research investigating our hypothesis that the male Cactus mouse possesses an adaptive reproductive phenotype to mitigate water-loss from ejaculate. This study reports genes under positive selection in the male Cactus mouse reproductive transcriptome relative to transcriptomes from Peromyscus maniculatus (deer mouse and Mus musculus. Thus, this study expands upon existing genetic research in this species, and we provide a high quality transcriptome to enable further explorations of our proposed hypothesis for male Cactus mouse reproductive adaptations to minimize seminal fluid loss.

Y chromosome diversity, human expansion, drift, and cultural evolution.

Science.gov (United States)

Chiaroni, Jacques; Underhill, Peter A; Cavalli-Sforza, Luca L

2009-12-01

The relative importance of the roles of adaptation and chance in determining genetic diversity and evolution has received attention in the last 50 years, but our understanding is still incomplete. All statements about the relative effects of evolutionary factors, especially drift, need confirmation by strong demographic observations, some of which are easier to obtain in a species like ours. Earlier quantitative studies on a variety of data have shown that the amount of genetic differentiation in living human populations indicates that the role of positive (or directional) selection is modest. We observe geographic peculiarities with some Y chromosome mutants, most probably due to a drift-related phenomenon called the surfing effect. We also compare the overall genetic diversity in Y chromosome DNA data with that of other chromosomes and their expectations under drift and natural selection, as well as the rate of fall of diversity within populations known as the serial founder effect during the recent "Out of Africa" expansion of modern humans to the whole world. All these observations are difficult to explain without accepting a major relative role for drift in the course of human expansions. The increasing role of human creativity and the fast diffusion of inventions seem to have favored cultural solutions for many of the problems encountered in the expansion. We suggest that cultural evolution has been subrogating biologic evolution in providing natural selection advantages and reducing our dependence on genetic mutations, especially in the last phase of transition from food collection to food production.

Establishment of a tamoxifen-inducible Cre-driver mouse strain for widespread and temporal genetic modification in adult mice.

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Ichise, Hirotake; Hori, Akiko; Shiozawa, Seiji; Kondo, Saki; Kanegae, Yumi; Saito, Izumu; Ichise, Taeko; Yoshida, Nobuaki

2016-07-29

Temporal genetic modification of mice using the ligand-inducible Cre/loxP system is an important technique that allows the bypass of embryonic lethal phenotypes and access to adult phenotypes. In this study, we generated a tamoxifen-inducible Cre-driver mouse strain for the purpose of widespread and temporal Cre recombination. The new line, named CM32, expresses the GFPneo-fusion gene in a wide variety of tissues before FLP recombination and tamoxifen-inducible Cre after FLP recombination. Using FLP-recombined CM32 mice (CM32Δ mice) and Cre reporter mouse lines, we evaluated the efficiency of Cre recombination with and without tamoxifen administration to adult mice, and found tamoxifen-dependent induction of Cre recombination in a variety of adult tissues. In addition, we demonstrated that conditional activation of an oncogene could be achieved in adults using CM32Δ mice. CM32Δ;T26 mice, which harbored a Cre recombination-driven, SV40 large T antigen-expressing transgene, were viable and fertile. No overt phenotype was found in the mice up to 3 months after birth. Although they displayed pineoblastomas (pinealoblastomas) and/or thymic enlargement due to background Cre recombination by 6 months after birth, they developed epidermal hyperplasia when administered tamoxifen. Collectively, our results suggest that the CM32Δ transgenic mouse line can be applied to the assessment of adult phenotypes in mice with loxP-flanked transgenes.

Translating human genetics into mouse: the impact of ultra-rapid in vivo genome editing.

Science.gov (United States)

Aida, Tomomi; Imahashi, Risa; Tanaka, Kohichi

2014-01-01

Gene-targeted mutant animals, such as knockout or knockin mice, have dramatically improved our understanding of the functions of genes in vivo and the genetic diversity that characterizes health and disease. However, the generation of targeted mice relies on gene targeting in embryonic stem (ES) cells, which is a time-consuming, laborious, and expensive process. The recent groundbreaking development of several genome editing technologies has enabled the targeted alteration of almost any sequence in any cell or organism. These technologies have now been applied to mouse zygotes (in vivo genome editing), thereby providing new avenues for simple, convenient, and ultra-rapid production of knockout or knockin mice without the need for ES cells. Here, we review recent achievements in the production of gene-targeted mice by in vivo genome editing. © 2013 The Authors Development, Growth & Differentiation © 2013 Japanese Society of Developmental Biologists.

External Volume Expansion in Irradiated Tissue: Effects on the Recipient Site.

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Chin, Michael S; Lujan-Hernandez, Jorge; Babchenko, Oksana; Bannon, Elizabeth; Perry, Dylan J; Chappell, Ava G; Lo, Yuan-Chyuan; Fitzgerald, Thomas J; Lalikos, Janice F

2016-05-01

External volume expansion prepares recipient sites to improve outcomes of fat grafting. For patients receiving radiotherapy after mastectomy, results with external volume expansion vary, and the relationship between radiotherapy and expansion remains unexplored. Thus, the authors developed a new translational model to investigate the effects in chronic skin fibrosis after radiation exposure. Twenty-four SKH1-E mice received 50 Gy of β-radiation to each flank and were monitored until fibrosis developed (8 weeks). External volume expansion was then applied at -25 mmHg to one side for 6 hours for 5 days. The opposite side served as the control. Perfusion changes were assessed with hyperspectral imaging. Mice were euthanized at 5 (n = 12) and 15 days (n = 12) after the last expansion application. Tissue samples were analyzed with immunohistochemistry for CD31 and Ki67, Masson trichrome for skin thickness, and picrosirius red to analyze collagen composition. All animals developed skin fibrosis 8 weeks after radiotherapy and became hypoperfused based on hyperspectral imaging. Expansion induced edema on treated sides after stimulation. Perfusion was decreased by 13 percent on the expansion side (p External volume expansion temporarily reduces perfusion, likely because of transient ischemia or edema. Together with mechanotransduction, these effects encourage a proangiogenic and proliferative environment in fibrotic tissue after radiotherapy in the authors' mouse model. Further studies are needed to assess these changes in fat graft retention.

A mouse model of the human Fragile X syndrome I304N mutation.

Directory of Open Access Journals (Sweden)

Julie B Zang

2009-12-01

Full Text Available The mental retardation, autistic features, and behavioral abnormalities characteristic of the Fragile X mental retardation syndrome result from the loss of function of the RNA-binding protein FMRP. The disease is usually caused by a triplet repeat expansion in the 5'UTR of the FMR1 gene. This leads to loss of function through transcriptional gene silencing, pointing to a key function for FMRP, but precluding genetic identification of critical activities within the protein. Moreover, antisense transcripts (FMR4, ASFMR1 in the same locus have been reported to be silenced by the repeat expansion. Missense mutations offer one means of confirming a central role for FMRP in the disease, but to date, only a single such patient has been described. This patient harbors an isoleucine to asparagine mutation (I304N in the second FMRP KH-type RNA-binding domain, however, this single case report was complicated because the patient harbored a superimposed familial liver disease. To address these issues, we have generated a new Fragile X Syndrome mouse model in which the endogenous Fmr1 gene harbors the I304N mutation. These mice phenocopy the symptoms of Fragile X Syndrome in the existing Fmr1-null mouse, as assessed by testicular size, behavioral phenotyping, and electrophysiological assays of synaptic plasticity. I304N FMRP retains some functions, but has specifically lost RNA binding and polyribosome association; moreover, levels of the mutant protein are markedly reduced in the brain specifically at a time when synapses are forming postnatally. These data suggest that loss of FMRP function, particularly in KH2-mediated RNA binding and in synaptic plasticity, play critical roles in pathogenesis of the Fragile X Syndrome and establish a new model for studying the disorder.

Contemporary paternal genetic landscape of Polish and German populations: from early medieval Slavic expansion to post-World War II resettlements.

Science.gov (United States)

Rębała, Krzysztof; Martínez-Cruz, Begoña; Tönjes, Anke; Kovacs, Peter; Stumvoll, Michael; Lindner, Iris; Büttner, Andreas; Wichmann, H-Erich; Siváková, Daniela; Soták, Miroslav; Quintana-Murci, Lluís; Szczerkowska, Zofia; Comas, David

2013-04-01

Homogeneous Proto-Slavic genetic substrate and/or extensive mixing after World War II were suggested to explain homogeneity of contemporary Polish paternal lineages. Alternatively, Polish local populations might have displayed pre-war genetic heterogeneity owing to genetic drift and/or gene flow with neighbouring populations. Although sharp genetic discontinuity along the political border between Poland and Germany indisputably results from war-mediated resettlements and homogenisation, it remained unknown whether Y-chromosomal diversity in ethnically/linguistically defined populations was clinal or discontinuous before the war. In order to answer these questions and elucidate early Slavic migrations, 1156 individuals from several Slavic and German populations were analysed, including Polish pre-war regional populations and an autochthonous Slavic population from Germany. Y chromosomes were assigned to 39 haplogroups and genotyped for 19 STRs. Genetic distances revealed similar degree of differentiation of Slavic-speaking pre-war populations from German populations irrespective of duration and intensity of contacts with German speakers. Admixture estimates showed minor Slavic paternal ancestry (~20%) in modern eastern Germans and hardly detectable German paternal ancestry in Slavs neighbouring German populations for centuries. BATWING analysis of isolated Slavic populations revealed that their divergence was preceded by rapid demographic growth, undermining theory that Slavic expansion was primarily linguistic rather than population spread. Polish pre-war regional populations showed within-group heterogeneity and lower STR variation within R-M17 subclades compared with modern populations, which might have been homogenised by war resettlements. Our results suggest that genetic studies on early human history in the Vistula and Oder basins should rely on reconstructed pre-war rather than modern populations.

Genetics

International Nuclear Information System (INIS)

Hubitschek, H.E.

1975-01-01

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

Genetic diversity and striatal gene networks: focus on the heterogeneous stock-collaborative cross (HS-CC mouse

Directory of Open Access Journals (Sweden)

Belknap John

2010-10-01

Full Text Available Abstract Background The current study focused on the extent genetic diversity within a species (Mus musculus affects gene co-expression network structure. To examine this issue, we have created a new mouse resource, a heterogeneous stock (HS formed from the same eight inbred strains that have been used to create the collaborative cross (CC. The eight inbred strains capture > 90% of the genetic diversity available within the species. For contrast with the HS-CC, a C57BL/6J (B6 × DBA/2J (D2 F2 intercross and the HS4, derived from crossing the B6, D2, BALB/cJ and LP/J strains, were used. Brain (striatum gene expression data were obtained using the Illumina Mouse WG 6.1 array, and the data sets were interrogated using a weighted gene co-expression network analysis (WGCNA. Results Genes reliably detected as expressed were similar in all three data sets as was the variability of expression. As measured by the WGCNA, the modular structure of the transcriptome networks was also preserved both on the basis of module assignment and from the perspective of the topological overlap maps. Details of the HS-CC gene modules are provided; essentially identical results were obtained for the HS4 and F2 modules. Gene ontology annotation of the modules revealed a significant overrepresentation in some modules for neuronal processes, e.g., central nervous system development. Integration with known protein-protein interactions data indicated significant enrichment among co-expressed genes. We also noted significant overlap with markers of central nervous system cell types (neurons, oligodendrocytes and astrocytes. Using the Allen Brain Atlas, we found evidence of spatial co-localization within the striatum for several modules. Finally, for some modules it was possible to detect an enrichment of transcription binding sites. The binding site for Wt1, which is associated with neurodegeneration, was the most significantly overrepresented. Conclusions Despite the marked

Rapid, global demographic expansions after the origins of agriculture.

Science.gov (United States)

Gignoux, Christopher R; Henn, Brenna M; Mountain, Joanna L

2011-04-12

The invention of agriculture is widely assumed to have driven recent human population growth. However, direct genetic evidence for population growth after independent agricultural origins has been elusive. We estimated population sizes through time from a set of globally distributed whole mitochondrial genomes, after separating lineages associated with agricultural populations from those associated with hunter-gatherers. The coalescent-based analysis revealed strong evidence for distinct demographic expansions in Europe, southeastern Asia, and sub-Saharan Africa within the past 10,000 y. Estimates of the timing of population growth based on genetic data correspond neatly to dates for the initial origins of agriculture derived from archaeological evidence. Comparisons of rates of population growth through time reveal that the invention of agriculture facilitated a fivefold increase in population growth relative to more ancient expansions of hunter-gatherers.

The perfect host: a mouse host embryo facilitating more efficient germ line transmission of genetically modified embryonic stem cells.

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Robert A Taft

Full Text Available There is a continual need to improve efficiency in creating precise genetic modifications in mice using embryonic stem cells (ESCs. We describe a novel approach resulting in 100% germline transmission from competent injected ESCs. We developed an F1 mouse host embryo (Perfect Host, PH that selectively ablates its own germ cells via tissue-specific induction of diphtheria toxin. This approach allows competent microinjected ESCs to fully dominate the germline, eliminating competition for this critical niche in the developing and adult animal. This is in contrast to conventional methods, where competition from host germ cells results in offspring derived from host cells and ESCs, necessitating extensive breeding of chimeras and genotyping to identify germline. The germline transmission process is also complicated by variability in the actual number of ESCs that colonize the germline niche and the proportion that are germline competent. To validate the PH approach we used ESC lines derived from 129 F1, BALB/cByJ, and BTBR backgrounds as well as an iPS line. Resulting chimeric males produced 194 offspring, all paternally derived from the introduced stem cells, with no offspring being derived from the host genome. We further tested this approach using eleven genetically modified C57BL/6N ESC lines (International Knockout Mouse Consortium. ESC germline transmission was observed in 9/11 (82% lines using PH blastocysts, compared to 6/11 (55% when conventional host blastocysts were used. Furthermore, less than 35% (83/240 of mice born in the first litters from conventional chimeras were confirmed to be of ESC-origin. By comparison, 100% (137/137 of the first litter offspring of PH chimeras were confirmed as ESC-derived. Together, these data demonstrate that the PH approach increases the probability of germline transmission and speeds the generation of ESC derived animals from chimeras. Collectively, this approach reduces the time and costs inherent in the

Mouse genome-wide association and systems genetics identify Asxl2 as a regulator of bone mineral density and osteoclastogenesis.

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Charles R Farber

2011-04-01

Full Text Available Significant advances have been made in the discovery of genes affecting bone mineral density (BMD; however, our understanding of its genetic basis remains incomplete. In the current study, genome-wide association (GWA and co-expression network analysis were used in the recently described Hybrid Mouse Diversity Panel (HMDP to identify and functionally characterize novel BMD genes. In the HMDP, a GWA of total body, spinal, and femoral BMD revealed four significant associations (-log10P>5.39 affecting at least one BMD trait on chromosomes (Chrs. 7, 11, 12, and 17. The associations implicated a total of 163 genes with each association harboring between 14 and 112 genes. This list was reduced to 26 functional candidates by identifying those genes that were regulated by local eQTL in bone or harbored potentially functional non-synonymous (NS SNPs. This analysis revealed that the most significant BMD SNP on Chr. 12 was a NS SNP in the additional sex combs like-2 (Asxl2 gene that was predicted to be functional. The involvement of Asxl2 in the regulation of bone mass was confirmed by the observation that Asxl2 knockout mice had reduced BMD. To begin to unravel the mechanism through which Asxl2 influenced BMD, a gene co-expression network was created using cortical bone gene expression microarray data from the HMDP strains. Asxl2 was identified as a member of a co-expression module enriched for genes involved in the differentiation of myeloid cells. In bone, osteoclasts are bone-resorbing cells of myeloid origin, suggesting that Asxl2 may play a role in osteoclast differentiation. In agreement, the knockdown of Asxl2 in bone marrow macrophages impaired their ability to form osteoclasts. This study identifies a new regulator of BMD and osteoclastogenesis and highlights the power of GWA and systems genetics in the mouse for dissecting complex genetic traits.

Mouse ENU Mutagenesis to Understand Immunity to Infection: Methods, Selected Examples, and Perspectives

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Grégory Caignard

2014-09-01

Full Text Available Infectious diseases are responsible for over 25% of deaths globally, but many more individuals are exposed to deadly pathogens. The outcome of infection results from a set of diverse factors including pathogen virulence factors, the environment, and the genetic make-up of the host. The completion of the human reference genome sequence in 2004 along with technological advances have tremendously accelerated and renovated the tools to study the genetic etiology of infectious diseases in humans and its best characterized mammalian model, the mouse. Advancements in mouse genomic resources have accelerated genome-wide functional approaches, such as gene-driven and phenotype-driven mutagenesis, bringing to the fore the use of mouse models that reproduce accurately many aspects of the pathogenesis of human infectious diseases. Treatment with the mutagen N-ethyl-N-nitrosourea (ENU has become the most popular phenotype-driven approach. Our team and others have employed mouse ENU mutagenesis to identify host genes that directly impact susceptibility to pathogens of global significance. In this review, we first describe the strategies and tools used in mouse genetics to understand immunity to infection with special emphasis on chemical mutagenesis of the mouse germ-line together with current strategies to efficiently identify functional mutations using next generation sequencing. Then, we highlight illustrative examples of genes, proteins, and cellular signatures that have been revealed by ENU screens and have been shown to be involved in susceptibility or resistance to infectious diseases caused by parasites, bacteria, and viruses.

Mouse Chromosome Engineering for Modeling Human Disease

OpenAIRE

van der Weyden, Louise; Bradley, Allan

2006-01-01

Chromosomal rearrangements occur frequently in humans and can be disease-associated or phenotypically neutral. Recent technological advances have led to the discovery of copy-number changes previously undetected by cytogenetic techniques. To understand the genetic consequences of such genomic changes, these mutations need to be modeled in experimentally tractable systems. The mouse is an excellent organism for this analysis because of its biological and genetic similarity to humans, and the e...

An increase in immature β-cells lacking Glut2 precedes the expansion of β-cell mass in the pregnant mouse.

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Christine A Beamish

Full Text Available A compensatory increase in β-cell mass occurs during pregnancy to counter the associated insulin resistance, and a failure in adaptation is thought to contribute to gestational diabetes. Insulin-expressing but glucose-transporter-2-low (Ins+Glut2LO progenitor cells are present in mouse and human pancreas, being predominantly located in extra-islet β-cell clusters, and contribute to the regeneration of the endocrine pancreas following induced ablation. We therefore sought to investigate the contribution of Ins+Glut2LO cells to β-cell mass expansion during pregnancy. Female C57Bl/6 mice were time mated and pancreata were collected at gestational days (GD 6, 9, 12, 15, and 18, and postpartum D7 (n = 4/time-point and compared to control (non-pregnant animals. Beta cell mass, location, proliferation (Ki67+, and proportion of Ins+Glut2LO cells were measured using immunohistochemistry and bright field or confocal microscopy. Beta cell mass tripled by GD18 and β-cell proliferation peaked at GD12 in islets (≥6 β-cells and small β-cell clusters (1-5 β-cells. The proportion and fraction of Ins+Glut2LO cells undergoing proliferation increased significantly at GD9 in both islets and clusters, preceding the increase in β-cell mass and proliferation, and their proliferation within clusters persisted until GD15. The overall number of clusters increased significantly at GD9. Quantitative PCR showed a significant increase in Pdx1 presence at GD9 vs. GD18 or control pancreas, and Pdx1 was visualized by immunohistochemistry within both Ins+Glut2LO and Ins+Glut2HI cells within clusters. These results indicate that Ins+Glut2LO cells are likely to contribute to β-cell mass expansion during pregnancy.

Glucose metabolism, islet architecture, and genetic homogeneity in imprinting of [Ca2+](i and insulin rhythms in mouse islets.

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Craig S Nunemaker

2009-12-01

Full Text Available We reported previously that islets isolated from individual, outbred Swiss-Webster mice displayed oscillations in intracellular calcium ([Ca2+](i that varied little between islets of a single mouse but considerably between mice, a phenomenon we termed "islet imprinting." We have now confirmed and extended these findings in several respects. First, imprinting occurs in both inbred (C57BL/6J as well as outbred mouse strains (Swiss-Webster; CD1. Second, imprinting was observed in NAD(PH oscillations, indicating a metabolic component. Further, short-term exposure to a glucose-free solution, which transiently silenced [Ca2+](i oscillations, reset the oscillatory patterns to a higher frequency. This suggests a key role for glucose metabolism in maintaining imprinting, as transiently suppressing the oscillations with diazoxide, a K(ATP-channel opener that blocks [Ca2+](i influx downstream of glucose metabolism, did not change the imprinted patterns. Third, imprinting was not as readily observed at the level of single beta cells, as the [Ca2+](i oscillations of single cells isolated from imprinted islets exhibited highly variable, and typically slower [Ca2+](i oscillations. Lastly, to test whether the imprinted [Ca2+](i patterns were of functional significance, a novel microchip platform was used to monitor insulin release from multiple islets in real time. Insulin release patterns correlated closely with [Ca2+](i oscillations and showed significant mouse-to-mouse differences, indicating imprinting. These results indicate that islet imprinting is a general feature of islets and is likely to be of physiological significance. While islet imprinting did not depend on the genetic background of the mice, glucose metabolism and intact islet architecture may be important for the imprinting phenomenon.

Allele-specific deletions in mouse tumors identify Fbxw7 as germline modifier of tumor susceptibility.

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Jesus Perez-Losada

Full Text Available Genome-wide association studies (GWAS have been successful in finding associations between specific genetic variants and cancer susceptibility in human populations. These studies have identified a range of highly statistically significant associations between single nucleotide polymorphisms (SNPs and susceptibility to development of a range of human tumors. However, the effect of each SNP in isolation is very small, and all of the SNPs combined only account for a relatively minor proportion of the total genetic risk (5-10%. There is therefore a major requirement for alternative routes to the discovery of genetic risk factors for cancer. We have previously shown using mouse models that chromosomal regions harboring susceptibility genes identified by linkage analysis frequently exhibit allele-specific genetic alterations in tumors. We demonstrate here that the Fbxw7 gene, a commonly mutated gene in a wide range of mouse and human cancers, shows allele-specific deletions in mouse lymphomas and skin tumors. Lymphomas from three different F1 hybrids show 100% allele-specificity in the patterns of allelic loss. Parental alleles from 129/Sv or Spretus/Gla mice are lost in tumors from F1 hybrids with C57BL/6 animals, due to the presence of a specific non-synonymous coding sequence polymorphism at the N-terminal portion of the gene. A specific genetic test of association between this SNP and lymphoma susceptibility in interspecific backcross mice showed a significant linkage (p = 0.001, but only in animals with a functional p53 gene. These data therefore identify Fbxw7 as a p53-dependent tumor susceptibility gene. Increased p53-dependent tumor susceptibility and allele-specific losses were also seen in a mouse skin model of skin tumor development. We propose that analysis of preferential allelic imbalances in tumors may provide an efficient means of uncovering genetic variants that affect mouse and human tumor susceptibility.

A roadmap for the genetic analysis of renal aging.

Science.gov (United States)

Noordmans, Gerda A; Hillebrands, Jan-Luuk; van Goor, Harry; Korstanje, Ron

2015-10-01

Several studies show evidence for the genetic basis of renal disease, which renders some individuals more prone than others to accelerated renal aging. Studying the genetics of renal aging can help us to identify genes involved in this process and to unravel the underlying pathways. First, this opinion article will give an overview of the phenotypes that can be observed in age-related kidney disease. Accurate phenotyping is essential in performing genetic analysis. For kidney aging, this could include both functional and structural changes. Subsequently, this article reviews the studies that report on candidate genes associated with renal aging in humans and mice. Several loci or candidate genes have been found associated with kidney disease, but identification of the specific genetic variants involved has proven to be difficult. CUBN, UMOD, and SHROOM3 were identified by human GWAS as being associated with albuminuria, kidney function, and chronic kidney disease (CKD). These are promising examples of genes that could be involved in renal aging, and were further mechanistically evaluated in animal models. Eventually, we will provide approaches for performing genetic analysis. We should leverage the power of mouse models, as testing in humans is limited. Mouse and other animal models can be used to explain the underlying biological mechanisms of genes and loci identified by human GWAS. Furthermore, mouse models can be used to identify genetic variants associated with age-associated histological changes, of which Far2, Wisp2, and Esrrg are examples. A new outbred mouse population with high genetic diversity will facilitate the identification of genes associated with renal aging by enabling high-resolution genetic mapping while also allowing the control of environmental factors, and by enabling access to renal tissues at specific time points for histology, proteomics, and gene expression. © 2015 The Authors. Aging Cell published by the Anatomical Society and John

A roadmap for the genetic analysis of renal aging

Science.gov (United States)

Noordmans, Gerda A; Hillebrands, Jan-Luuk; van Goor, Harry; Korstanje, Ron

2015-01-01

Several studies show evidence for the genetic basis of renal disease, which renders some individuals more prone than others to accelerated renal aging. Studying the genetics of renal aging can help us to identify genes involved in this process and to unravel the underlying pathways. First, this opinion article will give an overview of the phenotypes that can be observed in age-related kidney disease. Accurate phenotyping is essential in performing genetic analysis. For kidney aging, this could include both functional and structural changes. Subsequently, this article reviews the studies that report on candidate genes associated with renal aging in humans and mice. Several loci or candidate genes have been found associated with kidney disease, but identification of the specific genetic variants involved has proven to be difficult. CUBN, UMOD, and SHROOM3 were identified by human GWAS as being associated with albuminuria, kidney function, and chronic kidney disease (CKD). These are promising examples of genes that could be involved in renal aging, and were further mechanistically evaluated in animal models. Eventually, we will provide approaches for performing genetic analysis. We should leverage the power of mouse models, as testing in humans is limited. Mouse and other animal models can be used to explain the underlying biological mechanisms of genes and loci identified by human GWAS. Furthermore, mouse models can be used to identify genetic variants associated with age-associated histological changes, of which Far2, Wisp2, and Esrrg are examples. A new outbred mouse population with high genetic diversity will facilitate the identification of genes associated with renal aging by enabling high-resolution genetic mapping while also allowing the control of environmental factors, and by enabling access to renal tissues at specific time points for histology, proteomics, and gene expression. PMID:26219736

Meeting Report: The Twelfth International Mouse Genome Conference

Energy Technology Data Exchange (ETDEWEB)

Manolakou, Katerina; Cross, Sally H.; Simpson, Eleanor H.; Jackson, Ian J.

1998-10-01

The annual International Mouse Genome Conference (IMGC) is where, scientifically speaking, classical mouse genetics meets the relative newcomer of genomics. The 12th meeting took place last October in the delightful Bavarian village of Garmisch-Partenkirchen, and we were greeted by the sight on the mountains of the first snowfall of the season. However the discussions left little time for exploration. Minds of participants in Garmisch were focused by a recent document produced by the NIH and by discussions within other funding agencies worldwide. If implemented, the proposals will further enhance the status of the mouse as the principal model for study of the function of the human genome.

Radiation-induced intestinal neoplasia in a genetically-predisposed mouse (Min)

International Nuclear Information System (INIS)

Ellender, M.; Larder, S.M.; Harrison, J.D.; Cox, R.; Silver, A.R.J.

1997-01-01

A mouse lineage with inherited predisposition to multiple intestinal neoplasia (min) has been proposed as a model to study human colorectal cancer. Min mice are heterozygous for the adenomatous polyposis coli (Apc) gene implicated in human familial adenomatous polyposis (FAP). There is an increased risk of intestinal cancer in humans following radiation exposure and the min mouse model may be used to further our understanding of the molecular mechanisms involved. The present study showed a 2 Gy dose of x-rays doubles the tumour numbers in the murine gastrointestinal tract of F1 min heterozygotes. The distribution of tumours through the gut was also recorded. (authors)

Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma.

Science.gov (United States)

McFadden, David G; Politi, Katerina; Bhutkar, Arjun; Chen, Frances K; Song, Xiaoling; Pirun, Mono; Santiago, Philip M; Kim-Kiselak, Caroline; Platt, James T; Lee, Emily; Hodges, Emily; Rosebrock, Adam P; Bronson, Roderick T; Socci, Nicholas D; Hannon, Gregory J; Jacks, Tyler; Varmus, Harold

2016-10-18

Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity.

Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma

Science.gov (United States)

McFadden, David G.; Politi, Katerina; Bhutkar, Arjun; Chen, Frances K.; Song, Xiaoling; Pirun, Mono; Santiago, Philip M.; Kim-Kiselak, Caroline; Platt, James T.; Lee, Emily; Hodges, Emily; Rosebrock, Adam P.; Bronson, Roderick T.; Socci, Nicholas D.; Hannon, Gregory J.; Jacks, Tyler; Varmus, Harold

2016-01-01

Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity. PMID:27702896

Immunological characteristics and response to lipopolysaccharide of mouse lines selectively bred with natural and acquired immunities.

Science.gov (United States)

Narahara, Hiroki; Sakai, Eri; Katayama, Masafumi; Ohtomo, Yukiko; Yamamoto, Kanako; Takemoto, Miki; Aso, Hisashi; Ohwada, Shyuichi; Mohri, Yasuaki; Nishimori, Katsuhiko; Isogai, Emiko; Yamaguchi, Takahiro; Fukuda, Tomokazu

2012-05-01

Genetic improvement of resistance to infectious diseases is a challenging goal in animal breeding. Infection resistance involves multiple immunological characteristics, including natural and acquired immunity. In the present study, we developed an experimental model based on genetic selection, to improve immunological phenotypes. We selectively established three mouse lines based on phagocytic activity, antibody production and the combination of these two phenotypes. We analyzed the immunological characteristics of these lines using a lipopolysaccharide (LPS), which is one of the main components of Gram-negative bacteria. An intense immunological reaction was induced in each of the three mouse lines. Severe loss of body weight and liver damage were observed, and a high level of cytokine messenger RNA was detected in the liver tissue. The mouse line established using a combination of the two selection standards showed unique characteristics relative to the mouse lines selected on the basis of a single phenotype. Our results indicate that genetic selection and breeding is effective, even for immunological phenotypes with a relatively low heritability. Thus, it may be possible to improve resistance to infectious diseases by means of genetic selection. © 2011 The Authors. Animal Science Journal © 2011 Japanese Society of Animal Science.

The genetic basis of strain-dependent differences in the early phase of radiation injury in mouse lung

International Nuclear Information System (INIS)

Franko, A.J.; Sharplin, J.; Ward, W.F.; Hinz, J.M.

1991-01-01

Substantial differences between mouse strains have been reported in the lesions present in the lung during the early phase of radiation injury. Some strains show only classical pneumonitis, while other strains develop substantial fibrosis and hyaline membranes which contribute appreciably to respiratory insufficiency, in addition to pneumonitis. Other strains are intermediate between these extremes. These differences correlate with intrinsic differences in activities of lung plasminogen activator and angiotensin converting enzyme. The genetic basis of these differences was assessed by examining histologically the early reaction in lungs of seven murine hybrids available commercially after whole-thorax irradiation. Crosses between fibrosing and nonfibrosing parents were uniformly nonfibrosing, and crosses between fibrosing and intermediate parents were uniformly intermediate. No evidence of sex linkage was seen. Thus the phenotype in which fibrosis is found is controlled by autosomal recessive determinants. Strains prone to radiation-induced pulmonary fibrosis and hyaline membranes exhibited intrinsically lower activities of lung plasminogen activator and angiotensin converting enzyme than either the nonfibrosing strains or the nonfibrosing hybrid crosses. The median time of death of the hybrids was genetically determined primarily by the longest-lived parent regardless of the types of lesions expressed

Expansion of the gateway multisite recombination cloning toolkit.

Science.gov (United States)

Shearin, Harold K; Dvarishkis, Alisa R; Kozeluh, Craig D; Stowers, R Steven

2013-01-01

Precise manipulation of transgene expression in genetic model organisms has led to advances in understanding fundamental mechanisms of development, physiology, and genetic disease. Transgene construction is, however, a precondition of transgene expression, and often limits the rate of experimental progress. Here we report an expansion of the modular Gateway MultiSite recombination-cloning platform for high efficiency transgene assembly. The expansion includes two additional destination vectors and entry clones for the LexA binary transcription system, among others. These new tools enhance the expression levels possible with Gateway MultiSite generated transgenes and make possible the generation of LexA drivers and reporters with Gateway MultiSite cloning. In vivo data from transgenic Drosophila functionally validating each novel component are presented and include neuronal LexA drivers, LexAop2 red and green fluorescent synaptic vesicle reporters, TDC2 and TRH LexA, GAL4, and QF drivers, and LexAop2, UAS, and QUAS channelrhodopsin2 T159C reporters.

A catalog of the mouse gut metagenome

DEFF Research Database (Denmark)

Xiao, Liang; Feng, Qiang; Liang, Suisha

2015-01-01

laboratories and fed either a low-fat or high-fat diet. Similar to the human gut microbiome, >99% of the cataloged genes are bacterial. We identified 541 metagenomic species and defined a core set of 26 metagenomic species found in 95% of the mice. The mouse gut microbiome is functionally similar to its human......We established a catalog of the mouse gut metagenome comprising ∼2.6 million nonredundant genes by sequencing DNA from fecal samples of 184 mice. To secure high microbiome diversity, we used mouse strains of diverse genetic backgrounds, from different providers, kept in different housing...... counterpart, with 95.2% of its Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologous groups in common. However, only 4.0% of the mouse gut microbial genes were shared (95% identity, 90% coverage) with those of the human gut microbiome. This catalog provides a useful reference for future studies....

genetics, epigenetics and the story of mutual antagonisms

Indian Academy of Sciences (India)

Recent years have seen a rapid growth in mouse genetics resources that support research into fundamental mechanisms in organogenesis, including those controlling mammalian sex determinations. Numerous mouse mutants have shed light on molecular pathways of cell fate specification during gonadogenesis and the ...

Genetic deletion of amphiregulin restores the normal skin phenotype in a mouse model of the human skin disease tylosis

Directory of Open Access Journals (Sweden)

Vishnu Hosur

2017-08-01

Full Text Available In humans, gain-of-function (GOF mutations in RHBDF2 cause the skin disease tylosis. We generated a mouse model of human tylosis and show that GOF mutations in RHBDF2 cause tylosis by enhancing the amount of amphiregulin (AREG secretion. Furthermore, we show that genetic disruption of AREG ameliorates skin pathology in mice carrying the human tylosis disease mutation. Collectively, our data suggest that RHBDF2 plays a critical role in regulating EGFR signaling and its downstream events, including development of tylosis, by facilitating enhanced secretion of AREG. Thus, targeting AREG could have therapeutic benefit in the treatment of tylosis.

Humanized mouse models: Application to human diseases.

Science.gov (United States)

Ito, Ryoji; Takahashi, Takeshi; Ito, Mamoru

2018-05-01

Humanized mice are superior to rodents for preclinical evaluation of the efficacy and safety of drug candidates using human cells or tissues. During the past decade, humanized mouse technology has been greatly advanced by the establishment of novel platforms of genetically modified immunodeficient mice. Several human diseases can be recapitulated using humanized mice due to the improved engraftment and differentiation capacity of human cells or tissues. In this review, we discuss current advanced humanized mouse models that recapitulate human diseases including cancer, allergy, and graft-versus-host disease. © 2017 Wiley Periodicals, Inc.

Population structure and expansion of kuruma shrimp ( Penaeus ...

African Journals Online (AJOL)

Sequence analyses on the specific intron from the elongation factor-1α gene were conducted to examine the population genetic structure and expansion of kuruma shrimp (Penaeus japonicus) off Taiwan. Five populations including 119 individuals were separately sampled from the north of East China Sea (ECS), west of ...

The neurological mouse mutations jittery and hesitant are allelic and map to the region of mouse chromosome 10 homologous to 19p13.3

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Kapfhamer, D.; Sufalko, D.; Warren, S. [Univ. of Michigan, Ann Arbor, MI (United States)] [and others

1996-08-01

Jittery (ji) is a recessive mouse mutation on Chromosome 10 characterized by progressive ataxic gait, dystonic movements, spontaneus seizures, and death by dehydration/starvation before fertility. Recently, a viable neurological recessive mutation, hesitant, was discovered. It is characterized by hesitant, uncoordinated movements, exaggerated stepping of the hind limbs, and reduced fertility in males. In a complementation test and by genetic mapping we have shown here that hesitant and jittery are allelic. Using several large intersubspecific backcrosses and intercrosses we have genetically mapped ji near the marker Amh and microsatellite markers D10Mit7, D10Mit21, and D10Mit23. The linked region of mouse Chromosome 10 is homologous to human 19p13.3, to which several human ataxia loci have recently been mapped. By excluding genes that map to human 21q22.3 (Pfkl) and 12q23 (Nfyb), we conclude that jittery is not likely to be a genetic mouse model for human Unverricht-Lundborg progressive myoclonus epilepsy (EPM1) on 21q22.3 nor for spinocerebellar ataxia II (SCA2) on 12q22-q24. The closely linked markers presented here will facilitate positional cloning of the ji gene. 31 refs., 2 figs.

Genetic conflict outweighs heterogametic incompatibility in the mouse hybrid zone?

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Dufková Petra

2008-10-01

Full Text Available Abstract Background The Mus musculus musculus/M. m. domesticus contact zone in Europe is characterised by sharp frequency discontinuities for sex chromosome markers at the centre of wider clines in allozyme frequencies. Results We identify a triangular area (approximately 330 km2 where the musculus Y chromosome introgresses across this front for up to 22 km into domesticus territory. Introgression of the Y chromosome is accompanied by a perturbation of the census sex ratio: the sex ratio is significantly female biased in musculus localities and domesticus localities lacking Y chromosome introgression. In contrast, where the musculus Y is detected in domesticus localities, the sex ratio is close to parity, and significantly different from both classes of female biased localities. The geographic position of an abrupt cline in an X chromosome marker, and autosomal clines centred on the same position, seem unaffected by the musculus Y introgression. Conclusion We conclude that sex ratio distortion is playing a role in the geographic separation of speciation genes in this section of the mouse hybrid zone. We suggest that clines for genes involved in sex-ratio distortion have escaped from the centre of the mouse hybrid zone, causing a decay in the barrier to gene flow between the two house mouse taxa.

Shrub expansion in SW Greenland

DEFF Research Database (Denmark)

Jørgensen, Rasmus Halfdan

Arctic regions have experienced higher temperatures in recent decades, and the warming trend is projected to continue in the coming years. Arctic ecosystems are considered to be particularly vulnerable to climate change. Expansion of shrubs has been observed widely in tundra areas across the Arctic......, and has a range of ecosystem effects where it occurs. Shrub expansion has to a large extend been attributed to increasing temperatures over the past century, while grazing and human disturbance have received less attention. Alnus viridis ssp. crispa is a common arctic species that contributes...... to increasing shrub cover. Despite this, there is only limited experimental evidence that growth of the species responds to warming. Plant populations in fragmented and isolated locations could face problems adapting to a warming climate due to limited genetic variation and restricted migration from southern...

A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression.

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Bruno L Lima

2010-11-01

Full Text Available Marfan syndrome is an autosomal dominant disease of connective tissue caused by mutations in the fibrillin-1 encoding gene FBN1. Patients present cardiovascular, ocular and skeletal manifestations, and although being fully penetrant, MFS is characterized by a wide clinical variability both within and between families. Here we describe a new mouse model of MFS that recapitulates the clinical heterogeneity of the syndrome in humans. Heterozygotes for the mutant Fbn1 allele mgΔloxPneo, carrying the same internal deletion of exons 19-24 as the mgΔ mouse model, present defective microfibrillar deposition, emphysema, deterioration of aortic wall and kyphosis. However, the onset of a clinical phenotypes is earlier in the 129/Sv than in C57BL/6 background, indicating the existence of genetic modifiers of MFS between these two mouse strains. In addition, we characterized a wide clinical variability within the 129/Sv congenic heterozygotes, suggesting involvement of epigenetic factors in disease severity. Finally, we show a strong negative correlation between overall levels of Fbn1 expression and the severity of the phenotypes, corroborating the suggested protective role of normal fibrillin-1 in MFS pathogenesis, and supporting the development of therapies based on increasing Fbn1 expression.

Anti-angiogenesis therapy based on the bone marrow-derived stromal cells genetically engineered to express sFlt-1 in mouse tumor model

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Chen X-C

2008-10-01

Full Text Available Abstract Background Bone marrow-derived stromal cells (BMSCs are important for development, tissue cell replenishment, and wound healing in physiological and pathological conditions. BMSCs were found to preferably reach sites undergoing the process of cell proliferation, such as wound and tumor, suggesting that BMSCs may be used as a vehicle for gene therapy of tumor. Methods Mouse BMSCs were loaded with recombinant adenoviruses which express soluble Vascular Endothelial Growth Factor Receptor-1 (sFlt-1. The anti-angiogenesis of sFlt-1 in BMSCs was determined using endothelial cells proliferation inhibition assay and alginate encapsulation assay. The anti-tumor effects of BMSCs expressing sFlt-1 through tail-vein infusion were evaluated in two mouse tumor metastases models. Results BMSCs genetically modified with Adv-GFP-sFlt-1 could effectively express and secret sFlt-1. BMSCs loaded with sFlt-1 gene could preferentially home to tumor loci and decrease lung metastases and prolong lifespan in mouse tumor model through inducing anti-angiogenesis and apoptosis in tumors. Conclusion We demonstrated that BMSCs might be employed as a promising vehicle for tumor gene therapy which can effectively not only improve the concentration of anticancer therapeutics in tumors, but also modify the tumor microenvironment.

Polarization in Raman spectroscopy helps explain bone brittleness in genetic mouse models

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Makowski, Alexander J.; Pence, Isaac J.; Uppuganti, Sasidhar; Zein-Sabatto, Ahbid; Huszagh, Meredith C.; Mahadevan-Jansen, Anita; Nyman, Jeffry S.

2014-11-01

Raman spectroscopy (RS) has been extensively used to characterize bone composition. However, the link between bone biomechanics and RS measures is not well established. Here, we leveraged the sensitivity of RS polarization to organization, thereby assessing whether RS can explain differences in bone toughness in genetic mouse models for which traditional RS peak ratios are not informative. In the selected mutant mice-activating transcription factor 4 (ATF4) or matrix metalloproteinase 9 (MMP9) knock-outs-toughness is reduced but differences in bone strength do not exist between knock-out and corresponding wild-type controls. To incorporate differences in the RS of bone occurring at peak shoulders, a multivariate approach was used. Full spectrum principal components analysis of two paired, orthogonal bone orientations (relative to laser polarization) improved genotype classification and correlation to bone toughness when compared to traditional peak ratios. When applied to femurs from wild-type mice at 8 and 20 weeks of age, the principal components of orthogonal bone orientations improved age classification but not the explanation of the maturation-related increase in strength. Overall, increasing polarization information by collecting spectra from two bone orientations improves the ability of multivariate RS to explain variance in bone toughness, likely due to polarization sensitivity to organizational changes in both mineral and collagen.

Mouse Models of Gastric Cancer

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Hayakawa, Yoku; Fox, James G.; Gonda, Tamas; Worthley, Daniel L.; Muthupalani, Sureshkumar; Wang, Timothy C.

2013-01-01

Animal models have greatly enriched our understanding of the molecular mechanisms of numerous types of cancers. Gastric cancer is one of the most common cancers worldwide, with a poor prognosis and high incidence of drug-resistance. However, most inbred strains of mice have proven resistant to gastric carcinogenesis. To establish useful models which mimic human gastric cancer phenotypes, investigators have utilized animals infected with Helicobacter species and treated with carcinogens. In addition, by exploiting genetic engineering, a variety of transgenic and knockout mouse models of gastric cancer have emerged, such as INS-GAS mice and TFF1 knockout mice. Investigators have used the combination of carcinogens and gene alteration to accelerate gastric cancer development, but rarely do mouse models show an aggressive and metastatic gastric cancer phenotype that could be relevant to preclinical studies, which may require more specific targeting of gastric progenitor cells. Here, we review current gastric carcinogenesis mouse models and provide our future perspectives on this field. PMID:24216700

Mouse models of Fanconi anemia

International Nuclear Information System (INIS)

Parmar, Kalindi; D'Andrea, Alan; Niedernhofer, Laura J.

2009-01-01

Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis of proliferating cells. To date, 13 complementation groups of Fanconi anemia were identified. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability.

Mouse models of Fanconi anemia

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Parmar, Kalindi; D' Andrea, Alan [Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115 (United States); Niedernhofer, Laura J., E-mail: niedernhoferl@upmc.edu [Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine and Cancer Institute, 5117 Centre Avenue, Hillman Cancer Center, Research Pavilion 2.6, Pittsburgh, PA 15213-1863 (United States)

2009-07-31

Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis of proliferating cells. To date, 13 complementation groups of Fanconi anemia were identified. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability.

Genetic risks of ionizing radiation

International Nuclear Information System (INIS)

Sankaranarayanan, K.

1990-01-01

Quantitative genetic risk estimation is made using two methods: the direct method, and the doubling dose (DD) method. The doubling dose currently used is 1 Gy for low LET, low dose, low dose rate irradiation, and is based on mouse data. Tables present the 1988 UNSCEAR estimates of genetic risk using both methods. (L.L.) (Tab.)

PPARγ ligand production is tightly linked to clonal expansion during initiation of adipocyte differentiation

DEFF Research Database (Denmark)

Hallenborg, Philip; Petersen, Rasmus Koefoed; Feddersen, Søren

2014-01-01

of differentiation. Concomitant with agonist production, murine fibroblasts undergo two rounds of mitosis referred to as mitotic clonal expansion. Here we show that mouse embryonic fibroblasts deficient in either of two cell cycle inhibitors, the transcription factor p53 or its target gene encoding the cyclin...... cycle inhibitory compounds decreased PPAR ligand production in differentiating 3T3-L1 preadipocytes. Furthermore, these inhibitors abolished the release of arachidonic acid induced by the hormonal cocktail initiating adipogenesis. Collectively, our results suggest that murine fibroblasts require clonal...... expansion for PPAR ligand production at the onset of adipocyte differentiation....

Evolution of density-dependent movement during experimental range expansions.

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Fronhofer, E A; Gut, S; Altermatt, F

2017-12-01

Range expansions and biological invasions are prime examples of transient processes that are likely impacted by rapid evolutionary changes. As a spatial process, range expansions are driven by dispersal and movement behaviour. Although it is widely accepted that dispersal and movement may be context-dependent, for instance density-dependent, and best represented by reaction norms, the evolution of density-dependent movement during range expansions has received little experimental attention. We therefore tested current theory predicting the evolution of increased movement at low densities at range margins using highly replicated and controlled range expansion experiments across multiple genotypes of the protist model system Tetrahymena thermophila. Although rare, we found evolutionary changes during range expansions even in the absence of initial standing genetic variation. Range expansions led to the evolution of negatively density-dependent movement at range margins. In addition, we report the evolution of increased intrastrain competitive ability and concurrently decreased population growth rates in range cores. Our findings highlight the importance of understanding movement and dispersal as evolving reaction norms and plastic life-history traits of central relevance for range expansions, biological invasions and the dynamics of spatially structured systems in general. © 2017 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2017 European Society For Evolutionary Biology.

GABAergic synapse properties may explain genetic variation in hippocampal network oscillations in mice

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Tim S Heistek

2010-06-01

Full Text Available Cognitive ability and the properties of brain oscillation are highly heritable in humans. Genetic variation underlying oscillatory activity might give rise to differences in cognition and behavior. How genetic diversity translates into altered properties of oscillations and synchronization of neuronal activity is unknown. To address this issue, we investigated cellular and synaptic mechanisms of hippocampal fast network oscillations in eight genetically distinct inbred mouse strains. The frequency of carbachol-induced oscillations differed substantially between mouse strains. Since GABAergic inhibition sets oscillation frequency, we studied the properties of inhibitory synaptic inputs (IPSCs received by CA3 and CA1 pyramidal cells of three mouse strains that showed the highest, lowest and intermediate frequencies of oscillations. In CA3 pyramidal cells, the frequency of rhythmic IPSC input showed the same strain differences as the frequency of field oscillations. Furthermore, IPSC decay times in both CA1 and CA3 pyramidal cells were faster in mouse strains with higher oscillation frequencies than in mouse strains with lower oscillation frequency, suggesting that differences in GABAA-receptor subunit composition exist between these strains. Indeed, gene expression of GABAA-receptor β2 (Gabrb2 and β3 (Gabrb2 subunits was higher in mouse strains with faster decay kinetics compared with mouse strains with slower decay kinetics. Hippocampal pyramidal neurons in mouse strains with higher oscillation frequencies and faster decay kinetics fired action potential at higher frequencies. These data indicate that differences in genetic background may result in different GABAA-receptor subunit expression, which affects the rhythm of pyramidal neuron firing and fast network activity through GABA synapse kinetics.

The mouse as a model organism in aging research: usefulness, pitfalls and possibilities.

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Vanhooren, Valerie; Libert, Claude

2013-01-01

The mouse has become the favorite mammalian model. Among the many reasons for this privileged position of mice is their genetic proximity to humans, the possibilities of genetically manipulating their genomes and the availability of many tools, mutants and inbred strains. Also in the field of aging, mice have become very robust and reliable research tools. Since laboratory mice have a life expectancy of only a few years, genetic approaches and other strategies for intervening in aging can be tested by examining their effects on life span and aging parameters during the relatively short period of, for example, a PhD project. Moreover, experiments on mice with an extended life span as well as on mice demonstrating signs of (segmental) premature aging, together with genetic mapping strategies, have provided novel insights into the fundamental processes that drive aging. Finally, the results of studies on caloric restriction and pharmacological anti-aging treatments in mice have a high degree of relevance to humans. In this paper, we review a number of recent genetic mapping studies that have yielded novel insights into the aging process. We discuss the value of the mouse as a model for testing interventions in aging, such as caloric restriction, and we critically discuss mouse strains with an extended or a shortened life span as models of aging. Copyright © 2012 Elsevier B.V. All rights reserved.

Genetic dissection of a cell-autonomous neurodegenerative disorder: lessons learned from mouse models of Niemann-Pick disease type C

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Manuel E. Lopez

2013-09-01

Full Text Available Understanding neurodegenerative disease progression and its treatment requires the systematic characterization and manipulation of relevant cell types and molecular pathways. The neurodegenerative lysosomal storage disorder Niemann-Pick disease type C (NPC is highly amenable to genetic approaches that allow exploration of the disease biology at the organismal, cellular and molecular level. Although NPC is a rare disease, genetic analysis of the associated neuropathology promises to provide insight into the logic of disease neural circuitry, selective neuron vulnerability and neural-glial interactions. The ability to control the disorder cell-autonomously and in naturally occurring spontaneous animal models that recapitulate many aspects of the human disease allows for an unparalleled dissection of the disease neurobiology in vivo. Here, we review progress in mouse-model-based studies of NPC disease, specifically focusing on the subtype that is caused by a deficiency in NPC1, a sterol-binding late endosomal membrane protein involved in lipid trafficking. We also discuss recent findings and future directions in NPC disease research that are pertinent to understanding the cellular and molecular mechanisms underlying neurodegeneration in general.

Cellular, molecular and functional characterisation of YAC transgenic mouse models of Friedreich ataxia.

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Sara Anjomani Virmouni

Full Text Available Friedreich ataxia (FRDA is an autosomal recessive neurodegenerative disorder, caused by a GAA repeat expansion mutation within intron 1 of the FXN gene. We have previously established and performed preliminary characterisation of several human FXN yeast artificial chromosome (YAC transgenic FRDA mouse models containing GAA repeat expansions, Y47R (9 GAA repeats, YG8R (90 and 190 GAA repeats and YG22R (190 GAA repeats.We now report extended cellular, molecular and functional characterisation of these FXN YAC transgenic mouse models. FXN transgene copy number analysis of the FRDA mice demonstrated that the YG22R and Y47R lines each have a single copy of the FXN transgene while the YG8R line has two copies. Single integration sites of all transgenes were confirmed by fluorescence in situ hybridisation (FISH analysis of metaphase and interphase chromosomes. We identified significant functional deficits, together with a degree of glucose intolerance and insulin hypersensitivity, in YG8R and YG22R FRDA mice compared to Y47R and wild-type control mice. We also confirmed increased somatic GAA repeat instability in the cerebellum and brain of YG22R and YG8R mice, together with significantly reduced levels of FXN mRNA and protein in the brain and liver of YG8R and YG22R compared to Y47R.Together these studies provide a detailed characterisation of our GAA repeat expansion-based YAC transgenic FRDA mouse models that will help investigations of FRDA disease mechanisms and therapy.

A mouse model of spontaneous preterm birth based on the genetic ablation of biglycan and decorin

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Calmus, Megan L.; Macksoud, Elyse E.; Tucker, Richard; Iozzo, Renato V.; Lechner, Beatrice E.

2011-01-01

Preterm premature rupture of membranes is responsible for one third of preterm births. Ehlers-Danlos syndrome (EDS) is associated with preterm premature rupture of membranes in humans. Notably, an EDS variant is caused by a genetic mutation resulting in abnormal secretion of biglycan and decorin, two small leucine-rich proteoglycans highly expressed in reproductive tissues. Because biglycan/decorin null mutant (Bgn−/−Dcn−/−) mice demonstrate phenotypic changes similar to EDS, we utilized this model to test whether either or both biglycan and decorin play a role in the attainment of successful term gestation. Wild-type, biglycan null mutant, decorin null mutant and biglycan/decorin null mutant pregnancies were assessed for length of gestation, pup and placenta weight and litter size. Quantitative real-time polymerase chain reaction was performed to measure biglycan and decorin gene expression and immunohistochemistry was performed to assess protein expression in placenta and fetal membranes at embryonic day E12, E15 and E18. Bgn−/−Dcn−/− dams displayed preterm birth, whereas the possession of at least two biglycan or decorin wild-type alleles was protective of preterm birth. Bgn−/−Dcn−/− pups were decreased at postnatal day P1 but not at E18. Biglycan and decorin were upregulated in the placenta in each other’s absence and were developmentally regulated in fetal membranes, suggesting that these two proteoglycans demonstrate genetic complementation and contribute to gestational success in a dose dependent manner. Thus, the biglycan/decorin null mutant mouse is a model of genetically induced preterm birth and perinatal loss. This model presents novel targets for preventive or therapeutic manipulation of preterm birth. PMID:21502335

An attempt to distinguish a modified genetic response of the mouse testis to X-ray exposure by the action of a spermatogonial chalone

International Nuclear Information System (INIS)

Cattanach, B.M.; Jones, J.T.; Andrews, S.J.; Crocker, M.

1979-01-01

The results of an experiment designed to distinguish whether the action of a spermatogonial chalone in the mouse testis could modify the genetic response of a depleted stem spermatogonial population to X-radiation are reported. The results are consistent with the view that the stem cell population of the depleted adult testis a few days after damage closely approximates that of the early post-natal or immature animal, do not provide any indication that the testis extract in any way influence the response of the depleted testis to the 500-rad challenging dose. The yield of genetic damage was almost identical to that in the two control groups and the sterile period and testis weight data provided little reason to suspect that the amount of spermatogonial killing was altered. (Auth.)

Genetic evidence of paleolithic colonization and neolithic expansion of modern humans on the tibetan plateau.

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Qi, Xuebin; Cui, Chaoying; Peng, Yi; Zhang, Xiaoming; Yang, Zhaohui; Zhong, Hua; Zhang, Hui; Xiang, Kun; Cao, Xiangyu; Wang, Yi; Ouzhuluobu; Basang; Ciwangsangbu; Bianba; Gonggalanzi; Wu, Tianyi; Chen, Hua; Shi, Hong; Su, Bing

2013-08-01

Tibetans live on the highest plateau in the world, their current population size is approximately 5 million, and most of them live at an altitude exceeding 3,500 m. Therefore, the Tibetan Plateau is a remarkable area for cultural and biological studies of human population history. However, the chronological profile of the Tibetan Plateau's colonization remains an unsolved question of human prehistory. To reconstruct the prehistoric colonization and demographic history of modern humans on the Tibetan Plateau, we systematically sampled 6,109 Tibetan individuals from 41 geographic populations across the entire region of the Tibetan Plateau and analyzed the phylogeographic patterns of both paternal (n = 2,354) and maternal (n = 6,109) lineages as well as genome-wide single nucleotide polymorphism markers (n = 50) in Tibetan populations. We found that there have been two distinct, major prehistoric migrations of modern humans into the Tibetan Plateau. The first migration was marked by ancient Tibetan genetic signatures dated to approximately 30,000 years ago, indicating that the initial peopling of the Tibetan Plateau by modern humans occurred during the Upper Paleolithic rather than Neolithic. We also found evidences for relatively young (only 7-10 thousand years old) shared Y chromosome and mitochondrial DNA haplotypes between Tibetans and Han Chinese, suggesting a second wave of migration during the early Neolithic. Collectively, the genetic data indicate that Tibetans have been adapted to a high altitude environment since initial colonization of the Tibetan Plateau in the early Upper Paleolithic, before the last glacial maximum, followed by a rapid population expansion that coincided with the establishment of farming and yak pastoralism on the Plateau in the early Neolithic.

Genetics and developmental biology

International Nuclear Information System (INIS)

Barnett, W.E.

1975-01-01

Progress is reported on research activities in the fields of mutagenesis in Haemophilus influenzae and Escherichia coli; radioinduced chromosomal aberrations in mammalian germ cells; effects of uv radiation on xeroderma pigmentosum skin cells; mutations in Chinese hamster ovary cells; radioinduced hemoglobin variants in the mouse; analysis of mutants in yeast; Drosophila genetics; biochemical genetics of Neurospora; DNA polymerase activity in Xenopus laevis oocytes; uv-induced damage in Bacillus subtilis; and others

A genome survey sequencing of the Java mouse deer (Tragulus javanicus) adds new aspects to the evolution of lineage specific retrotransposons in Ruminantia (Cetartiodactyla).

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Gallus, S; Kumar, V; Bertelsen, M F; Janke, A; Nilsson, M A

2015-10-25

Ruminantia, the ruminating, hoofed mammals (cow, deer, giraffe and allies) are an unranked artiodactylan clade. Around 50-60 million years ago the BovB retrotransposon entered the ancestral ruminantian genome through horizontal gene transfer. A survey genome screen using 454-pyrosequencing of the Java mouse deer (Tragulus javanicus) and the lesser kudu (Tragelaphus imberbis) was done to investigate and to compare the landscape of transposable elements within Ruminantia. The family Tragulidae (mouse deer) is the only representative of Tragulina and phylogenetically important, because it represents the earliest divergence in Ruminantia. The data analyses show that, relative to other ruminantian species, the lesser kudu genome has seen an expansion of BovB Long INterspersed Elements (LINEs) and BovB related Short INterspersed Elements (SINEs) like BOVA2. In comparison the genome of Java mouse deer has fewer BovB elements than other ruminants, especially Bovinae, and has in addition a novel CHR-3 SINE most likely propagated by LINE-1. By contrast the other ruminants have low amounts of CHR SINEs but high numbers of actively propagating BovB-derived and BovB-propagated SINEs. The survey sequencing data suggest that the transposable element landscape in mouse deer (Tragulina) is unique among Ruminantia, suggesting a lineage specific evolutionary trajectory that does not involve BovB mediated retrotransposition. This shows that the genomic landscape of mobile genetic elements can rapidly change in any lineage. Copyright © 2015 Elsevier B.V. All rights reserved.

Stimulation of growth in the little mouse.

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Beamer, W H; Eicher, E M

1976-10-01

The new mouse mutation little (lit) in the homozygous state causes a pituitary deficiency involving at least growth hormone (GH) and prolactin. The resultant growth failure of lit/lit mice was shown to be reversed by experimental conditions that enhanced levels of GH or GH and prolactin in the circulation. Two measures of growth, actual weight gain and bone dimension, were significantly improved by the physiological processes of pregnancy and pseudopregnancy, by extra-sellar graft of a normal mouse pituitary, and by treatment with GH but not prolactin. These data confirmed pituitary dysfunction as the basic defect caused by the mutation lit and showed that the GH deficiency is responsible for growth failure. However, the biological site of gene action, the pituitary or hypothalamus, has not been established. Little mice exhibit a number of characteristics similar to those of human genetic ateleotic dwarfism Type 1, namely genetic inheritance, time of onset of growth retardation, proportionate skeletal size reduction, and pituitary GH deficiency.

Huntingtin interacting proteins are genetic modifiers of neurodegeneration.

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Linda S Kaltenbach

2007-05-01

Full Text Available Huntington's disease (HD is a fatal neurodegenerative condition caused by expansion of the polyglutamine tract in the huntingtin (Htt protein. Neuronal toxicity in HD is thought to be, at least in part, a consequence of protein interactions involving mutant Htt. We therefore hypothesized that genetic modifiers of HD neurodegeneration should be enriched among Htt protein interactors. To test this idea, we identified a comprehensive set of Htt interactors using two complementary approaches: high-throughput yeast two-hybrid screening and affinity pull down followed by mass spectrometry. This effort led to the identification of 234 high-confidence Htt-associated proteins, 104 of which were found with the yeast method and 130 with the pull downs. We then tested an arbitrary set of 60 genes encoding interacting proteins for their ability to behave as genetic modifiers of neurodegeneration in a Drosophila model of HD. This high-content validation assay showed that 27 of 60 orthologs tested were high-confidence genetic modifiers, as modification was observed with more than one allele. The 45% hit rate for genetic modifiers seen among the interactors is an order of magnitude higher than the 1%-4% typically observed in unbiased genetic screens. Genetic modifiers were similarly represented among proteins discovered using yeast two-hybrid and pull-down/mass spectrometry methods, supporting the notion that these complementary technologies are equally useful in identifying biologically relevant proteins. Interacting proteins confirmed as modifiers of the neurodegeneration phenotype represent a diverse array of biological functions, including synaptic transmission, cytoskeletal organization, signal transduction, and transcription. Among the modifiers were 17 loss-of-function suppressors of neurodegeneration, which can be considered potential targets for therapeutic intervention. Finally, we show that seven interacting proteins from among 11 tested were able to

The synthesis paradigm in genetics.

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Rice, William R

2014-02-01

Experimental genetics with model organisms and mathematically explicit genetic theory are generally considered to be the major paradigms by which progress in genetics is achieved. Here I argue that this view is incomplete and that pivotal advances in genetics--and other fields of biology--are also made by synthesizing disparate threads of extant information rather than generating new information from experiments or formal theory. Because of the explosive expansion of information in numerous "-omics" data banks, and the fragmentation of genetics into numerous subdisciplines, the importance of the synthesis paradigm will likely expand with time.

Engineered artificial antigen presenting cells facilitate direct and efficient expansion of tumor infiltrating lymphocytes

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Coukos George

2011-08-01

Full Text Available Abstract Background Development of a standardized platform for the rapid expansion of tumor-infiltrating lymphocytes (TILs with anti-tumor function from patients with limited TIL numbers or tumor tissues challenges their clinical application. Methods To facilitate adoptive immunotherapy, we applied genetically-engineered K562 cell-based artificial antigen presenting cells (aAPCs for the direct and rapid expansion of TILs isolated from primary cancer specimens. Results TILs outgrown in IL-2 undergo rapid, CD28-independent expansion in response to aAPC stimulation that requires provision of exogenous IL-2 cytokine support. aAPCs induce numerical expansion of TILs that is statistically similar to an established rapid expansion method at a 100-fold lower feeder cell to TIL ratio, and greater than those achievable using anti-CD3/CD28 activation beads or extended IL-2 culture. aAPC-expanded TILs undergo numerical expansion of tumor antigen-specific cells, remain amenable to secondary aAPC-based expansion, and have low CD4/CD8 ratios and FOXP3+ CD4+ cell frequencies. TILs can also be expanded directly from fresh enzyme-digested tumor specimens when pulsed with aAPCs. These "young" TILs are tumor-reactive, positively skewed in CD8+ lymphocyte composition, CD28 and CD27 expression, and contain fewer FOXP3+ T cells compared to parallel IL-2 cultures. Conclusion Genetically-enhanced aAPCs represent a standardized, "off-the-shelf" platform for the direct ex vivo expansion of TILs of suitable number, phenotype and function for use in adoptive immunotherapy.

Effect of external volume expansion on the survival of fat grafts

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Raghuveer Reddy

2016-01-01

Full Text Available Introduction: External volume expansion (EVE is one method, which has been utilised for increasing the survival of adipose tissue grafts. EVE releases positive pressure from the graft and also induces intense levels of edema that decreases diffusion of metabolites essential for graft survival initially. The ideal timing of external volume expansion in relation to the injection of the fat to facilitate survival is not yet clear. Aims and Objectives: This study was undertaken to evaluate and compare the efficacy of external volume expansion applied at variable time points in relation to the injection of the fat. Materials and Methods: Athymic mouse was the animal model and human lipo-aspirate mixed with PRP was used as graft. An indigenous dome shaped silicone device was fabricated to deliver a negative pressure of -30 mm of Hg. The EVE was applied at variable time intervals. At the end of 4 weeks visual, histological and radiological features of the injected fat were compared. The adipose tissue was stained with human vimentin to ascertain the origin of the retained fat. Results: All the grafts, which had EVE, had significantly better volume retention and vascularity. The groups which underwent a delayed EVE or prior expansion followed by concomitant graft injection and expansion showed the most optimal vascularity and graft retention. Conclusions: A delayed EVE or prior expansion followed by concomitant graft injection and expansion may be the most ideal combinations to optimize graft take. However, on account of the relatively small sample size, there was a limitation in drawing statistically significant conclusions for certain variables.

Tbx3 Promotes Liver Bud Expansion During Mouse Development by Suppression of Cholangiocyte Differentiation

NARCIS (Netherlands)

Lüdtke, Timo H.-W.; Christoffels, Vincent M.; Petry, Marianne; Kispert, Andreas

2009-01-01

After specification of the hepatic endoderm, mammalian liver organogenesis progresses through a series of morphological stages that culminate in the migration of hepatocytes into the underlying mesenchyme to populate the hepatic lobes. Here, we show that in the mouse the transcriptional repressor

The endoplasmic reticulum exerts control over organelle streaming during cell expansion.

Science.gov (United States)

Stefano, Giovanni; Renna, Luciana; Brandizzi, Federica

2014-03-01

Cytoplasmic streaming is crucial for cell homeostasis and expansion but the precise driving forces are largely unknown. In plants, partial loss of cytoplasmic streaming due to chemical and genetic ablation of myosins supports the existence of yet-unknown motors for organelle movement. Here we tested a role of the endoplasmic reticulum (ER) as propelling force for cytoplasmic streaming during cell expansion. Through quantitative live-cell analyses in wild-type Arabidopsis thaliana cells and mutants with compromised ER structure and streaming, we demonstrate that cytoplasmic streaming undergoes profound changes during cell expansion and that it depends on motor forces co-exerted by the ER and the cytoskeleton.

Dentate gyrus network dysfunctions precede the symptomatic phase in a genetic mouse model of seizures

Directory of Open Access Journals (Sweden)

Oana eToader

2013-08-01

Full Text Available Neuronal circuit disturbances that lead to hyperexcitability in the cortico-hippocampal network are one of the landmarks of temporal lobe epilepsy. The dentate gyrus (DG network plays an important role in regulating the excitability of the entire hippocampus by filtering and integrating information received via the perforant path. Here, we investigated possible epileptogenic abnormalities in the function of the DG neuronal network in the Synapsin II (Syn II knockout mouse (Syn II-/-, a genetic mouse model of epilepsy. Syn II is a presynaptic protein whose deletion in mice reproducibly leads to generalized seizures starting at the age of two months. We made use of a high-resolution microelectrode array (4096 electrodes and patch-clamp recordings, and found that in acute hippocampal slices of young pre-symptomatic (3-6 weeks-old Syn II-/- mice excitatory synaptic output of the mossy fibers is reduced. Moreover, we showed that the main excitatory neurons present in the polymorphic layer of the DG, hilar mossy cells, display a reduced excitability. We also provide evidence of a predominantly inhibitory regulatory output from mossy cells to granule cells, through feed-forward inhibition, and show that the excitatory-inhibitory ratio is increased in both pre-symptomatic and symptomatic Syn II-/- mice. These results support the key role of the hilar mossy neurons in maintaining the normal excitability of the hippocampal network and show that the late epileptic phenotype of the Syn II-/- mice is preceded by neuronal circuitry dysfunctions. Our data provide new insights into the mechanisms of epileptogenesis in the Syn II-/- mice and open the possibility for early diagnosis and therapeutic interventions.

Sparse Statistical Deformation Model for the Analysis of Craniofacial Malformations in the Crouzon Mouse

DEFF Research Database (Denmark)

Ólafsdóttir, Hildur; Hansen, Michael Sass; Sjöstrand, Karl

2007-01-01

Crouzon syndrome is characterised by the premature fusion of cranial sutures. Recently the first genetic Crouzon mouse model was generated. In this study, Micro CT skull scannings of wild-type mice and Crouzon mice were investigated. Using nonrigid registration, a wild-type mouse atlas was built...

Structural covariance networks in the mouse brain.

Science.gov (United States)

Pagani, Marco; Bifone, Angelo; Gozzi, Alessandro

2016-04-01

The presence of networks of correlation between regional gray matter volume as measured across subjects in a group of individuals has been consistently described in several human studies, an approach termed structural covariance MRI (scMRI). Complementary to prevalent brain mapping modalities like functional and diffusion-weighted imaging, the approach can provide precious insights into the mutual influence of trophic and plastic processes in health and pathological states. To investigate whether analogous scMRI networks are present in lower mammal species amenable to genetic and experimental manipulation such as the laboratory mouse, we employed high resolution morphoanatomical MRI in a large cohort of genetically-homogeneous wild-type mice (C57Bl6/J) and mapped scMRI networks using a seed-based approach. We show that the mouse brain exhibits robust homotopic scMRI networks in both primary and associative cortices, a finding corroborated by independent component analyses of cortical volumes. Subcortical structures also showed highly symmetric inter-hemispheric correlations, with evidence of distributed antero-posterior networks in diencephalic regions of the thalamus and hypothalamus. Hierarchical cluster analysis revealed six identifiable clusters of cortical and sub-cortical regions corresponding to previously described neuroanatomical systems. Our work documents the presence of homotopic cortical and subcortical scMRI networks in the mouse brain, thus supporting the use of this species to investigate the elusive biological and neuroanatomical underpinnings of scMRI network development and its derangement in neuropathological states. The identification of scMRI networks in genetically homogeneous inbred mice is consistent with the emerging view of a key role of environmental factors in shaping these correlational networks. Copyright © 2016 Elsevier Inc. All rights reserved.

A transgenic mouse line for molecular genetic analysis of excitatory glutamatergic neurons

DEFF Research Database (Denmark)

Borgius, Lotta; Restrepo, C. Ernesto; Leao, Richardson N.

2010-01-01

Excitatory glutamatergic neurons are part of most of the neuronal circuits in the mammalian nervous system. We have used BAC-technology to generate a BAC-Vglut2::Cre mouse line where Cre expression is driven by the vesicular glutamate transporter 2 (Vglut2) promotor. This BAC-Vglut2::Cre mouse line...... showed specific expression of Cre in Vglut2 positive cells in the spinal cord with no ectopic expression in GABAergic or glycinergic neurons. This mouse line also showed specific Cre expression in Vglut2 positive structures in the brain such as thalamus, hypothalamus, superior colliculi, inferior...... colliculi and deep cerebellar nuclei together with nuclei in the midbrain and hindbrain. Cre-mediated recombination was restricted to Cre expressing cells in the spinal cord and brain and occurred as early as E 12.5. Known Vglut2 positive neurons showed normal electrophysiological properties in the BAC...

Identification of genetic determinants of the sexual dimorphism in CNS autoimmunity.

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Frank Bearoff

Full Text Available Multiple sclerosis (MS is a debilitating chronic inflammatory disease of the nervous system that affects approximately 2.3 million individuals worldwide, with higher prevalence in females, and a strong genetic component. While over 200 MS susceptibility loci have been identified in GWAS, the underlying mechanisms whereby they contribute to disease susceptibility remains ill-defined. Forward genetics approaches using conventional laboratory mouse strains are useful in identifying and functionally dissecting genes controlling disease-relevant phenotypes, but are hindered by the limited genetic diversity represented in such strains. To address this, we have combined the powerful chromosome substitution (consomic strain approach with the genetic diversity of a wild-derived inbred mouse strain. Using experimental allergic encephalomyelitis (EAE, a mouse model of MS, we evaluated genetic control of disease course among a panel of 26 consomic strains of mice inheriting chromosomes from the wild-derived PWD strain on the C57BL/6J background, which models the genetic diversity seen in human populations. Nineteen linkages on 18 chromosomes were found to harbor loci controlling EAE. Of these 19 linkages, six were male-specific, four were female-specific, and nine were non-sex-specific, consistent with a differential genetic control of disease course between males and females. An MS-GWAS candidate-driven bioinformatic analysis using orthologous genes linked to EAE course identified sex-specific and non-sex-specific gene networks underlying disease pathogenesis. An analysis of sex hormone regulation of genes within these networks identified several key molecules, prominently including the MAP kinase family, known hormone-dependent regulators of sex differences in EAE course. Importantly, our results provide the framework by which consomic mouse strains with overall genome-wide genetic diversity, approximating that seen in humans, can be used as a rapid and

Efficacy of Sunitinib and Radiotherapy in Genetically Engineered Mouse Model of Soft-Tissue Sarcoma

International Nuclear Information System (INIS)

Yoon, Sam S.; Stangenberg, Lars; Lee, Yoon-Jin; Rothrock, Courtney; Dreyfuss, Jonathan M.; Baek, Kwan-Hyuck; Waterman, Peter R.; Nielsen, G. Petur; Weissleder, Ralph; Mahmood, Umar; Park, Peter J.; Jacks, Tyler

2009-01-01

Purpose: Sunitinib (SU) is a multitargeted receptor tyrosine kinase inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors. The present study examined SU and radiotherapy (RT) in a genetically engineered mouse model of soft tissue sarcoma (STS). Methods and Materials: Primary extremity STSs were generated in genetically engineered mice. The mice were randomized to treatment with SU, RT (10 Gy x 2), or both (SU+RT). Changes in the tumor vasculature before and after treatment were assessed in vivo using fluorescence-mediated tomography. The control and treated tumors were harvested and extensively analyzed. Results: The mean fluorescence in the tumors was not decreased by RT but decreased 38-44% in tumors treated with SU or SU+RT. The control tumors grew to a mean of 1378 mm 3 after 12 days. SU alone or RT alone delayed tumor growth by 56% and 41%, respectively, but maximal growth inhibition (71%) was observed with the combination therapy. SU target effects were confirmed by loss of target receptor phosphorylation and alterations in SU-related gene expression. Cancer cell proliferation was decreased and apoptosis increased in the SU and RT groups, with a synergistic effect on apoptosis observed in the SU+RT group. RT had a minimal effect on the tumor microvessel density and endothelial cell-specific apoptosis, but SU alone or SU+RT decreased the microvessel density by >66% and induced significant endothelial cell apoptosis. Conclusion: SU inhibited STS growth by effects on both cancer cells and tumor vasculature. SU also augmented the efficacy of RT, suggesting that this combination strategy could improve local control of STS.

Genetic background influences age-related decline in visual and nonvisual retinal responses, circadian rhythms, and sleep☆

Science.gov (United States)

Banks, Gareth; Heise, Ines; Starbuck, Becky; Osborne, Tamzin; Wisby, Laura; Potter, Paul; Jackson, Ian J.; Foster, Russell G.; Peirson, Stuart N.; Nolan, Patrick M.

2015-01-01

The circadian system is entrained to the environmental light/dark cycle via retinal photoreceptors and regulates numerous aspects of physiology and behavior, including sleep. These processes are all key factors in healthy aging showing a gradual decline with age. Despite their importance, the exact mechanisms underlying this decline are yet to be fully understood. One of the most effective tools we have to understand the genetic factors underlying these processes are genetically inbred mouse strains. The most commonly used reference mouse strain is C57BL/6J, but recently, resources such as the International Knockout Mouse Consortium have started producing large numbers of mouse mutant lines on a pure genetic background, C57BL/6N. Considering the substantial genetic diversity between mouse strains we expect there to be phenotypic differences, including differential effects of aging, in these and other strains. Such differences need to be characterized not only to establish how different mouse strains may model the aging process but also to understand how genetic background might modify age-related phenotypes. To ascertain the effects of aging on sleep/wake behavior, circadian rhythms, and light input and whether these effects are mouse strain-dependent, we have screened C57BL/6J, C57BL/6N, C3H-HeH, and C3H-Pde6b+ mouse strains at 5 ages throughout their life span. Our data show that sleep, circadian, and light input parameters are all disrupted by the aging process. Moreover, we have cataloged a number of strain-specific aging effects, including the rate of cataract development, decline in the pupillary light response, and changes in sleep fragmentation and the proportion of time spent asleep. PMID:25179226

Genetic background influences age-related decline in visual and nonvisual retinal responses, circadian rhythms, and sleep.

Science.gov (United States)

Banks, Gareth; Heise, Ines; Starbuck, Becky; Osborne, Tamzin; Wisby, Laura; Potter, Paul; Jackson, Ian J; Foster, Russell G; Peirson, Stuart N; Nolan, Patrick M

2015-01-01

The circadian system is entrained to the environmental light/dark cycle via retinal photoreceptors and regulates numerous aspects of physiology and behavior, including sleep. These processes are all key factors in healthy aging showing a gradual decline with age. Despite their importance, the exact mechanisms underlying this decline are yet to be fully understood. One of the most effective tools we have to understand the genetic factors underlying these processes are genetically inbred mouse strains. The most commonly used reference mouse strain is C57BL/6J, but recently, resources such as the International Knockout Mouse Consortium have started producing large numbers of mouse mutant lines on a pure genetic background, C57BL/6N. Considering the substantial genetic diversity between mouse strains we expect there to be phenotypic differences, including differential effects of aging, in these and other strains. Such differences need to be characterized not only to establish how different mouse strains may model the aging process but also to understand how genetic background might modify age-related phenotypes. To ascertain the effects of aging on sleep/wake behavior, circadian rhythms, and light input and whether these effects are mouse strain-dependent, we have screened C57BL/6J, C57BL/6N, C3H-HeH, and C3H-Pde6b+ mouse strains at 5 ages throughout their life span. Our data show that sleep, circadian, and light input parameters are all disrupted by the aging process. Moreover, we have cataloged a number of strain-specific aging effects, including the rate of cataract development, decline in the pupillary light response, and changes in sleep fragmentation and the proportion of time spent asleep. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Fine-scale maps of recombination rates and hotspots in the mouse genome.

Science.gov (United States)

Brunschwig, Hadassa; Levi, Liat; Ben-David, Eyal; Williams, Robert W; Yakir, Benjamin; Shifman, Sagiv

2012-07-01

Recombination events are not uniformly distributed and often cluster in narrow regions known as recombination hotspots. Several studies using different approaches have dramatically advanced our understanding of recombination hotspot regulation. Population genetic data have been used to map and quantify hotspots in the human genome. Genetic variation in recombination rates and hotspots usage have been explored in human pedigrees, mouse intercrosses, and by sperm typing. These studies pointed to the central role of the PRDM9 gene in hotspot modulation. In this study, we used single nucleotide polymorphisms (SNPs) from whole-genome resequencing and genotyping studies of mouse inbred strains to estimate recombination rates across the mouse genome and identified 47,068 historical hotspots--an average of over 2477 per chromosome. We show by simulation that inbred mouse strains can be used to identify positions of historical hotspots. Recombination hotspots were found to be enriched for the predicted binding sequences for different alleles of the PRDM9 protein. Recombination rates were on average lower near transcription start sites (TSS). Comparing the inferred historical recombination hotspots with the recent genome-wide mapping of double-strand breaks (DSBs) in mouse sperm revealed a significant overlap, especially toward the telomeres. Our results suggest that inbred strains can be used to characterize and study the dynamics of historical recombination hotspots. They also strengthen previous findings on mouse recombination hotspots, and specifically the impact of sequence variants in Prdm9.

Genetic hazards of radiation

International Nuclear Information System (INIS)

Searle, A.G.

1987-01-01

The difficulties of quantifying genetic radiation effects are discussed, with reference to studies of atomic bomb survivors, and mouse germ-cells. Doubling dose methods of extrapolation and the problems of quantifying risks of diseases of irregular inheritance are also considered. (U.K.)

The European dimension for the mouse genome mutagenesis

Czech Academy of Sciences Publication Activity Database

Auwerx, J.; Avner, P.; Baldock, R.; Ballabio, A.; Balling, R.; Barbacid, M.; Berns, A.; Bradley, A.; Brown, S.; Carmeliet, P.; Chambon, P.; Cox, R.; Davidson, D.; Davies, K.; Duboule, D.; Forejt, Jiří; Granucci, F.; Hastie, N.; Angelis, M. H. de; Jackson, I.; Kioussis, D.; Kollias, G.; Lathrop, M.; Lendahl, U.; Malumbres, M.; von Melchner, H.; Müller, W.; Partanen, J.; Ricciardi-Castagnoli, P.; Rigby, P.; Rosen, B.; Rosenthal, N.; Skarnes, B.; Stewart, A. F.; Thornton, J.; Tocchini-Valentini, G.; Wagner, E.; Wahli, W.; Wurst, W.

2004-01-01

Roč. 16, - (2004), s. 925-927 ISSN 1061-4036 R&D Projects: GA MŠk(CZ) LN00A079 Institutional research plan: CEZ:AV0Z5052915 Keywords : The European Mouse Mutagenesis Consortium Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 24.695, year: 2004

Defined Conditions for the Isolation and Expansion of Basal Prostate Progenitor Cells of Mouse and Human Origin

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Thomas Höfner

2015-03-01

Full Text Available Methods to isolate and culture primary prostate epithelial stem/progenitor cells (PESCs have proven difficult and ineffective. Here, we present a method to grow and expand both murine and human basal PESCs long term in serum- and feeder-free conditions. The method enriches for adherent mouse basal PESCs with a Lin−SCA-1+CD49f+TROP2high phenotype. Progesterone and sodium selenite are additionally required for the growth of human Lin−CD49f+TROP2high PESCs. The gene-expression profiles of expanded basal PESCs show similarities to ESCs, and NF-kB function is critical for epithelial differentiation of sphere-cultured PESCs. When transplanted in combination with urogenital sinus mesenchyme, expanded mouse and human PESCs generate ectopic prostatic tubules, demonstrating their stem cell activity in vivo. This novel method will facilitate the molecular, genomic, and functional characterization of normal and pathologic prostate glands of mouse and human origin.

Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium.

Science.gov (United States)

Sato, Toshiro; Stange, Daniel E; Ferrante, Marc; Vries, Robert G J; Van Es, Johan H; Van den Brink, Stieneke; Van Houdt, Winan J; Pronk, Apollo; Van Gorp, Joost; Siersema, Peter D; Clevers, Hans

2011-11-01

We previously established long-term culture conditions under which single crypts or stem cells derived from mouse small intestine expand over long periods. The expanding crypts undergo multiple crypt fission events, simultaneously generating villus-like epithelial domains that contain all differentiated types of cells. We have adapted the culture conditions to grow similar epithelial organoids from mouse colon and human small intestine and colon. Based on the mouse small intestinal culture system, we optimized the mouse and human colon culture systems. Addition of Wnt3A to the combination of growth factors applied to mouse colon crypts allowed them to expand indefinitely. Addition of nicotinamide, along with a small molecule inhibitor of Alk and an inhibitor of p38, were required for long-term culture of human small intestine and colon tissues. The culture system also allowed growth of mouse Apc-deficient adenomas, human colorectal cancer cells, and human metaplastic epithelia from regions of Barrett's esophagus. We developed a technology that can be used to study infected, inflammatory, or neoplastic tissues from the human gastrointestinal tract. These tools might have applications in regenerative biology through ex vivo expansion of the intestinal epithelia. Studies of these cultures indicate that there is no inherent restriction in the replicative potential of adult stem cells (or a Hayflick limit) ex vivo. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

A genetic basis for a postmeiotic X versus Y chromosome intragenomic conflict in the mouse.

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Julie Cocquet

2012-09-01

Full Text Available Intragenomic conflicts arise when a genetic element favours its own transmission to the detriment of others. Conflicts over sex chromosome transmission are expected to have influenced genome structure, gene regulation, and speciation. In the mouse, the existence of an intragenomic conflict between X- and Y-linked multicopy genes has long been suggested but never demonstrated. The Y-encoded multicopy gene Sly has been shown to have a predominant role in the epigenetic repression of post meiotic sex chromatin (PMSC and, as such, represses X and Y genes, among which are its X-linked homologs Slx and Slxl1. Here, we produced mice that are deficient for both Sly and Slx/Slxl1 and observed that Slx/Slxl1 has an opposite role to that of Sly, in that it stimulates XY gene expression in spermatids. Slx/Slxl1 deficiency rescues the sperm differentiation defects and near sterility caused by Sly deficiency and vice versa. Slx/Slxl1 deficiency also causes a sex ratio distortion towards the production of male offspring that is corrected by Sly deficiency. All in all, our data show that Slx/Slxl1 and Sly have antagonistic effects during sperm differentiation and are involved in a postmeiotic intragenomic conflict that causes segregation distortion and male sterility. This is undoubtedly what drove the massive gene amplification on the mouse X and Y chromosomes. It may also be at the basis of cases of F1 male hybrid sterility where the balance between Slx/Slxl1 and Sly copy number, and therefore expression, is disrupted. To the best of our knowledge, our work is the first demonstration of a competition occurring between X and Y related genes in mammals. It also provides a biological basis for the concept that intragenomic conflict is an important evolutionary force which impacts on gene expression, genome structure, and speciation.

Genetic control of the radiosensitivity of lymphoid cells for antibody-forming ability in CXS series of recombinant inbred mouse strains

International Nuclear Information System (INIS)

Okumoto, M.; Mori, N.; Nishikawa, R.; Imai, S.; Hilgers, J.; Takamori, Y.; Yagasaki, O.

1992-01-01

Incidence of radiation-induced lymphomas differs remarkably among various mouse strains. BALB/cHeA (C) mice are highly susceptible to radiation induction of lymphomas, while STS/A (S) mice are resistant. Thus, the induction of the disease is controlled by some genetic factors. To examine an involvement of radiosensitivity of lymphoid cells in lymphomagenesis, we have compared genetic control of the radiosensitivity for antibody-forming ability with that of lymphoma development in BALB/cHeA, STS/A, (CXS)F 1 hybrids and CXS series of recombinant inbred strains. Decrease of number of splenic plaque-forming cell (PFC) in Jerne's method by 3 Gy of X-irradiation for BALB/cHeA mice was larger than that for STS/A mice by more than one order of magnitude. (CXS)F 1 hybrid mice showed small number of decrease of PFC similar to STS/A mice suggesting that phenotype of radioresistance was dominant over sensitivity. The best concordance between genetic markers and radiosensitivities of antibody-forming ability in recombinant inbred strains was observed in a region containing Igh locus on chromosome 12. The results show that one locus controlling the radioresistance of lymphoid cells for antibody-forming ability might exist in the region containing Igh locus, and that this region clearly differ from a region with Ifa locus on chromosome 4 which regulate the susceptibility to radiation-induced lymphomagenesis. (author)

Specific-locus mutation frequencies in mouse stem-cell spermatogonia at very low radiation dose rates, and their use in the estimation of genetic hazards of radiation in man

International Nuclear Information System (INIS)

Russell, W.L.; Kelly, E.M.

1982-01-01

Experiments were undertaken to augment the information on the lowest radiation dose rates feasible for scoring transmitted induced mutations detected by the specific-locus method in the mouse. This is the type of information most suitable for estimating genetic hazards of radiation in man. The results also aid in resolving conflicting possibilities about the relationship between mutation frequency and radiation dose at low dose rates

Integration of mouse and human genome-wide association data identifies KCNIP4 as an asthma gene

NARCIS (Netherlands)

Himes, Blanca E.; Sheppard, Keith; Berndt, Annerose; Leme, Adriana S.; Myers, Rachel A.; Gignoux, Christopher R.; Levin, Albert M.; Gauderman, W. James; Yang, James J.; Mathias, Rasika A.; Romieu, Isabelle; Torgerson, Dara G.; Roth, Lindsey A.; Huntsman, Scott; Eng, Celeste; Klanderman, Barbara; Ziniti, John; Senter-Sylvia, Jody; Szefler, Stanley J.; Lemanske, Robert F.; Zeiger, Robert S.; Strunk, Robert C.; Martinez, Fernando D.; Boushey, Homer; Chinchilli, Vernon M.; Israel, Elliot; Mauger, David; Koppelman, Gerard H.; Postma, Dirkje S.; Nieuwenhuis, Maartje A. E.; Vonk, Judith M.; Lima, John J.; Irvin, Charles G.; Peters, Stephen P.; Kubo, Michiaki; Tamari, Mayumi; Nakamura, Yusuke; Litonjua, Augusto A.; Tantisira, Kelan G.; Raby, Benjamin A.; Bleecker, Eugene R.; Meyers, Deborah A.; London, Stephanie J.; Barnes, Kathleen C.; Gilliland, Frank D.; Williams, L. Keoki; Burchard, Esteban G.; Nicolae, Dan L.; Ober, Carole; DeMeo, Dawn L.; Silverman, Edwin K.; Paigen, Beverly; Churchill, Gary; Shapiro, Steve D.; Weiss, Scott

2013-01-01

Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify

Qualitative analysis of mouse specific-locus mutations: information on genetic organization, gene expression, and the chromosomal nature of induced lesions

International Nuclear Information System (INIS)

Russell, L.B.

1982-01-01

Analysis of mouse specific-locus (SL) mutations at three loci has identified over 33 distinct complementation groups - most of which are probably overlapping deficiencies - and 13 to 14 new functional units. The complementation maps that have been generated for the d-se and c regions include numerous vital functions; however, some of the genes in these regions are non-vital. At such loci, hypomorphic mutants must represent intragenic alterations, and some viable nulls could conceivably be intragenic lesions also. Analysis of SL mutations has provided information on genetic expression. Homozygous deficiencies can be completely viable or can kill at any one of a range of developmental stages. Heterozygonus deficiencies of up to 6 cM or more in genetic length have been recovered and propagated. The time of death of homozygous and the degree of inviability of heterozygous deficiencies are related more to specific content of the missing segment than to its length. Combinations of deficiencies with x-autosome translocations that inactivate the homologous region in a mosaic fashion have shown that organismic lethals are not necessarily cell lethal. The spectrum of mutations induced depends on the nature of the mutagen and the type of germ cell exposed. Radiation of spermatogonia produces intragenic as well as null mutations. Spontaneous mutations have an admixture of types not present in populations of mutations induced in germ cells, and this raises doubts concerning the accuracy of doubling-dose calculations in genetic risk estimation. The analysis of SL mutations has yielded genetic tools for the construction of detailed gene-dosage series, cis-trans comparisons, the mapping of known genes and identification of new genes, genetic rescue of various types, and the identification and isolation of DNA sequences

Dantrolene is neuroprotective in Huntington's disease transgenic mouse model

Directory of Open Access Journals (Sweden)

Chen Xi

2011-11-01

Full Text Available Abstract Background Huntington's disease (HD is a progressive neurodegenerative disorder caused by a polyglutamine expansion in the Huntingtin protein which results in the selective degeneration of striatal medium spiny neurons (MSNs. Our group has previously demonstrated that calcium (Ca2+ signaling is abnormal in MSNs from the yeast artificial chromosome transgenic mouse model of HD (YAC128. Moreover, we demonstrated that deranged intracellular Ca2+ signaling sensitizes YAC128 MSNs to glutamate-induced excitotoxicity when compared to wild type (WT MSNs. In previous studies we also observed abnormal neuronal Ca2+ signaling in neurons from spinocerebellar ataxia 2 (SCA2 and spinocerebellar ataxia 3 (SCA3 mouse models and demonstrated that treatment with dantrolene, a ryanodine receptor antagonist and clinically relevant Ca2+ signaling stabilizer, was neuroprotective in experiments with these mouse models. The aim of the current study was to evaluate potential beneficial effects of dantrolene in experiments with YAC128 HD mouse model. Results The application of caffeine and glutamate resulted in increased Ca2+ release from intracellular stores in YAC128 MSN cultures when compared to WT MSN cultures. Pre-treatment with dantrolene protected YAC128 MSNs from glutamate excitotoxicty, with an effective concentration of 100 nM and above. Feeding dantrolene (5 mg/kg twice a week to YAC128 mice between 2 months and 11.5 months of age resulted in significantly improved performance in the beam-walking and gait-walking assays. Neuropathological analysis revealed that long-term dantrolene feeding to YAC128 mice significantly reduced the loss of NeuN-positive striatal neurons and reduced formation of Httexp nuclear aggregates. Conclusions Our results support the hypothesis that deranged Ca2+ signaling plays an important role in HD pathology. Our data also implicate the RyanRs as a potential therapeutic target for the treatment of HD and demonstrate that Ryan

Dantrolene is neuroprotective in Huntington's disease transgenic mouse model.

Science.gov (United States)

Chen, Xi; Wu, Jun; Lvovskaya, Svetlana; Herndon, Emily; Supnet, Charlene; Bezprozvanny, Ilya

2011-11-25

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine expansion in the Huntingtin protein which results in the selective degeneration of striatal medium spiny neurons (MSNs). Our group has previously demonstrated that calcium (Ca2+) signaling is abnormal in MSNs from the yeast artificial chromosome transgenic mouse model of HD (YAC128). Moreover, we demonstrated that deranged intracellular Ca2+ signaling sensitizes YAC128 MSNs to glutamate-induced excitotoxicity when compared to wild type (WT) MSNs. In previous studies we also observed abnormal neuronal Ca2+ signaling in neurons from spinocerebellar ataxia 2 (SCA2) and spinocerebellar ataxia 3 (SCA3) mouse models and demonstrated that treatment with dantrolene, a ryanodine receptor antagonist and clinically relevant Ca2+ signaling stabilizer, was neuroprotective in experiments with these mouse models. The aim of the current study was to evaluate potential beneficial effects of dantrolene in experiments with YAC128 HD mouse model. The application of caffeine and glutamate resulted in increased Ca2+ release from intracellular stores in YAC128 MSN cultures when compared to WT MSN cultures. Pre-treatment with dantrolene protected YAC128 MSNs from glutamate excitotoxicty, with an effective concentration of 100 nM and above. Feeding dantrolene (5 mg/kg) twice a week to YAC128 mice between 2 months and 11.5 months of age resulted in significantly improved performance in the beam-walking and gait-walking assays. Neuropathological analysis revealed that long-term dantrolene feeding to YAC128 mice significantly reduced the loss of NeuN-positive striatal neurons and reduced formation of Httexp nuclear aggregates. Our results support the hypothesis that deranged Ca2+ signaling plays an important role in HD pathology. Our data also implicate the RyanRs as a potential therapeutic target for the treatment of HD and demonstrate that RyanR inhibitors and Ca2+ signaling stabilizers such as

Evaluation of an in vitro toxicogenetic mouse model for hepatotoxicity

International Nuclear Information System (INIS)

Martinez, Stephanie M.; Bradford, Blair U.; Soldatow, Valerie Y.; Kosyk, Oksana; Sandot, Amelia; Witek, Rafal; Kaiser, Robert; Stewart, Todd; Amaral, Kirsten; Freeman, Kimberly; Black, Chris; LeCluyse, Edward L.; Ferguson, Stephen S.; Rusyn, Ivan

2010-01-01

Numerous studies support the fact that a genetically diverse mouse population may be useful as an animal model to understand and predict toxicity in humans. We hypothesized that cultures of hepatocytes obtained from a large panel of inbred mouse strains can produce data indicative of inter-individual differences in in vivo responses to hepato-toxicants. In order to test this hypothesis and establish whether in vitro studies using cultured hepatocytes from genetically distinct mouse strains are feasible, we aimed to determine whether viable cells may be isolated from different mouse inbred strains, evaluate the reproducibility of cell yield, viability and functionality over subsequent isolations, and assess the utility of the model for toxicity screening. Hepatocytes were isolated from 15 strains of mice (A/J, B6C3F1, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/EiJ, DBA/2J, FVB/NJ, BALB/cByJ, AKR/J, MRL/MpJ, NOD/LtJ, NZW/LacJ, PWD/PhJ and WSB/EiJ males) and cultured for up to 7 days in traditional 2-dimensional culture. Cells from B6C3F1, C57BL/6J, and NOD/LtJ strains were treated with acetaminophen, WY-14,643 or rifampin and concentration-response effects on viability and function were established. Our data suggest that high yield and viability can be achieved across a panel of strains. Cell function and expression of key liver-specific genes of hepatocytes isolated from different strains and cultured under standardized conditions are comparable. Strain-specific responses to toxicant exposure have been observed in cultured hepatocytes and these experiments open new opportunities for further developments of in vitro models of hepatotoxicity in a genetically diverse population.

Coordinate expansion of murine hematopoietic and mesenchymal stem cell compartments by SHIPi.

Science.gov (United States)

Brooks, R; Iyer, S; Akada, H; Neelam, S; Russo, C M; Chisholm, J D; Kerr, W G

2015-03-01

Promoting the expansion of adult stem cell populations offers the potential to ameliorate radiation or chemotherapy-induced bone marrow failure and allows for expedited recovery for patients undergoing these therapies. Previous genetic studies suggested a pivotal role for SH2 domain-containing inositol-5-phosphatase 1 (SHIP1) in limiting the size of the hematopoietic stem cell (HSC) compartment. The aim of this study was to determine whether our recent development of small molecule SHIP1 inhibitors offers the potential for pharmacological expansion of the HSC compartment in vivo. We show here that treatment of mice with aminosteroid inhibitors of SHIP1 (SHIPi) more than doubles the size of the adult mesenchymal stem cell (MSC) compartment while simultaneously expanding the HSC pool sixfold. Consistent with its ability to target SHIP1 function in vivo, SHIPi also significantly increases plasma granulocyte colony-stimulating factor (G-CSF) levels, a growth factor that supports proliferation of HSC. Here, we show that SHIPi-induced G-CSF production mediates HSC and MSC expansion, as in vivo neutralization of G-CSF abrogates the SHIPi-induced expansion of both the HSC and MSC compartments. Due to its expansionary effect on adult stem cell compartments, SHIPi represents a potential novel strategy to improve declining stem cell function in both therapy induced and genetically derived bone marrow failure syndromes. © 2014 AlphaMed Press.

Repeat interruptions in spinocerebellar ataxia type 10 expansions are strongly associated with epileptic seizures

Science.gov (United States)

McFarland, Karen N.; Liu, Jilin; Landrian, Ivette; Zeng, Desmond; Raskin, Salmo; Moscovich, Mariana; Gatto, Emilia M.; Ochoa, Adriana; Teive, Hélio A. G.; Rasmussen, Astrid; Ashizawa, Tetsuo

2014-01-01

Spinocerebellar ataxia type 10 (SCA10), an autosomal dominant neurodegenerative disorder, is the result of a non-coding, pentanucleotide repeat expansion within intron 9 of the Ataxin 10 gene. SCA10 patients present with pure cerebellar ataxia; yet, some families also have a high incidence of epilepsy. SCA10 expansions containing penta- and heptanucleotide interruption motifs, termed “ATCCT interruptions,” experience large contractions during germline transmission, particularly in paternal lineages. At the same time, these alleles confer an earlier age at onset which contradicts traditional rules of genetic anticipation in repeat expansions. Previously, ATCCT interruptions have been associated with a higher prevalence of epileptic seizures in one Mexican-American SCA10 family. In a large cohort of SCA10 families, we analyzed whether ATCCT interruptions confers a greater risk for developing seizures in these families. Notably, we find that the presence of repeat interruptions within the SCA10 expansion confers a 6.3-fold increase in the risk of an SCA10 patient developing epilepsy (6.2-fold when considering patients of Mexican ancestry only) and a 13.7-fold increase in having a positive family history of epilepsy (10.5-fold when considering patients of Mexican ancestry only). We conclude that the presence of repeat interruptions in SCA10 repeat expansion indicates a significant risk for the epilepsy phenotype and should be considered during genetic counseling. PMID:24318420

Mouse cell culture - Methods and protocols

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CarloAlberto Redi

2010-12-01

Full Text Available The mouse is, out of any doubt, the experimental animal par excellence for many many colleagues within the scientific community, notably for those working in mammalian biology (in a broad sense, from basic genetic to modeling human diseases, starting at least from 1664 Robert Hooke experiments on air’s propertyn. Not surprising then that mouse cell cultures is a well established field of research itself and that there are several handbooks devoted to this discipline. Here, Andrew Ward and David Tosh provide a necessary update of the protocols currently needed. In fact, nearly half of the book is devoted to stem cells culture protocols, mainly embryonic, from a list of several organs (kidney, lung, oesophagus and intestine, pancreas and liver to mention some........

DNA damage response during mouse oocyte maturation

Czech Academy of Sciences Publication Activity Database

Mayer, Alexandra; Baran, Vladimír; Sakakibara, Y.; Brzáková, Adéla; Ferencová, Ivana; Motlík, Jan; Kitajima, T.; Schultz, R. M.; Šolc, Petr

2016-01-01

Roč. 15, č. 4 (2016), s. 546-558 ISSN 1538-4101 R&D Projects: GA MŠk LH12057; GA MŠk ED2.1.00/03.0124 Institutional support: RVO:67985904 Keywords : double strand DNA breaks * DNA damage * MRE11 * meiotic maturation * mouse oocytes Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.530, year: 2016

The influence of fluorides on mouse sperm capacitation

Czech Academy of Sciences Publication Activity Database

Dvořáková-Hortová, K.; Šandera, M.; Jursová, M.; Vašinová, J.; Pěknicová, Jana

2008-01-01

Roč. 108, 1-2 (2008), s. 157-170 ISSN 0378-4320 R&D Projects: GA MŠk 1M06011 Institutional research plan: CEZ:AV0Z50520514; CEZ:AV0Z50520701 Keywords : mouse spermatozoa * capacitation * fluorides Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.890, year: 2008

Mouse models for gastric cancer: Matching models to biological questions

Science.gov (United States)

Poh, Ashleigh R; O'Donoghue, Robert J J

2016-01-01

Abstract Gastric cancer is the third leading cause of cancer‐related mortality worldwide. This is in part due to the asymptomatic nature of the disease, which often results in late‐stage diagnosis, at which point there are limited treatment options. Even when treated successfully, gastric cancer patients have a high risk of tumor recurrence and acquired drug resistance. It is vital to gain a better understanding of the molecular mechanisms underlying gastric cancer pathogenesis to facilitate the design of new‐targeted therapies that may improve patient survival. A number of chemically and genetically engineered mouse models of gastric cancer have provided significant insight into the contribution of genetic and environmental factors to disease onset and progression. This review outlines the strengths and limitations of current mouse models of gastric cancer and their relevance to the pre‐clinical development of new therapeutics. PMID:26809278

The Population Origins and Expansion of Feral Cats in Australia.

Science.gov (United States)

Spencer, Peter B S; Yurchenko, Andrey A; David, Victor A; Scott, Rachael; Koepfli, Klaus-Peter; Driscoll, Carlos; O'Brien, Stephen J; Menotti-Raymond, Marilyn

2016-03-01

The historical literature suggests that in Australia, the domestic cat (Felis catus) had a European origin [~200 years before present (ybp)], but it is unclear if cats arrived from across the Asian land bridge contemporaneously with the dingo (4000 ybp), or perhaps immigrated ~40000 ybp in association with Aboriginal settlement from Asia. The origin of cats in Australia is important because the continent has a complex and ancient faunal assemblage that is dominated by endemic rodents and marsupials and lacks the large placental carnivores found on other large continents. Cats are now ubiquitous across the entire Australian continent and have been implicit in the range contraction or extinction of its small to medium sized (cats using 15 short tandem repeat (STR) genomic markers. Their origin appears to come exclusively from European founders. Feral cats in continental Australia exhibit high genetic diversity in comparison with the low diversity found in populations of feral cats living on islands. The genetic structure is consistent with a rapid westerly expansion from eastern Australia and a limited expansion in coastal Western Australia. Australian cats show modest if any population structure and a close genetic alignment with European feral cats as compared to cats from Asia, the Christmas and Cocos (Keeling) Islands (Indian Ocean), and European wildcats (F. silvestris silvestris). © The American Genetic Association 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Systems Genetics Analysis to Identify the Genetic Modulation of a Glaucoma-Associated Gene.

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Chintalapudi, Sumana R; Jablonski, Monica M

2017-01-01

Loss of retinal ganglion cells (RGCs) is one of the hallmarks of retinal neurodegenerative diseases, glaucoma being one of the most common. Recently, γ-synuclein (SNCG) was shown to be highly expressed in the somas and axons of RGCs. In various mouse models of glaucoma, downregulation of Sncg gene expression correlates with RGC loss. To investigate the regulation of Sncg in RGCs, we used a systems genetics approach to identify a gene that modulates the expression of Sncg, followed by confirmatory studies in both healthy and diseased retinas. We found that chromosome 1 harbors an eQTL that modulates the expression of Sncg in the mouse retina and identified Pfdn2 as the candidate upstream modulator of Sncg expression. Downregulation of Pfdn2 in enriched RGCs causes a concomitant reduction in Sncg. In this chapter, we describe our strategy and methods for identifying and confirming a genetic modulation of a glaucoma-associated gene. A similar method can be applied to other genes expressed in other tissues.

A Mouse Model of Chronic West Nile Virus Disease.

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Jessica B Graham

2016-11-01

Full Text Available Infection with West Nile virus (WNV leads to a range of disease outcomes, including chronic infection, though lack of a robust mouse model of chronic WNV infection has precluded identification of the immune events contributing to persistent infection. Using the Collaborative Cross, a population of recombinant inbred mouse strains with high levels of standing genetic variation, we have identified a mouse model of persistent WNV disease, with persistence of viral loads within the brain. Compared to lines exhibiting no disease or marked disease, the F1 cross CC(032x013F1 displays a strong immunoregulatory signature upon infection that correlates with restraint of the WNV-directed cytolytic response. We hypothesize that this regulatory T cell response sufficiently restrains the immune response such that a chronic infection can be maintained in the CNS. Use of this new mouse model of chronic neuroinvasive virus will be critical in developing improved strategies to prevent prolonged disease in humans.

Mouse Models of the Skin: Models to Define Mechanisms of Skin Carcinogenesis

International Nuclear Information System (INIS)

Wheeler, D. L.; Verma, A. K.; Denning, M. F.

2013-01-01

The multistep model of mouse skin carcinogenesis has facilitated identification of irreversible genetic events of initiation and progression, and epigenetic events of tumor promotion. Mouse skin tumor initiation can be accomplished by a single exposure to a sufficiently small dose of a carcinogen, and this step is rapid and irreversible. However, promotion of skin tumor formation requires a repeated and prolonged exposure to a promoter, and that tumor promotion is reversible. Investigations focused on the mechanisms of mouse carcinogenesis have resulted in the identifications of potential molecular targets of cancer induction and progression useful in planning strategies for human cancer prevention trials. This special issue contains eight papers that focus on mouse models used to study individual proteins expressed in the mouse skin and the role they play in differentiation, tissue homeostasis, skin carcinogenesis, and chemo prevention of skin cancer.

Testing parasite 'intimacy': the whipworm Trichuris muris in the European house mouse hybrid zone.

Science.gov (United States)

Wasimuddin; Bryja, Josef; Ribas, Alexis; Baird, Stuart J E; Piálek, Jaroslav; Goüy de Bellocq, Joëlle

2016-05-01

Host-parasite interaction studies across hybrid zones often focus on host genetic variation, treating parasites as homogeneous. 'Intimately' associated hosts and parasites might be expected to show similar patterns of genetic structure. In the literature, factors such as no intermediate host and no free-living stage have been proposed as 'intimacy' factors likely constraining parasites to closely follow the evolutionary history of their hosts. To test whether the whipworm, Trichuris muris, is intimately associated with its house mouse host, we studied its population genetics across the European house mouse hybrid zone (HMHZ) which has a strong central barrier to gene flow between mouse taxa. T. muris has a direct life cycle and nonmobile free stage: if these traits constrain the parasite to an intimate association with its host we expect a geographic break in the parasite genetic structure across the HMHZ. We genotyped 205 worms from 56 localities across the HMHZ and additionally T. muris collected from sympatric woodmice (Apodemus spp.) and allopatric murine species, using mt-COX1, ITS1-5.8S-ITS2 rDNA and 10 microsatellites. We show four haplogroups of mt-COX1 and three clear ITS1-5.8S-ITS2 clades in the HMHZ suggesting a complex demographic/phylogeographic history. Microsatellites show strong structure between groups of localities. However, no marker type shows a break across the HMHZ. Whipworms from Apodemus in the HMHZ cluster, and share mitochondrial haplotypes, with those from house mice. We conclude Trichuris should not be regarded as an 'intimate' parasite of the house mouse: while its life history might suggest intimacy, passage through alternate hosts is sufficiently common to erase signal of genetic structure associated with any particular host taxon.

Stepwise development of MAIT cells in mouse and human.

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Emmanuel Martin

2009-03-01

Full Text Available Mucosal-associated invariant T (MAIT cells display two evolutionarily conserved features: an invariant T cell receptor (TCRalpha (iTCRalpha chain and restriction by the nonpolymorphic class Ib major histocompatibility complex (MHC molecule, MHC-related molecule 1 (MR1. MR1 expression on thymus epithelial cells is not necessary for MAIT cell development but their accumulation in the gut requires MR1 expressing B cells and commensal flora. MAIT cell development is poorly known, as these cells have not been found in the thymus so far. Herein, complementary human and mouse experiments using an anti-humanValpha7.2 antibody and MAIT cell-specific iTCRalpha and TCRbeta transgenic mice in different genetic backgrounds show that MAIT cell development is a stepwise process, with an intra-thymic selection followed by peripheral expansion. Mouse MAIT cells are selected in an MR1-dependent manner both in fetal thymic organ culture and in double iTCRalpha and TCRbeta transgenic RAG knockout mice. In the latter mice, MAIT cells do not expand in the periphery unless B cells are added back by adoptive transfer, showing that B cells are not required for the initial thymic selection step but for the peripheral accumulation. In humans, contrary to natural killer T (NKT cells, MAIT cells display a naïve phenotype in the thymus as well as in cord blood where they are in low numbers. After birth, MAIT cells acquire a memory phenotype and expand dramatically, up to 1%-4% of blood T cells. Finally, in contrast with NKT cells, human MAIT cell development is independent of the molecular adaptor SAP. Interestingly, mouse MAIT cells display a naïve phenotype and do not express the ZBTB16 transcription factor, which, in contrast, is expressed by NKT cells and the memory human MAIT cells found in the periphery after birth. In conclusion, MAIT cells are selected by MR1 in the thymus on a non-B non-T hematopoietic cell, and acquire a memory phenotype and expand in the

Revitalizing genetically-modified mouse strains using frozen-thawed sperm after up to 192 h of refrigerated epididymis transportation.

Science.gov (United States)

Moreno-Del Val, Gonzalo; Muñoz-Robledano, Patricia

2017-10-01

In the scientific interchange of genetically-modified mouse strains the transportation of refrigerated epididymis has several advantages over the transportation of live animals, especially with regard to the 3R (replacement, reduction and refinement) principles. The major limiting factor is the duration of the transportation. Previous reports have shown that sperm collected from transported epididymis maintained their fertility for around 72 h, but there are no published data with longer transportation times, and this window of time may be too short, especially for international shipments and where locations are not well connected. In this study live pups were born using frozen-thawed sperm after up to 192 h (8 days) of transportation, using a special in vitro fertilization design which resulted in a fertilization rate of 10.5%.

Two genetic determinants acquired late in Mus evolution regulate the inclusion of exon 5, which alters mouse APOBEC3 translation efficiency.

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Jun Li

2012-01-01

Full Text Available Mouse apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like editing complex 3 (mA3, an intracellular antiviral factor, has 2 allelic variations that are linked with different susceptibilities to beta- and gammaretrovirus infections among various mouse strains. In virus-resistant C57BL/6 (B6 mice, mA3 transcripts are more abundant than those in susceptible BALB/c mice both in the spleen and bone marrow. These strains of mice also express mA3 transcripts with different splicing patterns: B6 mice preferentially express exon 5-deficient (Δ5 mA3 mRNA, while BALB/c mice produce exon 5-containing full-length mA3 mRNA as the major transcript. Although the protein product of the Δ5 mRNA exerts stronger antiretroviral activities than the full-length protein, how exon 5 affects mA3 antiviral activity, as well as the genetic mechanisms regulating exon 5 inclusion into the mA3 transcripts, remains largely uncharacterized. Here we show that mA3 exon 5 is indeed a functional element that influences protein synthesis at a post-transcriptional level. We further employed in vitro splicing assays using genomic DNA clones to identify two critical polymorphisms affecting the inclusion of exon 5 into mA3 transcripts: the number of TCCT repeats upstream of exon 5 and the single nucleotide polymorphism within exon 5 located 12 bases upstream of the exon 5/intron 5 boundary. Distribution of the above polymorphisms among different Mus species indicates that the inclusion of exon 5 into mA3 mRNA is a relatively recent event in the evolution of mice. The widespread geographic distribution of this exon 5-including genetic variant suggests that in some Mus populations the cost of maintaining an effective but mutagenic enzyme may outweigh its antiviral function.

Mouse Y-Encoded Transcription Factor Zfy2 Is Essential for Sperm Head Remodelling and Sperm Tail Development

NARCIS (Netherlands)

Vernet, Nadege; Mahadevaiah, Shantha K.; Decarpentrie, Fanny; Longepied, Guy; de Rooij, Dirk G.; Burgoyne, Paul S.; Mitchell, Michael J.

2016-01-01

A previous study indicated that genetic information encoded on the mouse Y chromosome short arm (Yp) is required for efficient completion of the second meiotic division (that generates haploid round spermatids), restructuring of the sperm head, and development of the sperm tail. Using mouse models

Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype

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Johnathan Cooper-Knock

2017-11-01

Full Text Available Amyotrophic lateral sclerosis (ALS is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs. We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18. Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033. We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025. Our data are

The functional and anatomical dissection of somatosensory subpopulations using mouse genetics

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Claire E Le Pichon

2014-04-01

Full Text Available The word somatosensation comes from joining the Greek word for body (soma with a word for perception (sensation. Somatosensory neurons comprise the largest sensory system in mammals and have nerve endings coursing throughout the skin, viscera, muscle, and bone. Their cell bodies reside in a chain of ganglia adjacent to the dorsal spinal cord (the dorsal root ganglia and at the base of the skull (the trigeminal ganglia. While the neuronal cell bodies are intermingled within the ganglia, the somatosensory system is in reality composed of numerous sub-systems, each specialized to detect distinct stimuli, such as temperature and touch. Historically, somatosensory neurons have been classified using a diverse host of anatomical and physiological parameters, such as the size of the cell body, degree of myelination, histological labeling with markers, specialization of the nerve endings, projection patterns in the spinal cord and brainstem, receptive tuning, and conduction velocity of their action potentials. While useful, the picture that emerged was one of heterogeneity, with many markers at least partially overlapping. More recently, by capitalizing on advances in molecular techniques, researchers have identified specific ion channels and sensory receptors expressed in subsets of sensory neurons. These studies have proved invaluable as they allow genetic access to small subsets of neurons for further molecular dissection. Data being generated from transgenic mice favor the model whereby an array of dedicated neurons is responsible for selectively encoding different modalities. Here we review the current knowledge of the different sensory neuron subtypes in the mouse, the markers used to study them, and the neurogenetic strategies used to define their anatomical projections and functional roles.

Eugenics, Genetics, and the Minority Group Model of Disabilities: Implications for Social Work Advocacy

Science.gov (United States)

O'Brien, Gerald V.

2011-01-01

In the United States, genetic research, as well as policy and practice innovations based on this research, has expanded greatly over the past few decades. This expansion is indicated, for example, by the mapping of the human genome, an expansion of genetic counseling, and other biogenetic research. Also, a disability rights movement that in many…

A Rapid Embryonic Stem Cell-Based Mouse Model for B-cell Lymphomas Driven by Epstein-Barr Virus Protein LMP1.

Science.gov (United States)

Ba, Zhaoqing; Meng, Fei-Long; Gostissa, Monica; Huang, Pei-Yi; Ke, Qiang; Wang, Zhe; Dao, Mai N; Fujiwara, Yuko; Rajewsky, Klaus; Zhang, Baochun; Alt, Frederick W

2015-06-01

The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) contributes to oncogenic human B-cell transformation. Mouse B cells conditionally expressing LMP1 are not predisposed to B-cell malignancies, as LMP1-expressing B cells are eliminated by T cells. However, mice with conditional B-cell LMP1 expression and genetic elimination of α/β and γ/δ T cells ("CLT" mice) die early in association with B-cell lymphoproliferation and lymphomagenesis. Generation of CLT mice involves in-breeding multiple independently segregating alleles. Thus, although introduction of additional activating or knockout mutations into the CLT model is desirable for further B-cell expansion and immunosurveillance studies, doing such experiments by germline breeding is time-consuming, expensive, and sometimes unfeasible. To generate a more tractable model, we generated clonal CLT embryonic stem (ES) cells from CLT embryos and injected them into RAG2-deficient blastocysts to generate chimeric mice, which, like germline CLT mice, harbor splenic CLT B cells and lack T cells. CLT chimeric mice generated by this RAG2-deficient blastocyst complementation ("RDBC") approach die rapidly in association with B-cell lymphoproliferation and lymphoma. Because CLT lymphomas routinely express the activation-induced cytidine deaminase (AID) antibody diversifier, we tested potential AID roles by eliminating the AID gene in CLT ES cells and testing them via RDBC. We found that CLT and AID-deficient CLT ES chimeras had indistinguishable phenotypes, showing that AID is not essential for LMP1-induced lymphomagenesis. Beyond expanding accessibility and utility of CLT mice as a cancer immunotherapy model, our studies provide a new approach for facilitating generation of genetically complex mouse cancer models. ©2015 American Association for Cancer Research.

Genetic interactions between Shox2 and Hox genes during the regional growth and development of the mouse limb.

Science.gov (United States)

Neufeld, Stanley J; Wang, Fan; Cobb, John

2014-11-01

The growth and development of the vertebrate limb relies on homeobox genes of the Hox and Shox families, with their independent mutation often giving dose-dependent effects. Here we investigate whether Shox2 and Hox genes function together during mouse limb development by modulating their relative dosage and examining the limb for nonadditive effects on growth. Using double mRNA fluorescence in situ hybridization (FISH) in single embryos, we first show that Shox2 and Hox genes have associated spatial expression dynamics, with Shox2 expression restricted to the proximal limb along with Hoxd9 and Hoxa11 expression, juxtaposing the distal expression of Hoxa13 and Hoxd13. By generating mice with all possible dosage combinations of mutant Shox2 alleles and HoxA/D cluster deletions, we then show that their coordinated proximal limb expression is critical to generate normally proportioned limb segments. These epistatic interactions tune limb length, where Shox2 underexpression enhances, and Shox2 overexpression suppresses, Hox-mutant phenotypes. Disruption of either Shox2 or Hox genes leads to a similar reduction in Runx2 expression in the developing humerus, suggesting their concerted action drives cartilage maturation during normal development. While we furthermore provide evidence that Hox gene function influences Shox2 expression, this regulation is limited in extent and is unlikely on its own to be a major explanation for their genetic interaction. Given the similar effect of human SHOX mutations on regional limb growth, Shox and Hox genes may generally function as genetic interaction partners during the growth and development of the proximal vertebrate limb. Copyright © 2014 by the Genetics Society of America.

Selection shaped the evolution of mouse androgen-binding protein (ABP) function and promoted the duplication of Abp genes.

Science.gov (United States)

Karn, Robert C; Laukaitis, Christina M

2014-08-01

In the present article, we summarize two aspects of our work on mouse ABP (androgen-binding protein): (i) the sexual selection function producing incipient reinforcement on the European house mouse hybrid zone, and (ii) the mechanism behind the dramatic expansion of the Abp gene region in the mouse genome. Selection unifies these two components, although the ways in which selection has acted differ. At the functional level, strong positive selection has acted on key sites on the surface of one face of the ABP dimer, possibly to influence binding to a receptor. A different kind of selection has apparently driven the recent and rapid expansion of the gene region, probably by increasing the amount of Abp transcript, in one or both of two ways. We have shown previously that groups of Abp genes behave as LCRs (low-copy repeats), duplicating as relatively large blocks of genes by NAHR (non-allelic homologous recombination). The second type of selection involves the close link between the accumulation of L1 elements and the expansion of the Abp gene family by NAHR. It is probably predicated on an initial selection for increased transcription of existing Abp genes and/or an increase in Abp gene number providing more transcriptional sites. Either or both could increase initial transcript production, a quantitative change similar to increasing the volume of a radio transmission. In closing, we also provide a note on Abp gene nomenclature.

Range Expansion and the Origin of USA300 North American Epidemic Methicillin-Resistant Staphylococcus aureus

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Lavanya Challagundla

2018-01-01

Full Text Available The USA300 North American epidemic (USA300-NAE clone of methicillin-resistant Staphylococcus aureus has caused a wave of severe skin and soft tissue infections in the United States since it emerged in the early 2000s, but its geographic origin is obscure. Here we use the population genomic signatures expected from the serial founder effects of a geographic range expansion to infer the origin of USA300-NAE and identify polymorphisms associated with its spread. Genome sequences from 357 isolates from 22 U.S. states and territories and seven other countries are compared. We observe two significant signatures of range expansion, including decreases in genetic diversity and increases in derived allele frequency with geographic distance from the Pennsylvania region. These signatures account for approximately half of the core nucleotide variation of this clone, occur genome wide, and are robust to heterogeneity in temporal sampling of isolates, human population density, and recombination detection methods. The potential for positive selection of a gyrA fluoroquinolone resistance allele and several intergenic regions, along with a 2.4 times higher recombination rate in a resistant subclade, is noted. These results are the first to show a pattern of genetic variation that is consistent with a range expansion of an epidemic bacterial clone, and they highlight a rarely considered but potentially common mechanism by which genetic drift may profoundly influence bacterial genetic variation.

The STR/ort mouse model of spontaneous osteoarthritis - an update.

Science.gov (United States)

Staines, K A; Poulet, B; Wentworth, D N; Pitsillides, A A

2017-06-01

Osteoarthritis is a degenerative joint disease and a world-wide healthcare burden. Characterized by cartilage degradation, subchondral bone thickening and osteophyte formation, osteoarthritis inflicts much pain and suffering, for which there are currently no disease-modifying treatments available. Mouse models of osteoarthritis are proving critical in advancing our understanding of the underpinning molecular mechanisms. The STR/ort mouse is a well-recognized model which develops a natural form of osteoarthritis very similar to the human disease. In this Review we discuss the use of the STR/ort mouse in understanding this multifactorial disease with an emphasis on recent advances in its genetics and its bone, endochondral and immune phenotypes. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Genetic causes of amyotrophic lateral sclerosis: new genetic analysis methodologies entailing new opportunities and challenges

Science.gov (United States)

Marangi, Giuseppe; Traynor, Bryan J.

2018-01-01

The genetic architecture of amyotrophic lateral sclerosis (ALS) is being increasingly understood. In this far-reaching review, we examine what is currently known about ALS genetics and how these genes were initially identified. We also discuss the various types of mutations that might underlie this fatal neurodegenerative condition and outline some of the strategies that might be useful in untangling them. These include expansions of short repeat sequences, common and low-frequency genetic variations, de novo mutations, epigenetic changes, somatic mutations, epistasis, oligogenic and polygenic hypotheses. PMID:25316630

Mouse and human genetic analyses associate kalirin with ventral striatal activation during impulsivity and with alcohol misuse

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Yolanda ePeña-Oliver

2016-04-01

Full Text Available Impulsivity is associated with a spectrum of psychiatric disorders including drug addiction. To investigate genetic associations with impulsivity and initiation of drug taking, we took a two-step approach. First, we identified genes whose expression level in prefrontal cortex, striatum and accumbens were associated with impulsive behaviour in the 5-choice serial reaction time task across 10 BXD recombinant inbred (BXD RI mouse strains and their progenitor C57BL/6J and DBA2/J strains. Behavioural data were correlated with regional gene expression using GeneNetwork (www.genenetwork.org, to identify 44 genes whose probability of association with impulsivity exceeded a false discovery rate of <0.05. We then interrogated the IMAGEN database of 1423 adolescents for potential associations of SNPs in human homologues of those genes identified in the mouse study, with brain activation during impulsive performance in the Monetary Incentive Delay task, and with novelty seeking scores from the Temperament and Character Inventory, as well as alcohol-experience. There was a significant overall association between the human homologues of impulsivity-related genes and percentage of premature responses in the MID task and with fMRI BOLD-response in ventral striatum (VS during reward anticipation. In contrast, no significant association was found between the polygenic scores and anterior cingulate cortex activation. Univariate association analyses revealed that the G allele (major of the intronic SNP rs6438839 in the KALRN gene was significantly associated with increased VS activation. Additionally, the A-allele (minor of KALRN intronic SNP rs4634050, belonging to the same haplotype block, was associated with increased frequency of binge drinking.

Relict or colonizer? Extinction and range expansion of penguins in southern New Zealand

Science.gov (United States)

Boessenkool, Sanne; Austin, Jeremy J.; Worthy, Trevor H.; Scofield, Paul; Cooper, Alan; Seddon, Philip J.; Waters, Jonathan M.

2008-01-01

Recent human expansion into the Pacific initiated a dramatic avian extinction crisis, and surviving taxa are typically interpreted as declining remnants of previously abundant populations. As a case in point, New Zealand's endangered yellow-eyed penguin (Megadyptes antipodes) is widely considered to have been more abundant and widespread in the past. By contrast, our genetic and morphological analyses of prehistoric, historic and modern penguin samples reveal that this species expanded its range to the New Zealand mainland only in the last few hundred years. This range expansion was apparently facilitated by the extinction of M. antipodes' previously unrecognized sister species following Polynesian settlement in New Zealand. Based on combined genetic and morphological data, we describe this new penguin species, the first known to have suffered human-mediated extinction. The range expansion of M. antipodes so soon after the extinction of its sister species supports a historic paradigmatic shift in New Zealand Polynesian culture. Additionally, such a dynamic biological response to human predation reveals a surprising and less recognized potential for species to have benefited from the extinction of their ecologically similar sister taxa and highlights the complexity of large-scale extinction events. PMID:19019791

The Population Origins and Expansion of Feral Cats in Australia

Science.gov (United States)

Yurchenko, Andrey A.; David, Victor A.; Scott, Rachael; Koepfli, Klaus-Peter; Driscoll, Carlos; O’Brien, Stephen J.; Menotti-Raymond, Marilyn

2016-01-01

The historical literature suggests that in Australia, the domestic cat (Felis catus) had a European origin [~200 years before present (ybp)], but it is unclear if cats arrived from across the Asian land bridge contemporaneously with the dingo (4000 ybp), or perhaps immigrated ~40000 ybp in association with Aboriginal settlement from Asia. The origin of cats in Australia is important because the continent has a complex and ancient faunal assemblage that is dominated by endemic rodents and marsupials and lacks the large placental carnivores found on other large continents. Cats are now ubiquitous across the entire Australian continent and have been implicit in the range contraction or extinction of its small to medium sized (cats using 15 short tandem repeat (STR) genomic markers. Their origin appears to come exclusively from European founders. Feral cats in continental Australia exhibit high genetic diversity in comparison with the low diversity found in populations of feral cats living on islands. The genetic structure is consistent with a rapid westerly expansion from eastern Australia and a limited expansion in coastal Western Australia. Australian cats show modest if any population structure and a close genetic alignment with European feral cats as compared to cats from Asia, the Christmas and Cocos (Keeling) Islands (Indian Ocean), and European wildcats (F. silvestris silvestris). PMID:26647063

Paleoclimatic modeling and phylogeography of least killifish, Heterandria formosa: insights into Pleistocene expansion-contraction dynamics and evolutionary history of North American Coastal Plain freshwater biota.

Science.gov (United States)

Bagley, Justin C; Sandel, Michael; Travis, Joseph; Lozano-Vilano, María de Lourdes; Johnson, Jerald B

2013-10-09

Climatic and sea-level fluctuations throughout the last Pleistocene glacial cycle (~130-0 ka) profoundly influenced present-day distributions and genetic diversity of Northern Hemisphere biotas by forcing range contractions in many species during the glacial advance and allowing expansion following glacial retreat ('expansion-contraction' model). Evidence for such range dynamics and refugia in the unglaciated Gulf-Atlantic Coastal Plain stems largely from terrestrial species, and aquatic species Pleistocene responses remain relatively uninvestigated. Heterandria formosa, a wide-ranging regional endemic, presents an ideal system to test the expansion-contraction model within this biota. By integrating ecological niche modeling and phylogeography, we infer the Pleistocene history of this livebearing fish (Poeciliidae) and test for several predicted distributional and genetic effects of the last glaciation. Paleoclimatic models predicted range contraction to a single southwest Florida peninsula refugium during the Last Glacial Maximum, followed by northward expansion. We inferred spatial-population subdivision into four groups that reflect genetic barriers outside this refuge. Several other features of the genetic data were consistent with predictions derived from an expansion-contraction model: limited intraspecific divergence (e.g. mean mtDNA p-distance = 0.66%); a pattern of mtDNA diversity (mean Hd = 0.934; mean π = 0.007) consistent with rapid, recent population expansion; a lack of mtDNA isolation-by-distance; and clinal variation in allozyme diversity with higher diversity at lower latitudes near the predicted refugium. Statistical tests of mismatch distributions and coalescent simulations of the gene tree lent greater support to a scenario of post-glacial expansion and diversification from a single refugium than to any other model examined (e.g. multiple-refugia scenarios). Congruent results from diverse data indicate H. formosa fits the classic Pleistocene

Evaluation of the Genetic and Nutritional Control of Obesity and Type 2 Diabetes in a Novel Mouse Model on Chromosome 7: An Insight into Insulin Signaling and Glucose Homeostasis

Energy Technology Data Exchange (ETDEWEB)

Nelson, S.; Dhar, M.

2003-01-01

Obesity is the main cause of type 2 diabetes, accounting for 90-95% of all diabetes cases in the US. Human obesity is a complex trait and can be studied using appropriate mouse models. A novel polygenic mouse model for studying the genetic and environmental contributions to and the physiological ramifications of obesity and related phenotypes is found in specific lines of mice bred and maintained at Oak Ridge National Laboratory. Heterozygous mice with a maternally inherited copy of two radiation-induced deletions in the p region of mouse chromosome 7, p23DFioD and p30PUb, have significantly greater body fat and show hyperinsulinemia compared to the wild-type. A single gene, Atp10c, maps to this critical region and codes for a putative aminophospholipid translocase. Biochemical and molecular studies were initiated to gain insight into obesity and glucose homeostasis in these animals and to study the biological role of Atp10c in creating these phenotypes. Glucose and insulin tolerance tests were standardized for the heterozygous p23DFioD and control mice on a custom-made diet containing 20% protein, 70% carbohydrate, and 10% fat (kcal). Atp10c expression profiles were also generated using Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR). Heterozygous p23DFioD animals showed insulin resistance after receiving a dose of either 0.375 or 0.75 U/kg Illetin R insulin. RT-PCR data also shows differences in Atp10c expression in the mutants versus control mice. Using these standardized biochemical assays, future studies will further the understanding of genetic and nutritional controls of glucose homeostasis and obesity in animal models and subsequently in human populations.

Frozen Accident Pushing 50: Stereochemistry, Expansion, and Chance in the Evolution of the Genetic Code.

Science.gov (United States)

Koonin, Eugene V

2017-05-23

Nearly 50 years ago, Francis Crick propounded the frozen accident scenario for the evolution of the genetic code along with the hypothesis that the early translation system consisted primarily of RNA. Under the frozen accident perspective, the code is universal among modern life forms because any change in codon assignment would be highly deleterious. The frozen accident can be considered the default theory of code evolution because it does not imply any specific interactions between amino acids and the cognate codons or anticodons, or any particular properties of the code. The subsequent 49 years of code studies have elucidated notable features of the standard code, such as high robustness to errors, but failed to develop a compelling explanation for codon assignments. In particular, stereochemical affinity between amino acids and the cognate codons or anticodons does not seem to account for the origin and evolution of the code. Here, I expand Crick's hypothesis on RNA-only translation system by presenting evidence that this early translation already attained high fidelity that allowed protein evolution. I outline an experimentally testable scenario for the evolution of the code that combines a distinct version of the stereochemical hypothesis, in which amino acids are recognized via unique sites in the tertiary structure of proto-tRNAs, rather than by anticodons, expansion of the code via proto-tRNA duplication, and the frozen accident.

Mouse Models Recapitulating Human Adrenocortical Tumors: What is lacking?

Directory of Open Access Journals (Sweden)

Felicia Leccia

2016-07-01

Full Text Available Adrenal cortex tumors are divided into benign forms such as primary hyperplasias and adrenocortical adenomas (ACAs, and malignant forms or adrenocortical carcinomas (ACCs. Primary hyperplasias are rare causes of ACTH-independent hypercortisolism. ACAs are the most common type of adrenal gland tumors and they are rarely functional, i.e producing steroids. When functional, adenomas result in endocrine disorders such as Cushing’s syndrome (hypercortisolism or Conn’s syndrome (hyperaldosteronism. In contrast, ACCs are extremely rare but highly aggressive tumors that may also lead to hypersecreting syndromes. Genetic analyses of patients with sporadic or familial forms of adrenocortical tumors led to the identification of potentially causative genes, most of them being involved in PKA, Wnt/β-catenin and P53 signaling pathways. Development of mouse models is a crucial step to firmly establish the functional significance of candidate genes, to dissect mechanisms leading to tumors and endocrine disorders and in fine to provide in vivo tools for therapeutic screens. In this article we will provide an overview on the existing mouse models (xenografted and genetically engineered of adrenocortical tumors by focusing on the role of PKA and Wnt/β-catenin pathways in this context. We will discuss the advantages and limitations of models that have been developed heretofore and we will point out necessary improvements in the development of next generation mouse models of adrenal diseases.

Recombinase-mediated reprogramming and dystrophin gene addition in mdx mouse induced pluripotent stem cells.

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Chunli Zhao

Full Text Available A cell therapy strategy utilizing genetically-corrected induced pluripotent stem cells (iPSC may be an attractive approach for genetic disorders such as muscular dystrophies. Methods for genetic engineering of iPSC that emphasize precision and minimize random integration would be beneficial. We demonstrate here an approach in the mdx mouse model of Duchenne muscular dystrophy that focuses on the use of site-specific recombinases to achieve genetic engineering. We employed non-viral, plasmid-mediated methods to reprogram mdx fibroblasts, using phiC31 integrase to insert a single copy of the reprogramming genes at a safe location in the genome. We next used Bxb1 integrase to add the therapeutic full-length dystrophin cDNA to the iPSC in a site-specific manner. Unwanted DNA sequences, including the reprogramming genes, were then precisely deleted with Cre resolvase. Pluripotency of the iPSC was analyzed before and after gene addition, and ability of the genetically corrected iPSC to differentiate into myogenic precursors was evaluated by morphology, immunohistochemistry, qRT-PCR, FACS analysis, and intramuscular engraftment. These data demonstrate a non-viral, reprogramming-plus-gene addition genetic engineering strategy utilizing site-specific recombinases that can be applied easily to mouse cells. This work introduces a significant level of precision in the genetic engineering of iPSC that can be built upon in future studies.

Mouse Models as Predictors of Human Responses: Evolutionary Medicine.

Science.gov (United States)

Uhl, Elizabeth W; Warner, Natalie J

Mice offer a number of advantages and are extensively used to model human diseases and drug responses. Selective breeding and genetic manipulation of mice have made many different genotypes and phenotypes available for research. However, in many cases, mouse models have failed to be predictive. Important sources of the prediction problem have been the failure to consider the evolutionary basis for species differences, especially in drug metabolism, and disease definitions that do not reflect the complexity of gene expression underlying disease phenotypes. Incorporating evolutionary insights into mouse models allow for unique opportunities to characterize the effects of diet, different gene expression profiles, and microbiomics underlying human drug responses and disease phenotypes.

In Vivo SILAC-Based Proteomics Reveals Phosphoproteome Changes during Mouse Skin Carcinogenesis

NARCIS (Netherlands)

Zanivan, S.; Meves, A.; Behrendt, K.; Schoof, E.M.; Neilson, L.J.; Cox, J.; Tang, H.R.; Kalna, G.; Ree, J.H. van; Deursen, J.M.A. van; Trempus, C.S.; Machesky, L.M.; Linding, R.; Wickstrom, S.A.; Fassler, R.; Mann, M.

2013-01-01

Cancer progresses through distinct stages, and mouse models recapitulating traits of this progression are frequently used to explore genetic, morphological, and pharmacological aspects of tumor development. To complement genomic investigations of this process, we here quantify phosphoproteomic

C9ORF72 hexanucleotide repeat expansions are a frequent cause of Huntington disease phenocopies in the Greek population.

Science.gov (United States)

Koutsis, Georgios; Karadima, Georgia; Kartanou, Chrisoula; Kladi, Athina; Panas, Marios

2015-01-01

An expanded hexanucleotide repeat in C9ORF72 has been identified as the most common genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia in many populations, including the Greek. Recently, C9ORF72 expansions were reported as the most common genetic cause of Huntington disease (HD) phenocopies in a UK population. In the present study, we screened a selected cohort of 40 Greek patients with HD phenocopies for C9ORF72 hexanucleotide repeat expansions using repeat-primed polymerase chain reaction. We identified 2 patients (5%) with pathologic expansions. The first patient had chorea, behavioral-psychiatric disturbance, cognitive impairment, and a positive family history, fulfilling the strictest criteria for HD phenocopy. The second patient was sporadic and had parkinsonism, behavioral-psychiatric disturbance, and cognitive impairment, corresponding to a broader definition of HD phenocopy. These findings identify C9ORF72 expansions as a frequent cause of HD phenocopies in the Greek population, confirming recent findings in other populations and supporting proposed diagnostic testing for C9ORF72 expansions in patients with HD-like syndromes. Copyright © 2015 Elsevier Inc. All rights reserved.

Initial locomotor sensitivity to cocaine varies widely among inbred mouse strains.

Science.gov (United States)

Wiltshire, T; Ervin, R B; Duan, H; Bogue, M A; Zamboni, W C; Cook, S; Chung, W; Zou, F; Tarantino, L M

2015-03-01

Initial sensitivity to psychostimulants can predict subsequent use and abuse in humans. Acute locomotor activation in response to psychostimulants is commonly used as an animal model of initial drug sensitivity and has been shown to have a substantial genetic component. Identifying the specific genetic differences that lead to phenotypic differences in initial drug sensitivity can advance our understanding of the processes that lead to addiction. Phenotyping inbred mouse strain panels are frequently used as a first step for studying the genetic architecture of complex traits. We assessed locomotor activation following a single, acute 20 mg/kg dose of cocaine (COC) in males from 45 inbred mouse strains and observed significant phenotypic variation across strains indicating a substantial genetic component. We also measured levels of COC, the active metabolite, norcocaine and the major inactive metabolite, benzoylecgonine, in plasma and brain in the same set of inbred strains. Pharmacokinetic (PK) and behavioral data were significantly correlated, but at a level that indicates that PK alone does not account for the behavioral differences observed across strains. Phenotypic data from this reference population of inbred strains can be utilized in studies aimed at examining the role of psychostimulant-induced locomotor activation on drug reward and reinforcement and to test theories about addiction processes. Moreover, these data serve as a starting point for identifying genes that alter sensitivity to the locomotor stimulatory effects of COC. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Screening for the C9ORF72 repeat expansion in a greek frontotemporal dementia cohort.

Science.gov (United States)

Kartanou, Chrisoula; Karadima, Georgia; Koutsis, Georgios; Breza, Marianthi; Papageorgiou, Sokratis G; Paraskevas, George P; Kapaki, Elisabeth; Panas, Marios

2018-02-01

The C9orf72 repeat expansion is a common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in European populations. A previous study has reported a high frequency of the expansion in Greek ALS. However, no data have been reported on the frequency of the expansion in Greek FTD. Currently, we investigated the frequency of the C9orfF72 expansion in a well-characterized cohort of 64 Greek FTD patients. We detected the C9orf72 repeat expansion in 9.3% of cases. Overall, 27.7% of familial and 2.2% of sporadic cases were expansion-positive. Five out of 6 cases had a diagnosis of behavioral variant FTD. All expansion-positive cases had fairly typical FTD presentations. Clinical features included motor neuron disease, Parkinsonism and hallucinations. We conclude that the overall frequency of C9orf72-positive cases in Greek FTD is high, comparable to Greek ALS, similar to some Western European, but significantly higher than some Mediterranean FTD populations.

Cross-species analysis of genetically engineered mouse models of MAPK-driven colorectal cancer identifies hallmarks of the human disease

Directory of Open Access Journals (Sweden)

Peter J. Belmont

2014-06-01

Full Text Available Effective treatment options for advanced colorectal cancer (CRC are limited, survival rates are poor and this disease continues to be a leading cause of cancer-related deaths worldwide. Despite being a highly heterogeneous disease, a large subset of individuals with sporadic CRC typically harbor relatively few established ‘driver’ lesions. Here, we describe a collection of genetically engineered mouse models (GEMMs of sporadic CRC that combine lesions frequently altered in human patients, including well-characterized tumor suppressors and activators of MAPK signaling. Primary tumors from these models were profiled, and individual GEMM tumors segregated into groups based on their genotypes. Unique allelic and genotypic expression signatures were generated from these GEMMs and applied to clinically annotated human CRC patient samples. We provide evidence that a Kras signature derived from these GEMMs is capable of distinguishing human tumors harboring KRAS mutation, and tracks with poor prognosis in two independent human patient cohorts. Furthermore, the analysis of a panel of human CRC cell lines suggests that high expression of the GEMM Kras signature correlates with sensitivity to targeted pathway inhibitors. Together, these findings implicate GEMMs as powerful preclinical tools with the capacity to recapitulate relevant human disease biology, and support the use of genetic signatures generated in these models to facilitate future drug discovery and validation efforts.

Major genomic mitochondrial lineages delineate early human expansions

Directory of Open Access Journals (Sweden)

Flores Carlos

2001-08-01

Full Text Available Abstract Background The phylogeographic distribution of human mitochondrial DNA variations allows a genetic approach to the study of modern Homo sapiens dispersals throughout the world from a female perspective. As a new contribution to this study we have phylogenetically analysed complete mitochondrial DNA(mtDNA sequences from 42 human lineages, representing major clades with known geographic assignation. Results We show the relative relationships among the 42 lineages and present more accurate temporal calibrations than have been previously possible to give new perspectives as how modern humans spread in the Old World. Conclusions The first detectable expansion occurred around 59,000–69,000 years ago from Africa, independently colonizing western Asia and India and, following this southern route, swiftly reaching east Asia. Within Africa, this expansion did not replace but mixed with older lineages detectable today only in Africa. Around 39,000–52,000 years ago, the western Asian branch spread radially, bringing Caucasians to North Africa and Europe, also reaching India, and expanding to north and east Asia. More recent migrations have entangled but not completely erased these primitive footprints of modern human expansions.

Lipidomic and metabolomic characterization of a genetically modified mouse model of the early stages of human type 1 diabetes pathogenesis

DEFF Research Database (Denmark)

Overgaard, Anne Julie; Weir, Jacquelyn M; De Souza, David Peter

2016-01-01

as methionine deficits were detected in the pre-type 1 diabetic mice. Additionally higher lysophosphatidylinositol levels and low phosphatidylglycerol levels where novel findings in the pre-type 1 diabetic mice. These observations suggest that metabolomic disturbances precede the onset of T1D.......The early mechanisms regulating progression towards beta cell failure in type 1 diabetes (T1D) are poorly understood, but it is generally acknowledged that genetic and environmental components are involved. The metabolomic phenotype is sensitive to minor variations in both, and accordingly reflects...... changes that may lead to the development of T1D. We used two different extraction methods in combination with both liquid- and gas chromatographic techniques coupled to mass spectrometry to profile the metabolites in a transgenic non-diabetes prone C57BL/6 mouse expressing CD154 under the control...

Comparative mapping in the beige-satin region of mouse chromosome 13

Energy Technology Data Exchange (ETDEWEB)

Perou, C.M.; Pryor, R.; Kaplan, J. [Univ. of Utah School of Medicine, Salt Lake City, UT (United States)] [and others

1997-01-15

The proximal end of mouse chromosome (Chr) 13 contains regions conserved on human chromosomes 1q42-q44, 6p23-p21, and 7p22-p13. This region also contains mutations that may be models for human disease, including beige (human Chediak-Higashi syndrome). An interspecific backcross of SB/Le and Mus spretus mice was used to generate a molecular genetic linkage map of mouse chromosome 13 with an emphasis on the proximal region including beige (bg) and satin (sa). This map provides the gene order of the two phenotypic markers bg and sa relative to restriction fragment length polymorphisms and simple sequence length polymorphisms in 131 backcross animals. In parallel, we have created a physical map of the region using Nidogen (Nid) as a molecular starting point for cloning a YAC contig that was used to identify the beige gene. The physical map provides the fine-structure order of genes and anonymous DNA fragments that was not resolved by the genetic linkage mapping. The results show that the bg region of mouse Chr 13 is highly conserved on human Chr 1q42-q44 and provide a starting point for a complete functional analysis of the entire bg-sa interval. 37 refs., 4 figs., 1 tab.

Population genetic structure of Diaphorina citri Kuwayama (Hemiptera: Liviidae): host-driven genetic differentiation in China.

Science.gov (United States)

Meng, Lixue; Wang, Yongmo; Wei, Wen-Hua; Zhang, Hongyu

2018-01-24

The Asian citrus psyllid Diaphorina citri Kuwayama is a major pest in citrus production, transmitting Candidatus Liberibacter asiaticus. It has spread widely across eastern and southern China. Unfortunately, little is known about the genetic diversity and population structure of D. citri, making pest control difficult. In this study, nine specifically developed SSR markers and three known mitochondrial DNA were used for population genetics study of D. citri using 225 samples collected from all 7 distribution regions in China. Based on the SSR data, D. citri was found highly diverse with a mean observed heterozygosity of 0.50, and three subgroups were structured by host plant: (i) Shatangju, NF mandarin and Ponkan; (ii) Murraya paniculata and Lemon; (iii) Citrus unshiu, Bingtangcheng, Summer orange and Navel. No significant genetic differences were found with mtDNA data. We suggested the host-associated divergence is likely to have occurred very recently. A unimodal distribution of paired differences, the negative and significant Tajima's D and Fu's F S parameters among mtDNA suggested a recent demographic expansion. The extensive citrus cultivation and increased suitable living habitat was recommended as a key for this expansion event.

Phylogeographic analyses and genetic structure illustrate the complex evolutionary history of Phragmites australis in Mexico.

Science.gov (United States)

Colin, Ricardo; Eguiarte, Luis E

2016-05-01

Genetic data suggest that three lineages of Phragmites australis are found in North America: the Native North American lineage, the Gulf Coast lineage, and the Invasive lineage. In Mexico, P. australis is a common species, but nothing is known about the distribution or ecology of these lineages. We examined the phylogeography of P. australis to analyze the current geographic distribution of genetic variation, demographic history, and dispersal patterns to better understand its evolutionary history in Mexico. We sampled 427 individuals from 28 populations. We used two noncoding regions of chloroplast DNA to estimate the levels of genetic variation and identified the genetic groups across the species' geographical range in Mexico. We compared the genealogical relationships among haplotypes with those previously reported. A hypothesis of demographic expansion was also tested for the Mexican P. australis lineages. We found 13 new haplotypes native to Mexico that might be undergoing an active process of expansion and diversification. Genealogical analyses provided evidence that two independent lineages of P. australis are present in Mexico. The invasive lineage was not detected with our sampling. Our estimates of population expansions in Mexico ranged from 0.202 to 0.726 mya. Phragmites australis is a native species that has been in Mexico for thousands of years. Genetic data suggest that climatic changes during the Pleistocene played an important role in the demographic expansion of the populations that constitute the different genetic groups of P. australis in Mexico. © 2016 Botanical Society of America.

Chromosomal localization of the human and mouse hyaluronan synthase genes

Energy Technology Data Exchange (ETDEWEB)

Spicer, A.P.; McDonald, J.A. [Mayo Clinic Scottsdale, AZ (United States); Seldin, M.F. [Univ. of California Davis, CA (United States)] [and others

1997-05-01

We have recently identified a new vertebrate gene family encoding putative hyaluronan (HA) synthases. Three highly conserved related genes have been identified, designated HAS1, HAS2, and HAS3 in humans and Has1, Has2, and Has3 in the mouse. All three genes encode predicted plasma membrane proteins with multiple transmembrane domains and approximately 25% amino acid sequence identity to the Streptococcus pyogenes HA synthase, HasA. Furthermore, expression of any one HAS gene in transfected mammalian cells leads to high levels of HA biosynthesis. We now report the chromosomal localization of the three HAS genes in human and in mouse. The genes localized to three different positions within both the human and the mouse genomes. HAS1 was localized to the human chromosome 19q13.3-q13.4 boundary and Has1 to mouse Chr 17. HAS2 was localized to human chromosome 8q24.12 and Has2 to mouse Chr 15. HAS3 was localized to human chromosome 16q22.1 and Has3 to mouse Chr 8. The map position for HAS1 reinforces the recently reported relationship between a small region of human chromosome 19q and proximal mouse chromosome 17. HAS2 mapped outside the predicted critical region delineated for the Langer-Giedion syndrome and can thus be excluded as a candidate gene for this genetic syndrome. 33 refs., 2 figs.

Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis.

Science.gov (United States)

Duarte, Tiago L; Caldas, Carolina; Santos, Ana G; Silva-Gomes, Sandro; Santos-Gonçalves, Andreia; Martins, Maria João; Porto, Graça; Lopes, José Manuel

2017-04-01

In hereditary hemochromatosis, iron deposition in the liver parenchyma may lead to fibrosis, cirrhosis and hepatocellular carcinoma. Most cases are ascribed to a common mutation in the HFE gene, but the extent of clinical expression is greatly influenced by the combined action of yet unidentified genetic and/or environmental modifying factors. In mice, transcription factor NRF2 is a critical determinant of hepatocyte viability during exposure to acute dietary iron overload. We evaluated if the genetic disruption of Nrf2 would prompt the development of liver damage in Hfe -/- mice (an established model of human HFE-hemochromatosis). Wild-type, Nrf2 -/- , Hfe -/- and double knockout (Hfe/Nrf2 -/- ) female mice on C57BL/6 genetic background were sacrificed at the age of 6 (young), 12-18 (middle-aged) or 24 months (old) for evaluation of liver pathology. Despite the parenchymal iron accumulation, Hfe -/- mice presented no liver injury. The combination of iron overload (Hfe -/- ) and defective antioxidant defences (Nrf2 -/- ) increased the number of iron-related necroinflammatory lesions (sideronecrosis), possibly due to the accumulation of toxic oxidation products such as 4-hydroxy-2-nonenal-protein adducts. The engulfment of dead hepatocytes led to a gradual accumulation of iron within macrophages, featuring large aggregates. Myofibroblasts recruited towards the injury areas produced substantial amounts of collagen fibers involving the liver parenchyma of double-knockout animals with increased hepatic fibrosis in an age-dependent manner. The genetic disruption of Nrf2 promotes the transition from iron accumulation (siderosis) to liver injury in Hfe -/- mice, representing the first demonstration of spontaneous hepatic fibrosis in the long term in a mouse model of hereditary hemochromatosis displaying mildly elevated liver iron. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Genome wide analysis of inbred mouse lines identifies a locus containing Ppar-gamma as contributing to enhanced malaria survival.

Directory of Open Access Journals (Sweden)

Selina E R Bopp

2010-05-01

Full Text Available The genetic background of a patient determines in part if a person develops a mild form of malaria and recovers, or develops a severe form and dies. We have used a mouse model to detect genes involved in the resistance or susceptibility to Plasmodium berghei malaria infection. To this end we first characterized 32 different mouse strains infected with P. berghei and identified survival as the best trait to discriminate between the strains. We found a locus on chromosome 6 by linking the survival phenotypes of the mouse strains to their genetic variations using genome wide analyses such as haplotype associated mapping and the efficient mixed-model for association. This new locus involved in malaria resistance contains only two genes and confirms the importance of Ppar-gamma in malaria infection.

Mechanical control of notochord morphogenesis by extra-embryonic tissues in mouse embryos.

Science.gov (United States)

Imuta, Yu; Koyama, Hiroshi; Shi, Dongbo; Eiraku, Mototsugu; Fujimori, Toshihiko; Sasaki, Hiroshi

2014-05-01

Mammalian embryos develop in coordination with extraembryonic tissues, which support embryonic development by implanting embryos into the uterus, supplying nutrition, providing a confined niche, and also providing patterning signals to embryos. Here, we show that in mouse embryos, the expansion of the amniotic cavity (AC), which is formed between embryonic and extraembryonic tissues, provides the mechanical forces required for a type of morphogenetic movement of the notochord known as convergent extension (CE) in which the cells converge to the midline and the tissue elongates along the antero-posterior (AP) axis. The notochord is stretched along the AP axis, and the expansion of the AC is required for CE. Both mathematical modeling and physical simulation showed that a rectangular morphology of the early notochord caused the application of anisotropic force along the AP axis to the notochord through the isotropic expansion of the AC. AC expansion acts upstream of planar cell polarity (PCP) signaling, which regulates CE movement. Our results highlight the importance of extraembryonic tissues as a source of the forces that control the morphogenesis of embryos. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The genetics of radiation-induced osteosarcoma

International Nuclear Information System (INIS)

Rosemann, M.; Kuosaite, V.; Nathrath, M.; Atkinson, M.J.

2002-01-01

Individual genetic variation can influence susceptibility to the carcinogenic effects of many environmental carcinogens. In radiation-exposed populations those individuals with a greater genetically determined susceptibility would be at greater risk of developing cancer. To include this modification of risk into radiation protection schemes it is necessary to identify the genes responsible for determining individual sensitivity. Alpha-particle-induced osteosarcoma in the mouse has been adopted as a model of human radiation carcinogenesis, and genome-wide screens have been conducted for allelic imbalance and genetic linkage. These studies have revealed a series of genes involved in determining the sensitivity to radiogenic osteosarcoma formation. (author)

The evolving genetic risk for sporadic ALS.

Science.gov (United States)

Gibson, Summer B; Downie, Jonathan M; Tsetsou, Spyridoula; Feusier, Julie E; Figueroa, Karla P; Bromberg, Mark B; Jorde, Lynn B; Pulst, Stefan M

2017-07-18

To estimate the genetic risk conferred by known amyotrophic lateral sclerosis (ALS)-associated genes to the pathogenesis of sporadic ALS (SALS) using variant allele frequencies combined with predicted variant pathogenicity. Whole exome sequencing and repeat expansion PCR of C9orf72 and ATXN2 were performed on 87 patients of European ancestry with SALS seen at the University of Utah. DNA variants that change the protein coding sequence of 31 ALS-associated genes were annotated to determine which were rare and deleterious as predicted by MetaSVM. The percentage of patients with SALS with a rare and deleterious variant or repeat expansion in an ALS-associated gene was calculated. An odds ratio analysis was performed comparing the burden of ALS-associated genes in patients with SALS vs 324 normal controls. Nineteen rare nonsynonymous variants in an ALS-associated gene, 2 of which were found in 2 different individuals, were identified in 21 patients with SALS. Further, 5 deleterious C9orf72 and 2 ATXN2 repeat expansions were identified. A total of 17.2% of patients with SALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene. The genetic burden of ALS-associated genes in patients with SALS as predicted by MetaSVM was significantly higher than in normal controls. Previous analyses have identified SALS-predisposing variants only in terms of their rarity in normal control populations. By incorporating variant pathogenicity as well as variant frequency, we demonstrated that the genetic risk contributed by these genes for SALS is substantially lower than previous estimates. © 2017 American Academy of Neurology.

The first mouse mutants of D14Abb1e (Fam208a) show that it is critical for early development

Czech Academy of Sciences Publication Activity Database

Harten, S.K.; Bruxner, T.J.; Bharti, V.; Blewitt, M.; Nguyen, T.M.T.; Whitelaw, E.; Epp, Trevor

2014-01-01

Roč. 25, 7-8 (2014), s. 293-303 ISSN 0938-8990 Institutional support: RVO:68378050 Keywords : embryogenesis * forward genetics * mouse mutant Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.068, year: 2014

Single Nucleotide Polymorphism Markers for Genetic Mapping in Drosophila melanogaster

OpenAIRE

Hoskins, Roger A.; Phan, Alexander C.; Naeemuddin, Mohammed; Mapa, Felipa A.; Ruddy, David A.; Ryan, Jessica J.; Young, Lynn M.; Wells, Trent; Kopczynski, Casey; Ellis, Michael C.

2001-01-01

For nearly a century, genetic analysis in Drosophila melanogaster has been a powerful tool for analyzing gene function, yet Drosophila lacks the molecular genetic mapping tools that recently have revolutionized human, mouse, and plant genetics. Here, we describe the systematic characterization of a dense set of molecular markers in Drosophila by using a sequence tagged site-based physical map of the genome. We identify 474 biallelic markers in standard laboratory strains of Drosophila that sp...

Range expansion drives dispersal evolution in an equatorial three-species symbiosis.

Science.gov (United States)

Léotard, Guillaume; Debout, Gabriel; Dalecky, Ambroise; Guillot, Sylvain; Gaume, Laurence; McKey, Doyle; Kjellberg, Finn

2009-01-01

Recurrent climatic oscillations have produced dramatic changes in species distributions. This process has been proposed to be a major evolutionary force, shaping many life history traits of species, and to govern global patterns of biodiversity at different scales. During range expansions selection may favor the evolution of higher dispersal, and symbiotic interactions may be affected. It has been argued that a weakness of climate fluctuation-driven range dynamics at equatorial latitudes has facilitated the persistence there of more specialized species and interactions. However, how much the biology and ecology of species is changed by range dynamics has seldom been investigated, particularly in equatorial regions. We studied a three-species symbiosis endemic to coastal equatorial rainforests in Cameroon, where the impact of range dynamics is supposed to be limited, comprised of two species-specific obligate mutualists--an ant-plant and its protective ant--and a species-specific ant parasite of this mutualism. We combined analyses of within-species genetic diversity and of phenotypic variation in a transect at the southern range limit of this ant-plant system. All three species present congruent genetic signatures of recent gradual southward expansion, a result compatible with available regional paleoclimatic data. As predicted, this expansion has been accompanied by the evolution of more dispersive traits in the two ant species. In contrast, we detected no evidence of change in lifetime reproductive strategy in the tree, nor in its investment in food resources provided to its symbiotic ants. Despite the decreasing investment in protective workers and the increasing investment in dispersing females by both the mutualistic and the parasitic ant species, there was no evidence of destabilization of the symbiosis at the colonization front. To our knowledge, we provide here the first evidence at equatorial latitudes that biological traits associated with dispersal are

Genetic regulation of immunoglobulin E level in different pathological states: integration of mouse and human genetics

Czech Academy of Sciences Publication Activity Database

Gusareva, Elena; Kurey, Irina; Grekov, Igor; Lipoldová, Marie

2014-01-01

Roč. 89, č. 2 (2014), s. 375-405 ISSN 1464-7931 R&D Projects: GA ČR GA310/08/1697; GA MŠk LH12049 Institutional support: RVO:68378050 Keywords : Genetic control of complex diseases * Immunoglobulin E * Epistasis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 9.670, year: 2014

Circuit Mechanisms Governing Local vs. Global Motion Processing in Mouse Visual Cortex

DEFF Research Database (Denmark)

Rasmussen, Rune; Yonehara, Keisuke

2017-01-01

components represented by component direction-selective (CDS) cells. However, how PDS and CDS cells develop their distinct response properties is still unresolved. The visual cortex of the mouse is an attractive model for experimentally solving this issue due to the large molecular and genetic toolbox...... literature on global motion processing based on works in primates and mice. Lastly, we propose what types of experiments could illuminate what circuit mechanisms are governing cortical global visual motion processing. We propose that PDS cells in mouse visual cortex appear as the perfect arena...

Searching for Grendel: origin and global spread of the C9ORF72 repeat expansion.

Science.gov (United States)

Pliner, Hannah A; Mann, David M; Traynor, Bryan J

2014-03-01

Recent advances are uncovering more and more of the genetic architecture underlying amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative condition that affects ~6,000 Americans annually. Chief among these was the discovery that a large repeat expansion in the C9ORF72 gene is responsible for an unprecedented portion of familial and sporadic ALS cases. Much has been published on how this expansion disrupts neuronal homeostasis and how gene-based therapy might be an effective treatment in the future. Nevertheless, it is instructive to look back at the origins of this important mutation. In this opinion piece, we attempt to answer three key questions concerning C9ORF72. First, how many times did the expansion occur throughout human history? Second, how old is the expansion? And finally and perhaps most importantly, how did the expansion spread throughout Europe? We speculate that the expansion occurred only once in the past, that this event took place in the Finnish population and that the Vikings and their descendants were responsible for disseminating this mutation throughout the rest of the continent.

Expression of human erythropoietin gene in the mammary gland of a transgenic mouse

Czech Academy of Sciences Publication Activity Database

Mikuš, Tomáš; Malý, Petr; Poplštein, M.; Landa, Vladimír; Trefil, P.; Lidický, J.

2001-01-01

Roč. 47, č. 6 (2001), s. 187-195 ISSN 0015-5500 Institutional research plan: CEZ:AV0Z5052915 Keywords : erythropoietin, mammary gland, transgenic mouse Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.519, year: 2001

Dissection of a locus on mouse chromosome 5 reveals arthritis promoting and inhibitory genes

DEFF Research Database (Denmark)

Lindvall, Therese; Karlsson, Jenny; Holmdahl, Rikard

2009-01-01

with Eae39 congenic- and sub-interval congenic mice, carrying RIIIS/J genes on the B10.RIII genetic background, revealed three loci within Eae39 that control disease and anti-collagen antibody titers. Two of the loci promoted disease and the third locus was protecting from collagen induced arthritis...... development. By further breeding of mice with small congenic fragments, we identified a 3.2 Megabasepair (Mbp) interval that regulates disease. CONCLUSIONS: Disease promoting- and protecting genes within the Eae39 locus on mouse chromosome 5, control susceptibility to collagen induced arthritis. A disease......-protecting locus in the telomeric part of Eae39 results in lower anti-collagen antibody responses. The study shows the importance of breeding sub-congenic mouse strains to reveal genetic effects on complex diseases....

QTL and systems genetics analysis of mouse grooming and behavioral responses to novelty in an open field.

Science.gov (United States)

Delprato, A; Algéo, M-P; Bonheur, B; Bubier, J A; Lu, L; Williams, R W; Chesler, E J; Crusio, W E

2017-11-01

The open field is a classic test used to assess exploratory behavior, anxiety and locomotor activity in rodents. Here, we mapped quantitative trait loci (QTLs) underlying behaviors displayed in an open field, using a panel of 53 BXD recombinant inbred mouse strains with deep replication (10 per strain and sex). The use of these strains permits the integration and comparison of data obtained in different laboratories, and also offers the possibility to study trait covariance by exploiting powerful bioinformatics tools and resources. We quantified behavioral traits during 20-min test sessions including (1) percent time spent and distance traveled near the wall (thigmotaxis), (2) leaning against the wall, (3) rearing, (4) jumping, (5) grooming duration, (6) grooming frequency, (7) locomotion and (8) defecation. All traits exhibit moderate heritability making them amenable to genetic analysis. We identified a significant QTL on chromosome M.m. 4 at approximately 104 Mb that modulates grooming duration in both males and females (likelihood ratio statistic values of approximately 18, explaining 25% and 14% of the variance, respectively) and a suggestive QTL modulating locomotion that maps to the same locus. Bioinformatic analysis indicates Disabled 1 (Dab1, a key protein in the reelin signaling pathway) as a particularly strong candidate gene modulating these behaviors. We also found 2 highly suggestive QTLs for a sex by strain interaction for grooming duration on chromosomes 13 and 17. In addition, we identified a pairwise epistatic interaction between loci on chromosomes 12 at 36-37 Mb and 14 at 34-36 Mb that influences rearing frequency in males. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Genetic mapping of xenotropic murine leukemia virus-inducing loci in five mouse strains.

Science.gov (United States)

Kozak, C A; Rowe, W P

1980-07-01

A single mendelian gene was identified for induction of the endogenous xenotropic murine leukemia virus in five mouse strains (C57BL/10, C57L, C57BR, AKR, and BALB/c). This locus, designated Bxv-1, mapped to the same site on chromosome 1 in all strains: Id-1-Pep-3-[Bxv-1-Lp]. Thus, inducibility loci for xenotropic virus are more limited in number and chromosomal distribution than ecotropic inducibility loci. Virus expression in mice with Bxv-1 was induced by treatment of fibroblasts with 5-iododeoxyuridine or by exposure of spleen cells to a B cell mitogen, bacterial lipopolysaccharide. An analysis of the hamster X mouse somatic cell hybrids indicated that chromosome 1, alone, was sufficient for virus induction.

Genetic risks from radiation

International Nuclear Information System (INIS)

Selby, P.B.

Two widely-recognized committees, UNSCEAR and BEIR, have reevaluated their estimates of genetic risks from radiation. Their estimates for gene mutations are based on two different approaches, one being the doubling-dose approach and the other being a new direct approach based on an empirical determination of the amount of dominant induced damage in the skeletons of mice in the first generation following irradiation. The estimates made by these committees are in reasonably good agreement and suggest that the genetic risks from present exposures resultng from nuclear power production are small. There is room for much improvement in the reliability of the risk estimates. The relatively new approach of measuring the amount of induced damage to the mouse skeleton shows great promise of improving knowledge about how changes in the mutation frequency affect the incidence of genetic disorders. Such findings may have considerable influence on genetic risk estimates for radiation and on the development of risk estimates for other less-well-understood environmental mutagens. (author)

Structural Variation Shapes the Landscape of Recombination in Mouse.

Science.gov (United States)

Morgan, Andrew P; Gatti, Daniel M; Najarian, Maya L; Keane, Thomas M; Galante, Raymond J; Pack, Allan I; Mott, Richard; Churchill, Gary A; de Villena, Fernando Pardo-Manuel

2017-06-01

Meiotic recombination is an essential feature of sexual reproduction that ensures faithful segregation of chromosomes and redistributes genetic variants in populations. Multiparent populations such as the Diversity Outbred (DO) mouse stock accumulate large numbers of crossover (CO) events between founder haplotypes, and thus present a unique opportunity to study the role of genetic variation in shaping the recombination landscape. We obtained high-density genotype data from [Formula: see text] DO mice, and localized 2.2 million CO events to intervals with a median size of 28 kb. The resulting sex-averaged genetic map of the DO population is highly concordant with large-scale (order 10 Mb) features of previously reported genetic maps for mouse. To examine fine-scale (order 10 kb) patterns of recombination in the DO, we overlaid putative recombination hotspots onto our CO intervals. We found that CO intervals are enriched in hotspots compared to the genomic background. However, as many as [Formula: see text] of CO intervals do not overlap any putative hotspots, suggesting that our understanding of hotspots is incomplete. We also identified coldspots encompassing 329 Mb, or [Formula: see text] of observable genome, in which there is little or no recombination. In contrast to hotspots, which are a few kilobases in size, and widely scattered throughout the genome, coldspots have a median size of 2.1 Mb and are spatially clustered. Coldspots are strongly associated with copy-number variant (CNV) regions, especially multi-allelic clusters, identified from whole-genome sequencing of 228 DO mice. Genes in these regions have reduced expression, and epigenetic features of closed chromatin in male germ cells, which suggests that CNVs may repress recombination by altering chromatin structure in meiosis. Our findings demonstrate how multiparent populations, by bridging the gap between large-scale and fine-scale genetic mapping, can reveal new features of the recombination

Spallanzani's mouse: a model of restoration and regeneration.

Science.gov (United States)

Heber-Katz, E; Leferovich, J M; Bedelbaeva, K; Gourevitch, D

2004-01-01

The ability to regenerate is thought to be a lost phenotype in mammals, though there are certainly sporadic examples of mammalian regeneration. Our laboratory has identified a strain of mouse, the MRL mouse, which has a unique capacity to heal complex tissue in an epimorphic fashion, i.e., to restore a damaged limb or organ to its normal structure and function. Initial studies using through-and-through ear punches showed rapid full closure of the ear holes with cartilage growth, new hair follicles, and normal tissue architecture reminiscent of regeneration seen in amphibians as opposed to the scarring usually seen in mammals. Since the ear hole closure phenotype is a quantitative trait, this has been used to show-through extensive breeding and backcrossing--that the trait is heritable. Such analysis reveals that there is a complex genetic basis for this trait with multiple loci. One of the major phenotypes of the MRL mouse is a potent remodeling response with the absence or a reduced level of scarring. MRL healing is associated with the upregulation of the metalloproteinases MMP-2 and MMP-9 and the downregulation of their inhibitors TIMP-2 and TIMP-3, both present in inflammatory cells such as neutrophils and macrophages. This model has more recently been extended to the heart. In this case, a cryoinjury to the right ventricle leads to near complete scarless healing in the MRL mouse whereas scarring is seen in the control mouse. In the MRL heart, bromodeoxyuridine uptake by cardiomyocytes filling the wound site can be seen 60 days after injury. This does not occur in the control mouse. Function in the MRL heart, as measured by echocardiography, returns to normal.

Mouse genetic model for clinical and immunological heterogeneity of leishmaniasis

Czech Academy of Sciences Publication Activity Database

Lipoldová, Marie; Svobodová, M.; Havelková, Helena; Krulová, Magdalena; Badalová, Jana; Nohýnková, E.; Hart, A. A. M.; Schlegel, David; Volf, P.; Demant, P.

2002-01-01

Roč. 54, č. 3 (2002), s. 174-183 ISSN 0093-7711 R&D Projects: GA MZd NM28; GA ČR GA310/00/0760; GA MŠk OK 394 Grant - others:Howard Hughes Medical Institute(US) HHMI55000323; WHO(XX) TDR I.D. 970772; EC(XE) ERBI-C15-CT98-0317; EC(XE) BIO-4-CT98-0445 Institutional research plan: CEZ:AV0Z5052915 Keywords : Leishmaniasis * mouse model * complex disease Subject RIV: EC - Immunology Impact factor: 2.475, year: 2002

Genetic modifications associated with ketogenic diet treatment in the BTBRT+Tf/J mouse model of autism spectrum disorder.

Science.gov (United States)

Mychasiuk, Richelle; Rho, Jong M

2017-03-01

Autism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder characterized by hallmark behavioral features. The spectrum of disorders that fall within the ASD umbrella encompass a distinct but overlapping symptom complex that likely results from an array of molecular and genetic aberrations rather than a single genetic mutation. The ketogenic diet (KD) is a high-fat low-carbohydrate anti-seizure and neuroprotective diet that has demonstrated efficacy in the treatment of ASD-like behaviors in animal and human studies. We investigated changes in mRNA and gene expression in the BTBR mouse model of ASD that may contribute to the behavioral phenotype. In addition, we sought to examine changes in gene expression following KD treatment in BTBR mice. Despite significant behavioral abnormalities, expression changes in BTBR mice did not differ substantially from controls; only 33 genes were differentially expressed in the temporal cortex, and 48 in the hippocampus. Examination of these differentially expressed genes suggested deficits in the stress response and in neuronal signaling/communication. After treatment with the KD, both brain regions demonstrated improvements in ASD deficits associated with myelin formation and white matter development. Although our study supports many of the previously known impairments associated with ASD, such as excessive myelin formation and impaired GABAergic transmission, the RNAseq data and pathway analysis utilized here identified new therapeutic targets for analysis, such as Vitamin D pathways and cAMP signaling. Autism Res 2017, 10: 456-471. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

In-silico QTL mapping of postpubertal mammary ductal development in the mouse uncovers potential human breast cancer risk loci

Science.gov (United States)

Genetic background plays a dominant role in mammary gland development and breast cancer (BrCa). Despite this, the role of genetics is only partially understood. This study used strain-dependent variation in an inbred mouse mapping panel, to identify quantitative trait loci (QTL) underlying structura...

Expression of human eryhropoietin gene in the mammary gland of a transgenic mouse

Czech Academy of Sciences Publication Activity Database

Mikuš, T.; Malý, Petr; Poplštein, M.; Landa, Vladimír; Trefil, P.; Lidický, J.

2001-01-01

Roč. 47, č. 6 (2001), s. 187-195 ISSN 0015-5500 R&D Projects: GA MPO PP-Z1/09/96 Keywords : erythropoietin * recombinant protein * transgenic mouse Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.519, year: 2001

Intraspecific Genetic dynamics under Climate Change

DEFF Research Database (Denmark)

Florez Rodriguez, Alexander

Climate change has a deep influence on the maintenance and generation of global biodiversity. Past contractions, expansions and shifts in species’ ranges drove to changes in species genetic diversity. Noteworthy, the interaction among: climate change, range, population size and extinction is often...

Risk assessment in man and mouse.

Science.gov (United States)

Balci, Fuat; Freestone, David; Gallistel, Charles R

2009-02-17

Human and mouse subjects tried to anticipate at which of 2 locations a reward would appear. On a randomly scheduled fraction of the trials, it appeared with a short latency at one location; on the complementary fraction, it appeared after a longer latency at the other location. Subjects of both species accurately assessed the exogenous uncertainty (the probability of a short versus a long trial) and the endogenous uncertainty (from the scalar variability in their estimates of an elapsed duration) to compute the optimal target latency for a switch from the short- to the long-latency location. The optimal latency was arrived at so rapidly that there was no reliably discernible improvement over trials. Under these nonverbal conditions, humans and mice accurately assess risks and behave nearly optimally. That this capacity is well-developed in the mouse opens up the possibility of a genetic approach to the neurobiological mechanisms underlying risk assessment.

Esophageal Cancer: Insights from Mouse Models

Directory of Open Access Journals (Sweden)

Marie-Pier Tétreault

2015-01-01

Full Text Available Esophageal cancer is the eighth leading cause of cancer and the sixth most common cause of cancer-related death worldwide. Despite recent advances in the development of surgical techniques in combination with the use of radiotherapy and chemotherapy, the prognosis for esophageal cancer remains poor. The cellular and molecular mechanisms that drive the pathogenesis of esophageal cancer are still poorly understood. Hence, understanding these mechanisms is crucial to improving outcomes for patients with esophageal cancer. Mouse models constitute valuable tools for modeling human cancers and for the preclinical testing of therapeutic strategies in a manner not possible in human subjects. Mice are excellent models for studying human cancers because they are similar to humans at the physiological and molecular levels and because they have a shorter gestation time and life cycle. Moreover, a wide range of well-developed technologies for introducing genetic modifications into mice are currently available. In this review, we describe how different mouse models are used to study esophageal cancer.

Population genetic structure in a Robertsonian race of house mice: evidence from microsatellite polymorphism

NARCIS (Netherlands)

Dallas, J.F.; Bonhomme, F.; Boursot, P.; Britton-Davidian, J.; Bauchau, V.

1998-01-01

Genetic evidence was assessed for inbreeding and population subdivision in a Robertsonian fusion (Rb) race of the western European form of house mouse, Mus musculus domesticus, in central Belgium. Inbreeding, and the factors responsible for subdivision (genetic drift and extinction-recolonization)

Physiological characterization of formyl peptide receptor expressing cells in the mouse vomeronasal organ

Directory of Open Access Journals (Sweden)

Tobias eAckels

2014-11-01

Full Text Available The mouse vomeronasal organ (VNO is a chemosensory structure that detects both hetero- and conspecific social cues. Based on largely monogenic expression of either type 1 or 2 vomeronasal receptors (V1Rs / V2Rs or members of the formyl peptide receptor (FPR family, the vomeronasal sensory epithelium harbors at least three neuronal subpopulations. While various neurophysiological properties of both V1R- and V2R-expressing neurons have been described using genetically engineered mouse models, the basic biophysical characteristics of the more recently identified FPR-expressing vomeronasal neurons have not been studied. Here, we employ a transgenic mouse strain that coexpresses an enhanced variant of yellow fluorescent protein together with FPR-rs3 allowing to identify and analyze FPR-rs3-expressing neurons in acute VNO tissue slices. Single neuron electrophysiological recordings allow comparative characterization of the biophysical properties inherent to a prototypical member of the FPR-expressing subpopulation of VNO neurons. In this study, we provide an in-depth analysis of both passive and active membrane properties, including detailed characterization of several types of voltage-activated conductances and action potential discharge patterns, in fluorescently labeled versus unmarked vomeronasal neurons. Our results reveal striking similarities in the basic (electrophysiological architecture of both transgene-expressing and non-expressing neurons, confirming the suitability of this genetically engineered mouse model for future studies addressing more specialized issues in vomeronasal FPR neurobiology.

Transmission Network Expansion Planning Considering Phase-Shifter Transformers

Directory of Open Access Journals (Sweden)

Celso T. Miasaki

2012-01-01

Full Text Available This paper presents a novel mathematical model for the transmission network expansion planning problem. Main idea is to consider phase-shifter (PS transformers as a new element of the transmission system expansion together with other traditional components such as transmission lines and conventional transformers. In this way, PS are added in order to redistribute active power flows in the system and, consequently, to diminish the total investment costs due to new transmission lines. Proposed mathematical model presents the structure of a mixed-integer nonlinear programming (MINLP problem and is based on the standard DC model. In this paper, there is also applied a specialized genetic algorithm aimed at optimizing the allocation of candidate components in the network. Results obtained from computational simulations carried out with IEEE-24 bus system show an outstanding performance of the proposed methodology and model, indicating the technical viability of using these nonconventional devices during the planning process.

Maternal Supply of Cas9 to Zygotes Facilitates the Efficient Generation of Site-Specific Mutant Mouse Models

Science.gov (United States)

Cebrian-Serrano, Alberto; Zha, Shijun; Hanssen, Lars; Biggs, Daniel; Preece, Christopher

2017-01-01

Genome manipulation in the mouse via microinjection of CRISPR/Cas9 site-specific nucleases has allowed the production time for genetically modified mouse models to be significantly reduced. Successful genome manipulation in the mouse has already been reported using Cas9 supplied by microinjection of a DNA construct, in vitro transcribed mRNA and recombinant protein. Recently the use of transgenic strains of mice overexpressing Cas9 has been shown to facilitate site-specific mutagenesis via maternal supply to zygotes and this route may provide an alternative to exogenous supply. We have investigated the feasibility of supplying Cas9 genetically in more detail and for this purpose we report the generation of a transgenic mice which overexpress Cas9 ubiquitously, via a CAG-Cas9 transgene targeted to the Gt(ROSA26)Sor locus. We show that zygotes prepared from female mice harbouring this transgene are sufficiently loaded with maternally contributed Cas9 for efficient production of embryos and mice harbouring indel, genomic deletion and knock-in alleles by microinjection of guide RNAs and templates alone. We compare the mutagenesis rates and efficacy of mutagenesis using this genetic supply with exogenous Cas9 supply by either mRNA or protein microinjection. In general, we report increased generation rates of knock-in alleles and show that the levels of mutagenesis at certain genome target sites are significantly higher and more consistent when Cas9 is supplied genetically relative to exogenous supply. PMID:28081254

Moralistic gods, supernatural punishment and the expansion of human sociality.

Science.gov (United States)

Purzycki, Benjamin Grant; Apicella, Coren; Atkinson, Quentin D; Cohen, Emma; McNamara, Rita Anne; Willard, Aiyana K; Xygalatas, Dimitris; Norenzayan, Ara; Henrich, Joseph

2016-02-18

Since the origins of agriculture, the scale of human cooperation and societal complexity has dramatically expanded. This fact challenges standard evolutionary explanations of prosociality because well-studied mechanisms of cooperation based on genetic relatedness, reciprocity and partner choice falter as people increasingly engage in fleeting transactions with genetically unrelated strangers in large anonymous groups. To explain this rapid expansion of prosociality, researchers have proposed several mechanisms. Here we focus on one key hypothesis: cognitive representations of gods as increasingly knowledgeable and punitive, and who sanction violators of interpersonal social norms, foster and sustain the expansion of cooperation, trust and fairness towards co-religionist strangers. We tested this hypothesis using extensive ethnographic interviews and two behavioural games designed to measure impartial rule-following among people (n = 591, observations = 35,400) from eight diverse communities from around the world: (1) inland Tanna, Vanuatu; (2) coastal Tanna, Vanuatu; (3) Yasawa, Fiji; (4) Lovu, Fiji; (5) Pesqueiro, Brazil; (6) Pointe aux Piments, Mauritius; (7) the Tyva Republic (Siberia), Russia; and (8) Hadzaland, Tanzania. Participants reported adherence to a wide array of world religious traditions including Christianity, Hinduism and Buddhism, as well as notably diverse local traditions, including animism and ancestor worship. Holding a range of relevant variables constant, the higher participants rated their moralistic gods as punitive and knowledgeable about human thoughts and actions, the more coins they allocated to geographically distant co-religionist strangers relative to both themselves and local co-religionists. Our results support the hypothesis that beliefs in moralistic, punitive and knowing gods increase impartial behaviour towards distant co-religionists, and therefore can contribute to the expansion of prosociality.

Population Expansion and Genetic Structure in Carcharhinus brevipinna in the Southern Indo-Pacific

Science.gov (United States)

Geraghty, Pascal T.; Williamson, Jane E.; Macbeth, William G.; Wintner, Sabine P.; Harry, Alastair V.; Ovenden, Jennifer R.; Gillings, Michael R.

2013-01-01

Background Quantifying genetic diversity and metapopulation structure provides insights into the evolutionary history of a species and helps develop appropriate management strategies. We provide the first assessment of genetic structure in spinner sharks (Carcharhinus brevipinna), a large cosmopolitan carcharhinid, sampled from eastern and northern Australia and South Africa. Methods and Findings Sequencing of the mitochondrial DNA NADH dehydrogenase subunit 4 gene for 430 individuals revealed 37 haplotypes and moderately high haplotype diversity (h = 0.6770 ±0.025). While two metrics of genetic divergence (ΦST and F ST) revealed somewhat different results, subdivision was detected between South Africa and all Australian locations (pairwise ΦST, range 0.02717–0.03508, p values ≤ 0.0013; pairwise F ST South Africa vs New South Wales = 0.04056, p = 0.0008). Evidence for fine-scale genetic structuring was also detected along Australia’s east coast (pairwise ΦST = 0.01328, p Indo-Pacific. PMID:24086462

Pou4f2 knock-in Cre mouse: A multifaceted genetic tool for vision researchers.

Science.gov (United States)

Simmons, Aaron B; Bloomsburg, Samuel J; Billingslea, Samuel A; Merrill, Morgan M; Li, Shuai; Thomas, Marshall W; Fuerst, Peter G

2016-01-01

superior colliculus. Pou4f2(Cre) provides multiple uses for the vision researcher's genetic toolkit. First, Pou4f2(Cre) is a knock-in allele that can be used to eliminate Pou4f2, resulting in depletion of RGCs. Second, expression of Cre in male germ cells makes this strain an efficient germline activator of recombination, for example, to target LoxP-flanked sequences in the whole mouse. Third, Pou4f2(Cre) efficiently targets RGCs, amacrine cells, bipolar cells, horizontal cells, and a small number of photoreceptors within the retina, as well as the visual centers in the brain. Unlike other Cre recombinase lines that target retinal neurons, no recombination was observed in Müller or other retinal glia. These properties make this Cre recombinase line a useful tool for vision researchers.

Genomes of the Mouse Collaborative Cross.

Science.gov (United States)

Srivastava, Anuj; Morgan, Andrew P; Najarian, Maya L; Sarsani, Vishal Kumar; Sigmon, J Sebastian; Shorter, John R; Kashfeen, Anwica; McMullan, Rachel C; Williams, Lucy H; Giusti-Rodríguez, Paola; Ferris, Martin T; Sullivan, Patrick; Hock, Pablo; Miller, Darla R; Bell, Timothy A; McMillan, Leonard; Churchill, Gary A; de Villena, Fernando Pardo-Manuel

2017-06-01

The Collaborative Cross (CC) is a multiparent panel of recombinant inbred (RI) mouse strains derived from eight founder laboratory strains. RI panels are popular because of their long-term genetic stability, which enhances reproducibility and integration of data collected across time and conditions. Characterization of their genomes can be a community effort, reducing the burden on individual users. Here we present the genomes of the CC strains using two complementary approaches as a resource to improve power and interpretation of genetic experiments. Our study also provides a cautionary tale regarding the limitations imposed by such basic biological processes as mutation and selection. A distinct advantage of inbred panels is that genotyping only needs to be performed on the panel, not on each individual mouse. The initial CC genome data were haplotype reconstructions based on dense genotyping of the most recent common ancestors (MRCAs) of each strain followed by imputation from the genome sequence of the corresponding founder inbred strain. The MRCA resource captured segregating regions in strains that were not fully inbred, but it had limited resolution in the transition regions between founder haplotypes, and there was uncertainty about founder assignment in regions of limited diversity. Here we report the whole genome sequence of 69 CC strains generated by paired-end short reads at 30× coverage of a single male per strain. Sequencing leads to a substantial improvement in the fine structure and completeness of the genomes of the CC. Both MRCAs and sequenced samples show a significant reduction in the genome-wide haplotype frequencies from two wild-derived strains, CAST/EiJ and PWK/PhJ. In addition, analysis of the evolution of the patterns of heterozygosity indicates that selection against three wild-derived founder strains played a significant role in shaping the genomes of the CC. The sequencing resource provides the first description of tens of thousands of

Thermal expansion

International Nuclear Information System (INIS)

Yun, Y.

2015-01-01

Thermal expansion of fuel pellet is an important property which limits the lifetime of the fuels in reactors, because it affects both the pellet and cladding mechanical interaction and the gap conductivity. By fitting a number of available measured data, recommended equations have been presented and successfully used to estimate thermal expansion coefficient of the nuclear fuel pellet. However, due to large scatter of the measured data, non-consensus data have been omitted in formulating the equations. Also, the equation is strongly governed by the lack of appropriate experimental data. For those reasons, it is important to develop theoretical methodologies to better describe thermal expansion behaviour of nuclear fuel. In particular, first-principles and molecular dynamics simulations have been certainly contributed to predict reliable thermal expansion without fitting the measured data. Furthermore, the two theoretical techniques have improved on understanding the change of fuel dimension by describing the atomic-scale processes associated with lattice expansion in the fuels. (author)

A Mathematical Model of Skeletal Muscle Disease and Immune Response in the mdx Mouse

Directory of Open Access Journals (Sweden)

Abdul Salam Jarrah

2014-01-01

Full Text Available Duchenne muscular dystrophy (DMD is a genetic disease that results in the death of affected boys by early adulthood. The genetic defect responsible for DMD has been known for over 25 years, yet at present there is neither cure nor effective treatment for DMD. During early disease onset, the mdx mouse has been validated as an animal model for DMD and use of this model has led to valuable but incomplete insights into the disease process. For example, immune cells are thought to be responsible for a significant portion of muscle cell death in the mdx mouse; however, the role and time course of the immune response in the dystrophic process have not been well described. In this paper we constructed a simple mathematical model to investigate the role of the immune response in muscle degeneration and subsequent regeneration in the mdx mouse model of Duchenne muscular dystrophy. Our model suggests that the immune response contributes substantially to the muscle degeneration and regeneration processes. Furthermore, the analysis of the model predicts that the immune system response oscillates throughout the life of the mice, and the damaged fibers are never completely cleared.

Low-temperature thermal expansion

International Nuclear Information System (INIS)

Collings, E.W.

1986-01-01

This chapter discusses the thermal expansion of insulators and metals. Harmonicity and anharmonicity in thermal expansion are examined. The electronic, magnetic, an other contributions to low temperature thermal expansion are analyzed. The thermodynamics of the Debye isotropic continuum, the lattice-dynamical approach, and the thermal expansion of metals are discussed. Relative linear expansion at low temperatures is reviewed and further calculations of the electronic thermal expansion coefficient are given. Thermal expansions are given for Cu, Al and Ti. Phenomenologic thermodynamic relationships are also discussed

Histologic scoring of gastritis and gastric cancer in mouse models.

Science.gov (United States)

Rogers, Arlin B

2012-01-01

Histopathology is a defining endpoint in mouse models of experimental gastritis and gastric adenocarcinoma. Presented here is an overview of the histology of gastritis and gastric cancer in mice experimentally infected with Helicobacter pylori or H. felis. A modular histopathologic scoring scheme is provided that incorporates relevant disease-associated changes. Whereas the guide uses Helicobacter infection as the prototype challenge, features may be applied to chemical and genetically engineered mouse models of stomach cancer as well. Specific criteria included in the combined gastric histologic activity index (HAI) include inflammation, epithelial defects, oxyntic atrophy, hyperplasia, pseudopyloric metaplasia, and dysplasia or neoplasia. Representative photomicrographs accompany descriptions for each lesion grade. Differentiation of genuine tumor invasion from pseudoinvasion is highlighted. A brief comparison of normal rodent versus human stomach anatomy and physiology is accompanied by an introduction to mouse-specific lesions including mucous metaplasia and eosinophilic droplets (hyalinosis). In conjunction with qualified pathology support, this guide is intended to assist research scientists, postdoctoral fellows, graduate students, and medical professionals from affiliated disciplines in the interpretation and histologic grading of chronic gastritis and gastric carcinoma in mouse models.

Characterization of the bovine type I IFN locus: rearrangements, expansions, and novel subfamilies

Directory of Open Access Journals (Sweden)

Walker Angela M

2009-04-01

Full Text Available Abstract Background The Type I interferons (IFN have major roles in the innate immune response to viruses, a function that is believed to have led to expansion in the number and complexity of their genes, although these genes have remained confined to single chromosomal region in all mammals so far examined. IFNB and IFNE define the limits of the locus, with all other Type I IFN genes except IFNK distributed between these boundaries, strongly suggesting that the locus has broadened as IFN genes duplicated and then evolved into a series of distinct families. Results The Type I IFN locus in Bos taurus has undergone significant rearrangement and expansion compared to mouse and human, however, with the constituent genes separated into two sub-loci separated by >700 kb. The IFNW family is greatly expanded, comprising 24 potentially functional genes and at least 8 pseudogenes. The IFNB (n = 6, represented in human and mouse by one copy, are also present as multiple copies in Bos taurus. The IFNT, which encode a non-virally inducible, ruminant-specific IFN secreted by the pre-implantation conceptus, are represented by three genes and two pseudogenes. The latter have sequences intermediate between IFNT and IFNW. A new Type I IFN family (IFNX of four members, one of which is a pseudogene, appears to have diverged from the IFNA lineage at least 83 million years ago, but is absent in all other sequenced genomes with the possible exception of the horse, a non-ruminant herbivore. Conclusion In summary, we have provided the first comprehensive annotation of the Type I IFN locus in Bos taurus, thereby providing an insight into the functional evolution of the Type I IFN in ruminants. The diversity and global spread of the ruminant species may have required an expansion of the Type I IFN locus and its constituent genes to provide broad anti-viral protection required for foraging and foregut fermentation.

Aurora kinase A is essential for correct chromosome segregation in mouse zygote

Czech Academy of Sciences Publication Activity Database

Kovaříková, V.; Burkus, J.; Rehák, P.; Brzáková, Adéla; Šolc, Petr; Baran, V.

2016-01-01

Roč. 24, č. 3 (2016), s. 326-337 ISSN 0967-1994 R&D Projects: GA MŠk ED2.1.00/03.0124 Institutional support: RVO:67985904 Keywords : apoptosis * aurora A * MLN8237 * mouse zygote * spindle Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.053, year: 2016

Nanoparticle-mediated knockdown of DNA repair sensitizes cells to radiotherapy and extends survival in a genetic mouse model of glioblastoma.

Science.gov (United States)

Kievit, Forrest M; Wang, Kui; Ozawa, Tatsuya; Tarudji, Aria W; Silber, John R; Holland, Eric C; Ellenbogen, Richard G; Zhang, Miqin

2017-10-01

Glioblastoma (GBM) remains incurable, and recurrent tumors rarely respond to standard-of-care radiation and chemo-therapies. Therefore, strategies that enhance the effects of these therapies should provide significant benefits to GBM patients. We have developed a nanoparticle delivery vehicle that can stably bind and protect nucleic acids for specific delivery into brain tumor cells. These nanoparticles can deliver therapeutic siRNAs to sensitize GBM cells to radiotherapy and improve GBM treatment via systemic administration. We show that nanoparticle-mediated knockdown of the DNA repair protein apurinic endonuclease 1 (Ape1) sensitizes GBM cells to radiotherapy and extend survival in a genetic mouse model of GBM. Specific knockdown of Ape1 activity by 30% in brain tumor tissue doubled the extended survival achieved with radiotherapy alone. Ape1 is a promising target for increasing the effectiveness of radiotherapy, and nanoparticle-mediated delivery of siRNA is a promising strategy for tumor specific knockdown of Ape1. Copyright © 2017. Published by Elsevier Inc.

Mouse oocytes nucleoli rescue embryonic development of porcine enucleolated oocytes

Czech Academy of Sciences Publication Activity Database

Morovic, M.; Strejček, F.; Nakagawa, S.; Deshmukh, R.S.; Murin, M.; Benc, M.; Fulka, Helena; Kyogoku, H.; Pendovski, L.; Fulka, J.; Laurinčik, Jozef

2017-01-01

Roč. 25, č. 6 (2017), s. 675-685 ISSN 0967-1994 R&D Projects: GA MŠk EF15_003/0000460 Institutional support: RVO:68378050 ; RVO:67985904 Keywords : Embryo * Interspecies nucleolar transfer * Mouse * Nucleolus * Olcytes * Pig Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Reproductive biology (medical aspects to be 3); Developmental biology (UZFG-Y) Impact factor: 1.053, year: 2016

Optimisation of expansion liquefaction processes using mixed refrigerant N_2–CH_4

International Nuclear Information System (INIS)

Ding, He; Sun, Heng; He, Ming

2016-01-01

Highlights: • A refrigerant composition matching method for N_2–CH_4 expansion processes. • Efficiency improvements for propane pre-cooled N_2–CH_4 expansion processes. • The process shows good adaptability to varying natural gas compositions. - Abstract: An expansion process with a pre-cooling system is simulated and optimised by Aspen HYSYS and MATLAB"™. Taking advantage of higher specific refrigeration effect of methane and easily reduced refrigeration temperature of nitrogen, the designed process adopts N_2–CH_4 as a mixed refrigerant. Based on the different thermodynamic properties and sensitivity difference of N_2 and CH_4 over the same heat transfer temperature range, this work proposes a novel method of matching refrigerant composition which aims at single-stage or multi-stage series expansion liquefaction processes with pre-cooling systems. This novel method is applied successfully in propane pre-cooled N_2–CH_4 expansion process, and the unit power consumption is reduced to 7.09 kWh/kmol, which is only 5.35% higher than the global optimised solutions obtained by genetic algorithm. This novel method can fulfil the accomplishments of low energy consumption and high liquefaction rate, and thus decreases the gap between the mixed refrigerant and expansion processes in energy consumption. Furthermore, the high exergy efficiency of the process indicates good adaptability to varying natural gas compositions.

Gene expression profiling in the striatum of inbred mouse strains with distinct opioid-related phenotypes

Directory of Open Access Journals (Sweden)

Piechota Marcin

2006-06-01

Full Text Available Abstract Background Mouse strains with a contrasting response to morphine provide a unique model for studying the genetically determined diversity of sensitivity to opioid reward, tolerance and dependence. Four inbred strains selected for this study exhibit the most distinct opioid-related phenotypes. C57BL/6J and DBA/2J mice show remarkable differences in morphine-induced antinociception, self-administration and locomotor activity. 129P3/J mice display low morphine tolerance and dependence in contrast to high sensitivity to precipitated withdrawal observed in SWR/J and C57BL/6J strains. In this study, we attempted to investigate the relationships between genetic background and basal gene expression profile in the striatum, a brain region involved in the mechanism of opioid action. Results Gene expression was studied by Affymetrix Mouse Genome 430v2.0 arrays with probes for over 39.000 transcripts. Analysis of variance with the control for false discovery rate (q Khdrbs1 and ATPase Na+/K+ alpha2 subunit (Atp1a2 with morphine self-administration and analgesic effects, respectively. Finally, the examination of transcript structure demonstrated a possible inter-strain variability of expressed mRNA forms as for example the catechol-O-methyltransferase (Comt gene. Conclusion The presented study led to the recognition of differences in the gene expression that may account for distinct phenotypes. Moreover, results indicate strong contribution of genetic background to differences in gene transcription in the mouse striatum. The genes identified in this work constitute promising candidates for further animal studies and for translational genetic studies in the field of addictive and analgesic properties of opioids.

Layer- and column-specific knockout of NMDA receptors in pyramidal neurons of the mouse barrel cortex.

Directory of Open Access Journals (Sweden)

Rachel Aronoff

2007-11-01

Full Text Available Viral vectors injected into the mouse brain offer the possibility for localized genetic modifications in a highly controlled manner. Lentivector injection into mouse neocortex transduces cells within a diameter of approximately 200µm, which closely matches the lateral scale of a column in barrel cortex. The depth and volume of the injection determines which cortical layer is transduced. Furthermore, transduced gene expression from the lentivector can be limited to predominantly pyramidal neurons by using a 1.3kb fragment of the αCaMKII promoter. This technique therefore allows genetic manipulation of a specific cell type in defined columns and layers of the neocortex. By expressing Cre recombinase from such a lentivector in gene-targeted mice carrying a floxed gene, highly specific genetic lesions can be induced. Here, we demonstrate the utility of this approach by specifically knocking out NMDA receptors (NMDARs in pyramidal neurons in the somatosensory barrel cortex of gene-targeted mice carrying floxed NMDAR 1 genes. Neurons transduced with lentivector encoding GFP and Cre recombinase exhibit not only reductions in NMDAR 1 mRNA levels, but reduced NMDAR-dependent currents and pairing-induced synaptic potentiation. This technique for knockout of NMDARs in a cell type, column- and layer-specific manner in the mouse somatosensory cortex may help further our understanding of the functional roles of NMDARs in vivo during sensory perception and learning.

Overexpression of mouse TTF-2 gene causes cleft palate

Science.gov (United States)

Meng, Tian; Shi, Jia-Yu; Wu, Min; Wang, Yan; Li, Ling; Liu, Yan; Zheng, Qian; Huang, Lei; Shi, Bing

2012-01-01

In humans, mutations of the gene encoding for thyroid transcription factor-2 (TTF-2 or FOXE1) result in Bamforth syndrome. Bamforth syndrome is characterized by agenesis, cleft palate, spiky hair and choanal atresia. TTF-2 null mice (TTF-2−/−) also exhibit cleft palate, suggesting its involvement in the palatogenesis. However, the molecular pathology and genetic regulation by TTF2 remain largely unknown. In the present study, the recombinant expression vector pBROAD3-TTF-2 containing the promoter of the mouse ROSA26 gene was created to form the structural gene of mouse TTF-2 and was microinjected into the male pronuclei of fertilized ova. Sequence analysis confirmed that the TTF-2 transgenic mouse model was established successfully. The transgenic mice displayed a phenotype of cleft palate. In addition, we found that TTF-2 was highly expressed in the medial edge epithelium (MEE) from the embryonic day 12.5 (E12.5) to E14.5 in TTF-2 transgenic mice. These observations suggest that overexpression of TTF-2 during palatogenesis may contribute to formation of cleft palate. PMID:22304410

4D atlas of the mouse embryo for precise morphological staging.

Science.gov (United States)

Wong, Michael D; van Eede, Matthijs C; Spring, Shoshana; Jevtic, Stefan; Boughner, Julia C; Lerch, Jason P; Henkelman, R Mark

2015-10-15

After more than a century of research, the mouse remains the gold-standard model system, for it recapitulates human development and disease and is quickly and highly tractable to genetic manipulations. Fundamental to the power and success of using a mouse model is the ability to stage embryonic mouse development accurately. Past staging systems were limited by the technologies of the day, such that only surface features, visible with a light microscope, could be recognized and used to define stages. With the advent of high-throughput 3D imaging tools that capture embryo morphology in microscopic detail, we now present the first 4D atlas staging system for mouse embryonic development using optical projection tomography and image registration methods. By tracking 3D trajectories of every anatomical point in the mouse embryo from E11.5 to E14.0, we established the first 4D atlas compiled from ex vivo 3D mouse embryo reference images. The resulting 4D atlas comprises 51 interpolated 3D images in this gestational range, resulting in a temporal resolution of 72 min. From this 4D atlas, any mouse embryo image can be subsequently compared and staged at the global, voxel and/or structural level. Assigning an embryonic stage to each point in anatomy allows for unprecedented quantitative analysis of developmental asynchrony among different anatomical structures in the same mouse embryo. This comprehensive developmental data set offers developmental biologists a new, powerful staging system that can identify and compare differences in developmental timing in wild-type embryos and shows promise for localizing deviations in mutant development. © 2015. Published by The Company of Biologists Ltd.

Germ-line CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2

DEFF Research Database (Denmark)

Vinther-Jensen, Tua; Ek, Jakob; Duno, Morten

2013-01-01

The spinocerebellar ataxias (SCA) are a genetically and clinically heterogeneous group of diseases, characterized by dominant inheritance, progressive cerebellar ataxia and diverse extracerebellar symptoms. A subgroup of the ataxias is caused by unstable CAG-repeat expansions in their respective ...... of paternal germ-line repeat sequence instability of the expanded SCA2 locus.European Journal of Human Genetics advance online publication, 10 October 2012; doi:10.1038/ejhg.2012.231....

Development of organoids from mouse and human endometrium showing endometrial epithelium physiology and long-term expandability.

Science.gov (United States)

Boretto, Matteo; Cox, Benoit; Noben, Manuel; Hendriks, Nikolai; Fassbender, Amelie; Roose, Heleen; Amant, Frédéric; Timmerman, Dirk; Tomassetti, Carla; Vanhie, Arne; Meuleman, Christel; Ferrante, Marc; Vankelecom, Hugo

2017-05-15

The endometrium, which is of crucial importance for reproduction, undergoes dynamic cyclic tissue remodeling. Knowledge of its molecular and cellular regulation is poor, primarily owing to a lack of study models. Here, we have established a novel and promising organoid model from both mouse and human endometrium. Dissociated endometrial tissue, embedded in Matrigel under WNT-activating conditions, swiftly formed organoid structures that showed long-term expansion capacity, and reproduced the molecular and histological phenotype of the tissue's epithelium. The supplemented WNT level determined the type of mouse endometrial organoids obtained: high WNT yielded cystic organoids displaying a more differentiated phenotype than the dense organoids obtained in low WNT. The organoids phenocopied physiological responses of endometrial epithelium to hormones, including increased cell proliferation under estrogen and maturation upon progesterone. Moreover, the human endometrial organoids replicated the menstrual cycle under hormonal treatment at both the morpho-histological and molecular levels. Together, we established an organoid culture system for endometrium, reproducing tissue epithelium physiology and allowing long-term expansion. This novel model provides a powerful tool for studying mechanisms underlying the biology as well as the pathology of this key reproductive organ. © 2017. Published by The Company of Biologists Ltd.

Mitochondrial DNA Analyses Indicate High Diversity, Expansive Population Growth and High Genetic Connectivity of Vent Copepods (Dirivultidae) across Different Oceans.

Science.gov (United States)

Gollner, Sabine; Stuckas, Heiko; Kihara, Terue C; Laurent, Stefan; Kodami, Sahar; Martinez Arbizu, Pedro

2016-01-01

Communities in spatially fragmented deep-sea hydrothermal vents rich in polymetallic sulfides could soon face major disturbance events due to deep-sea mineral mining, such that unraveling patterns of gene flow between hydrothermal vent populations will be an important step in the development of conservation policies. Indeed, the time required by deep-sea populations to recover following habitat perturbations depends both on the direction of gene flow and the number of migrants available for re-colonization after disturbance. In this study we compare nine dirivultid copepod species across various geological settings. We analyze partial nucleotide sequences of the mtCOI gene and use divergence estimates (FST) and haplotype networks to infer intraspecific population connectivity between vent sites. Furthermore, we evaluate contrasting scenarios of demographic population expansion/decline versus constant population size (using, for example, Tajima's D). Our results indicate high diversity, population expansion and high connectivity of all copepod populations in all oceans. For example, haplotype diversity values range from 0.89 to 1 and FST values range from 0.001 to 0.11 for Stygiopontius species from the Central Indian Ridge, Mid Atlantic Ridge, East Pacific Rise, and Eastern Lau Spreading Center. We suggest that great abundance and high site occupancy by these species favor high genetic diversity. Two scenarios both showed similarly high connectivity: fast spreading centers with little distance between vent fields and slow spreading centers with greater distance between fields. This unexpected result may be due to some distinct frequency of natural disturbance events, or to aspects of individual life histories that affect realized rates of dispersal. However, our statistical performance analyses showed that at least 100 genomic regions should be sequenced to ensure accurate estimates of migration rate. Our demography parameters demonstrate that dirivultid

Gene expression and functional annotation of the human and mouse choroid plexus epithelium.

Directory of Open Access Journals (Sweden)

Sarah F Janssen

Full Text Available BACKGROUND: The choroid plexus epithelium (CPE is a lobed neuro-epithelial structure that forms the outer blood-brain barrier. The CPE protrudes into the brain ventricles and produces the cerebrospinal fluid (CSF, which is crucial for brain homeostasis. Malfunction of the CPE is possibly implicated in disorders like Alzheimer disease, hydrocephalus or glaucoma. To study human genetic diseases and potential new therapies, mouse models are widely used. This requires a detailed knowledge of similarities and differences in gene expression and functional annotation between the species. The aim of this study is to analyze and compare gene expression and functional annotation of healthy human and mouse CPE. METHODS: We performed 44k Agilent microarray hybridizations with RNA derived from laser dissected healthy human and mouse CPE cells. We functionally annotated and compared the gene expression data of human and mouse CPE using the knowledge database Ingenuity. We searched for common and species specific gene expression patterns and function between human and mouse CPE. We also made a comparison with previously published CPE human and mouse gene expression data. RESULTS: Overall, the human and mouse CPE transcriptomes are very similar. Their major functionalities included epithelial junctions, transport, energy production, neuro-endocrine signaling, as well as immunological, neurological and hematological functions and disorders. The mouse CPE presented two additional functions not found in the human CPE: carbohydrate metabolism and a more extensive list of (neural developmental functions. We found three genes specifically expressed in the mouse CPE compared to human CPE, being ACE, PON1 and TRIM3 and no human specifically expressed CPE genes compared to mouse CPE. CONCLUSION: Human and mouse CPE transcriptomes are very similar, and display many common functionalities. Nonetheless, we also identified a few genes and pathways which suggest that the CPE

Late Pleistocene climate change and the global expansion of anatomically modern humans

Science.gov (United States)

Eriksson, Anders; Betti, Lia; Friend, Andrew D.; Lycett, Stephen J.; Singarayer, Joy S.; von Cramon-Taubadel, Noreen; Valdes, Paul J.; Balloux, Francois; Manica, Andrea

2012-01-01

The extent to which past climate change has dictated the pattern and timing of the out-of-Africa expansion by anatomically modern humans is currently unclear [Stewart JR, Stringer CB (2012) Science 335:1317–1321]. In particular, the incompleteness of the fossil record makes it difficult to quantify the effect of climate. Here, we take a different approach to this problem; rather than relying on the appearance of fossils or archaeological evidence to determine arrival times in different parts of the world, we use patterns of genetic variation in modern human populations to determine the plausibility of past demographic parameters. We develop a spatially explicit model of the expansion of anatomically modern humans and use climate reconstructions over the past 120 ky based on the Hadley Centre global climate model HadCM3 to quantify the possible effects of climate on human demography. The combinations of demographic parameters compatible with the current genetic makeup of worldwide populations indicate a clear effect of climate on past population densities. Our estimates of this effect, based on population genetics, capture the observed relationship between current climate and population density in modern hunter–gatherers worldwide, providing supporting evidence for the realism of our approach. Furthermore, although we did not use any archaeological and anthropological data to inform the model, the arrival times in different continents predicted by our model are also broadly consistent with the fossil and archaeological records. Our framework provides the most accurate spatiotemporal reconstruction of human demographic history available at present and will allow for a greater integration of genetic and archaeological evidence. PMID:22988099

Cryopreservation of mouse embryos by ethylene glycol-based vitrification.

Science.gov (United States)

Mochida, Keiji; Hasegawa, Ayumi; Taguma, Kyuichi; Yoshiki, Atsushi; Ogura, Atsuo

2011-11-18

Cryopreservation of mouse embryos is a technological basis that supports biomedical sciences, because many strains of mice have been produced by genetic modifications and the number is consistently increasing year by year. Its technical development started with slow freezing methods in the 1970s(1), then followed by vitrification methods developed in the late 1980s(2). Generally, the latter technique is advantageous in its quickness, simplicity, and high survivability of recovered embryos. However, the cryoprotectants contained are highly toxic and may affect subsequent embryo development. Therefore, the technique was not applicable to certain strains of mice, even when the solutions are cooled to 4°C to mitigate the toxic effect during embryo handling. At the RIKEN BioResource Center, more than 5000 mouse strains with different genetic backgrounds and phenotypes are maintained(3), and therefore we have optimized a vitrification technique with which we can cryopreserve embryos from many different strains of mice, with the benefits of high embryo survival after vitrifying and thawing (or liquefying, more precisely) at the ambient temperature(4). Here, we present a vitrification method for mouse embryos that has been successfully used at our center. The cryopreservation solution contains ethylene glycol instead of DMSO to minimize the toxicity to embryos(5). It also contains Ficoll and sucrose for prevention of devitrification and osmotic adjustment, respectively. Embryos can be handled at room temperature and transferred into liquid nitrogen within 5 min. Because the original method was optimized for plastic straws as containers, we have slightly modified the protocol for cryotubes, which are more easily accessible in laboratories and more resistant to physical damages. We also describe the procedure of thawing vitrified embryos in detail because it is a critical step for efficient recovery of live mice. These methodologies would be helpful to researchers and

India, a paradise for Genetic Studies

Indian Academy of Sciences (India)

First page Back Continue Last page Overview Graphics. India, a paradise for Genetic Studies. The second land to be occupied by man. Human settlements & expansion 50,000 years. Sub-divided Gene pool, Nature's experiment. Sympatrically isolated gene pools. (living in the same place without mixing). may be ...

Radiation carcinogenesis in mouse thymic lymphomas

International Nuclear Information System (INIS)

Kominami, Ryo; Niwa, Ohtsura

2006-01-01

Ionizing radiation is a well-known carcinogen for various human tissues and a complete carcinogen that is able to initiate and promote neoplastic progression. Studies of radiation-induced mouse thymic lymphomas, one of the classic models in radiation carcinogenesis, demonstrated that even the unirradiated thymus is capable of developing into full malignancy when transplanted into the kidney capsule or subcutaneous tissue of irradiated mice. This suggests that radiation targets tissues other than thymocytes to allow expansion of cells with tumorigenic potential in the thymus. The idea is regarded as the ''indirect mechanism'' for tumor development. This paper reviews the indirect mechanism and genes affecting the development of thymic lymphomas that we have analyzed. One is the Bcl11b/Rit1 tumor suppressor gene and the other is Mtf-1 gene affecting tumor susceptibility. (author)

Urban landscape genetics: canopy cover predicts gene flow between white-footed mouse (Peromyscus leucopus) populations in New York City.

Science.gov (United States)

Munshi-South, Jason

2012-03-01

In this study, I examine the influence of urban canopy cover on gene flow between 15 white-footed mouse (Peromyscus leucopus) populations in New York City parklands. Parks in the urban core are often highly fragmented, leading to rapid genetic differentiation of relatively nonvagile species. However, a diverse array of 'green' spaces may provide dispersal corridors through 'grey' urban infrastructure. I identify urban landscape features that promote genetic connectivity in an urban environment and compare the success of two different landscape connectivity approaches at explaining gene flow. Gene flow was associated with 'effective distances' between populations that were calculated based on per cent tree canopy cover using two different approaches: (i) isolation by effective distance (IED) that calculates the single best pathway to minimize passage through high-resistance (i.e. low canopy cover) areas, and (ii) isolation by resistance (IBR), an implementation of circuit theory that identifies all low-resistance paths through the landscape. IBR, but not IED, models were significantly associated with three measures of gene flow (Nm from F(ST) , BayesAss+ and Migrate-n) after factoring out the influence of isolation by distance using partial Mantel tests. Predicted corridors for gene flow between city parks were largely narrow, linear parklands or vegetated spaces that are not managed for wildlife, such as cemeteries and roadway medians. These results have implications for understanding the impacts of urbanization trends on native wildlife, as well as for urban reforestation efforts that aim to improve urban ecosystem processes. © 2012 Blackwell Publishing Ltd.

The novel Hsp90 inhibitor NXD30001 induces tumor regression in a genetically engineered mouse model of glioblastoma multiforme.

Science.gov (United States)

Zhu, Haihao; Woolfenden, Steve; Bronson, Roderick T; Jaffer, Zahara M; Barluenga, Sofia; Winssinger, Nicolas; Rubenstein, Allan E; Chen, Ruihong; Charest, Al

2010-09-01

Glioblastoma multiforme (GBM) has an abysmal prognosis. We now know that the epidermal growth factor receptor (EGFR) signaling pathway and the loss of function of the tumor suppressor genes p16Ink4a/p19ARF and PTEN play a crucial role in GBM pathogenesis: initiating the early stages of tumor development, sustaining tumor growth, promoting infiltration, and mediating resistance to therapy. We have recently shown that this genetic combination is sufficient to promote the development of GBM in adult mice. Therapeutic agents raised against single targets of the EGFR signaling pathway have proven rather inefficient in GBM therapy, showing the need for combinatorial therapeutic approaches. An effective strategy for concurrent disruption of multiple signaling pathways is via the inhibition of the molecular chaperone heat shock protein 90 (Hsp90). Hsp90 inhibition leads to the degradation of so-called client proteins, many of which are key effectors of GBM pathogenesis. NXD30001 is a novel second generation Hsp90 inhibitor that shows improved pharmacokinetic parameters. Here we show that NXD30001 is a potent inhibitor of GBM cell growth in vitro consistent with its capacity to inhibit several key targets and regulators of GBM biology. We also show the efficacy of NXD30001 in vivo in an EGFR-driven genetically engineered mouse model of GBM. Our findings establish that the Hsp90 inhibitor NXD30001 is a therapeutically multivalent molecule, whose actions strike GBM at the core of its drivers of tumorigenesis and represent a compelling rationale for its use in GBM treatment.

Gene × Environment Interactions in Schizophrenia: Evidence from Genetic Mouse Models.

Science.gov (United States)

Moran, Paula; Stokes, Jennifer; Marr, Julia; Bock, Gavin; Desbonnet, Lieve; Waddington, John; O'Tuathaigh, Colm

2016-01-01

The study of gene × environment, as well as epistatic interactions in schizophrenia, has provided important insight into the complex etiopathologic basis of schizophrenia. It has also increased our understanding of the role of susceptibility genes in the disorder and is an important consideration as we seek to translate genetic advances into novel antipsychotic treatment targets. This review summarises data arising from research involving the modelling of gene × environment interactions in schizophrenia using preclinical genetic models. Evidence for synergistic effects on the expression of schizophrenia-relevant endophenotypes will be discussed. It is proposed that valid and multifactorial preclinical models are important tools for identifying critical areas, as well as underlying mechanisms, of convergence of genetic and environmental risk factors, and their interaction in schizophrenia.

Gene × Environment Interactions in Schizophrenia: Evidence from Genetic Mouse Models

Science.gov (United States)

Marr, Julia; Bock, Gavin; Desbonnet, Lieve; Waddington, John

2016-01-01

The study of gene × environment, as well as epistatic interactions in schizophrenia, has provided important insight into the complex etiopathologic basis of schizophrenia. It has also increased our understanding of the role of susceptibility genes in the disorder and is an important consideration as we seek to translate genetic advances into novel antipsychotic treatment targets. This review summarises data arising from research involving the modelling of gene × environment interactions in schizophrenia using preclinical genetic models. Evidence for synergistic effects on the expression of schizophrenia-relevant endophenotypes will be discussed. It is proposed that valid and multifactorial preclinical models are important tools for identifying critical areas, as well as underlying mechanisms, of convergence of genetic and environmental risk factors, and their interaction in schizophrenia. PMID:27725886

Negative thermal expansion materials: technological key for control of thermal expansion

OpenAIRE

Koshi Takenaka

2012-01-01

Most materials expand upon heating. However, although rare, some materials contract upon heating. Such negative thermal expansion (NTE) materials have enormous industrial merit because they can control the thermal expansion of materials. Recent progress in materials research enables us to obtain materials exhibiting negative coefficients of linear thermal expansion over −30 ppm K−1. Such giant NTE is opening a new phase of control of thermal expansion in composites. Specifically examining pra...

Mechanistic Insight into the Pathology of Polyalanine Expansion Disorders Revealed by a Mouse Model for X Linked Hypopituitarism

Science.gov (United States)

Hughes, James; Piltz, Sandra; Rogers, Nicholas; McAninch, Dale; Rowley, Lynn; Thomas, Paul

2013-01-01

Polyalanine expansions in transcription factors have been associated with eight distinct congenital human diseases. It is thought that in each case the polyalanine expansion causes misfolding of the protein that abrogates protein function. Misfolded proteins form aggregates when expressed in vitro; however, it is less clear whether aggregation is of relevance to these diseases in vivo. To investigate this issue, we used targeted mutagenesis of embryonic stem (ES) cells to generate mice with a polyalanine expansion mutation in Sox3 (Sox3-26ala) that is associated with X-linked Hypopituitarism (XH) in humans. By investigating both ES cells and chimeric mice, we show that endogenous polyalanine expanded SOX3 does not form protein aggregates in vivo but rather is present at dramatically reduced levels within the nucleus of mutant cells. Importantly, the residual mutant protein of chimeric embryos is able to rescue a block in gastrulation but is not sufficient for normal development of the hypothalamus, a region that is functionally compromised in Sox3 null embryos and individuals with XH. Together, these data provide the first definitive example of a disease-relevant PA mutant protein that is both nuclear and functional, thereby manifesting as a partial loss-of-function allele. PMID:23505376

The tobacco mouse and its relatives: a "tail" of coat colors, chromosomes, hybridization and speciation

Czech Academy of Sciences Publication Activity Database

Hauffe, H. C.; Panithanarak, T.; Dallas, J. F.; Piálek, Jaroslav; Gündüz, I.; Searle, J. B.

2004-01-01

Roč. 105, 2-4 (2004), s. 395-405 ISSN 1424-8581 Institutional research plan: CEZ:AV0Z6093917 Keywords : mouse * mitochondrial DNA * hybrid zones Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.341, year: 2004

The impact of mouse passaging of Mycobacterium tuberculosis strains prior to virulence testing in the mouse and guinea pig aerosol models.

Directory of Open Access Journals (Sweden)

Paul J Converse

2010-04-01

Full Text Available It has been hypothesized that the virulence of lab-passaged Mycobacterium tuberculosis and recombinant M. tuberculosis mutants might be reduced due to multiple in vitro passages, and that virulence might be augmented by passage of these strains through mice before quantitative virulence testing in the mouse or guinea pig aerosol models.By testing three M. tuberculosis H37Rv samples, one deletion mutant, and one recent clinical isolate for survival by the quantitative organ CFU counting method in mouse or guinea pig aerosol or intravenous infection models, we could discern no increase in bacterial fitness as a result of passaging of M. tuberculosis strains in mice prior to quantitative virulence testing in two animal models. Surface lipid expression as assessed by neutral red staining and thin-layer chromatography for PDIM analysis also failed to identify virulence correlates.These results indicate that animal passaging of M. tuberculosis strains prior to quantitative virulence testing in mouse or guinea pig models does not enhance or restore potency to strains that may have lost virulence due to in vitro passaging. It is critical to verify virulence of parental strains before genetic manipulations are undertaken and comparisons are made.

Following Surgically Assisted Rapid Palatal Expansion, Do Tooth-Borne or Bone-Borne Appliances Provide More Skeletal Expansion and Dental Expansion?

Science.gov (United States)

Hamedi-Sangsari, Adrien; Chinipardaz, Zahra; Carrasco, Lee

2017-10-01

The aim of this study was to compare outcome measurements of skeletal and dental expansion with bone-borne (BB) versus tooth-borne (TB) appliances after surgically assisted rapid palatal expansion (SARPE). This study was performed to provide quantitative measurements that will help the oral surgeon and orthodontist in selecting the appliance with, on average, the greatest amount of skeletal expansion and the least amount of dental expansion. A computerized database search was performed using PubMed, EBSCO, Cochrane, Scopus, Web of Science, and Google Scholar on publications in reputable oral surgery and orthodontic journals. A systematic review and meta-analysis was completed with the predictor variable of expansion appliance (TB vs BB) and outcome measurement of expansion (in millimeters). Of 487 articles retrieved from the 6 databases, 5 articles were included, 4 with cone-beam computed tomographic (CBCT) data and 1 with non-CBCT 3-dimensional cast data. There was a significant difference in skeletal expansion (standardized mean difference [SMD], 0.92; 95% confidence interval [CI], 0.54-1.30; P appliances. However, there was no significant difference in dental expansion (SMD, 0.05; 95% CI, -0.24 to 0.34; P = .03). According to the literature, to achieve more effective skeletal expansion and minimize dental expansion after SARPE, a BB appliance should be favored. Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Range expansion drives dispersal evolution in an equatorial three-species symbiosis.

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Guillaume Léotard

Full Text Available Recurrent climatic oscillations have produced dramatic changes in species distributions. This process has been proposed to be a major evolutionary force, shaping many life history traits of species, and to govern global patterns of biodiversity at different scales. During range expansions selection may favor the evolution of higher dispersal, and symbiotic interactions may be affected. It has been argued that a weakness of climate fluctuation-driven range dynamics at equatorial latitudes has facilitated the persistence there of more specialized species and interactions. However, how much the biology and ecology of species is changed by range dynamics has seldom been investigated, particularly in equatorial regions.We studied a three-species symbiosis endemic to coastal equatorial rainforests in Cameroon, where the impact of range dynamics is supposed to be limited, comprised of two species-specific obligate mutualists--an ant-plant and its protective ant--and a species-specific ant parasite of this mutualism. We combined analyses of within-species genetic diversity and of phenotypic variation in a transect at the southern range limit of this ant-plant system. All three species present congruent genetic signatures of recent gradual southward expansion, a result compatible with available regional paleoclimatic data. As predicted, this expansion has been accompanied by the evolution of more dispersive traits in the two ant species. In contrast, we detected no evidence of change in lifetime reproductive strategy in the tree, nor in its investment in food resources provided to its symbiotic ants.Despite the decreasing investment in protective workers and the increasing investment in dispersing females by both the mutualistic and the parasitic ant species, there was no evidence of destabilization of the symbiosis at the colonization front. To our knowledge, we provide here the first evidence at equatorial latitudes that biological traits associated

Genetic mapping in mice reveals the involvement of Pcdh9 in long-term social and object recognition and sensorimotor development

NARCIS (Netherlands)

Bruining, Hilgo; Matsui, Asuka; Oguro-Ando, Asami; Kahn, René S.; Van'T Spijker, Heleen M.; Akkermans, Guus; Stiedl, Oliver; Van Engeland, Herman; Koopmans, Bastijn; Van Lith, Hein A.; Oppelaar, Hugo; Tieland, Liselotte; Nonkes, Lourens J.; Yagi, Takeshi; Kaneko, Ryosuke; Burbach, J. Peter H; Yamamoto, Nobuhiko; Kas, Martien J.

2015-01-01

Background Quantitative genetic analysis of basic mouse behaviors is a powerful tool to identify novel genetic phenotypes contributing to neurobehavioral disorders. Here, we analyzed genetic contributions to single-trial, long-term social and nonsocial recognition and subsequently studied the

Genetic Mapping in Mice Reveals the Involvement of Pcdh9 in Long-Term Social and Object Recognition and Sensorimotor Development

NARCIS (Netherlands)

Bruining, Hilgo; Matsui, Asuka; Oguro-Ando, Asami; Kahn, René S; Van't Spijker, Heleen M; Akkermans, Guus; Stiedl, Oliver; van Engeland, Herman; Koopmans, Bastijn; van Lith, Hein A; Oppelaar, Hugo; Tieland, Liselotte; Nonkes, Lourens J; Yagi, Takeshi; Kaneko, Ryosuke; Burbach, J Peter H; Yamamoto, Nobuhiko; Kas, Martien J

2015-01-01

BACKGROUND: Quantitative genetic analysis of basic mouse behaviors is a powerful tool to identify novel genetic phenotypes contributing to neurobehavioral disorders. Here, we analyzed genetic contributions to single-trial, long-term social and nonsocial recognition and subsequently studied the

An antibiotic-responsive mouse model of fulminant ulcerative colitis.

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Silvia S Kang

2008-03-01

Full Text Available BACKGROUND: The constellation of human inflammatory bowel disease (IBD includes ulcerative colitis and Crohn's disease, which both display a wide spectrum in the severity of pathology. One theory is that multiple genetic hits to the host immune system may contribute to the susceptibility and severity of IBD. However, experimental proof of this concept is still lacking. Several genetic mouse models that each recapitulate some aspects of human IBD have utilized a single gene defect to induce colitis. However, none have produced pathology clearly distinguishable as either ulcerative colitis or Crohn's disease, in part because none of them reproduce the most severe forms of disease that are observed in human patients. This lack of severe IBD models has posed a challenge for research into pathogenic mechanisms and development of new treatments. We hypothesized that multiple genetic hits to the regulatory machinery that normally inhibits immune activation in the intestine would generate more severe, reproducible pathology that would mimic either ulcerative colitis or Crohn's disease. METHODS AND FINDINGS: We generated a novel mouse line (dnKO that possessed defects in both TGFbetaRII and IL-10R2 signaling. These mice rapidly and reproducibly developed a disease resembling fulminant human ulcerative colitis that was quite distinct from the much longer and more variable course of pathology observed previously in mice possessing only single defects. Pathogenesis was driven by uncontrolled production of proinflammatory cytokines resulting in large part from T cell activation. The disease process could be significantly ameliorated by administration of antibodies against IFNgamma and TNFalpha and was completely inhibited by a combination of broad-spectrum antibiotics. CONCLUSIONS: Here, we develop to our knowledge the first mouse model of fulminant ulcerative colitis by combining multiple genetic hits in immune regulation and demonstrate that the resulting

Long-Term Expansion, Enhanced Chondrogenic Potential, and Suppression of Endochondral Ossification of Adult Human MSCs via WNT Signaling Modulation

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Roberto Narcisi

2015-03-01

Full Text Available Mesenchymal stem cells (MSCs are a potential source of chondrogenic cells for the treatment of cartilage disorders, but loss of chondrogenic potential during in vitro expansion and the propensity of cartilage to undergo hypertrophic maturation impede their therapeutic application. Here we report that the signaling protein WNT3A, in combination with FGF2, supports long-term expansion of human bone marrow-derived MSCs. The cells retained their chondrogenic potential and other phenotypic and functional properties of multipotent MSCs, which were gradually lost in the absence of WNT3A. Moreover, we discovered that endogenous WNT signals are the main drivers of the hypertrophic maturation that follows chondrogenic differentiation. Inhibition of WNT signals during differentiation prevented calcification and maintained cartilage properties following implantation in a mouse model. By maintaining potency during expansion and preventing hypertrophic maturation following differentiation, the modulation of WNT signaling removes two major obstacles that impede the clinical application of MSCs in cartilage repair.

The scarless heart and the MRL mouse.

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Heber-Katz, Ellen; Leferovich, John; Bedelbaeva, Khamilia; Gourevitch, Dmitri; Clark, Lise

2004-05-29

The ability to regenerate tissues and limbs in its most robust form is seen in many non-mammalian species. The serendipitous discovery that the MRL mouse has a profound capacity for regeneration in some ways rivalling the classic newt and axolotl species raises the possibility that humans, too, may have an innate regenerative ability. The adult MRL mouse regrows cartilage, skin, hair follicles and myocardium with near perfect fidelity and without scarring. This is seen in the ability to close through-and-through ear holes, which are generally used for lifelong identification of mice, and the anatomic and functional recovery of myocardium after a severe cryo-injury. We present histological, biochemical and genetic data indicating that the enhanced breakdown of scar-like tissue may be an underlying factor in the MRL regenerative response. Studies as to the source of the cells in the regenerating MRL tissue are discussed. Such studies appear to support multiple mechanisms for cell replacement.

Age-related mutations associated with clonal hematopoietic expansion and malignancies.

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Xie, Mingchao; Lu, Charles; Wang, Jiayin; McLellan, Michael D; Johnson, Kimberly J; Wendl, Michael C; McMichael, Joshua F; Schmidt, Heather K; Yellapantula, Venkata; Miller, Christopher A; Ozenberger, Bradley A; Welch, John S; Link, Daniel C; Walter, Matthew J; Mardis, Elaine R; Dipersio, John F; Chen, Feng; Wilson, Richard K; Ley, Timothy J; Ding, Li

2014-12-01

Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. The Cancer Genome Atlas (TCGA) provides a unique resource for comprehensive discovery of mutations and genes in blood that may contribute to the clonal expansion of hematopoietic stem/progenitor cells. Here, we analyzed blood-derived sequence data from 2,728 individuals from TCGA and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia and/or lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5-6% of people older than 70 years) contain mutations that may represent premalignant events that cause clonal hematopoietic expansion.

Sequential Shh expression in the development of the mouse upper functional incisor

Czech Academy of Sciences Publication Activity Database

Hovořáková, Mária; Smrčková, Lucie; Lesot, H.; Lochovská, Kateřina; Peterka, Miroslav; Peterková, Renata

2013-01-01

Roč. 320, č. 7 (2013), s. 455-464 ISSN 1552-5007 R&D Projects: GA ČR GA304/09/1579; GA ČR(CZ) GAP305/12/1766 Institutional support: RVO:68378041 Keywords : mouse * craniofacial * ED13.5 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.876, year: 2013

Analysis of the cartilage proteome from three different mouse models of genetic skeletal diseases reveals common and discrete disease signatures

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Peter A. Bell

2013-06-01

Pseudoachondroplasia and multiple epiphyseal dysplasia are genetic skeletal diseases resulting from mutations in cartilage structural proteins. Electron microscopy and immunohistochemistry previously showed that the appearance of the cartilage extracellular matrix (ECM in targeted mouse models of these diseases is disrupted; however, the precise changes in ECM organization and the pathological consequences remain unknown. Our aim was to determine the effects of matrilin-3 and COMP mutations on the composition and extractability of ECM components to inform how these detrimental changes might influence cartilage organization and degeneration. Cartilage was sequentially extracted using increasing denaturants and the extraction profiles of specific proteins determined using SDS-PAGE/Western blotting. Furthermore, the relative composition of protein pools was determined using mass spectrometry for a non-biased semi-quantitative analysis. Western blotting revealed changes in the extraction of matrilins, COMP and collagen IX in mutant cartilage. Mass spectrometry confirmed quantitative changes in the extraction of structural and non-structural ECM proteins, including proteins with roles in cellular processes such as protein folding and trafficking. In particular, genotype-specific differences in the extraction of collagens XII and XIV and tenascins C and X were identified; interestingly, increased expression of several of these genes has recently been implicated in susceptibility and/or progression of murine osteoarthritis. We demonstrated that mutation of matrilin-3 and COMP caused changes in the extractability of other cartilage proteins and that proteomic analyses of Matn3 V194D, Comp T585M and Comp DelD469 mouse models revealed both common and discrete disease signatures that provide novel insight into skeletal disease mechanisms and cartilage degradation.

Gene × Environment Interactions in Schizophrenia: Evidence from Genetic Mouse Models

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Paula Moran

2016-01-01

Full Text Available The study of gene × environment, as well as epistatic interactions in schizophrenia, has provided important insight into the complex etiopathologic basis of schizophrenia. It has also increased our understanding of the role of susceptibility genes in the disorder and is an important consideration as we seek to translate genetic advances into novel antipsychotic treatment targets. This review summarises data arising from research involving the modelling of gene × environment interactions in schizophrenia using preclinical genetic models. Evidence for synergistic effects on the expression of schizophrenia-relevant endophenotypes will be discussed. It is proposed that valid and multifactorial preclinical models are important tools for identifying critical areas, as well as underlying mechanisms, of convergence of genetic and environmental risk factors, and their interaction in schizophrenia.

A genetic map of mouse chromosome 1 near the Lsh-Ity-Bcg disease resistance locus.

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Mock, B; Krall, M; Blackwell, J; O'Brien, A; Schurr, E; Gros, P; Skamene, E; Potter, M

1990-05-01

Isozyme and restriction fragment length polymorphism (RFLP) analyses of backcross progeny, recombinant inbred strains, and congenic strains of mice positioned eight genetic markers with respect to the Lsh-Ity-Bcg disease resistance locus. Allelic isoforms of Idh-1 and Pep-3 and RFLPs detected by Southern hybridization for Myl-1, Cryg, Vil, Achrg, bcl-2, and Ren-1,2, between BALB/cAnPt and DBA/2NPt mice, were utilized to examine the cosegregation of these markers with the Lsh-Ity-Bcg resistance phenotype in 103 backcross progeny. An additional 47 backcross progeny from a cross between C57BL/10ScSn and B10.L-Lshr/s mice were examined for the cosegregation of Myl-1 and Vil RFLPs with Lsh phenotypic differences. Similarly, BXD recombinant inbred strains were typed for RFLPs upon hybridization with Vil and Achrg. Recombination frequencies generated in the different test systems were statistically similar, and villin (Vil) was identified as the molecular marker closest (1.7 +/- 0.8 cM) to the Lsh-Ity-Bcg locus. Two other DNA sequences, nebulin (Neb) and an anonymous DNA fragment (D2S3), which map to a region of human chromosome 2q that is homologous to proximal mouse chromosome 1, were not closely linked to the Lsh-Ity-Bcg locus. This multipoint linkage analysis of chromosome 1 surrounding the Lsh-Ity-Bcg locus provides a basis for the eventual isolation of the disease gene.

Diffusion tensor imaging using multiple coils for mouse brain connectomics.

Science.gov (United States)

Nouls, John C; Badea, Alexandra; Anderson, Robert B J; Cofer, Gary P; Allan Johnson, G

2018-04-19

The correlation between brain connectivity and psychiatric or neurological diseases has intensified efforts to develop brain connectivity mapping techniques on mouse models of human disease. The neural architecture of mouse brain specimens can be shown non-destructively and three-dimensionally by diffusion tensor imaging, which enables tractography, the establishment of a connectivity matrix and connectomics. However, experiments on cohorts of animals can be prohibitively long. To improve throughput in a 7-T preclinical scanner, we present a novel two-coil system in which each coil is shielded, placed off-isocenter along the axis of the magnet and connected to a receiver circuit of the scanner. Preservation of the quality factor of each coil is essential to signal-to-noise ratio (SNR) performance and throughput, because mouse brain specimen imaging at 7 T takes place in the coil-dominated noise regime. In that regime, we show a shielding configuration causing no SNR degradation in the two-coil system. To acquire data from several coils simultaneously, the coils are placed in the magnet bore, around the isocenter, in which gradient field distortions can bias diffusion tensor imaging metrics, affect tractography and contaminate measurements of the connectivity matrix. We quantified the experimental alterations in fractional anisotropy and eigenvector direction occurring in each coil. We showed that, when the coils were placed 12 mm away from the isocenter, measurements of the brain connectivity matrix appeared to be minimally altered by gradient field distortions. Simultaneous measurements on two mouse brain specimens demonstrated a full doubling of the diffusion tensor imaging throughput in practice. Each coil produced images devoid of shading or artifact. To further improve the throughput of mouse brain connectomics, we suggested a future expansion of the system to four coils. To better understand acceptable trade-offs between imaging throughput and connectivity

A Phenotype-Driven Approach to Generate Mouse Models with Pathogenic mtDNA Mutations Causing Mitochondrial Disease

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Johanna H.K. Kauppila

2016-09-01

Full Text Available Mutations of mtDNA are an important cause of human disease, but few animal models exist. Because mammalian mitochondria cannot be transfected, the development of mice with pathogenic mtDNA mutations has been challenging, and the main strategy has therefore been to introduce mutations found in cell lines into mouse embryos. Here, we describe a phenotype-driven strategy that is based on detecting clonal expansion of pathogenic mtDNA mutations in colonic crypts of founder mice derived from heterozygous mtDNA mutator mice. As proof of concept, we report the generation of a mouse line transmitting a heteroplasmic pathogenic mutation in the alanine tRNA gene of mtDNA displaying typical characteristics of classic mitochondrial disease. In summary, we describe a straightforward and technically simple strategy based on mouse breeding and histology to generate animal models of mtDNA-mutation disease, which will be of great importance for studies of disease pathophysiology and preclinical treatment trials.

Establishment of new murine embryonic stem cell lines for the generation of mouse models of human genetic diseases

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M.A. Sukoyan

2002-05-01

Full Text Available Embryonic stem cells are totipotent cells derived from the inner cell mass of blastocysts. Recently, the development of appropriate culture conditions for the differentiation of these cells into specific cell types has permitted their use as potential therapeutic agents for several diseases. In addition, manipulation of their genome in vitro allows the creation of animal models of human genetic diseases and for the study of gene function in vivo. We report the establishment of new lines of murine embryonic stem cells from preimplantation stage embryos of 129/Sv mice. Most of these cells had a normal karyotype and an XY sex chromosome composition. The pluripotent properties of the cell lines obtained were analyzed on the basis of their alkaline phosphatase activity and their capacity to form complex embryoid bodies with rhythmically contracting cardiomyocytes. Two lines, USP-1 and USP-3, with the best in vitro characteristics of pluripotency were used in chimera-generating experiments. The capacity to contribute to the germ line was demonstrated by the USP-1 cell line. This cell line is currently being used to generate mouse models of human diseases.

The rate of beneficial mutations surfing on the wave of a range expansion.

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Rémi Lehe

Full Text Available Many theoretical and experimental studies suggest that range expansions can have severe consequences for the gene pool of the expanding population. Due to strongly enhanced genetic drift at the advancing frontier, neutral and weakly deleterious mutations can reach large frequencies in the newly colonized regions, as if they were surfing the front of the range expansion. These findings raise the question of how frequently beneficial mutations successfully surf at shifting range margins, thereby promoting adaptation towards a range-expansion phenotype. Here, we use individual-based simulations to study the surfing statistics of recurrent beneficial mutations on wave-like range expansions in linear habitats. We show that the rate of surfing depends on two strongly antagonistic factors, the probability of surfing given the spatial location of a novel mutation and the rate of occurrence of mutations at that location. The surfing probability strongly increases towards the tip of the wave. Novel mutations are unlikely to surf unless they enjoy a spatial head start compared to the bulk of the population. The needed head start is shown to be proportional to the inverse fitness of the mutant type, and only weakly dependent on the carrying capacity. The precise location dependence of surfing probabilities is derived from the non-extinction probability of a branching process within a moving field of growth rates. The second factor is the mutation occurrence which strongly decreases towards the tip of the wave. Thus, most successful mutations arise at an intermediate position in the front of the wave. We present an analytic theory for the tradeoff between these factors that allows to predict how frequently substitutions by beneficial mutations occur at invasion fronts. We find that small amounts of genetic drift increase the fixation rate of beneficial mutations at the advancing front, and thus could be important for adaptation during species invasions.

A new mouse model for mania shares genetic correlates with human bipolar disorder.

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Michael C Saul

Full Text Available Bipolar disorder (BPD is a debilitating heritable psychiatric disorder. Contemporary rodent models for the manic pole of BPD have primarily utilized either single locus transgenics or treatment with psychostimulants. Our lab recently characterized a mouse strain termed Madison (MSN that naturally displays a manic phenotype, exhibiting elevated locomotor activity, increased sexual behavior, and higher forced swimming relative to control strains. Lithium chloride and olanzapine treatments attenuate this phenotype. In this study, we replicated our locomotor activity experiment, showing that MSN mice display generationally-stable mania relative to their outbred ancestral strain, hsd:ICR (ICR. We then performed a gene expression microarray experiment to compare hippocampus of MSN and ICR mice. We found dysregulation of multiple transcripts whose human orthologs are associated with BPD and other psychiatric disorders including schizophrenia and ADHD, including: Epor, Smarca4, Cmklr1, Cat, Tac1, Npsr1, Fhit, and P2rx7. RT-qPCR confirmed dysregulation for all of seven transcripts tested. Using a novel genome enrichment algorithm, we found enrichment in genome regions homologous to human loci implicated in BPD in replicated linkage studies including homologs of human cytobands 1p36, 3p14, 3q29, 6p21-22, 12q24, 16q24, and 17q25. Using a functional network analysis, we found dysregulation of a gene system related to chromatin packaging, a result convergent with recent human findings on BPD. Our findings suggest that MSN mice represent a polygenic model for the manic pole of BPD showing much of the genetic systems complexity of the corresponding human disorder. Further, the high degree of convergence between our findings and the human literature on BPD brings up novel questions about evolution by analogy in mammalian genomes.

Functional organization of the genome may shape the species boundary in the house mouse

Czech Academy of Sciences Publication Activity Database

Janoušek, Václav; Munclinger, P.; Wang, L.; Teeter, K. C.; Tucker, P. K.

2015-01-01

Roč. 32, č. 5 (2015), s. 1208-1220 ISSN 0737-4038 R&D Projects: GA MŠk EE2.3.20.0303 Institutional support: RVO:68081766 Keywords : hybrid zone * mouse genome * speciation Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 13.649, year: 2015

Plasmodium vivax populations revisited: mitochondrial genomes of temperate strains in Asia suggest ancient population expansion

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Miao Miao

2012-02-01

Full Text Available Abstract Background Plasmodium vivax is the most widely distributed human malaria parasite outside of Africa, and its range extends well into the temperate zones. Previous studies provided evidence for vivax population differentiation, but temperate vivax parasites were not well represented in these analyses. Here we address this deficit by using complete mitochondrial (mt genome sequences to elucidate the broad genetic diversity and population structure of P. vivax from temperate regions in East and Southeast Asia. Results From the complete mtDNA sequences of 99 clinical samples collected in China, Myanmar and Korea, a total of 30 different haplotypes were identified from 26 polymorphic sites. Significant differentiation between different East and Southeast Asian parasite populations was observed except for the comparison between populations from Korea and southern China. Haplotype patterns and structure diversity analysis showed coexistence of two different groups in East Asia, which were genetically related to the Southeast Asian population and Myanmar population, respectively. The demographic history of P. vivax, examined using neutrality tests and mismatch distribution analyses, revealed population expansion events across the entire P. vivax range and the Myanmar population. Bayesian skyline analysis further supported the occurrence of ancient P. vivax population expansion. Conclusions This study provided further resolution of the population structure and evolution of P. vivax, especially in temperate/warm-temperate endemic areas of Asia. The results revealed divergence of the P. vivax populations in temperate regions of China and Korea from other populations. Multiple analyses confirmed ancient population expansion of this parasite. The extensive genetic diversity of the P. vivax populations is consistent with phenotypic plasticity of the parasites, which has implications for malaria control.

Effect of intraovarian factors on porcine follicular cells: cumulus expansion, granulosa and cumulus cell progesterone production

Czech Academy of Sciences Publication Activity Database

Ježová, M.; Scsuková, S.; Nagyová, Eva; Vranová, J.; Procházka, Radek; Kolena, J.

2001-01-01

Roč. 65, - (2001), s. 115-126 ISSN 0378-4320 R&D Projects: GA ČR GA524/98/0231; GA AV ČR KSK5052113 Keywords : pig-ovary * cumulus expansion * luteinization stimulator Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.196, year: 2001

Strain-specific outcomes of repeated social defeat and chronic fluoxetine treatment in the mouse.

Science.gov (United States)

Razzoli, Maria; Carboni, Lucia; Andreoli, Michela; Michielin, Francesca; Ballottari, Alice; Arban, Roberto

2011-01-01

Social stress is a risk factor for affective disorders in vulnerable individuals. Although the biological nature of stress susceptibility/resilience remains to be elucidated, genetic variation is considered amongst the principal contributors to brain disorders. Furthermore, genetic predisposition may be determinant for the therapeutic outcome, as proposed for antidepressant treatments. In the present studies we compared the inherently diverse genetic backgrounds of 2 mouse strains by assessing the efficacy of a chronic antidepressant treatment in a repeated social stress procedure. C57BL/6J and BalbC mice underwent 10-day social defeats followed by 28-day fluoxetine treatment (10 mg/kg/mL, p.o.). In C57BL/6J, most of the social defeat-induced changes were of metabolic nature including persistently altered feed efficiency and decreased abdominal fat stores that were ameliorated by fluoxetine. BalbC mouse behavior was persistently affected by social defeat both in the social avoidance and the forced swim tests, and in either procedure it was restored by chronic fluoxetine, whereas their endocrine parameters were mostly unaffected. The highlighted strain-specific responsivity to the metabolic and behavioral consequences of social defeat and to the chronic antidepressant treatment offers a promising research tool to further explore the underlying neural mechanisms and genetic basis of stress susceptibility and treatment response. Copyright © 2010 Elsevier Inc. All rights reserved.

Mouse ribosomal RNA genes contain multiple differentially regulated variants.

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Hung Tseng

2008-03-01

Full Text Available Previous cytogenetic studies suggest that various rDNA chromosomal loci are not equally active in different cell types. Consistent with this variability, rDNA polymorphism is well documented in human and mouse. However, attempts to identify molecularly rDNA variant types, which are regulated individually (i.e., independent of other rDNA variants and tissue-specifically, have not been successful. We report here the molecular cloning and characterization of seven mouse rDNA variants (v-rDNA. The identification of these v-rDNAs was based on restriction fragment length polymorphisms (RFLPs, which are conserved among individuals and mouse strains. The total copy number of the identified variants is less than 100 and the copy number of each individual variant ranges from 4 to 15. Sequence analysis of the cloned v-rDNA identified variant-specific single nucleotide polymorphisms (SNPs in the transcribed region. These SNPs were used to develop a set of variant-specific PCR assays, which permitted analysis of the v-rDNAs' expression profiles in various tissues. These profiles show that three v-rDNAs are expressed in all tissues (constitutively active, two are expressed in some tissues (selectively active, and two are not expressed (silent. These expression profiles were observed in six individuals from three mouse strains, suggesting the pattern is not randomly determined. Thus, the mouse rDNA array likely consists of genetically distinct variants, and some are regulated tissue-specifically. Our results provide the first molecular evidence for cell-type-specific regulation of a subset of rDNA.

Multiple Requirements of PLK1 during Mouse Oocyte Maturation

Czech Academy of Sciences Publication Activity Database

Šolc, Petr; Kitajima, T.; Yoshida, S.; Brzáková, Adéla; Kaido, M.; Baran, V.; Mayer, Alexandra; Šámalová, P.; Motlík, Jan; Ellenberg, J.

2015-01-01

Roč. 10, č. 2 (2015) E-ISSN 1932-6203 R&D Projects: GA MŠk LH12057; GA ČR(CZ) GPP301/11/P081; GA ČR(CZ) GC301/09/J036; GA ČR GAP502/11/0593; GA MŠk ED2.1.00/03.0124 Institutional support: RVO:67985904 Keywords : PLK1 * meiosis * mouse oocytes Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.057, year: 2015

Transgenic mouse - Methods and protocols, 2nd edition

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Carlo Alberto Redi

2011-09-01

Full Text Available Marten H. Hofner (from the Dept. of Pathology of the Groningen University and Jan M. van Deursen (from the Mayo College of Medicine at Rochester, MN, USA provided us with the valuable second edition of Transgenic mouse: in fact, eventhough we are in the –omics era and already equipped with the state-of-the-art techniques in whatsoever field, still we need to have gene(s functional analysis data to understand common and complex deseases. Transgenesis is still an irreplaceable method and protocols to well perform it are more than welcome. Here, how to get genetic modified mice (the quintessential model of so many human deseases considering how much of the human genes are conserved in the mouse and the great block of genic synteny existing between the two genomes is analysed in deep and presented in clearly detailed step by step protocols....

Carboxylesterases in lipid metabolism: from mouse to human

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Jihong Lian

2017-07-01

Full Text Available ABSTRACT Mammalian carboxylesterases hydrolyze a wide range of xenobiotic and endogenous compounds, including lipid esters. Physiological functions of carboxylesterases in lipid metabolism and energy homeostasis in vivo have been demonstrated by genetic manipulations and chemical inhibition in mice, and in vitro through (overexpression, knockdown of expression, and chemical inhibition in a variety of cells. Recent research advances have revealed the relevance of carboxylesterases to metabolic diseases such as obesity and fatty liver disease, suggesting these enzymes might be potential targets for treatment of metabolic disorders. In order to translate pre-clinical studies in cellular and mouse models to humans, differences and similarities of carboxylesterases between mice and human need to be elucidated. This review presents and discusses the research progress in structure and function of mouse and human carboxylesterases, and the role of these enzymes in lipid metabolism and metabolic disorders.

Journal of Genetics | Indian Academy of Sciences

Indian Academy of Sciences (India)

These results suggest that sexual preference may be influenced in a significant proportion of homosexual men by a biological/genetic factor that also controls direction of hair-whorl rotation. pp 257-263 Research Article. Cloning of a novel gene, Cymg1, related to family 2 cystatins and expressed at specific stages of mouse ...

DYNAMIC PROGRAMMING – EFFICIENT TOOL FOR POWER SYSTEM EXPANSION PLANNING

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SIMO A.

2015-03-01

Full Text Available The paper isfocusing on dynamic programming use for power system expansion planning (EP – transmission network (TNEP and distribution network (DNEP. The EP problem has been approached from the retrospective and prospective point of view. To achieve this goal, the authors are developing two software-tools in Matlab environment. Two techniques have been tackled: particle swarm optimization (PSO and genetic algorithms (GA. The case study refers to Test 25 buses test power system developed within the Power Systems Department.

Histological and reference system for the analysis of mouse intervertebral disc.

Science.gov (United States)

Tam, Vivian; Chan, Wilson C W; Leung, Victor Y L; Cheah, Kathryn S E; Cheung, Kenneth M C; Sakai, Daisuke; McCann, Matthew R; Bedore, Jake; Séguin, Cheryle A; Chan, Danny

2018-01-01

A new scoring system based on histo-morphology of mouse intervertebral disc (IVD) was established to assess changes in different mouse models of IVD degeneration and repair. IVDs from mouse strains of different ages, transgenic mice, or models of artificially induced IVD degeneration were assessed. Morphological features consistently observed in normal, and early/later stages of degeneration were categorized into a scoring system focused on nucleus pulposus (NP) and annulus fibrosus (AF) changes. "Normal NP" exhibited a highly cellularized cell mass that decreased with natural ageing and in disc degeneration. "Normal AF" consisted of distinct concentric lamellar structures, which was disrupted in severe degeneration. NP/AF clefts indicated more severe changes. Consistent scores were obtained between experienced and new users. Altogether, our scoring system effectively differentiated IVD changes in various strains of wild-type and genetically modified mice and in induced models of IVD degeneration, and is applicable from the post-natal stage to the aged mouse. This scoring tool and reference resource addresses a pressing need in the field for studying IVD changes and cross-study comparisons in mice, and facilitates a means to normalize mouse IVD assessment between different laboratories. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:233-243, 2018. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Genome wide association studies on yield components using a lentil genetic diversity panel

Science.gov (United States)

The cool season food legume research community are now at the threshold of deploying the cutting-edge molecular genetics and genomics tools that have led to significant and rapid expansion of gene discovery, knowledge of gene function (including tolerance to biotic and abiotic stresses) and genetic ...

Mitochondrial DNA analyses and ecological niche modeling reveal post-LGM expansion of the Assam macaque (Macaca assamensis) in the foothills of Nepal Himalaya.

Science.gov (United States)

Khanal, Laxman; Chalise, Mukesh K; He, Kai; Acharya, Bipin K; Kawamoto, Yoshi; Jiang, Xuelong

2018-03-01

Genetic diversity of a species is influenced by multiple factors, including the Quaternary glacial-interglacial cycles and geophysical barriers. Such factors are not yet well documented for fauna from the southern border of the Himalayan region. This study used mitochondrial DNA (mtDNA) sequences and ecological niche modeling (ENM) to explore how the late Pleistocene climatic fluctuations and complex geography of the Himalayan region have shaped genetic diversity, population genetic structure, and demographic history of the Nepalese population of Assam macaques (Macaca assamensis) in the Himalayan foothills. A total of 277 fecal samples were collected from 39 wild troops over almost the entire distribution of the species in Nepal. The mtDNA fragment encompassing the complete control region (1121 bp) was recovered from 208 samples, thus defining 54 haplotypes. Results showed low nucleotide diversity (0.0075 ± SD 0.0001) but high haplotype diversity (0.965 ± SD 0.004). The mtDNA sequences revealed a shallow population genetic structure with a moderate but statistically significant effect of isolation by distance. Demographic history analyses using mtDNA sequences suggested a post-pleistocene population expansion. Paleodistribution reconstruction projected that the potential habitat of the Assam macaque was confined to the lower elevations of central Nepal during the Last Glacial Maximum. With the onset of the Holocene climatic optimum, the glacial refugia population experienced eastward range expansion to higher elevations. We conclude that the low genetic diversity and shallow population genetic structure of the Assam macaque population in the Nepal Himalaya region are the consequence of recent demographic and spatial expansion. © 2018 Wiley Periodicals, Inc.

Conditional reverse tet-transactivator mouse strains for the efficient induction of TRE-regulated transgenes in mice.

Directory of Open Access Journals (Sweden)

Lukas E Dow

Full Text Available Tetracycline or doxycycline (dox-regulated control of genetic elements allows inducible, reversible and tissue specific regulation of gene expression in mice. This approach provides a means to investigate protein function in specific cell lineages and at defined periods of development and disease. Efficient and stable regulation of cDNAs or non-coding elements (e.g. shRNAs downstream of the tetracycline-regulated element (TRE requires the robust expression of a tet-transactivator protein, commonly the reverse tet-transactivator, rtTA. Most rtTA strains rely on tissue specific promoters that often do not provide sufficient rtTA levels for optimal inducible expression. Here we describe the generation of two mouse strains that enable Cre-dependent, robust expression of rtTA3, providing tissue-restricted and consistent induction of TRE-controlled transgenes. We show that these transgenic strains can be effectively combined with established mouse models of disease, including both Cre/LoxP-based approaches and non Cre-dependent disease models. The integration of these new tools with established mouse models promises the development of more flexible genetic systems to uncover the mechanisms of development and disease pathogenesis.

The genetic analysis of repeated measures II: The Karhunen-Loeve expansion.

NARCIS (Netherlands)

Molenaar, P.C.M.; Boomsma, D.I.

1987-01-01

Outlines the Karhunen-Loeve (N. Ahmed and K. R. Rao, 1975) approach to the genetic analysis of time series of arbitrary length and with arbitrary covariance function. This approach is based on the simultaneous eigenvalue decomposition of the covariance matrices of the original time series obtained

Enhanced fear expression in a psychopathological mouse model of trait anxiety: pharmacological interventions.

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Simone B Sartori

Full Text Available The propensity to develop an anxiety disorder is thought to be determined by genetic and environmental factors. Here we investigated the relationship between a genetic predisposition to trait anxiety and experience-based learned fear in a psychopathological mouse model. Male CD-1 mice selectively bred for either high (HAB, or normal (NAB anxiety-related behaviour on the elevated plus maze were subjected to classical fear conditioning. During conditioning both mouse lines showed increased fear responses as assessed by freezing behaviour. However, 24 h later, HAB mice displayed more pronounced conditioned responses to both a contextual or cued stimulus when compared with NAB mice. Interestingly, 6 h and already 1 h after fear conditioning, freezing levels were high in HAB mice but not in NAB mice. These results suggest that trait anxiety determines stronger fear memory and/or a weaker ability to inhibit fear responses in the HAB line. The enhanced fear response of HAB mice was attenuated by treatment with either the α(2,3,5-subunit selective benzodiazepine partial agonist L-838,417, corticosterone or the selective neurokinin-1 receptor antagonist L-822,429. Overall, the HAB mouse line may represent an interesting model (i for identifying biological factors underlying misguided conditioned fear responses and (ii for studying novel anxiolytic pharmacotherapies for patients with fear-associated disorders, including post-traumatic stress disorder and phobias.

Population genetic structure and demographic history of Atrina pectinata based on mitochondrial DNA and microsatellite markers.

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Dong-Xiu Xue

Full Text Available The pen shell, Atrina pectinata, is one of the commercial bivalves in East Asia and thought to be recently affected by anthropogenic pressure (habitat destruction and/or fishing pressure. Information on its population genetic structure is crucial for the conservation of A. pectinata. Considering its long pelagic larval duration and iteroparity with high fecundity, the genetic structure for A. pectinata could be expected to be weak at a fine scale. However, the unusual oceanography in the coasts of China and Korea suggests potential for restricted dispersal of pelagic larvae and geographical differentiation. In addition, environmental changes associated with Pleistocene sea level fluctuations on the East China Sea continental shelf may also have strongly influenced historical population demography and genetic diversity of marine organisms. Here, partial sequences of the mitochondrial Cytochrome c oxidase subunit I (COI gene and seven microsatellite loci were used to estimate population genetic structure and demographic history of seven samples from Northern China coast and one sample from North Korea coast. Despite high levels of genetic diversity within samples, there was no genetic differentiation among samples from Northern China coast and low but significant genetic differentiation between some of the Chinese samples and the North Korean sample. A late Pleistocene population expansion, probably after the Last Glacial Maximum, was also demonstrated for A. pectinata samples. No recent genetic bottleneck was detected in any of the eight samples. We concluded that both historical recolonization (through population range expansion and demographic expansion in the late Pleistocene and current gene flow (through larval dispersal were responsible for the weak level of genetic structure detected in A. pectinata.

Negative thermal expansion materials

International Nuclear Information System (INIS)

Evans, J.S.O.

1997-01-01

The recent discovery of negative thermal expansion over an unprecedented temperature range in ZrW 2 O 8 (which contracts continuously on warming from below 2 K to above 1000 K) has stimulated considerable interest in this unusual phenomenon. Negative and low thermal expansion materials have a number of important potential uses in ceramic, optical and electronic applications. We have now found negative thermal expansion in a large new family of materials with the general formula A 2 (MO 4 ) 3 . Chemical substitution dramatically influences the thermal expansion properties of these materials allowing the production of ceramics with negative, positive or zero coefficients of thermal expansion, with the potential to control other important materials properties such as refractive index and dielectric constant. The mechanism of negative thermal expansion and the phase transitions exhibited by this important new class of low-expansion materials will be discussed. (orig.)

Negative thermal expansion materials: technological key for control of thermal expansion.

Science.gov (United States)

Takenaka, Koshi

2012-02-01

Most materials expand upon heating. However, although rare, some materials contract upon heating. Such negative thermal expansion (NTE) materials have enormous industrial merit because they can control the thermal expansion of materials. Recent progress in materials research enables us to obtain materials exhibiting negative coefficients of linear thermal expansion over -30 ppm K -1 . Such giant NTE is opening a new phase of control of thermal expansion in composites. Specifically examining practical aspects, this review briefly summarizes materials and mechanisms of NTE as well as composites containing NTE materials, based mainly on activities of the last decade.

Negative thermal expansion materials: technological key for control of thermal expansion

Directory of Open Access Journals (Sweden)

Koshi Takenaka

2012-01-01

Full Text Available Most materials expand upon heating. However, although rare, some materials contract upon heating. Such negative thermal expansion (NTE materials have enormous industrial merit because they can control the thermal expansion of materials. Recent progress in materials research enables us to obtain materials exhibiting negative coefficients of linear thermal expansion over −30 ppm K−1. Such giant NTE is opening a new phase of control of thermal expansion in composites. Specifically examining practical aspects, this review briefly summarizes materials and mechanisms of NTE as well as composites containing NTE materials, based mainly on activities of the last decade.

Negative thermal expansion materials: technological key for control of thermal expansion

International Nuclear Information System (INIS)

Takenaka, Koshi

2012-01-01

Most materials expand upon heating. However, although rare, some materials contract upon heating. Such negative thermal expansion (NTE) materials have enormous industrial merit because they can control the thermal expansion of materials. Recent progress in materials research enables us to obtain materials exhibiting negative coefficients of linear thermal expansion over −30 ppm K −1 . Such giant NTE is opening a new phase of control of thermal expansion in composites. Specifically examining practical aspects, this review briefly summarizes materials and mechanisms of NTE as well as composites containing NTE materials, based mainly on activities of the last decade. (topical review)

Translational Mouse Models of Autism: Advancing Toward Pharmacological Therapeutics

Science.gov (United States)

Kazdoba, Tatiana M.; Leach, Prescott T.; Yang, Mu; Silverman, Jill L.; Solomon, Marjorie

2016-01-01

Animal models provide preclinical tools to investigate the causal role of genetic mutations and environmental factors in the etiology of autism spectrum disorder (ASD). Knockout and humanized knock-in mice, and more recently knockout rats, have been generated for many of the de novo single gene mutations and copy number variants (CNVs) detected in ASD and comorbid neurodevelopmental disorders. Mouse models incorporating genetic and environmental manipulations have been employed for preclinical testing of hypothesis-driven pharmacological targets, to begin to develop treatments for the diagnostic and associated symptoms of autism. In this review, we summarize rodent behavioral assays relevant to the core features of autism, preclinical and clinical evaluations of pharmacological interventions, and strategies to improve the translational value of rodent models of autism. PMID:27305922

Characterization of mutations at the mouse phenylalanine hydroxylase locus

Energy Technology Data Exchange (ETDEWEB)

McDonald, J.D.; Charlton, C.K. [Wichita State Univ., KS (United States)

1997-02-01

Two genetic mouse models for human phenylketonuria have been characterized by DNA sequence analysis. For each, a distinct mutation was identified within the protein coding sequence of the phenylalanine hydroxylase gene. This establishes that the mutated locus is the same as that causing human phenylketonuria and allows a comparison between these mouse phenylketonuria models and the human disease. A genotype/phenotype relationship that is strikingly similar to the human disease emerges, underscoring the similarity of phenylketonuria in mouse and man. In PAH{sup ENU1}, the phenotype is mild. The Pah{sup enu1} mutation predicts a conservative valine to alanine amino acid substitution and is located in exon 3, a gene region where serious mutations are rare in humans. In PAH{sup ENU2} the phenotype is severe. The Pah{sup enu2} mutation predicts a radical phenylalanine to serine substitution and is located in exon 7, a gene region where serious mutations are common in humans. In PAH{sup ENU2}, the sequence information was used to devise a direct genotyping system based on the creation of a new Alw26I restriction endonuclease site. 26 refs., 2 figs., 1 tab.

Development of a Representative Mouse Model with Nonalcoholic Steatohepatitis.

Science.gov (United States)

Verbeek, Jef; Jacobs, Ans; Spincemaille, Pieter; Cassiman, David

2016-06-01

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the Western world. It represents a disease spectrum ranging from isolated steatosis to non-alcoholic steatohepatitis (NASH). In particular, NASH can evolve to fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. The development of novel treatment strategies is hampered by the lack of representative NASH mouse models. Here, we describe a NASH mouse model, which is based on feeding non-genetically manipulated C57BL6/J mice a 'Western style' high-fat/high-sucrose diet (HF-HSD). HF-HSD leads to early obesity, insulin resistance, and hypercholesterolemia. After 12 weeks of HF-HSD, all mice exhibit the complete spectrum of features of NASH, including steatosis, hepatocyte ballooning, and lobular inflammation, together with fibrosis in the majority of mice. Hence, this model closely mimics the human disease. Implementation of this mouse model will lead to a standardized setup for the evaluation of (i) underlying mechanisms that contribute to the progression of NAFLD to NASH, and (ii) therapeutic interventions for NASH. © 2016 by John Wiley & Sons, Inc. Copyright © 2016 John Wiley & Sons, Inc.

Genotypic and phenotypic characterization of the Sdccag8Tn(sb-Tyr2161B.CA1C2Ove mouse model.

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Katie Weihbrecht

Full Text Available Nephronophthisis-related ciliopathies (NPHP-RC are a group of disorders that present with end-stage renal failure in childhood/adolescence, kidney cysts, retinal degeneration, and cerebellar hypoplasia. One disorder that shares clinical features with NPHP-RC is Bardet-Biedl Syndrome (BBS. Serologically defined colon cancer antigen 8 (SDCCAG8; also known as NPHP10 and BBS16 is an NPHP gene that is also associated with BBS. To better understand the patho-mechanisms of NPHP and BBS caused by loss of SDCCAG8 function, we characterized an SDCCAG8 mouse model (Sdccag8Tn(sb-Tyr2161B.CA1C2Ove generated by Sleeping Beauty Transposon (SBT-mediated insertion mutagenesis. Consistent with the previously reported, independent SDCCAG8 mouse models, our mutant mice display pre-axial polydactyly in their hind limbs. In addition, we report patterning defects in the secondary palate, brain abnormalities, as well as neonatal lethality associated with developmental defects in the lung in our mouse model. The neonatal lethality phenotype is genetic background dependent and rescued by introducing 129S6/SvEvTac background. Genetic modifier(s responsible for this effect were mapped to a region between SNPs rs3714172 and rs3141832 on chromosome 11. While determining the precise genetic lesion in our mouse model, we found that SBT insertion resulted in a deletion of multiple exons from both Sdccag8 and its neighboring gene Akt3. We ascribe the patterning defects in the limb and the secondary palate as well as lung abnormalities to loss of SDCCAG8, while the developmental defects in the brain are likely due to the loss of AKT3. This mouse model may be useful to study features not observed in other SDCCAG8 models but cautions are needed in interpreting data.

AC transmission network expansion planning considering circuits repowering and location of capacitors

Directory of Open Access Journals (Sweden)

Jaime A. López-López

2016-07-01

Full Text Available This paper deals with the Transmission Network Expansion Planning (TNEP problem. The TNEP consists of finding a set of new circuits on a power system, which is needed to attend a future demand. In its classical version, the TNEP only considers as solution candidates the addition of new lines and transformers. The main contribution of this paper consists in the inclusion of nonconventional solution candidates, namely the repowering of existing circuits and the location of capacitor banks. To take into account these last ones an AC model of the transmission network is considered. The solution of the proposed model is carried out using a Hybrid Genetic Algorithm. Results are compared and validated with previous works in the technical literature. The test systems used are the Garver system and IEEE 24 bus system. The results obtained in both systems showed that the inclusion of the non-conventional candidates, proposed in this paper, allows to reduce the cost of network expansion. This fact may be useful as an indicator for the system planner to consider new possibilities in the expansion studies.

Mouse models of estrogen receptor-positive breast cancer

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Shakur Mohibi

2011-01-01

Full Text Available Breast cancer is the most frequent malignancy and second leading cause of cancer-related deaths among women. Despite advances in genetic and biochemical analyses, the incidence of breast cancer and its associated mortality remain very high. About 60 - 70% of breast cancers are Estrogen Receptor alpha (ER-α positive and are dependent on estrogen for growth. Selective estrogen receptor modulators (SERMs have therefore provided an effective targeted therapy to treat ER-α positive breast cancer patients. Unfortunately, development of resistance to endocrine therapy is frequent and leads to cancer recurrence. Our understanding of molecular mechanisms involved in the development of ER-α positive tumors and their resistance to ER antagonists is currently limited due to lack of experimental models of ER-α positive breast cancer. In most mouse models of breast cancer, the tumors that form are typically ER-negative and independent of estrogen for their growth. However, in recent years more attention has been given to develop mouse models that develop different subtypes of breast cancers, including ER-positive tumors. In this review, we discuss the currently available mouse models that develop ER-α positive mammary tumors and their potential use to elucidate the molecular mechanisms of ER-α positive breast cancer development and endocrine resistance.

Thermal expansion of coking coals

Energy Technology Data Exchange (ETDEWEB)

Orlik, M.; Klimek, J. (Vyzkumny a Zkusebni Ustav Nova Hut, Ostrava (Czechoslovakia))

1992-12-01

Analyzes expansion of coal mixtures in coke ovens during coking. Methods for measuring coal expansion on both a laboratory and pilot plant scale are comparatively evaluated. The method, developed, tested and patented in Poland by the Institute for Chemical Coal Processing in Zabrze (Polish standard PN-73/G-04522), is discussed. A laboratory device developed by the Institute for measuring coal expansion is characterized. Expansion of black coal from 10 underground mines in the Ostrava-Karvina coal district and from 9 coal mines in the Upper Silesia basin in Poland is comparatively evaluated. Investigations show that coal expansion reaches a maximum for coal types with a volatile matter ranging from 20 to 25%. With increasing volatile matter in coal, its expansion decreases. Coal expansion increases with increasing swelling index. Coal expansion corresponds with coal dilatation. With increasing coal density its expansion increases. Coal mixtures should be selected in such a way that their expansion does not cause a pressure exceeding 40 MPa. 11 refs.

A novel surgical approach for intratracheal administration of bioactive agents in a fetal mouse model.

Science.gov (United States)

Carlon, Marianne S; Toelen, Jaan; da Cunha, Marina Mori; Vidović, Dragana; Van der Perren, Anke; Mayer, Steffi; Sbragia, Lourenço; Nuyts, Johan; Himmelreich, Uwe; Debyser, Zeger; Deprest, Jan

2012-10-31

Prenatal pulmonary delivery of cells, genes or pharmacologic agents could provide the basis for new therapeutic strategies for a variety of genetic and acquired diseases. Apart from congenital or inherited abnormalities with the requirement for long-term expression of the delivered gene, several non-inherited perinatal conditions, where short-term gene expression or pharmacological intervention is sufficient to achieve therapeutic effects, are considered as potential future indications for this kind of approach. Candidate diseases for the application of short-term prenatal therapy could be the transient neonatal deficiency of surfactant protein B causing neonatal respiratory distress syndrome(1,2) or hyperoxic injuries of the neonatal lung(3). Candidate diseases for permanent therapeutic correction are Cystic Fibrosis (CF)(4), genetic variants of surfactant deficiencies(5) and α1-antitrypsin deficiency(6). Generally, an important advantage of prenatal gene therapy is the ability to start therapeutic intervention early in development, at or even prior to clinical manifestations in the patient, thus preventing irreparable damage to the individual. In addition, fetal organs have an increased cell proliferation rate as compared to adult organs, which could allow a more efficient gene or stem cell transfer into the fetus. Furthermore, in utero gene delivery is performed when the individual's immune system is not completely mature. Therefore, transplantation of heterologous cells or supplementation of a non-functional or absent protein with a correct version should not cause immune sensitization to the cell, vector or transgene product, which has recently been proven to be the case with both cellular and genetic therapies(7). In the present study, we investigated the potential to directly target the fetal trachea in a mouse model. This procedure is in use in larger animal models such as rabbits and sheep(8), and even in a clinical setting(9), but has to date not been

Use of Genetic Models to Study the Urinary Concentrating Mechanism

DEFF Research Database (Denmark)

Olesen, Emma Tina Bisgaard; Kortenoeven, Marleen L.A.; Fenton, Robert A.

2015-01-01

technology is providing critical new information about urinary concentrating processes and thus mechanisms for maintaining body water homeostasis. In this chapter we provide a brief overview of genetic mouse model generation, and then summarize findings in transgenic and knockout mice pertinent to our...

Virial Expansion Bounds

Science.gov (United States)

Tate, Stephen James

2013-10-01

In the 1960s, the technique of using cluster expansion bounds in order to achieve bounds on the virial expansion was developed by Lebowitz and Penrose (J. Math. Phys. 5:841, 1964) and Ruelle (Statistical Mechanics: Rigorous Results. Benjamin, Elmsford, 1969). This technique is generalised to more recent cluster expansion bounds by Poghosyan and Ueltschi (J. Math. Phys. 50:053509, 2009), which are related to the work of Procacci (J. Stat. Phys. 129:171, 2007) and the tree-graph identity, detailed by Brydges (Phénomènes Critiques, Systèmes Aléatoires, Théories de Jauge. Les Houches 1984, pp. 129-183, 1986). The bounds achieved by Lebowitz and Penrose can also be sharpened by doing the actual optimisation and achieving expressions in terms of the Lambert W-function. The different bound from the cluster expansion shows some improvements for bounds on the convergence of the virial expansion in the case of positive potentials, which are allowed to have a hard core.

Biology and therapy of inherited retinal degenerative disease: insights from mouse models

Science.gov (United States)

Veleri, Shobi; Lazar, Csilla H.; Chang, Bo; Sieving, Paul A.; Banin, Eyal; Swaroop, Anand

2015-01-01

Retinal neurodegeneration associated with the dysfunction or death of photoreceptors is a major cause of incurable vision loss. Tremendous progress has been made over the last two decades in discovering genes and genetic defects that lead to retinal diseases. The primary focus has now shifted to uncovering disease mechanisms and designing treatment strategies, especially inspired by the successful application of gene therapy in some forms of congenital blindness in humans. Both spontaneous and laboratory-generated mouse mutants have been valuable for providing fundamental insights into normal retinal development and for deciphering disease pathology. Here, we provide a review of mouse models of human retinal degeneration, with a primary focus on diseases affecting photoreceptor function. We also describe models associated with retinal pigment epithelium dysfunction or synaptic abnormalities. Furthermore, we highlight the crucial role of mouse models in elucidating retinal and photoreceptor biology in health and disease, and in the assessment of novel therapeutic modalities, including gene- and stem-cell-based therapies, for retinal degenerative diseases. PMID:25650393

A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis.

Directory of Open Access Journals (Sweden)

Nina Fransén-Pettersson

Full Text Available Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders.

Centralized mouse repositories.

Science.gov (United States)

Donahue, Leah Rae; Hrabe de Angelis, Martin; Hagn, Michael; Franklin, Craig; Lloyd, K C Kent; Magnuson, Terry; McKerlie, Colin; Nakagata, Naomi; Obata, Yuichi; Read, Stuart; Wurst, Wolfgang; Hörlein, Andreas; Davisson, Muriel T

2012-10-01

Because the mouse is used so widely for biomedical research and the number of mouse models being generated is increasing rapidly, centralized repositories are essential if the valuable mouse strains and models that have been developed are to be securely preserved and fully exploited. Ensuring the ongoing availability of these mouse strains preserves the investment made in creating and characterizing them and creates a global resource of enormous value. The establishment of centralized mouse repositories around the world for distributing and archiving these resources has provided critical access to and preservation of these strains. This article describes the common and specialized activities provided by major mouse repositories around the world.

Eugenics, genetics, and the minority group model of disabilities: implications for social work advocacy.

Science.gov (United States)

O'Brien, Gerald V

2011-10-01

In the United States, genetic research, as well as policy and practice innovations based on this research, has expanded greatly over the past few decades. This expansion is indicated, for example, by the mapping of the human genome, an expansion of genetic counseling, and other biogenetic research. Also, a disability rights movement that in many ways parallels other "minority" rights campaigns has expanded. The coexistence of these developments poses intriguing challenges for social work that the profession has yet to address in a meaningful way. These issues are especially pertinent for social work professionals in the crucial role as advocates for marginalized populations. This article describes some ofthe concerns of disability rights activists relative to genetic innovations and goals as well as the instrumental role of the social work community in this important debate.

Maternal separation with early weaning: a novel mouse model of early life neglect

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Elwafi Hani M

2010-09-01

Full Text Available Abstract Background Childhood adversity is associated with increased risk for mood, anxiety, impulse control, and substance disorders. Although genetic and environmental factors contribute to the development of such disorders, the neurobiological mechanisms involved are poorly understood. A reliable mouse model of early life adversity leading to lasting behavioral changes would facilitate progress in elucidating the molecular mechanisms underlying these adverse effects. Maternal separation is a commonly used model of early life neglect, but has led to inconsistent results in the mouse. Results In an effort to develop a mouse model of early life neglect with long-lasting behavioral effects in C57BL/6 mice, we designed a new maternal separation paradigm that we call Maternal Separation with Early Weaning (MSEW. We tested the effects of MSEW on C57BL/6 mice as well as the genetically distinct DBA/2 strain and found significant MSEW effects on several behavioral tasks (i.e., the open field, elevated plus maze, and forced swim test when assessed more than two months following the MSEW procedure. Our findings are consistent with MSEW causing effects within multiple behavioral domains in both strains, and suggest increased anxiety, hyperactivity, and behavioral despair in the MSEW offspring. Analysis of pup weights and metabolic parameters showed no evidence for malnutrition in the MSEW pups. Additionally, strain differences in many of the behavioral tests suggest a role for genetic factors in the response to early life neglect. Conclusions These results suggest that MSEW may serve as a useful model to examine the complex behavioral abnormalities often apparent in individuals with histories of early life neglect, and may lead to greater understanding of these later life outcomes and offer insight into novel therapeutic strategies.

A genetic atlas of human admixture history.

Science.gov (United States)

Hellenthal, Garrett; Busby, George B J; Band, Gavin; Wilson, James F; Capelli, Cristian; Falush, Daniel; Myers, Simon

2014-02-14

Modern genetic data combined with appropriate statistical methods have the potential to contribute substantially to our understanding of human history. We have developed an approach that exploits the genomic structure of admixed populations to date and characterize historical mixture events at fine scales. We used this to produce an atlas of worldwide human admixture history, constructed by using genetic data alone and encompassing over 100 events occurring over the past 4000 years. We identified events whose dates and participants suggest they describe genetic impacts of the Mongol empire, Arab slave trade, Bantu expansion, first millennium CE migrations in Eastern Europe, and European colonialism, as well as unrecorded events, revealing admixture to be an almost universal force shaping human populations.

Genetic mapping of species differences via in vitro crosses in mouse embryonic stem cells

NARCIS (Netherlands)

Lazzarano, S. (Stefano); Kučka, M. (Marek); Castro, J.P.L. (João P. L.); Naumann, R. (Ronald); Medina, P. (Paloma); Fletcher, M.N.C. (Michael N. C.); Wombacher, R. (Rebecka); J.H. Gribnau (Joost); Hochepied, T. (Tino); Van Montagu, M. (Marc); C. Libert; Chan, Y.F. (Yingguang Frank)

2018-01-01

textabstractDiscovering the genetic changes underlying species differences is a central goal in evolutionary genetics. However, hybrid crosses between species in mammals often suffer from hybrid sterility, greatly complicating genetic mapping of trait variation across species. Here, we describe a

Ultra-low thermal expansion realized in giant negative thermal expansion materials through self-compensation

Science.gov (United States)

Shen, Fei-Ran; Kuang, Hao; Hu, Feng-Xia; Wu, Hui; Huang, Qing-Zhen; Liang, Fei-Xiang; Qiao, Kai-Ming; Li, Jia; Wang, Jing; Liu, Yao; Zhang, Lei; He, Min; Zhang, Ying; Zuo, Wen-Liang; Sun, Ji-Rong; Shen, Bao-Gen

2017-10-01

Materials with zero thermal expansion (ZTE) or precisely tailored thermal expansion are in urgent demand of modern industries. However, the overwhelming majority of materials show positive thermal expansion. To develop ZTE or negative thermal expansion (NTE) materials as compensators has become an important challenge. Here, we present the evidence for the realization of ultra-low thermal expansion in Mn-Co-Ge-In particles. The bulk with the Ni2In-type hexagonal structure undergoes giant NTE owing to a martensitic magnetostructural transition. The major finding is that the thermal expansion behavior can be totally controlled by modulating the crystallinity degree and phase transition from atomic scale. Self-compensation effect leads to ultra-low thermal expansion with a linear expansion coefficient as small as +0.68 × 10-6/K over a wide temperature range around room temperature. The present study opens an avenue to reach ZTE particularly from the large class of giant NTE materials based on phase transition.

Ultra-low thermal expansion realized in giant negative thermal expansion materials through self-compensation

Directory of Open Access Journals (Sweden)

Fei-Ran Shen

2017-10-01

Full Text Available Materials with zero thermal expansion (ZTE or precisely tailored thermal expansion are in urgent demand of modern industries. However, the overwhelming majority of materials show positive thermal expansion. To develop ZTE or negative thermal expansion (NTE materials as compensators has become an important challenge. Here, we present the evidence for the realization of ultra-low thermal expansion in Mn–Co–Ge–In particles. The bulk with the Ni2In-type hexagonal structure undergoes giant NTE owing to a martensitic magnetostructural transition. The major finding is that the thermal expansion behavior can be totally controlled by modulating the crystallinity degree and phase transition from atomic scale. Self-compensation effect leads to ultra-low thermal expansion with a linear expansion coefficient as small as +0.68 × 10−6/K over a wide temperature range around room temperature. The present study opens an avenue to reach ZTE particularly from the large class of giant NTE materials based on phase transition.

Optimization of a water resource system expansion using the Genetic Algorithm and Simulated Annealing methods; Optimizacion de la expansion de un sistema de recursos hidricos utilizados las metodologias del algoritmo genetico y el recocido simulado

Energy Technology Data Exchange (ETDEWEB)

Sanchez Camacho, Enrique; Andreu Alvarez, Joaquin [Universidad Politecnica de Valencia (Spain)

2001-06-01

Two numerical procedures, based on the Genetic Algorithm (GA) and the Simulated Annealing (SA), are developed to solve the problem of the expansion of capacity of a water resource system. The problem was divided into two subproblems: capital availability and operation policy. Both are optimisation-simulation models, the first one is solved by means of the GA and SA, in each case, while the second one is solved using the Out-of-kilter algorithm (OKA), in both models. The objective function considers the usual benefits and costs in this kind of systems, such as irrigation and hydropower benefits, costs of dam construction and system maintenance. The strength and weakness of both models are evaluated by comparing their results with those obtained with the branch and bound technique, which was classically used to solve this kind of problems. [Spanish] Un par de metodos numericos fundamentados en dos tecnicas de busqueda globales. Algoritmos Genetico (AG) y Recocido Simulado (RS), son desarrollados para resolver el problema de expansion de capacidad de un sistema de recursos hidricos. La estrategia ha sido dividir al problema en dos subproblemas: el de disponibilidad de capital y el de la politica de operacion. Ambos modelos son de optimizacion-simulacion, el primero se realiza mediante los algoritmos del RS y el AG en cada caso, en tanto que el segundo lleva a cabo a traves del algoritmo del Out-of-kilter (AOK) en los dos modelos. La funcion objetivo con que se trabaja considera los beneficios y costos mas comunes en este tipo de sistema, tales como beneficios por riego, por hidroelectricidad y costos de construccion de los embalses y mantenimiento del sistema. La potencia y debilidades delos dos modelos se evaluan mediante la comparacion con los resultados obtenidos a traves de una de las tecnicas mas usadas en este tipo de problemas: la de ramificacion y acotacion.

Control of expansive growth in water deficit: from phenotyping to field simulations

OpenAIRE

Parent , Boris; Cabrera Bosquet , Llorenç; Cané , Maria Angela; Chaumont , François; Alvarez Prado , Santiago; CALDEIRA JuNIOR , Cecilio Frois; Lacube , Sébastien; Fleury , Delphine; Welcker , Claude; Tuberosa , Roberto; Tardieu , Francois

2015-01-01

Maintenance of expansive growth under water deficit has been selected as a key target trait of DROPS because of its early response in drying conditions, its large genetic variability, its partially common control with reproductive growth and its consequences on light interception and transpiration. Development of methods to measure shoot growth in Phenotyping platforms (PhenoArch and Phenodyn, M3P, Montpellier, France; The Plant Accelerator, Adelaide, Australia) allowed identification of a...

Three loci on mouse chromosome 5 and 10 modulate sex determination in XX Ods/+ mice.

Science.gov (United States)

Poirier, Christophe; Moran, Jennifer L; Kovanci, Ertug; Petit, Deborah C; Beier, David R; Bishop, Colin E

2007-07-01

In mouse, XY embryos are committed to the male sex determination pathway after the transient expression of the Y-linked Sry gene in the Sertoli cell lineage between 10.5 and 12.5 dpc. In the C57BL/6J strain, male sex determination program can be modulated by some autosomal genes. The C57BL/6J alleles at these autosomal loci can antagonize male sex determination in combination with specific Sry alleles. In this report, the authors have identified an effect of these C57BL/6J specific alleles in combination with a mutated Sox9 allele, Sox9(Ods). Authors report the mapping of three of these genetic loci on mouse chromosome 5 and 10 in a backcross of the Ods mutation to the C57BL/6J background. Our study confirms the importance of the strain C57BL/6J for the investigation of the genetic mechanisms that control sex determination.

Ultra-low thermal expansion realized in giant negative thermal expansion materials through self-compensation

OpenAIRE

Fei-Ran Shen; Hao Kuang; Feng-Xia Hu; Hui Wu; Qing-Zhen Huang; Fei-Xiang Liang; Kai-Ming Qiao; Jia Li; Jing Wang; Yao Liu; Lei Zhang; Min He; Ying Zhang; Wen-Liang Zuo; Ji-Rong Sun

2017-01-01

Materials with zero thermal expansion (ZTE) or precisely tailored thermal expansion are in urgent demand of modern industries. However, the overwhelming majority of materials show positive thermal expansion. To develop ZTE or negative thermal expansion (NTE) materials as compensators has become an important challenge. Here, we present the evidence for the realization of ultra-low thermal expansion in Mn–Co–Ge–In particles. The bulk with the Ni2In-type hexagonal structure undergoes giant NTE o...

Genetic diversity and population structure of Sitodiplosis mosellana in Northern China.

Directory of Open Access Journals (Sweden)

Yun Duan

Full Text Available The wheat midge, Sitodiplosis mosellana, is an important pest in Northern China. We tested the hypothesis that the population structure of this species arises during a range expansion over the past 30 years. This study used microsatellite and mitochondrial loci to conduct population genetic analysis of S. mosellana across its distribution range in China. We found strong genetic structure among the 16 studied populations, including two genetically distinct groups (the eastern and western groups, broadly consistent with the geography and habitat fragmentation. These results underline the importance of natural barriers in impeding dispersal and gene flow of S. mosellana populations. Low to moderate genetic diversity among the populations and moderate genetic differentiation (F ST = 0.117 between the two groups were also found. The populations in the western group had lower genetic diversity, higher genetic differentiation and lower gene flow (F ST = 0.116, Nm = 1.89 than those in the eastern group (F ST = 0.049, Nm = 4.91. Genetic distance between populations was positively and significantly correlated with geographic distance (r = 0.56, P<0.001. The population history of this species provided no evidence for population expansion or bottlenecks in any of these populations. Our data suggest that the distribution of genetic diversity, genetic differentiation and population structure of S. mosellana have resulted from a historical event, reflecting its adaptation to diverse habitats and forming two different gene pools. These results may be the outcome of a combination of restricted gene flow due to geographical and environmental factors, population history, random processes of genetic drift and individual dispersal patterns. Given the current risk status of this species in China, this study can offer useful information for forecasting outbreaks and designing effective pest management programs.

The future: genetics advances in MEN1 therapeutic approaches and management strategies.

Science.gov (United States)

Agarwal, Sunita K

2017-10-01

The identification of the multiple endocrine neoplasia type 1 ( MEN1 ) gene in 1997 has shown that germline heterozygous mutations in the MEN1 gene located on chromosome 11q13 predisposes to the development of tumors in the MEN1 syndrome. Tumor development occurs upon loss of the remaining normal copy of the MEN1 gene in MEN1-target tissues. Therefore, MEN1 is a classic tumor suppressor gene in the context of MEN1. This tumor suppressor role of the protein encoded by the MEN1 gene, menin, holds true in mouse models with germline heterozygous Men1 loss, wherein MEN1-associated tumors develop in adult mice after spontaneous loss of the remaining non-targeted copy of the Men1 gene. The availability of genetic testing for mutations in the MEN1 gene has become an essential part of the diagnosis and management of MEN1. Genetic testing is also helping to exclude mutation-negative cases in MEN1 families from the burden of lifelong clinical screening. In the past 20 years, efforts of various groups world-wide have been directed at mutation analysis, molecular genetic studies, mouse models, gene expression studies, epigenetic regulation analysis, biochemical studies and anti-tumor effects of candidate therapies in mouse models. This review will focus on the findings and advances from these studies to identify MEN1 germline and somatic mutations, the genetics of MEN1-related states, several protein partners of menin, the three-dimensional structure of menin and menin-dependent target genes. The ongoing impact of all these studies on disease prediction, management and outcomes will continue in the years to come. © 2017 Society for Endocrinology.

Imaging of Chromosome Dynamics in Mouse Testis Tissue by Immuno-FISH.

Science.gov (United States)

Scherthan, Harry

2017-01-01

The mouse (Mus musculus) represents the central mammalian genetic model system for biomedical and developmental research. Mutant mouse models have provided important insights into chromosome dynamics during the complex meiotic differentiation program that compensates for the genome doubling at fertilization. Homologous chromosomes (homologues) undergo dynamic pairing and recombine during first meiotic prophase before they become partitioned into four haploid sets by two consecutive meiotic divisions that lack an intervening S-phase. Fluorescence in situ hybridization (FISH) has been instrumental in the visualization and imaging of the dynamic reshaping of chromosome territories and mobility during prophase I, in which meiotic telomeres were found to act as pacemakers for the chromosome pairing dance. FISH combined with immunofluorescence (IF) co-staining of nuclear proteins has been instrumental for the visualization and imaging of mammalian meiotic chromosome behavior. This chapter describes FISH and IF methods for the analysis of chromosome dynamics in nuclei of paraffin-embedded mouse testes. The techniques have proven useful for fresh and archived paraffin testis material of several mammalian species.

Thermal expansion of granite rocks

International Nuclear Information System (INIS)

Stephansson, O.

1978-04-01

The thermal expansion of rocks is strongly controlled by the thermal expansion of the minerals. The theoretical thermal expansion of the Stripa Granite is gound to be 21 . 10 -6 [deg C] -1 at 25 deg C and 38 . 10 -6 [deg C] -1 at 400 deg C. The difference in expansion for the rock forming minerals causes micro cracking at heating. The expansion due to micro cracks is found to be of the same order as the mineral expansion. Most of the micro cracks will close at pressures of the order of 10 - 20 MPa. The thermal expansion of a rock mass including the effect of joints is determined in the pilot heater test in the Stripa Mine

Age-related cancer mutations associated with clonal hematopoietic expansion

Science.gov (United States)

Xie, Mingchao; Lu, Charles; Wang, Jiayin; McLellan, Michael D.; Johnson, Kimberly J.; Wendl, Michael C.; McMichael, Joshua F.; Schmidt, Heather K.; Yellapantula, Venkata; Miller, Christopher A.; Ozenberger, Bradley A.; Welch, John S.; Link, Daniel C.; Walter, Matthew J.; Mardis, Elaine R.; Dipersio, John F.; Chen, Feng; Wilson, Richard K.; Ley, Timothy J.; Ding, Li

2015-01-01

Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. We analyzed blood-derived sequence data from 2,728 individuals within The Cancer Genome Atlas, and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia/lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5–6% of people older than 70 years) contain mutations that may represent premalignant, initiating events that cause clonal hematopoietic expansion. PMID:25326804

Institute of Genetics and of Toxicology of Fissile Materials. Progress report on research and development work in 1992

International Nuclear Information System (INIS)

1993-03-01

In the year under report, the institute's scope of investigations comprised the seven topics surveyed in the following together with the most recent research results obtained. These were genetic repair and genetic regulation mechanisms, biologic carcinogenesis, molecular genetics of eukaryotic genes, genetic mouse models of human disorders, toxicology of radioactive and non-radioactive heavy metals as well as environmental toxicology at the molecular and cellular levels. (orig./MG) [de

Atkinesin-13A Modulates Cell-Wall Synthesis and Cell Expansion in Arabidopsis thaliana via the THESEUS1 Pathway

Science.gov (United States)

Fujikura, Ushio; Elsaesser, Lore; Breuninger, Holger; Sánchez-Rodríguez, Clara; Ivakov, Alexander; Laux, Thomas; Findlay, Kim; Persson, Staffan; Lenhard, Michael

2014-01-01

Growth of plant organs relies on cell proliferation and expansion. While an increasingly detailed picture about the control of cell proliferation is emerging, our knowledge about the control of cell expansion remains more limited. We demonstrate here that the internal-motor kinesin AtKINESIN-13A (AtKIN13A) limits cell expansion and cell size in Arabidopsis thaliana, with loss-of-function atkin13a mutants forming larger petals with larger cells. The homolog, AtKINESIN-13B, also affects cell expansion and double mutants display growth, gametophytic and early embryonic defects, indicating a redundant role of the two genes. AtKIN13A is known to depolymerize microtubules and influence Golgi motility and distribution. Consistent with this function, AtKIN13A interacts genetically with ANGUSTIFOLIA, encoding a regulator of Golgi dynamics. Reduced AtKIN13A activity alters cell wall structure as assessed by Fourier-transformed infrared-spectroscopy and triggers signalling via the THESEUS1-dependent cell-wall integrity pathway, which in turn promotes the excess cell expansion in the atkin13a mutant. Thus, our results indicate that the intracellular activity of AtKIN13A regulates cell expansion and wall architecture via THESEUS1, providing a compelling case of interplay between cell wall integrity sensing and expansion. PMID:25232944

The role of retrotransposons in gene family expansions in the human and mouse genomes

Czech Academy of Sciences Publication Activity Database

Janoušek, Václav; Laukaitis, C. M.; Yanchukov, Alexey; Karn, R. C.

2016-01-01

Roč. 8, č. 9 (2016), s. 2632-2650 ISSN 1759-6653 R&D Projects: GA MŠk EE2.3.20.0303 Institutional support: RVO:68081766 Keywords : gene families * transposable elements * retrotransposons * LINE * LTR * SINE Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.979, year: 2016

Genetic localization of Cd63, a member of the transmembrane 4 superfamily, reveals two distinct loci in the mouse genome

Energy Technology Data Exchange (ETDEWEB)

Gwynn, B.; Eicher, E.M.; Peters, L.L. [Jackson Lab., Bar Harbor, ME (United States)

1996-07-15

The membrane protein CD63, a molecular marker for early stages of melanoma progression, has been associated with platelet storage pool deficiency disorders (SPD). CD63 localizes to the membranes of platelets, lysosomes, and melanosomes, all of which are affected in a specific subgroup of SPD. The cDNA encoding CD63 detects two closely related sequences that map to different regions of the mouse genome. One locus maps to mouse Chromosome (Chr) 10 in a region that shares linkage homology with the human chromosome encoding human CD63. The second locus maps to mouse Chr 18 in a region that bears no known human CD63-related genes. No SPD has been localized to these regions of either the mouse or the human chromosomes. 15 refs., 2 figs.

Allelic Imbalance Is a Prevalent and Tissue-Specific Feature of the Mouse Transcriptome

Science.gov (United States)

Pinter, Stefan F.; Colognori, David; Beliveau, Brian J.; Sadreyev, Ruslan I.; Payer, Bernhard; Yildirim, Eda; Wu, Chao-ting; Lee, Jeannie T.

2015-01-01

In mammals, several classes of monoallelic genes have been identified, including those subject to X-chromosome inactivation (XCI), genomic imprinting, and random monoallelic expression (RMAE). However, the extent to which these epigenetic phenomena are influenced by underlying genetic variation is unknown. Here we perform a systematic classification of allelic imbalance in mouse hybrids derived from reciprocal crosses of divergent strains. We observe that deviation from balanced biallelic expression is common, occurring in ∼20% of the mouse transcriptome in a given tissue. Allelic imbalance attributed to genotypic variation is by far the most prevalent class and typically is tissue-specific. However, some genotype-based imbalance is maintained across tissues and is associated with greater genetic variation, especially in 5′ and 3′ termini of transcripts. We further identify novel random monoallelic and imprinted genes and find that genotype can modify penetrance of parental origin even in the setting of large imprinted regions. Examination of nascent transcripts in single cells from inbred parental strains reveals that genes showing genotype-based imbalance in hybrids can also exhibit monoallelic expression in isogenic backgrounds. This surprising observation may suggest a competition between alleles and/or reflect the combined impact of cis- and trans-acting variation on expression of a given gene. Our findings provide novel insights into gene regulation and may be relevant to human genetic variation and disease. PMID:25858912

Genetics of sweet taste preferences†

OpenAIRE

Bachmanov, Alexander A; Bosak, Natalia P; Floriano, Wely B; Inoue, Masashi; Li, Xia; Lin, Cailu; Murovets, Vladimir O; Reed, Danielle R; Zolotarev, Vasily A; Beauchamp, Gary K

2011-01-01

Sweet taste is a powerful factor influencing food acceptance. There is considerable variation in sweet taste perception and preferences within and among species. Although learning and homeostatic mechanisms contribute to this variation in sweet taste, much of it is genetically determined. Recent studies have shown that variation in the T1R genes contributes to within- and between-species differences in sweet taste. In addition, our ongoing studies using the mouse model demonstrate that a sign...

The landscape of chromosomal aberrations in breast cancer mouse models reveals driver-specific routes to tumorigenesis

NARCIS (Netherlands)

Ben-David, Uri; Ha, Gavin; Khadka, Prasidda; Jin, Xin; Wong, Bang; Franke, Lude; Golub, Todd R.

Aneuploidy and copy-number alterations (CNAs) are a hallmark of human cancer. Although genetically engineered mouse models (GEMMs) are commonly used to model human cancer, their chromosomal landscapes remain underexplored. Here we use gene expression profiles to infer CNAs in 3,108 samples from 45

Sculpting the Transcriptome During the Oocyte-to-Embryo Transition in Mouse

Czech Academy of Sciences Publication Activity Database

Svoboda, Petr; Franke, V.; Schultz, R.M.

2015-01-01

Roč. 113, Jul 29 (2015), s. 305-349 ISSN 0070-2153 R&D Projects: GA ČR(CZ) GBP305/12/G034; GA MŠk LH13084 EU Projects: European Commission 315997 Grant - others:GA AV ČR(CZ) M200521202 Institutional support: RVO:68378050 Keywords : Genome activation * Maternal mRNA * Mouse oocyte * RNA degradation * Small RNA Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.677, year: 2015

Genetic surfing, not allopatric divergence, explains spatial sorting of mitochondrial haplotypes in venomous coralsnakes.

Science.gov (United States)

Streicher, Jeffrey W; McEntee, Jay P; Drzich, Laura C; Card, Daren C; Schield, Drew R; Smart, Utpal; Parkinson, Christopher L; Jezkova, Tereza; Smith, Eric N; Castoe, Todd A

2016-07-01

Strong spatial sorting of genetic variation in contiguous populations is often explained by local adaptation or secondary contact following allopatric divergence. A third explanation, spatial sorting by stochastic effects of range expansion, has been considered less often though theoretical models suggest it should be widespread, if ephemeral. In a study designed to delimit species within a clade of venomous coralsnakes, we identified an unusual pattern within the Texas coral snake (Micrurus tener): strong spatial sorting of divergent mitochondrial (mtDNA) lineages over a portion of its range, but weak sorting of these lineages elsewhere. We tested three alternative hypotheses to explain this pattern-local adaptation, secondary contact following allopatric divergence, and range expansion. Collectively, near panmixia of nuclear DNA, the signal of range expansion associated sampling drift, expansion origins in the Gulf Coast of Mexico, and species distribution modeling suggest that the spatial sorting of divergent mtDNA lineages within M. tener has resulted from genetic surfing of standing mtDNA variation-not local adaptation or allopatric divergence. Our findings highlight the potential for the stochastic effects of recent range expansion to mislead estimations of population divergence made from mtDNA, which may be exacerbated in systems with low vagility, ancestral mtDNA polymorphism, and male-biased dispersal. © 2016 The Author(s).

Genetic Architecture of Group A Streptococcal Necrotizing Soft Tissue Infections in the Mouse

DEFF Research Database (Denmark)

Chella Krishnan, Karthickeyan; Mukundan, Santhosh; Alagarsamy, Jeyashree

2016-01-01

Host genetic variations play an important role in several pathogenic diseases, and we have previously provided strong evidences that these genetic variations contribute significantly to differences in susceptibility and clinical outcomes of invasive Group A Streptococcus (GAS) infections, includi...

Genetic diversity and population genetic structure analysis of Echinococcus granulosus sensu stricto complex based on mitochondrial DNA signature.

Directory of Open Access Journals (Sweden)

Monika Sharma

Full Text Available The genetic diversity and population genetics of the Echinococcus granulosus sensu stricto complex were investigated based on sequencing of mitochondrial DNA (mtDNA. Total 81 isolates of hydatid cyst collected from ungulate animals from different geographical areas of North India were identified by sequencing of cytochrome c oxidase subunit1 (coxi gene. Three genotypes belonging to E. granulosus sensu stricto complex were identified (G1, G2 and G3 genotypes. Further the nucleotide sequences (retrieved from GenBank for the coxi gene from seven populations of E. granulosus sensu stricto complex covering 6 continents, were compared with sequences of isolates analysed in this study. Molecular diversity indices represent overall high mitochondrial DNA diversity for these populations, but low nucleotide diversity between haplotypes. The neutrality tests were used to analyze signatures of historical demographic events. The Tajima's D test and Fu's FS test showed negative value, indicating deviations from neutrality and both suggested recent population expansion for the populations. Pairwise fixation index was significant for pairwise comparison of different populations (except between South America and East Asia, Middle East and Europe, South America and Europe, Africa and Australia, indicating genetic differentiation among populations. Based on the findings of the present study and those from earlier studies, we hypothesize that demographic expansion occurred in E. granulosus after the introduction of founder haplotype particular by anthropogenic movements.

Genetic and immunohistochemical analysis of HSPA5 in mouse and human retinas

OpenAIRE

Chintalapudi, Sumana R.; Wang, XiaoFei; Li, Huiling; Lau, Yin H. Chan; Williams, Robert W.; Jablonski, Monica M.

2016-01-01

Purpose Photoreceptor degenerative diseases?are among the leading causes of vision loss. Although the causative genetic mutations are often known, mechanisms leading to photoreceptor degeneration remain poorly defined. We have previously demonstrated that the photoreceptor membrane-associated protein XAP-1 antigen is a product of the HSPA5 gene. In this study, we used systems genetic methods, statistical modeling, and immunostaining to identify and analyze candidate genes that modulate Hspa5 ...

Mouse models in liver cancer research: A review of current literature

Science.gov (United States)

Leenders, Martijn WH; Nijkamp, Maarten W; Rinkes, Inne HM Borel

2008-01-01

Primary liver cancer remains one of the most lethal malignancies worldwide. Due to differences in prevalence of etiological factors the incidence of primary liver cancer varies among the world, with a peak in East-Asia. As this disease is still lethal in most of the cases, research has to be done to improve our understanding of the disease, offering insights for possible treatment options. For this purpose, animal models are widely used, especially mouse models. In this review, we describe the different types of mouse models used in liver cancer research, with emphasis on genetically engineered mice used in this field. We focus on hepatocellular carcinoma (HCC), as this is by far the most common type of primary liver cancer, accounting for 70%-85% of cases. PMID:19058325

Cracking anxiety in the mouse : a quantitative (epi)genetic approach

NARCIS (Netherlands)

Labots, M.

2017-01-01

The aim of this thesis was to improve existing methodologies and apply genetic strategies in order to identify (main-effect, epistatic, multiple and pleiotropic) quantitative trait loci and to decipher functional candidate genes for anxiety-related behavior and baseline blood plasma total

The underlying mechanisms of genetic innovation and speciation in the family Corynebacteriaceae: A phylogenomics approach.

Science.gov (United States)

Zhi, Xiao-Yang; Jiang, Zhao; Yang, Ling-Ling; Huang, Ying

2017-02-01

The pangenome of a bacterial species population is formed by genetic reduction and genetic expansion over the long course of evolution. Gene loss is a pervasive source of genetic reduction, and (exogenous and endogenous) gene gain is the main driver of genetic expansion. To understand the genetic innovation and speciation of the family Corynebacteriaceae, which cause a wide range of serious infections in humans and animals, we analyzed the pangenome of this family, and reconstructed its phylogeny using a phylogenomics approach. Genetic variations have occurred throughout the whole evolutionary history of the Corynebacteriaceae. Gene loss has been the primary force causing genetic changes, not only in terms of the number of protein families affected, but also because of its continuity on the time series. The variation in metabolism caused by these genetic changes mainly occurred for membrane transporters, two-component systems, and metabolism related to amino acids and carbohydrates. Interestingly, horizontal gene transfer (HGT) not only caused changes related to pathogenicity, but also triggered the acquisition of antimicrobial resistance. The Darwinian theory of evolution did not adequately explain the effects of dispersive HGT and/or gene loss in the evolution of the Corynebacteriaceae. These findings provide new insight into the evolution and speciation of Corynebacteriaceae and advance our understanding of the genetic innovation in microbial populations. Copyright © 2016 Elsevier Inc. All rights reserved.

Segmental trisomy of chromosome 17: a mouse model of human aneuploidy syndromes

Czech Academy of Sciences Publication Activity Database

Vacík, Tomáš; Ort, Michael; Gregorová, Soňa; Strnad, P.; Conte, N.; Bradley, A.; Blatný, Radek; Bureš, Jan; Forejt, Jiří

2005-01-01

Roč. 102, č. 12 (2005), s. 4500-4505 ISSN 0027-8424 R&D Projects: GA ČR(CZ) GA309/03/0715 Grant - others:Howard Hughes Medical Institute(US) 55000306 Institutional research plan: CEZ:AV0Z5011922; CEZ:AV0Z50110509 Keywords : dosage-sensitive genes * Down's syndrome * mouse segmental trisomy Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 10.231, year: 2005

Resonant state expansions

International Nuclear Information System (INIS)

Lind, P.

1993-02-01

The completeness properties of the discrete set of bound state, virtual states and resonances characterizing the system of a single nonrelativistic particle moving in a central cutoff potential is investigated. From a completeness relation in terms of these discrete states and complex scattering states one can derive several Resonant State Expansions (RSE). It is interesting to obtain purely discrete expansion which, if valid, would significantly simplify the treatment of the continuum. Such expansions can be derived using Mittag-Leffler (ML) theory for a cutoff potential and it would be nice to see if one can obtain the same expansions starting from an eigenfunction theory that is not restricted to a finite sphere. The RSE of Greens functions is especially important, e.g. in the continuum RPA (CRPA) method of treating giant resonances in nuclear physics. The convergence of RSE is studied in simple cases using square well wavefunctions in order to achieve high numerical accuracy. Several expansions can be derived from each other by using the theory of analytic functions and one can the see how to obtain a natural discretization of the continuum. Since the resonance wavefunctions are oscillating with an exponentially increasing amplitude, and therefore have to be interpreted through some regularization procedure, every statement made about quantities involving such states is checked by numerical calculations.Realistic nuclear wavefunctions, generated by a Wood-Saxon potential, are used to test also the usefulness of RSE in a realistic nuclear calculation. There are some fundamental differences between different symmetries of the integral contour that defines the continuum in RSE. One kind of symmetry is necessary to have an expansion of the unity operator that is idempotent. Another symmetry must be used if we want purely discrete expansions. These are found to be of the same form as given by ML. (29 refs.)

A genetic atlas of human admixture history

Science.gov (United States)

Hellenthal, Garrett; Busby, George B.J.; Band, Gavin; Wilson, James F.; Capelli, Cristian

2014-01-01

Modern genetic data combined with appropriate statistical methods have the potential to contribute substantially to our understanding of human history. We have developed an approach that exploits the genomic structure of admixed populations to date and characterize historical mixture events at fine scales. We used this to produce an atlas of worldwide human admixture history, constructed using genetic data alone and encompassing over 100 events occurring over the past 4,000 years. We identify events whose dates and participants suggest they describe genetic impacts of the Mongol Empire, Arab slave trade, Bantu expansion, first millennium CE migrations in eastern Europe, and European colonialism, as well as unrecorded events, revealing admixture to be an almost universal force shaping human populations. PMID:24531965

Journal of Genetics | Indian Academy of Sciences

Indian Academy of Sciences (India)

There are evidences to show that response to ionizing radiations have genetic influence. To investigate this further, reciprocal F1 hybrids were genereted by crossbreeding the radiation-susceptible BALB/c mouse strain with resistant C57BL/6 in a sex-specific manner (BALB/c♂×C57BL/6♀ = B6BcF1; C57BL/6♂× BALB/c♀ ...

The International Mouse Phenotyping Consortium Web Portal, a unified point of access for knockout mice and related phenotyping data

Science.gov (United States)

Koscielny, Gautier; Yaikhom, Gagarine; Iyer, Vivek; Meehan, Terrence F.; Morgan, Hugh; Atienza-Herrero, Julian; Blake, Andrew; Chen, Chao-Kung; Easty, Richard; Di Fenza, Armida; Fiegel, Tanja; Grifiths, Mark; Horne, Alan; Karp, Natasha A.; Kurbatova, Natalja; Mason, Jeremy C.; Matthews, Peter; Oakley, Darren J.; Qazi, Asfand; Regnart, Jack; Retha, Ahmad; Santos, Luis A.; Sneddon, Duncan J.; Warren, Jonathan; Westerberg, Henrik; Wilson, Robert J.; Melvin, David G.; Smedley, Damian; Brown, Steve D. M.; Flicek, Paul; Skarnes, William C.; Mallon, Ann-Marie; Parkinson, Helen

2014-01-01

The International Mouse Phenotyping Consortium (IMPC) web portal (http://www.mousephenotype.org) provides the biomedical community with a unified point of access to mutant mice and rich collection of related emerging and existing mouse phenotype data. IMPC mouse clinics worldwide follow rigorous highly structured and standardized protocols for the experimentation, collection and dissemination of data. Dedicated ‘data wranglers’ work with each phenotyping center to collate data and perform quality control of data. An automated statistical analysis pipeline has been developed to identify knockout strains with a significant change in the phenotype parameters. Annotation with biomedical ontologies allows biologists and clinicians to easily find mouse strains with phenotypic traits relevant to their research. Data integration with other resources will provide insights into mammalian gene function and human disease. As phenotype data become available for every gene in the mouse, the IMPC web portal will become an invaluable tool for researchers studying the genetic contributions of genes to human diseases. PMID:24194600

The circling mutant Pcdh15roda is a new mouse model for hearing loss.

Science.gov (United States)

Torres, Adriana Amorim; Rzadzinska, Agnieszka K; Ribeiro, Andrea Frozino; Silva, Daniel Almeida da Silva E; Guénet, Jean-Louis; Massironi, Sílvia Maria Gomes; Godard, Ana Lúcia Brunialti

2013-01-01

Mouse mutagenesis is a key tool for studying gene function and several mutant alleles have been described and constitute mouse models for human hereditary diseases. Genetic hearing loss represents over 50% of all hearing loss cases in children and, due to the heterogeneity of the disorder, there is still a demand for the isolation and characterization of new genes and alleles. Here we report phenotypic and molecular characterization of a new mouse model for hereditary hearing loss. The mutant rodador, isolated by Massironi and colleagues in 2006, presents an autosomal recessive disorder characterized by deafness and balance dysfunction associated with abnormal stereocilia in the inner ear. The mutation was mapped to mouse chromosome 10, and characterization of the gene Pcdh15 revealed an AT-to-GC transition in intron 23 of mutant animals. The alteration led to the switch of a dinucleotide ApA for ApG, creating a novel intronic acceptor splice site, which leads to incorporation of eight intronic bases into the processed mRNA and alteration of the downstream reading frame. In silico analysis indicated that the mutated protein is truncated and lacks two cadherin domains, and the transmembrane and cytoplasmic domains. Real Time PCR analyses revealed a significantly reduced Pcdh15 mRNA level in the brain of mutant mice, which might be due to the mechanism of non-sense mediated decay. In man, mutations in the orthologue PCDH15 cause non-syndromic deafness and Usher Syndrome Type 1F, a genetic disorder characterized by hearing loss and retinitis pigmentosa. Rodador mouse constitutes a new model for studying deafness in these conditions and may help in the comprehension of the pathogeneses of the disease, as well as of the mechanisms involved in the morphogenesis and function of inner ear stereocilia. This is a new ENU-induced allele and the first isolated in a BALB/c background. Copyright © 2013 Elsevier B.V. All rights reserved.

Mechanical feedback coordinates cell wall expansion and assembly in yeast mating morphogenesis

Science.gov (United States)

2018-01-01

The shaping of individual cells requires a tight coordination of cell mechanics and growth. However, it is unclear how information about the mechanical state of the wall is relayed to the molecular processes building it, thereby enabling the coordination of cell wall expansion and assembly during morphogenesis. Combining theoretical and experimental approaches, we show that a mechanical feedback coordinating cell wall assembly and expansion is essential to sustain mating projection growth in budding yeast (Saccharomyces cerevisiae). Our theoretical results indicate that the mechanical feedback provided by the Cell Wall Integrity pathway, with cell wall stress sensors Wsc1 and Mid2 increasingly activating membrane-localized cell wall synthases Fks1/2 upon faster cell wall expansion, stabilizes mating projection growth without affecting cell shape. Experimental perturbation of the osmotic pressure and cell wall mechanics, as well as compromising the mechanical feedback through genetic deletion of the stress sensors, leads to cellular phenotypes that support the theoretical predictions. Our results indicate that while the existence of mechanical feedback is essential to stabilize mating projection growth, the shape and size of the cell are insensitive to the feedback. PMID:29346368

Progress report on research and development work 1991 of the Institute of Genetics and Toxicology of Fissionable Materials, Karlsruhe Nuclear Research Center

International Nuclear Information System (INIS)

1991-03-01

The present annual report describes the results of research work done by the Institute of Genetics and Toxicology of Fissionable Materials (IGT) in 1991. The following eight subjects were dealt with: genetic repair; genetic regulation; biological carcinogenesis; molecular genetics of eukaryontic genes; genetic mouse models for human illnesses; radiation toxicology of actinides; molecular and cellular environmental toxicology, and in vivo fractionation and speciation of actinides. (MG) [de

Germline competence of mouse ES and iPS cell lines: Chimera technologies and genetic background.

Science.gov (United States)

Carstea, Ana Claudia; Pirity, Melinda K; Dinnyes, Andras

2009-12-31

In mice, gene targeting by homologous recombination continues to play an essential role in the understanding of functional genomics. This strategy allows precise location of the site of transgene integration and is most commonly used to ablate gene expression ("knock-out"), or to introduce mutant or modified alleles at the locus of interest ("knock-in"). The efficacy of producing live, transgenic mice challenges our understanding of this complex process, and of the factors which influence germline competence of embryonic stem cell lines. Increasingly, evidence indicates that culture conditions and in vitro manipulation can affect the germline-competence of Embryonic Stem cell (ES cell) lines by accumulation of chromosome abnormalities and/or epigenetic alterations of the ES cell genome. The effectiveness of ES cell derivation is greatly strain-dependent and it may also influence the germline transmission capability. Recent technical improvements in the production of germline chimeras have been focused on means of generating ES cells lines with a higher germline potential. There are a number of options for generating chimeras from ES cells (ES chimera mice); however, each method has its advantages and disadvantages. Recent developments in induced pluripotent stem (iPS) cell technology have opened new avenues for generation of animals from genetically modified somatic cells by means of chimera technologies. The aim of this review is to give a brief account of how the factors mentioned above are influencing the germline transmission capacity and the developmental potential of mouse pluripotent stem cell lines. The most recent methods for generating specifically ES and iPS chimera mice, including the advantages and disadvantages of each method are also discussed.

The Effects of Alpha Interferon on the Development of Autoimmune Thyroiditis in the NOD H2h4 Mouse

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Yael Oppenheim

2003-01-01

Full Text Available Alpha interferon (αIFN therapy is known to induce thyroid autoimmunity in up to 40% of patients. The mechanism is unknown, but Th1 switching has been hypothesized. The aim of our study was to examine whether αIFN accelerated the development of thyroiditis in genetically susceptible mice. We took advantage of NOD-H2h4, a genetically susceptible animal model, which develops thyroiditis when fed a high iodine diet. Six to eight week old male NOD H2h4 mice were injected with mouse αIFN (200 units or with saline three times a week for 8 weeks. All mice drank iodinated water (0.15%. Mice were sacrificed after 8 weeks of injection. Their thyroids were examined for histology and blood was tested for antithyroglobulin antibody levels. T4 and glucose levels were also assessed. In the IFN-injected group, 6/13 (46.2% developed thyroiditis and/or thyroid antibodies while in the saline-injected group, only 4/13 (30.8% developed thyroiditis and/or thyroid antibodies (p=0.4. The grade of thyroiditis was not different amongst the two groups. None of the mice developed clinical thyroiditis or diabetes mellitus. Our results showed that αIFN treatment did not accelerate thyroiditis in this mouse model. This may imply that αIFN induces thyroiditis in a non-genetically dependent manner, and this would not be detected in a genetically susceptible mouse model if the effect were small. Alternatively, it is possible that αIFN did not induce thyroiditis in mice because, unlike in humans, in mice αIFN does not induce Th1 switching.

Large-Scale Culture and Genetic Modification of Human Natural Killer Cells for Cellular Therapy.

Science.gov (United States)

Lapteva, Natalia; Parihar, Robin; Rollins, Lisa A; Gee, Adrian P; Rooney, Cliona M

2016-01-01

Recent advances in methods for the ex vivo expansion of human natural killer (NK) cells have facilitated the use of these powerful immune cells in clinical protocols. Further, the ability to genetically modify primary human NK cells following rapid expansion allows targeting and enhancement of their immune function. We have successfully adapted an expansion method for primary NK cells from peripheral blood mononuclear cells or from apheresis products in gas permeable rapid expansion devices (G-Rexes). Here, we describe an optimized protocol for rapid and robust NK cell expansion as well as a method for highly efficient retroviral transduction of these ex vivo expanded cells. These methodologies are good manufacturing practice (GMP) compliant and could be used for clinical-grade product manufacturing.

Calcium, potassium, iron, copper and zinc concentrations in the white and gray matter of the cerebellum and corpus callosum in brain of four genetic mouse strains

International Nuclear Information System (INIS)

Sergeant, C.; Vesvres, M.H.; Deves, G.; Guillou, F.

2005-01-01

In the central nervous system, metallic cations are involved in oligodendrocyte maturation and myelinogenesis. Moreover, the metallic cations have been associated with pathogenesis, particularly multiple sclerosis and malignant gliomas. The brain is vulnerable to either a deficit or an excess of available trace elements. Relationship between trace metals and myelinogenesis is important in understanding a severe human pathology : the multiple sclerosis, which remains without efficient treatment. One approach to understand this disease has used mutant or transgenic mice presenting myelin deficiency or excess. But to date, the concentration of trace metals and mineral elements in white and gray matter areas in wild type brain is unknown. The aim of this study is to establish the reference concentrations of trace metals (iron, copper and zinc) and minerals (potassium and calcium) in the white and gray matter of the mouse cerebellum and corpus callosum. The brains of four different genetic mouse strains (C57Black6/SJL, C57Black6/D2, SJL and C3H) were analyzed. The freeze-dried samples were prepared to allow PIXE (Proton-induced X-ray emission) and RBS (Rutherford backscattering spectrometry) analyses with the nuclear microprobe in Bordeaux. The results obtained give the first reference values. Furthermore, one species out of the fours testes exhibited differences in calcium, iron and zinc concentrations in the white matter

Calcium, potassium, iron, copper and zinc concentrations in the white and gray matter of the cerebellum and corpus callosum in brain of four genetic mouse strains

Energy Technology Data Exchange (ETDEWEB)

Sergeant, C. [CNRS-Universite de Bordeaux I, UMR 5084, Chimie Nucleaire Analytique et Bio environnementale, Le Haut Vigneau, BP120, 33175 Bordeaux-Gradignan (France)]. E-mail: sergeant@cenbg.in2p3.fr; Vesvres, M.H. [CNRS-Universite de Bordeaux I, UMR 5084, Chimie Nucleaire Analytique et Bio environnementale, Le Haut Vigneau, BP120, 33175 Bordeaux-Gradignan (France); Deves, G. [CNRS-Universite de Bordeaux I, UMR 5084, Chimie Nucleaire Analytique et Bio environnementale, Le Haut Vigneau, BP120, 33175 Bordeaux-Gradignan (France); Guillou, F. [INRA-CNRS-Universite de Tours-Haras nationaux, UMR 6175, Physiologie de la Reproduction et des Comportements, 37380 Nouzilly (France)

2005-04-01

In the central nervous system, metallic cations are involved in oligodendrocyte maturation and myelinogenesis. Moreover, the metallic cations have been associated with pathogenesis, particularly multiple sclerosis and malignant gliomas. The brain is vulnerable to either a deficit or an excess of available trace elements. Relationship between trace metals and myelinogenesis is important in understanding a severe human pathology : the multiple sclerosis, which remains without efficient treatment. One approach to understand this disease has used mutant or transgenic mice presenting myelin deficiency or excess. But to date, the concentration of trace metals and mineral elements in white and gray matter areas in wild type brain is unknown. The aim of this study is to establish the reference concentrations of trace metals (iron, copper and zinc) and minerals (potassium and calcium) in the white and gray matter of the mouse cerebellum and corpus callosum. The brains of four different genetic mouse strains (C57Black6/SJL, C57Black6/D2, SJL and C3H) were analyzed. The freeze-dried samples were prepared to allow PIXE (Proton-induced X-ray emission) and RBS (Rutherford backscattering spectrometry) analyses with the nuclear microprobe in Bordeaux. The results obtained give the first reference values. Furthermore, one species out of the fours testes exhibited differences in calcium, iron and zinc concentrations in the white matter.

PLK1 regulates spindle formation kinetics and APC/C activation in mouse zygote

Czech Academy of Sciences Publication Activity Database

Baran, V.; Brzáková, Adéla; Rehák, P.; Kovaříková, V.; Šolc, Petr

2016-01-01

Roč. 24, č. 3 (2016), s. 338-345 ISSN 0967-1994 R&D Projects: GA MŠk ED2.1.00/03.0124; GA MŠk LH12057 Institutional support: RVO:67985904 Keywords : APC/C * BI2536 * live cell imaging * mouse zygote * PLK1 * securin * spindle assembly Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.053, year: 2016

Isotropic Negative Thermal Expansion Metamaterials.

Science.gov (United States)

Wu, Lingling; Li, Bo; Zhou, Ji

2016-07-13

Negative thermal expansion materials are important and desirable in science and engineering applications. However, natural materials with isotropic negative thermal expansion are rare and usually unsatisfied in performance. Here, we propose a novel method to achieve two- and three-dimensional negative thermal expansion metamaterials via antichiral structures. The two-dimensional metamaterial is constructed with unit cells that combine bimaterial strips and antichiral structures, while the three-dimensional metamaterial is fabricated by a multimaterial 3D printing process. Both experimental and simulation results display isotropic negative thermal expansion property of the samples. The effective coefficient of negative thermal expansion of the proposed models is demonstrated to be dependent on the difference between the thermal expansion coefficient of the component materials, as well as on the circular node radius and the ligament length in the antichiral structures. The measured value of the linear negative thermal expansion coefficient of the three-dimensional sample is among the largest achieved in experiments to date. Our findings provide an easy and practical approach to obtaining materials with tunable negative thermal expansion on any scale.

Does query expansion limit our learning? A comparison of social-based expansion to content-based expansion for medical queries on the internet.

Science.gov (United States)

Pentoney, Christopher; Harwell, Jeff; Leroy, Gondy

2014-01-01

Searching for medical information online is a common activity. While it has been shown that forming good queries is difficult, Google's query suggestion tool, a type of query expansion, aims to facilitate query formation. However, it is unknown how this expansion, which is based on what others searched for, affects the information gathering of the online community. To measure the impact of social-based query expansion, this study compared it with content-based expansion, i.e., what is really in the text. We used 138,906 medical queries from the AOL User Session Collection and expanded them using Google's Autocomplete method (social-based) and the content of the Google Web Corpus (content-based). We evaluated the specificity and ambiguity of the expansion terms for trigram queries. We also looked at the impact on the actual results using domain diversity and expansion edit distance. Results showed that the social-based method provided more precise expansion terms as well as terms that were less ambiguous. Expanded queries do not differ significantly in diversity when expanded using the social-based method (6.72 different domains returned in the first ten results, on average) vs. content-based method (6.73 different domains, on average).

Property regime concerning genetic resources and traditional knowledge

Directory of Open Access Journals (Sweden)

Gabriel R. Nemogá Soto

2001-01-01

Full Text Available This article provides an historical account of the changes that have taken place regarding ownership, control and access over genetic resources. Once considered the common heritage of humanity, rights over genetic resources, it is argued, have undergone radical transformations. The global legal framework regarding genetic resources has shifted to legitimize and promote their appropriation and monopolization. This transformation embraced the expansion of intellectual property rights over genetic material and information, including living organisms, through the World Trade Organization´s Trade Related Aspects of Intellectual Property (TRIPs. This was coupled by the adoption of the United Nations Convention on Biological Diversity, which recognizes sovereign rights of the countries of origin over their genetic resources and, at the same time, obligates them to permit access to those resources. The Colombian Constitution of 1991 and unparalleled judicial decisions during the last decade reaffirmed sovereign rights over genetic resources in Colombia. Conversely, the genetic resources and the traditional knowledge of Indigenous peoples and local communities continue to be freely accessible resources within the current Colombian legal framework.

Peroxisome proliferator activated receptor alpha regulates a male-specific cytochrome P450 in mouse liver.

Science.gov (United States)

Jeffery, Brett; Choudhury, Agharul I; Horley, Neill; Bruce, Mary; Tomlinson, Simon R; Roberts, Ruth A; Gray, Tim J B; Barrett, David A; Shaw, P Nicholas; Kendall, David; Bell, David R

2004-09-15

We set out to find if the strain-specific, male-specific hepatic expression of Cyp4a protein in mouse was due to expression of Cyp4a12 and to understand the genetic basis for reported differences in expression. 12-Lauric acid hydroxylase (LAH) activity was found to show higher levels in male ddY, but not C57Bl/6, mouse liver microsomes. The expression of Cyp4a12 mRNA was studied using RNAase protection assays in male and female liver and kidney of nine mouse strains. Cyp4a12 was found to be highly expressed in male liver and kidney, but at much lower levels in female liver and kidney, in all strains studied. Western blotting with an antibody specific for Cyp4a12 confirmed that Cyp4a12 was expressed in a male specific fashion in C57Bl/6 mouse liver. RNAase protection analysis for Cyp4a10 and 14 in ddY mice revealed that neither of these genes showed male-specific expression. To further investigate genetic factors that control male-specific Cyp4a12 expression, PPARalpha+/+ and -/- mice were studied, showing that total P450 and 12-LAH activity was male-specific in +/+, but not -/- mice. RNAase protection assays were used to confirm that Cyp4a12 was lower in -/- mice. However, the male-specific Slp and MUP-1 genes retained hepatic male-specific levels of expression in +/+ and -/- mice, showing that the decrease in Cyp4a12 was not a general effect on male-specific expression. Thus, PPARalpha has a specific effect on constitutive expression of Cyp4a12.

DISC1 mouse models as a tool to decipher gene-environment interactions in psychiatric disorders

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Tyler eCash-Padgett

2013-09-01

Full Text Available DISC1 was discovered in a Scottish pedigree in which a chromosomal translocation that breaks this gene segregates with psychiatric disorders, mainly depression and schizophrenia. Linkage and association studies in diverse populations support DISC1 as a susceptibility gene to a variety of neuropsychiatric disorders. Many Disc1 mouse models have been generated to study its neuronal functions. These mouse models display variable phenotypes, some of them relevant to schizophrenia, others to depression.The Disc1 mouse models are popular genetic models for studying gene-environment interactions in schizophrenia. Five different Disc1 models have been combined with environmental factors. The environmental stressors employed can be classified as either early immune activation or later social paradigms. These studies cover major time points along the neurodevelopmental trajectory: prenatal, early postnatal, adolescence, and adulthood. Various combinations of molecular, anatomical and behavioral methods have been used to assess the outcomes. Additionally, three of the studies sought to rescue the resulting abnormalities.Here we provide background on the environmental paradigms used, summarize the results of these studies combining Disc1 mouse models with environmental stressors and discuss what we can learn and how to proceed. A major question is how the genetic and environmental factors determine which psychiatric disorder will be clinically manifested. To address this we can take advantage of the many Disc1 models available and expose them to the same environmental stressor. The complementary experiment would be to expose the same model to different environmental stressors. DISC1 is an ideal gene for this approach, since in the Scottish pedigree the same chromosomal translocation results in different psychiatric conditions.

Mouse allergen exposure and immunologic responses: IgE-mediated mouse sensitization and mouse specific IgG and IgG4 levels

NARCIS (Netherlands)

Matsui, Elizabeth C.; Krop, Esmeralda J. M.; Diette, Gregory B.; Aalberse, Rob C.; Smith, Abigail L.; Eggleston, Peyton A.

2004-01-01

Although there is evidence that contact with mice is associated with IgE-mediated mouse sensitization and mouse specific antibody responses, the exposure-response relationships remain unclear. To determine whether IgE-mediated mouse sensitization and mouse specific IgG (mIgG) and mIgG4 levels

Biology and therapy of inherited retinal degenerative disease: insights from mouse models

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Shobi Veleri

2015-02-01

Full Text Available Retinal neurodegeneration associated with the dysfunction or death of photoreceptors is a major cause of incurable vision loss. Tremendous progress has been made over the last two decades in discovering genes and genetic defects that lead to retinal diseases. The primary focus has now shifted to uncovering disease mechanisms and designing treatment strategies, especially inspired by the successful application of gene therapy in some forms of congenital blindness in humans. Both spontaneous and laboratory-generated mouse mutants have been valuable for providing fundamental insights into normal retinal development and for deciphering disease pathology. Here, we provide a review of mouse models of human retinal degeneration, with a primary focus on diseases affecting photoreceptor function. We also describe models associated with retinal pigment epithelium dysfunction or synaptic abnormalities. Furthermore, we highlight the crucial role of mouse models in elucidating retinal and photoreceptor biology in health and disease, and in the assessment of novel therapeutic modalities, including gene- and stem-cell-based therapies, for retinal degenerative diseases.

Trypsin digest protocol to analyze the retinal vasculature of a mouse model.

Science.gov (United States)

Chou, Jonathan C; Rollins, Stuart D; Fawzi, Amani A

2013-06-13

Trypsin digest is the gold standard method to analyze the retinal vasculature (1-5). It allows visualization of the entire network of complex three-dimensional retinal blood vessels and capillaries by creating a two-dimensional flat-mount of the interconnected vascular channels after digestion of the non-vascular components of the retina. This allows one to study various pathologic vascular changes, such as microaneurysms, capillary degeneration, and abnormal endothelial to pericyte ratios. However, the method is technically challenging, especially in mice, which have become the most widely available animal model to study the retina because of the ease of genetic manipulations (6,7). In the mouse eye, it is particularly difficult to completely remove the non-vascular components while maintaining the overall architecture of the retinal blood vessels. To date, there is a dearth of literature that describes the trypsin digest technique in detail in the mouse. This manuscript provides a detailed step-by-step methodology of the trypsin digest in mouse retina, while also providing tips on troubleshooting difficult steps.

Highways block gene flow and cause a rapid decline in genetic diversity of desert bighorn sheep

NARCIS (Netherlands)

Epps, CW; Palsboll, PJ; Wehausen, JD; Roderick, GK; Ramey, RR; McCullough, DR

2005-01-01

The rapid expansion of road networks has reduced connectivity among populations of flora and fauna. The resulting isolation is assumed to increase population extinction rates, in part because of the loss of genetic diversity. However, there are few cases where loss of genetic diversity has been

Population Genetic Structure and Genetic Diversity in Twisted-Jaw Fish, Belodontichthys truncatus Kottelat & Ng, 1999 (Siluriformes: Siluridae, from Mekong Basin

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Surapon Yodsiri

2017-01-01

Full Text Available The Mekong River and its tributaries possess the second highest diversity in fish species in the world. However, the fish biodiversity in this river is threatened by several human activities, such as hydropower plant construction. Understanding the genetic diversity and genetic structure of the species is important for natural resource management. Belodontichthys truncatus Kottelat & Ng is endemic to the Mekong River basin and is an important food source for people in this area. In this study, the genetic diversity, genetic structure, and demographic history of the twisted-jaw fish, B. truncatus, were investigated using mitochondrial cytochrome b gene sequences. A total of 124 fish specimens were collected from 10 locations in the Mekong and its tributaries. Relatively high genetic diversity was found in populations of B. truncatus compared to other catfish species in the Mekong River. The genetic structure analysis revealed that a population from the Chi River in Thailand was genetically significantly different from other populations, which is possibly due to the effect of genetic drift. Demographic history analysis indicated that B. truncatus has undergone recent demographic expansion dating back to the end of the Pleistocene glaciation.

Genetic Characterization of Dog Personality Traits.

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Ilska, Joanna; Haskell, Marie J; Blott, Sarah C; Sánchez-Molano, Enrique; Polgar, Zita; Lofgren, Sarah E; Clements, Dylan N; Wiener, Pamela

2017-06-01

The genetic architecture of behavioral traits in dogs is of great interest to owners, breeders, and professionals involved in animal welfare, as well as to scientists studying the genetics of animal (including human) behavior. The genetic component of dog behavior is supported by between-breed differences and some evidence of within-breed variation. However, it is a challenge to gather sufficiently large datasets to dissect the genetic basis of complex traits such as behavior, which are both time-consuming and logistically difficult to measure, and known to be influenced by nongenetic factors. In this study, we exploited the knowledge that owners have of their dogs to generate a large dataset of personality traits in Labrador Retrievers. While accounting for key environmental factors, we demonstrate that genetic variance can be detected for dog personality traits assessed using questionnaire data. We identified substantial genetic variance for several traits, including fetching tendency and fear of loud noises, while other traits revealed negligibly small heritabilities. Genetic correlations were also estimated between traits; however, due to fairly large SEs, only a handful of trait pairs yielded statistically significant estimates. Genomic analyses indicated that these traits are mainly polygenic, such that individual genomic regions have small effects, and suggested chromosomal associations for six of the traits. The polygenic nature of these traits is consistent with previous behavioral genetics studies in other species, for example in mouse, and confirms that large datasets are required to quantify the genetic variance and to identify the individual genes that influence behavioral traits. Copyright © 2017 by the Genetics Society of America.

C9orf72-related disorders: expanding the clinical and genetic spectrum of neurodegenerative diseases

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Paulo Victor Sgobbi de Souza

2015-03-01

Full Text Available Neurodegenerative diseases represent a heterogeneous group of neurological conditions primarily involving dementia, motor neuron disease and movement disorders. They are mostly related to different pathophysiological processes, notably in family forms in which the clinical and genetic heterogeneity are lush. In the last decade, much knowledge has been acumulated about the genetics of neurodegenerative diseases, making it essential in cases of motor neuron disease and frontotemporal dementia the repeat expansions of C9orf72 gene. This review analyzes the main clinical, radiological and genetic aspects of the phenotypes related to the hexanucleotide repeat expansions (GGGGCC of C9orf72 gene. Future studies will aim to further characterize the neuropsychological, imaging and pathological aspects of the extra-motor features of motor neuron disease, and will help to provide a new classification system that is both clinically and biologically relevant.

Genetic variability of Echinococcus granulosus based on the mitochondrial 16S ribosomal RNA gene.

Science.gov (United States)

Wang, Ning; Wang, Jiahai; Hu, Dandan; Zhong, Xiuqin; Jiang, Zhongrong; Yang, Aiguo; Deng, Shijin; Guo, Li; Tsering, Dawa; Wang, Shuxian; Gu, Xiaobin; Peng, Xuerong; Yang, Guangyou

2015-06-01

Echinococcus granulosus is the etiological agent of cystic echinococcosis, a major zoonotic disease of both humans and animals. In this study, we assessed genetic variability and genetic structure of E. granulosus in the Tibet plateau, using the complete mitochondrial 16 S ribosomal RNA gene for the first time. We collected and sequenced 62 isolates of E. granulosus from 3 populations in the Tibet plateau. A BLAST analysis indicated that 61 isolates belonged to E. granulosus sensu stricto (genotypes G1-G3), while one isolate belonged to E. canadensis (genotype G6). We detected 16 haplotypes with a haplotype network revealing a star-like expansion, with the most common haplotype occupying the center of the network. Haplotype diversity and nucleotide diversity were low, while negative values were observed for Tajima's D and Fu's Fs. AMOVA results and Fst values revealed that the three geographic populations were not genetically differentiated. Our results suggest that a population bottleneck or population expansion has occurred in the past, and that this explains the low genetic variability of E. granulosus in the Tibet Plateau.