Mouse Genetic Reference Population Research Articles

GQTL: A Web Application for QTL Analysis Using the Collaborative Cross Mouse Genetic Reference Population.

Multi-parental recombinant inbred populations, such as the Collaborative Cross (CC) mouse genetic reference population, are increasingly being used for analysis of quantitative trait loci (QTL). However specialized analytic software for these complex populations is typically built in R that works only on command-line, which limits the utility of these powerful resources for many users. To overcome analytic limitations, we developed gQTL, a web accessible, simple graphical user interface application based on the DOQTL platform in R to perform QTL mapping using data from CC mice.

The Collaborative Cross mouse model for dissecting genetic susceptibility to infectious diseases.

Infectious diseases, also known as communicable diseases, refer to a full range of maladies caused by pathogen invasion to the host body. Host response towards an infectious pathogen varies between individuals, and can be defined by responses from asymptomatic to lethal. Host response to infectious pathogens is considered as a complex trait controlled by gene-gene (host-pathogen) and gene-environment interactions, leading to the extensive phenotypic variations between individuals. With the advancement of the human genome mapping approaches and tools, various genome-wide association studies (GWAS) were performed, aimed at mapping the genetic basis underlying host susceptibility towards infectious pathogens. In parallel, immense efforts were invested in enhancing the genetic mapping resolution and gene-cloning efficacy, using advanced mouse models including advanced intercross lines; outbred populations; consomic, congenic; and recombinant inbred lines. Notwithstanding the evident advances achieved using these mouse models, the genetic diversity was low and quantitative trait loci (QTL) mapping resolution was inadequate. Consequently, the Collaborative Cross (CC) mouse model was established by full-reciprocal mating of eight divergent founder strains of mice (A/J, C57BL/6J, 129S1/SvImJ, NOD/LtJ, NZO/HiLtJ, CAST/Ei, PWK/PhJ, and WSB/EiJ) generating a next-generation mouse genetic reference population (CC lines). Presently, the CC mouse model population comprises a set of about 200 recombinant inbred CC lines exhibiting a unique high genetic diversity and which are accessible for multidisciplinary studies. The CC mouse model efficacy was validated by various studies in our lab and others, accomplishing high-resolution (< 1MB) QTL genomic mapping for a variety of complex traits, using about 50 CC lines (3-4 mice per line). Herein, we present a number of studies demonstrating the power of the CC mouse model, which has been utilized in our lab for mapping the genetic basis of host susceptibility to various infectious pathogens. These include Aspergillus fumigatus, Klebsiella pneumoniae, Porphyromonas gingivalis and Fusobacterium nucleatum (causing oral mixed infection), Pseudomonas aeruginosa, and the bacterial toxins Lipopolysaccharide and Lipoteichoic acid.

Inactivation of the E3 Ubiquitin Ligase IDOL Attenuates Diet-Induced Obesity and Metabolic Dysfunction in Mice.

Objective- The E3 ubiquitin ligase IDOL (inducible degrader of the LDLR [LDL (low-density lipoprotein) receptor]) is a post-transcriptional regulator of LDLR abundance. Model systems and human genetics support a role for IDOL in regulating circulating LDL levels. Whether IDOL plays a broader metabolic role and affects development of metabolic syndrome-associated comorbidities is unknown. Approach and Results- We studied WT (wild type) and Idol(-/-) (Idol-KO) mice in 2 models: physiological aging and diet-induced obesity. In both models, deletion of Idol protected mice from metabolic dysfunction. On a Western-type diet, Idol loss resulted in decreased circulating levels of cholesterol, triglycerides, glucose, and insulin. This was accompanied by protection from weight gain in short- and long-term dietary challenges, which could be attributed to reduced hepatosteatosis and fat mass in Idol-KO mice. Although feeding and intestinal fat uptake were unchanged in Idol-KO mice, their brown adipose tissue was protected from lipid accumulation and had elevated expression of UCP1 (uncoupling protein 1) and TH (tyrosine hydroxylase). Indirect calorimetry indicated a marked increase in locomotion and suggested a trend toward increased cumulative energy expenditure and fat oxidation. An increase in in vivo clearance of reconstituted lipoprotein particles in Idol-KO mice may sustain this energetic demand. In the BXD mouse genetic reference population, hepatic Idol expression correlates with multiple metabolic parameters, thus providing support for findings in the Idol-KO mice. Conclusions- Our study uncovers an unrecognized role for Idol in regulation of whole body metabolism in physiological aging and on a Western-type diet. These findings support Idol inhibition as a therapeutic strategy to target multiple metabolic syndrome-associated comorbidities.

An Integrated Systems Genetics and Omics Toolkit to Probe Gene Function.

Identifying genetic and environmental factors that impact complex traits and common diseases is a high biomedical priority. Here, we developed, validated, and implemented a series of multi-layered systems approaches, including (expression-based) phenome-wide association, transcriptome-/proteome-wide association, and (reverse-) mediation analysis, in an open-access web server (systems-genetics.org) to expedite the systems dissection of gene function. We applied these approaches to multi-omics datasets from the BXD mouse genetic reference population, and identified and validated associations between genes and clinical and molecular phenotypes, including previously unreported links between Rpl26 and body weight, and Cpt1a and lipidmetabolism. Furthermore, through mediation and reverse-mediation analysis we established regulatory relations between genes, such as the co-regulation of BCKDHA and BCKDHB protein levels, and identified targets of transcription factors E2F6, ZFP277, and ZKSCAN1. Our multifaceted toolkit enabled the identification of gene-gene and gene-phenotype links that are robust and that translate well across populations and species, and can be universally applied to any populations with multi-omics datasets.

Systems Genetics of Liver Fibrosis.

This systems genetics analysis comprises quantitative measurements of hepatic fibrogenesis in mouse models and mapping of quantitative traits in mouse genetic reference populations. It is part of a large mapping project of fibrogenic genes including the analyses of experimental crosses from different inbred mouse strains. Extensive quantitative trait loci (QTL) mapping of fibrosis phenotypes and liver expression profiling in combination with in silico mapping facilitated the identification of QTL regions and underlying candidate genes that confer fibrosis susceptibility also in humans. Moreover, the approach led to the identification of interacting QTLs and gene networks in liver fibrosis, providing a key experimental platform for the development of novel, more precise therapeutic interventions. Here, we provide a use case for the application of different analysis tools and the integration of multiple datasets determined in F2 intercrosses and BXD recombinant inbred lines to identify, finemap and affirm fibrosis susceptibility loci.

Dissection of Host Susceptibility to Bacterial Infections and Its Toxins.

Infection is one of the leading causes of human mortality and morbidity. Exposure to microbial agents is obviously required. However, also non-microbial environmental and host factors play a key role in the onset, development and outcome of infectious disease, resulting in large of clinical variability between individuals in a population infected with the same microbe. Controlled and standardized investigations of the genetics of susceptibility to infectious disease are almost impossible to perform in humans whereas mouse models allow application of powerful genomic techniques to identify and validate causative genes underlying human diseases with complex etiologies. Most of current animal models used in complex traits diseases genetic mapping have limited genetic diversity. This limitation impedes the ability to create incorporated network using genetic interactions, epigenetics, environmental factors, microbiota, and other phenotypes. A novel mouse genetic reference population for high-resolution mapping and subsequently identifying genes underlying the QTL, namely the Collaborative Cross (CC) mouse genetic reference population (GRP) was recently developed. In this chapter, we discuss a variety of approaches using CC mice for mapping genes underlying quantitative trait loci (QTL) to dissect the host response to polygenic traits, including infectious disease caused by bacterial agents and its toxins.

Systems Genetics Analysis of a Recombinant Inbred Mouse Cell Culture Panel Reveals Wnt Pathway Member Lrp6 as a Regulator of Adult Hippocampal Precursor Cell Proliferation.

In much animal research, genetic variation is rather avoided than used as a powerful tool to identify key regulatory genes in complex phenotypes. Adult hippocampal neurogenesis is one such highly complex polygenic trait, for which the understanding of the molecular basis is fragmented and incomplete, and for which novel genetic approaches are needed. In this study, we aimed at marrying the power of the BXD panel, a mouse genetic reference population, with the flexibility of a cell culture model of adult neural precursor proliferation and differentiation. We established adult-derived hippocampal precursor cell cultures from 20 strains of the BXD panel, including the parental strains C57BL/6J and DBA/2J. The rates of cell proliferation and neuronal differentiation were measured, and transcriptional profiles were obtained from proliferating cultures. Together with the published genotypes of all lines, these data allowed a novel systems genetics analysis combining quantitative trait locus analysis with transcript expression correlation at a cellular level to identify genes linked with the differences in proliferation. In a proof-of-principle analysis, we identified Lrp6, the gene encoding the coreceptor to Frizzled in the Wnt pathway, as a potential negative regulator of precursor proliferation. Overexpression and siRNA silencing confirmed the regulatory role of Lrp6. As well as adding to our knowledge of the pathway surrounding Wnt in adult hippocampal neurogenesis, this finding allows the new appreciation of a negative regulator within this system. In addition, the resource and associated methodology will allow the integration of regulatory mechanisms at a systems level.

Influenza H3N2 infection of the collaborative cross founder strains reveals highly divergent host responses and identifies a unique phenotype in CAST/EiJ mice.

BackgroundInfluenza A virus is a zoonotic pathogen that poses a major threat to human and animal health. The severe course of influenza infection is not only influenced by viral virulence factors but also by individual differences in the host response. To determine the extent to which the genetic background can modulate severity of an infection, we studied the host responses to influenza infections in the eight genetically highly diverse Collaborative Cross (CC) founder mouse strains.ResultsWe observed highly divergent host responses between the CC founder strains with respect to survival, body weight loss, hematological parameters in the blood, relative lung weight and viral load. Mouse strain was the main factor with highest effect size on body weight loss after infection, demonstrating that this phenotype was highly heritable. Sex represented another significant main effect, although it was less strong. Analysis of survival rates and mean time to death suggested three groups of susceptibility phenotypes: highly susceptible (A/J, CAST/EiJ, WSB/EiJ), intermediate susceptible (C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ) and highly resistant strains (NZO/HlLtJ, PWK/PhJ). These three susceptibility groups were significantly different with respect to death/survival counts. Viral load was significantly different between susceptible and resistant strains but not between intermediate and highly susceptible strains. CAST/EiJ mice showed a unique phenotype. Despite high viral loads in their lungs, CAST/EiJ mice exhibited low counts of infiltrating granulocytes and showed increased numbers of macrophages in the lung. Histological studies of infected lungs and transcriptome analyses of peripheral blood cells and lungs confirmed an abnormal response in the leukocyte recruitment in CAST/EiJ mice.ConclusionsThe eight CC founder strains exhibited a large diversity in their response to influenza infections. Therefore, the CC will represent an ideal mouse genetic reference population to study the influence of genetic variation on the susceptibility and resistance to influenza infections which will be important to understand individual variations of disease severity in humans. The unique phenotype combination in the CAST/EiJ strain resembles human leukocyte adhesion deficiency and may thus represent a new mouse model to understand this and related abnormal immune responses to infections in humans.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2483-y) contains supplementary material, which is available to authorized users.

High-fat-diet induced development of increased fasting glucose levels and impaired response to intraperitoneal glucose challenge in the collaborative cross mouse genetic reference population.

BackgroundThe prevalence of Type 2 Diabetes (T2D) mellitus in the past decades, has reached epidemic proportions. Several lines of evidence support the role of genetic variation in the pathogenesis of T2D and insulin resistance. Elucidating these factors could contribute to developing new medical treatments and tools to identify those most at risk. The aim of this study was to characterize the phenotypic response of the Collaborative Cross (CC) mouse genetic resource population to high-fat diet (HFD) induced T2D-like disease to evluate its suitability for this purpose.ResultsWe studied 683 mice of 21 different lines of the CC population. Of these, 265 mice (149 males and 116 females) were challenged by HFD (42 % fat); and 384 mice (239 males and145 females) of 17 of the 21 lines were reared as control group on standard Chow diet (18 % fat). Briefly, 8 week old mice were maintained on HFD until 20 weeks of age, and subsequently assessed by intraperitoneal glucose tolerance test (IPGTT). Biweekly body weight (BW), body length (BL), waist circumstance (WC), and body mass index (BMI) were measured. On statistical analysis, trait measurements taken at 20 weeks of age showed significant sex by diet interaction across the different lines and traits. Consequently, males and females were analyzed, separately. Differences among lines were analyzed by ANOVA and shown to be significant (P <0.05), for BW, WC, BMI, fasting blood glucose, and IPGTT-AUC. We use these data to infer broad sense heritability adjusted for number of mice tested in each line; coefficient of genetic variation; genetic correlations between the same trait in the two sexes, and phenotypic correlations between different traits in the same sex.ConclusionsThese results are consistent with the hypothesis that host susceptibility to HFD-induced T2D is a complex trait and controlled by multiple genetic factors and sex, and that the CC population can be a powerful tool for genetic dissection of this trait.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0321-x) contains supplementary material, which is available to authorized users.

Genetic variability to diet-induced hippocampal dysfunction in BXD recombinant inbred (RI) mouse strains

Evidence has emerged suggesting that diet-induced obesity can have a negative effect on cognitive function. Here, we exploited a mouse genetic reference population to look for the linkage between these two processes on a genome-wide scale. The focus of this report is to determine whether the various BXD RI strains exhibited different behavioral performance and hippocampal function under high fat dietary (HFD) condition. We quantified genetic variation in body weight gain and consequent influences on behavioral tests in a cohort of 14 BXD strains of mice (8–12 mice/strain, n=153), for which we have matched data on gene expression and neuroanatomical changes in the hippocampus. It showed that BXD66 was the most susceptible, whereas BXD77 was the least susceptible strain to dietary influences. The performance of spatial reference memory tasks was strongly correlated with body weight gain (P<0.05). The obesity-prone strains displayed more pronounced spatial memory defects compared to the obesity-resistant strains. These abnormalities were associated with neuroinflammation, synaptic dysfunction, and neuronal loss in the hippocampus. The biological relevance of DSCAM gene polymorphism was assessed using the trait correlation analysis tool in Genenetwork. Furthermore, a significant strain-dependent gene expression difference of DSCAM was detected in the hippocampus of obese BXD strains by real-time quantitative PCR. In conclusion, a variety of across-strain hippocampal alterations and genetic predispositions to diet-induced obesity were found in a set of BXD strains. The obesity-prone and obesity-resistant lines we have identified should be highly useful to study the molecular genetics of diet-induced cognitive decline.

Transcript co-variance with Nestin in two mouse genetic reference populations identifies Lef1 as a novel candidate regulator of neural precursor cell proliferation in the adult hippocampus

Adult neurogenesis, the lifelong production of new neurons in the adult brain, is under complex genetic control but many of the genes involved remain to be identified. In this study, we have integrated publicly available gene expression data from the BXD and CXB recombinant inbred mouse lines to discover genes co-expressed in the adult hippocampus with Nestin, a common marker of the neural precursor cell population. In addition, we incorporated spatial expression information to restrict candidates to genes with high differential gene expression in the hippocampal dentate gyrus. Incorporating data from curated protein-protein interaction databases revealed interactions between our candidate genes and those already known to be involved in adult neurogenesis. Enrichment analysis suggested a link to the Wnt/β-catenin pathway, known to be involved in adult neurogenesis. In particular, our candidates were enriched in targets of Lef1, a modulator of the Wnt pathway. In conclusion, our combination of bioinformatics approaches identified six novel candidate genes involved in adult neurogenesis; Amer3, Eya3, Mtdh, Nr4a3, Polr2a, and Tbkbp1. Further, we propose a role for Lef1 transcriptional control in the regulation of adult hippocampal precursor cell proliferation.

Integrative genetic analysis of allergic inflammation in the murine lung.

Airway allergen exposure induces inflammation among individuals with atopy that is characterized by altered airway gene expression, elevated levels of T helper type 2 cytokines, mucus hypersecretion, and airflow obstruction. To identify the genetic determinants of the airway allergen response, we employed a systems genetics approach. We applied a house dust mite mouse model of allergic airway disease to 151 incipient lines of the Collaborative Cross, a new mouse genetic reference population, and measured serum IgE, airway eosinophilia, and gene expression in the lung. Allergen-induced serum IgE and airway eosinophilia were not correlated. We detected quantitative trait loci (QTL) for airway eosinophilia on chromosome (Chr) 11 (71.802-87.098 megabases [Mb]) and allergen-induced IgE on Chr 4 (13.950-31.660 Mb). More than 4,500 genes expressed in the lung had gene expression QTL (eQTL), the majority of which were located near the gene itself. However, we also detected approximately 1,700 trans-eQTL, and many of these trans-eQTL clustered into two regions on Chr 2. We show that one of these loci (at 147.6 Mb) is associated with the expression of more than 100 genes, and, using bioinformatics resources, fine-map this locus to a 53 kb-long interval. We also use the gene expression and eQTL data to identify a candidate gene, Tlcd2, for the eosinophil QTL. Our results demonstrate that hallmark allergic airway disease phenotypes are associated with distinct genetic loci on Chrs 4 and 11, and that gene expression in the allergically inflamed lung is controlled by both cis and trans regulatory factors.

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

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 (UPR(mt)). UPR(mt) 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.

The Collaborative Cross – A next generation mouse genetic resource population for high resolution genomic analysis of complex traits

The Collaborative Cross (CC) is a next-generation mouse genetic reference population designed by the mouse genetics community for high resolution mapping of genetic factors of relevance to human health, such as susceptibility to infectious and chronic diseases, and response to medical interventions. However, it is a very flexible resource with very wide potential application to complex traits of interest for human medicine or livestock agriculture. The CC will eventually consist of a set of about 600 recombinant inbred lines of which some 350 are currently available for study. These lines were generated by reciprocal crosses between 8 founder lines, including 5 relatively unrelated classical laboratory strains, and 3 lines derived from recent wild accessions (two Mus subspecies, and one Mus domesticus). The CC resource contains extremely wide genetic diversity relative to existing mouse genetic resources, and has already demonstrated unprecedented power for high resolution QTL mapping. Genotypes and all generated phenotypes will be stored centrally and made publicly available making the CC a “Genotype once, phenotype once” resource.

Heritability and coefficient of genetic variation analyses of phenotypic traits provide strong basis for high-resolution QTL mapping in the Collaborative Cross mouse genetic reference population

Most biological traits of human importance are complex in nature; their manifestation controlled by the cumulative effect of many genetic factors interacting with one another and with the individual's life history. Because of this, mouse genetic reference populations (GRPs) consisting of collections of inbred lines or recombinant inbred lines (RIL) derived from crosses between inbred lines are of particular value in analysis of complex traits, since massive amounts of data can be accumulated on the individual lines. However, existing mouse GRPs are derived from inbred lines that share a common history, resulting in limited genetic diversity, and reduced mapping precision due to long-range gametic disequilibrium. To overcome these limitations, the Collaborative Cross (CC) a genetically highly diverse collection of mouse RIL was established. The CC, now in advanced stages of development, will eventually consist of about 500 RIL derived from reciprocal crosses of eight divergent founder strains of mice, including three wild subspecies. Previous studies have shown that the CC indeed contains enormous diversity at the DNA level, that founder haplotypes are inherited in expected frequency, and that long-range gametic disequilibrium is not present. We here present data, primarily from our own laboratory, documenting extensive genetic variation among CC lines as expressed in broad-sense heritability (H(2)) and by the well-known "coefficient of genetic variation," demonstrating the ability of the CC resource to provide unprecedented mapping precision leading to identification of strong candidate genes.

Genotype is an important determinant factor of host susceptibility to periodontitis in the Collaborative Cross and inbred mouse populations

BackgroundPeriodontal infection (Periodontitis) is a chronic inflammatory disease, which results in the breakdown of the supporting tissues of the teeth. Previous epidemiological studies have suggested that resistance to chronic periodontitis is controlled to some extent by genetic factors of the host. The aim of this study was to determine the phenotypic response of inbred and Collaborative Cross (CC) mouse populations to periodontal bacterial challenge, using an experimental periodontitis model. In this model, mice are co-infected with Porphyromonas gingivalis and Fusobacterium nucleatum, bacterial strains associated with human periodontal disease. Six weeks following the infection, the maxillary jaws were harvested and analyzed for alveolar bone loss relative to uninfected controls, using computerized microtomography (microCT). Initially, four commercial inbred mouse strains were examined to calibrate the procedure and test for gender effects. Subsequently, we applied the same protocol to 23 lines (at inbreeding generations 10–18) from the newly developed mouse genetic reference population, the Collaborative Cross (CC) to determine heritability and genetic variation of control bone volume prior to infection (CBV, naïve bone volume around the teeth of uninfected mice), and residual bone volume (RBV, bone volume after infection) and loss of bone volume (LBV, the difference between CBV and RBV) following infection.ResultsBALB/CJ mice were highly susceptible (P<0.05) whereas DBA/2J, C57BL/6J and A/J mice were resistant. Six lines of the tested CC population were susceptible, whereas the remaining lines were resistant to alveolar bone loss. Gender effects on bone volume were tested across the four inbred and 23 CC lines, and found not to be significant. Based on ANOVA analyses, broad-sense heritabilities were statistically significant and equal to 0.4 for CBV and 0.2 for LBV.ConclusionsThe moderate heritability values indicate that the variation in host susceptibility to the disease is controlled to an appreciable extent by genetic factors. These results strongly support the possibility of using the Collaborative Cross, as well as developing dedicated F2 (resistant x susceptible inbred strains) resource populations, for future dissection of genetic factors in periodontitis.

Meeting report of the European mouse complex genetics network SYSGENET

The second scientific meeting of the European systems genetics network for the study of complex genetic human disease using genetic reference populations (SYSGENET) took place at the Center for Cooperative Research in Biosciences in Bilbao, Spain, December 10-12, 2012. SYSGENET is funded by the European Cooperation in the Field of Scientific and Technological Research (COST) and represents a network of scientists in Europe that use mouse genetic reference populations (GRPs) to identify complex genetic factors influencing disease phenotypes (Schughart, Mamm Genome 21:331-336, 2010). About 50 researchers working in the field of systems genetics attended the meeting, which consisted of 27 oral presentations, a poster session, and a management committee meeting. Participants exchanged results, set up future collaborations, and shared phenotyping and data analysis methodologies. This meeting was particularly instrumental for conveying the current status of the US, Israeli, and Australian Collaborative Cross (CC) mouse GRP. The CC is an open source project initiated nearly a decade ago by members of the Complex Trait Consortium to aid the mapping of multigenetic traits (Threadgill, Mamm Genome 13:175-178, 2002). In addition, representatives of the International Mouse Phenotyping Consortium were invited to exchange ongoing activities between the knockout and complex genetics communities and to discuss and explore potential fields for future interactions.

BXD mouse lines as a genetic reference population for metabolic syndrome

Chronic multifactorial diseases as type 2 diabetes and obesity result from interaction of genes and environmental factors. In order to better understand this interaction, a mouse genetic reference population allowing control of both conditions was used in a pipeline of standardized metabolic tests (such as exercise endurance, adaptive thermogenesis, glucose tolerance test) in a diet‐induced obesity paradigm with chow diet (CD) groups versus high‐fat diet (HFD) groups over 29 weeks. A panel of 42 BXD recombinant inbred mouse lines, descending from C57BL/6J and DBA2/J strains, was used to identify quantitative trait loci (QTL) and gene networks that modulate metabolic activity.HFD groups showed a higher range in body weight increase than CD groups and significant differences in the BW loss after two weeks of voluntary exercise. Similarly, heterogeneity in the VO2 max, the cold resistance and the glucose tolerance is observed between strains and groups. After completion, the broad data set generated will enable QTL mapping strategies through the GeneNetwork resource.The outcome of this work will provide a better understanding of the metabolic syndrome with the identification of signaling pathways and network regulations and will initiate new strategies for diagnosis, prevention and therapy complex diseases associated with aging.

Accelerating discovery for complex neurological and behavioral disorders through systems genetics and integrative genomics in the laboratory mouse.

Recent advances in systems genetics and integrative functional genomics have greatly improved the study of complex neurological and behavioral traits. The methods developed for the integrated characterization of new, high-resolution mouse genetic reference populations and systems genetics enable behavioral geneticists an unprecedented opportunity to address questions of the molecular basis of neurological and psychiatric disorders and their comorbidities. Integrative genomics augment these strategies by enabling rapid informatics-assisted candidate gene prioritization, cross-species translation, and mechanistic comparison across related disorders from a wealth of existing data in mouse and other model organisms. Ultimately, through these complementary approaches, finding the mechanisms and sources of genetic variation underlying complex neurobehavioral disease related traits is becoming tractable. Furthermore, these methods enable categorization of neurobehavioral disorders through their underlying biological basis. Together, these model organism-based approaches can lead to a refinement of diagnostic categories and targeted treatment of neurological and psychiatric disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-012-0111-3) contains supplementary material, which is available to authorized users.

The Genome Architecture of the Collaborative Cross Mouse Genetic Reference Population

The Collaborative Cross Consortium reports here on the development of a unique genetic resource population. The Collaborative Cross (CC) is a multiparental recombinant inbred panel derived from eight laboratory mouse inbred strains. Breeding of the CC lines was initiated at multiple international sites using mice from The Jackson Laboratory. Currently, this innovative project is breeding independent CC lines at the University of North Carolina (UNC), at Tel Aviv University (TAU), and at Geniad in Western Australia (GND). These institutions aim to make publicly available the completed CC lines and their genotypes and sequence information. We genotyped, and report here, results from 458 extant lines from UNC, TAU, and GND using a custom genotyping array with 7500 SNPs designed to be maximally informative in the CC and used a novel algorithm to infer inherited haplotypes directly from hybridization intensity patterns. We identified lines with breeding errors and cousin lines generated by splitting incipient lines into two or more cousin lines at early generations of inbreeding. We then characterized the genome architecture of 350 genetically independent CC lines. Results showed that founder haplotypes are inherited at the expected frequency, although we also consistently observed highly significant transmission ratio distortion at specific loci across all three populations. On chromosome 2, there is significant overrepresentation of WSB/EiJ alleles, and on chromosome X, there is a large deficit of CC lines with CAST/EiJ alleles. Linkage disequilibrium decays as expected and we saw no evidence of gametic disequilibrium in the CC population as a whole or in random subsets of the population. Gametic equilibrium in the CC population is in marked contrast to the gametic disequilibrium present in a large panel of classical inbred strains. Finally, we discuss access to the CC population and to the associated raw data describing the genetic structure of individual lines. Integration of rich phenotypic and genomic data over time and across a wide variety of fields will be vital to delivering on one of the key attributes of the CC, a common genetic reference platform for identifying causative variants and genetic networks determining traits in mammals.