Article

Roberts A, De Villena FP-M, Wang W, McMillian L, Threadgill DW.. The polymorphism architecture of mouse genetic resources elucidated using genome-wide resequencing data: implications for QTL discovery and systems genetics. Mamm Genome 18: 473-481

Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.
Mammalian Genome (Impact Factor: 3.07). 08/2007; 18(6-7):473-81. DOI: 10.1007/s00335-007-9045-1
Source: PubMed

ABSTRACT

Mouse genetic resources include inbred strains, recombinant inbred lines, chromosome substitution strains, heterogeneous stocks, and the Collaborative Cross (CC). These resources were generated through various breeding designs that potentially produce different genetic architectures, including the level of diversity represented, the spatial distribution of the variation, and the allele frequencies within the resource. By combining sequencing data for 16 inbred strains and the recorded history of related strains, the architecture of genetic variation in mouse resources was determined. The most commonly used resources harbor only a fraction of the genetic diversity of Mus musculus, which is not uniformly distributed thus resulting in many blind spots. Only resources that include wild-derived inbred strains from subspecies other than M. m. domesticus have no blind spots and a uniform distribution of the variation. Unlike other resources that are primarily suited for gene discovery, the CC is the only resource that can support genome-wide network analysis, which is the foundation of systems genetics. The CC captures significantly more genetic diversity with no blind spots and has a more uniform distribution of the variation than all other resources. Furthermore, the distribution of allele frequencies in the CC resembles that seen in natural populations like humans in which many variants are found at low frequencies and only a minority of variants are common. We conclude that the CC represents a dramatic improvement over existing genetic resources for mammalian systems biology applications.

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Available from: Fernando Pardo-Manuel de Villena, Mar 10, 2014
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    • "Subsequently, high-density genotyping and whole-genome sequence has been generated and these data are publicly available (Yang et al. 2011; Keane et al. 2011). The addition of the wild-derived strains enabled the CC to capture 90% of genetic variation present in laboratory stocks of Mus musculus (Roberts et al. 2007), with the added advantage of making the spatial distribution of genetic variation quasi-uniform Figure 1 Body and reproductive organ weights in males from the eight founder strains of the CC. The colors represent the eight founder strains as follows: A/J, yellow; C57BL/6J, gray; 129S1/SvImJ, pink; NOD/ShiLtJ, dark blue; NZO/H1LtJ, light blue; CAST/EiJ, green; PWK/PhJ, red; and WSB/EiJ, purple. "
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    ABSTRACT: Surveys of inbred strains of mice are standard approaches to determine the heritability and range of phenotypic variation for biomedical traits. In addition, they may lead to the identification of novel phenotypes and models of human disease. Surprisingly, male reproductive phenotypes are among the least represented traits in the Mouse Phenome Database. Here we report the results of a broad survey of the eight founder inbred strains of both the Collaborative Cross (CC) and the Diversity Outbred populations, two new mouse resources that are being used as platforms for systems genetics and sources of mouse models of human diseases. Our survey includes representatives of the three main subspecies of the house mice and a mix of classical and wild-derived inbred strains. In addition to standard staples of male reproductive phenotyping such as reproductive organ weights, sperm counts and sperm morphology, our survey includes sperm motility and the first survey of testis histology. As expected for such a broad survey, heritability varies widely among traits. We conclude that although all eight inbred strains are fertile, most display a mix of advantageous and deleterious male reproductive traits. The CAST/EiJ strain is an outlier, with an unusual combination of deleterious male reproductive traits including low sperm counts, high levels of morphologically abnormal sperm, and poor motility. In contrast, sperm from the PWK/PhJ and WSB/EiJ strains had the highest percentages of normal morphology and vigorous motility. Finally, we report an abnormal testis phenotype that is highly heritable and restricted to the WSB/EiJ strain. This phenotype is characterized by the presence of a large, but variable, number of vacuoles in at least 10% of the seminiferous tubules. The onset of the phenotype between two and three weeks of age is temporally correlated with the formation of the blood-testis barrier. We speculate that this phenotype may play a role in high rates of extinction in the CC project and in the phenotypes associated with speciation in genetic crosses that use the WSB/EiJ strain as representative of the Mus muculus domesticus subspecies.
    Preview · Article · Oct 2015 · G3-Genes Genomes Genetics
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    • "Each family is then inbred for many generations (by brother-sister mating) to generate a single " recombinant inbred line " (RIL), containing the recombined chromosomes of the original founders (Broman, 2005). Thus, each RIL is a unique and independent genetic " mosaic " , combining a random assortment of segments of each of the founder lines in roughly equal proportions (see Fig. 2, and Roberts et al., 2007). Due to the inbreeding each line is the equivalent of a doubled haploid genome, so that all lines are informative for QTL mapping. "
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    ABSTRACT: Abstract 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 among them 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. Keywords Precision agriculture. Mouse Collaborative Cross; QTL mapping; Complex traits; Disease susceptibility
    Full-text · Article · May 2014 · Livestock Science
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    • "In previous studies we have demonstrated that the parental strains C57BL/6J and DBA/2J show significant phenotypic variation of key fibrogenic parameters and therefore differ in their fibrosis susceptibility [6], [7], [18]. Since these strains also vary in four million genetic sites across their genome [19], they provide the phenotypic and genetic diversity necessary for mapping studies in liver fibrosis. Furthermore, with more than 13,000 genetic markers and over 3,000 phenotypic records the BXD lines are one of the best-characterized murine reference panels [13], [20], [21]. "
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    ABSTRACT: The progression of liver fibrosis in response to chronic injury varies considerably among individual patients. The underlying genetics is highly complex due to large numbers of potential genes, environmental factors and cell types involved. Here, we provide the first toxicogenomic analysis of liver fibrosis induced by carbon tetrachloride in the murine 'genetic reference panel' of recombinant inbred BXD lines. Our aim was to define the core of risk genes and gene interaction networks that control fibrosis progression. Liver fibrosis phenotypes and gene expression profiles were determined in 35 BXD lines. Quantitative trait locus (QTL) analysis identified seven genomic loci influencing fibrosis phenotypes (pQTLs) with genome-wide significance on chromosomes 4, 5, 7, 12, and 17. Stepwise refinement was based on expression QTL mapping with stringent selection criteria, reducing the number of 1,351 candidate genes located in the pQTLs to a final list of 11 cis-regulated genes. Our findings demonstrate that the BXD reference population represents a powerful experimental resource for shortlisting the genes within a regulatory network that determine the liver's vulnerability to chronic injury.
    Full-text · Article · Feb 2014 · PLoS ONE
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