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      The polymorphism architecture of mouse genetic resources elucidated using genome-wide resequencing data: implications for QTL discovery and systems genetics

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          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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          Most cited references 39

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          Genealogies of mouse inbred strains.

          The mouse is a prime organism of choice for modelling human disease. Over 450 inbred strains of mice have been described, providing a wealth of different genotypes and phenotypes for genetic and other studies. As new strains are generated and others become extinct, it is useful to review periodically what strains are available and how they are related to each other, particularly in the light of available DNA polymorphism data from microsatellite and other markers. We describe the origins and relationships of inbred mouse strains, 90 years after the generation of the first inbred strain. Given the large collection of inbred strains available, and that published information on these strains is incomplete, we propose that all genealogical and genetic data on inbred strains be submitted to a common electronic database to ensure this valuable information resource is preserved and used efficiently.
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            A new set of BXD recombinant inbred lines from advanced intercross populations in mice

            Background Recombinant inbred (RI) strains are an important resource for mapping complex traits in many species. While large RI panels are available for Arabidopsis, maize, C. elegans, and Drosophila, mouse RI panels typically consist of fewer than 30 lines. This is a severe constraint on the power and precision of mapping efforts and greatly hampers analysis of epistatic interactions. Results In order to address these limitations and to provide the community with a more effective collaborative RI mapping panel we generated new BXD RI strains from two independent advanced intercrosses (AI) between C57BL/6J (B6) and DBA/2J (D2) progenitor strains. Progeny were intercrossed for 9 to 14 generations before initiating inbreeding, which is still ongoing for some strains. Since this AI base population is highly recombinant, the 46 advanced recombinant inbred (ARI) strains incorporate approximately twice as many recombinations as standard RI strains, a fraction of which are inevitably shared by descent. When combined with the existing BXD RI strains, the merged BXD strain set triples the number of previously available unique recombinations and quadruples the total number of recombinations in the BXD background. Conclusion The combined BXD strain set is the largest mouse RI mapping panel. It is a powerful tool for collaborative analysis of quantitative traits and gene function that will be especially useful to study variation in transcriptome and proteome data sets under multiple environments. Additional strains also extend the value of the extensive phenotypic characterization of the previously available strains. A final advantage of expanding the BXD strain set is that both progenitors have been sequenced, and approximately 1.8 million SNPs have been characterized. This provides unprecedented power in screening candidate genes and can reduce the effective length of QTL intervals. It also makes it possible to reverse standard mapping strategies and to explore downstream effects of known sequence variants.
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              Variation is the spice of life.

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                Author and article information

                Contributors
                dwt@med.unc.edu
                Journal
                Mamm Genome
                Mammalian Genome
                Springer-Verlag (New York )
                0938-8990
                1432-1777
                3 August 2007
                July 2007
                : 18
                : 6-7
                : 473-481
                Affiliations
                [1 ]Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 USA
                [2 ]Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 USA
                [3 ]Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 USA
                [4 ]Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 USA
                [5 ]Bioinformatics and Computational Biology Training Program, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 USA
                [6 ]Center for Environmental Health and Susceptibility and Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, 27599 USA
                [7 ]Department of Genetics, University of North Carolina at Chapel Hill, CB# 7264, 103 Mason Farm Road, Chapel Hill, NC 27599-7264 USA
                Article
                9045
                10.1007/s00335-007-9045-1
                1998888
                17674098
                © Springer Science+Business Media, LLC 2007
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                © Springer Science+Business Media, LLC 2007

                Genetics

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