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

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.

Host genetic and environmental effects on mouse intestinal microbiota

“…The CC will encompass a large number of inbred strains resulting from systematic crossing of eight genetically diverse founder strains that capture B90% of the known mouse genetic variability (Roberts et al, 2007). The CC was initiated at several research institutions including Oak Ridge National Laboratory (ORNL) (Chesler et al, 2008;Philip et al, 2011) and recently has been employed in quantitative trait analysis of a wide range of phenotypes (Aylor et al, 2011;Philip et al, 2011).…”

Complex Genetics of Obesity in Mouse Models

“…This was the conclusion reached by Roberts et al (47) after analysis of resequencing data representing 8.3 million SNPs in 11 classical inbred strains and four wild-derived strains. 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.…”

Ten Years of the Collaborative Cross

“…Genetic analysis revealed that the eight strains captured almost 90% of the known genetic variation present in laboratory mice originating from M. musculus and that the captured variation is randomly distributed across the genome (Roberts et al 2007).…”