New exome sequencing of wild derived inbred strains of mice significantly improves power to link phenotype and genotype Exome

The mouse has proven to be a powerful system to dissect the genetic and environmental influences on phenotypic variation, including the study of human diseases. In spite of a wealth of discoveries, most modern mouse strains have captured only a small fraction of genetic variation known to segregate in their wild progenitors, and are related to each other in complex ways. Wild-derived inbred strains of mice have received relatively little attention, but have the potential to increase the power of genetic studies with the addition of novel single genetic variation. Here, we perform exome-enrichment and high-throughput sequencing (~20X coverage) of exomes from 26 wild derived strains (known in the community as the “Montpellier strains”). Using a conservative customized pipeline, we identified 1.14 million SNPs in our dataset, approximately 20% of which are not currently known in existing databases of mouse genetic variation. Simulations show that these new genetic variants increase mapping resolution. In addition, there are over 300 genes with an early stop codon segregating in the first 50% of the protein, providing potential alternatives to existing knockout resources. The novel genetic variation discovered here promises to increase the power of mouse genetics.