PgmNr M5050: New exome sequencing of wild derived inbred strains of mice significantly improves power to link phenotype and genotype.

Authors:
Matt Dean 1 ; Peter Chang 1 ; Emily Kopania 1 ; Matt Salomon 1 ; Lorraine Provencio 1 ; Rachel Mangels 1 ; Sara Keeble 1 ; Brent Young 2 ; Annie Orth 2 ; Francois Bonhomme 3 ; Jeffrey Good 1


Institutes
1) University of Southern California, Los Angeles, CA; 2) Université Montpellier; 3) University of Montana.


Abstract:

The mouse has proven to be a powerful system to dissect the genetic and environmental influences on phenotypic variation, even informing the study of diseases in humans.  In spite of a wealth of discoveries, most modern mouse strains are related to each other in complex ways, and have captured only a small fraction of genetic variation known to segregate in their wild progenitors.  Wild-derived mice have the potential to increase power to connect phenotype to genotype by introducing novel single nucleotide polymorphisms (SNPs) to science.  Here, we enrich exomes from 26 wild derived strains (the so-called Montpellier strains) and perform high throughput sequencing to an average coverage of 20 X.  SNP’s were called using an extremely 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.