Unlocking the bottleneck in forward genetics using whole-genome sequencing and identity by descent to isolate causative mutations.

ABSTRACT: Forward genetics screens with N-ethyl-N-nitrosourea (ENU) provide a powerful way to illuminate gene function and generate mouse models of human disease; however, the identification of causative mutations remains a limiting step. Current strategies depend on conventional mapping, so the propagation of affected mice requires non-lethal screens; accurate tracking of phenotypes through pedigrees is complex and uncertain; out-crossing can introduce unexpected modifiers; and Sanger sequencing of candidate genes is inefficient. Here we show how these problems can be efficiently overcome using whole-genome sequencing (WGS) to detect the ENU mutations and then identify regions that are identical by descent (IBD) in multiple affected mice. In this strategy, we use a modification of the Lander-Green

SUBMITTER: Bull KR 

PROVIDER: S-EPMC3561070 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature