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 algorithm to isolate causative recessive and dominant mutations, even at low coverage, on a pure strain background. Analysis of the IBD regions also allows us to calculate the ENU mutation rate (1.54 mutations per Mb) and to model future strategies for genetic screens in mice. The introduction of this approach will accelerate the discovery of causal variants, permit broader and more informative lethal screens to be used, reduce animal costs, and herald a new era for ENU mutagenesis.

journal_name

PLoS Genet

journal_title

PLoS genetics

authors

Bull KR,Rimmer AJ,Siggs OM,Miosge LA,Roots CM,Enders A,Bertram EM,Crockford TL,Whittle B,Potter PK,Simon MM,Mallon AM,Brown SD,Beutler B,Goodnow CC,Lunter G,Cornall RJ

doi

10.1371/journal.pgen.1003219

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

e1003219

issue

1

eissn

1553-7390

issn

1553-7404

pii

PGENETICS-D-12-02054

journal_volume

9

pub_type

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