The International Complex Trait Consortium

Simultaneous Detection and Fine-mapping of Quantitative Trait Loci in Mice using Heterogeneous Stocks

Richard Mott, Jonathan Flint

Wellcome Trust Centre for Human Genetics
Oxford University, Oxford, OX3 7BN, UK

We describe a method to simultaneously detect and fine-map quantitative trait loci (QTL), especially suited to the mapping of modifier loci in mouse mutant models. The method exploits the high level of historical recombination present in a heterogeneous stock (HS), an outbred population of mice derived from known founder strains. The experimental design is an F2 cross between the HS and a genetically-distinct line, such as one carrying a knockout or transgene. QTL detection is performed by a standard genome scan with around 100 markers and fine-mapping by typing the same animals using densely-spaced markers over those candidate regions detected by the scan. The analysis uses an extension of the dynamic-programming technique employed previously to fine-map QTL in HS mice. We show by simulation that a QTL accounting for 5% of the total variance can be detected and fine-mapped with over 50% probability to within 3 cM by genotyping about 1500 animals. We also investigate ways to utilise HS animals for fine-mapping QTL in F1 HS x Inbred intercrosses. By working with large sibships (eg from frozen sperm) and using parental haplotype data we suggest that is is possible to reduce the genotyping effort in the F1 generation significantly.