A method for fine mapping quantitative trait loci in outbred animal stocks

High-resolution mapping of quantitative trait loci (QTL) in animals has pro ved to be difficult because the large effect sizes detected in crosses betw een inbred strains are often caused by numerous linked QTLs, each of small effect. In a study of fearfulness in mice, we have shown it is possible to fine map small-effect QTLs in a genetically heterogeneous Stock (HS). This strategy is a powerful general method of fine mapping QTLs, provided QTLs d etected in crosses between inbred strains that formed the HS can be reliabl y detected in the HS. We show here that single-marker association analysis identifies only two of five QTLs expected to be segregating in the HS and a pparently limits the strategy's usefulness for fine mapping. We solve this problem with a multipoint analysis that assigns the probability that an all ele descends from each progenitor in the HS. The analysis does not use pedi grees but instead requires information about the HS founder haplotypes. Wit h this method we mapped all three previously undetected loci [chromosome (C hr.) 1 logP 4.9. Chr. 10 logP 6.0, Chr. 15 logP 4.0]. We show that the reas on for the failure of single-marker association to detect QTLs is its inabi lity to distinguish opposing phenotypic effects when they occur on the same marker allele. We have developed a robust method of fine mapping QTLs in g enetically heterogeneous animals and suggest it is now cost effective to un dertake genome-wide high-resolution analysis of complex traits in parallel on the same set of mice.