This page contains information on a multipoint method for finding QTL in outbred populations descended from crosses between inbred lines. See
The technique has been used to map five QTL for emotionality in an outbred mouse population. The method is implemented in a C-program called HAPPY, which is available for download, and via our happy web-server. There is now an R version of HAPPY.
Most phenotypes of medical importance can be measured quantitatively, and in many cases the genetic contribution is substantial, accounting for 40% or more of the phenotypic variance. Considerable efforts have been made to isolate the genes responsible for quantitative genetic variation in human populations, but with little success, mostly because genetic loci contributing to quantitative traits (quantitative trait loci, QTL) have only a small effect on the phenotype. Association studies have been proposed as the most appropriate method for finding the genes that influence complex traits. However, family-based studies may not provide the resolution needed for positional cloning, unless they are very large, while environmental or genetic differences between cases and controls may confound population-based association studies.
These difficulties have led to the study of animal models of human traits. Studies using experimental crosses between inbred animal strains have been successful in mapping QTLs with effects on a number of different phenotypes, including behaviour, but attempts to fine-map QTLs in animals have often foundered on the discovery that a single QTL of large effect was in fact due to multiple loci of small effect positioned within the same chromosomal region. A further potential difficulty with detecting QTLs between inbred crosses is the significant reduction in genetic heterogeneity compared to the total genetic variation present in animal populations: a QTL segregating in the wild need not be present in the experimental cross.
In an attempt to circumvent the difficulties encountered with inbred crosses, we have been using a genetically heterogeneous stock (HS) of mice for which the ancestry is known. The heterogeneous stock was established from an 8 way cross of C57BL, BALB/c, RIII, AKR, DBA/2, I, A and C3H/2 inbred strains. Since its foundation 30 years ago, the stock has been maintained by breeding from 40 pairs and, at the time of this experiment, was in its 60th generation. Thus each chromosome from an HS animal is a fine-grained genetic mosaic of the founder strains, with an average distance between recombinants of 1/60 or 1.7 cM.
Theoretically, the HS offers at least a 30 fold increase in resolution for QTL mapping compared to an F2 intercross. The high level of recombination means that fine-mapping is possible using a relatively small number of animals; for QTLs of small to moderate effect, mapping to under 0.5 cM is possible with fewer than 2,000 animals. The large number of founders increases the genetic heterogeneity, and in theory one can map all QTLs that account for progenitor strain genetic differences. Potentially, the use of the HS offers a substantial improvement over current methods for QTL mapping.
HAPPY was written to find QTLs in HS animals. It uses a multipoint analysis which offers significant improvements in statistical power to detect QTLs over that achieved by single-marker association. Further details can be found in Proc. Natl. Acad. Sci. USA, 10.1073/pnas.230304397.