High resolution linkage disequilibrium mapping of QTLs

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High resolution mapping in future will rely increasingly not on the detection of linkage, but on the occurrence of linkage disequilibrium, that is non-random associations between pairs of loci detectable at the population level rather than the family or pedigree level. There is insufficient opportunity for enough recombination to accumulate over the course of a two or three generation pedigree to map QTLs with anything but very coarse precision, generally no better than about 20 cM resolution. However, appropriately designed resources can exploit the combined historical accumulation of recombination by utilizing linkage disequilibrium to map genes of interest to much higher resolution and therefore assist in their identification and use. Cardon and Abecasis (2003) have described preliminary progress in the human HapMap project which eventually aims to use many thousands of closely spaced single nucleotide polymorphism (SNP) markers to precisely map and identify loci affecting complex trait phenotypes in humans such as susceptibility to common diseases like asthma and diabetes. This same approach is also being used in domestic animals.

For inbred model organisms such as mice, various schemes are used to accumulate the additional recombination required to map QTLs at higher resolution than is possible in an F2 cross. The development of congenic lines via many generations of backcrossing is one strategy for accumulating the additional recombination, but this requires very extensive phe-notyping and genotyping and the creation of a large number of congenics - usually one or two per QTL detected in an F2 screen. Darvasi and Soller (1995) proposed an efficient strategy for accumulation of additional recombination by the development of what they termed advanced intercross lines or AILs, where a cross is taken to F10 or beyond, but with sufficient numbers of breeding animals that genetic drift will be relatively inconsequential. No genotyping or phenotyping is required in the intermediate generations. Map resolution of QTL positions can be improved by a factor of five or more. Iraqi (2000) has reported successful application of an AIL including positional cloning of the relevant genes.

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