Qtl Mapping to Qtl Cloning: Mice to the Rescue

With the availability of dense, highly informative marker maps, it has recently become feasible to map genes (Quantitative Trait Loci or QTL) accounting for part of the heritability of continuously distributed traits in experimental crosses as well as outbred populations. QTL mapping efforts have almost invariably revealed a limited number of loci with effects of a magnitude clearly departing from the predictions of the infinitesimal model (a model introduced to facilitate mathematical treatment of quantitative traits rather than to truly reflect their underlying biology). As most experimental designs would have limited detection power, which could lead to an overestimation of the identified gene effects, interpretation of results from QTL mapping studies must be viewed with caution. However, numerous independent confirmation studies leave little doubt that most quantitative traits indeed involve a limited suite of loci with major effect. This assertion seems to hold not only for QTL mapped in crosses between divergent lines, but—more importantly—for QTL segregating in outbred populations as well (for review, see Paterson 1995). Despite the sometimes unexpected magnitude of the identified QTL effects, the lack of simple correspondence between genotype and phenotype in complex trait analysis precludes the unambiguous identification of recombinant individuals. This may limit the achievable mapping resolution of QTL, posing a serious threat to the efficacy of positional (candidate) cloning for QTL considerably. QTL mapping efforts, whether performed in pedigrees or by exploiting linkage disequilibrium, are likely to leave geneticists with a portion of the genome that contains tens if not hundreds of genes and many DNA sequence polymorphisms to examine to identify the causal variant. Mutations causing monogenic inherited diseases are often destructive enough to leave little doubt about their causality. Even if the functional consequences of such mutations were less transparent, demonstration of a perfect correspondence between genotype and