16 Genomics of the Future: Identification of Quantitative Trait Loci in the Mouse

Abstract

Identifying genetic loci controlling complex traits (quantitative trait loci or QTLs) is one of the biggest challenges confronting genetics. These genes influence such traits as growth, morphology, and behavior and determine susceptibility and severity for nearly every disease. In particular, QTLs represent a gateway to the genetic factors controlling common, non-Mendelian diseases, such as heart disease and cancer, and affect many more people than the classic single gene diseases studied in the early days of positional cloning. These diseases have clear genetic components, yet the underlying genes have proven difficult to identify. Unfortunately, these genes are usually subtle in their expression and effect on the general phenotype of the organism; they interact with other genes and environmental effects making them difficult to isolate and they often have a low penetrance. Positional cloning of these QTLs in rodents has proved to be one of the most powerful tools for the functional identification of these genes (Georges 1997). The first step in this procedure is to map these loci to particular chromosomal regions, usually spanning anywhere from 10–40 cm. Over two thousand QTLs have been mapped (http://www.pubmed.com); however, the future narrowing of these regions and the subsequent identification of these QTLs are not easy (Flint et al. 2005). Sometimes, these QTLs contain polymorphisms resulting in obvious and deleterious effects on expression and function. More often, sequence differences are difficult to reconcile with the predicted phenotypes or cause expression and/or phenotypic variations that are subtler. Often there is no “smoking gun.” Given...