Dissection of genetically complex traits with extremely large pools of yeast segregants

Abstract

Discovering genetic basis of complex traits remains one of key challenges of today's genetic research. Current approaches cannot identify multiple loci with small effects because of the lack of statistical power. Ehrenreich et al. have developed a method that overcomes this problem. Working in yeast they use chemical resistance traits and mitochondrial function to demonstrate genetic complexity of many traits and that many of the underlying factors can be identified using their approach, which ultimately could be extended to other organisms. Complex heritable traits — such as human height and many human diseases — are caused by multiple genetic loci, each with small effects. It is hard to identify such loci, however, because of a lack of statistical power. Now, a method has been developed to overcome this problem. The method has been applied to chemical resistance traits and mitochondrial function in yeast, and has identified loci for each of these phenotypes. Most heritable traits, including many human diseases1, are caused by multiple loci. Studies in both humans and model organisms, such as yeast, have failed to detect a large fraction of the loci that underlie such complex traits2,3. A lack of statistical power to identify multiple loci with small effects is undoubtedly one of the primary reasons for this problem. We have developed a method in yeast that allows the use of much larger sample sizes than previously possible and hence permits the detection of multiple loci with small effects. The method involves generating very large numbers of progeny from a cross between two Saccharomyces cerevisiae strains and then phenotyping and genotyping pools of these offspring. We applied the method to 17 chemical resistance traits and mitochondrial function, and identified loci for each of these phenotypes. We show that the level of genetic complexity underlying these quantitative traits is highly variable, with some traits influenced by one major locus and others by at least 20 loci. Our results provide an empirical demonstration of the genetic complexity of a number of traits and show that it is possible to identify many of the underlying factors using straightforward techniques. Our method should have broad applications in yeast and can be extended to other organisms.