Finding the sources of missing heritability in a yeast cross

In a cross between two yeast strains, detected loci are found to explain nearly the entire additive contribution to heritable variation for a number of quantitative traits. Missing heritability 'disappears' on close examination Genome-wide studies have yielded important insights into the genetic basis of human disease but the identified loci explain only a minority of the heritable contribution to trait variation. In search of this 'missing heritability', Leonid Kruglyak and colleagues use a large cross between two yeast strains to analyse 46 quantitative traits in great detail. They find that the underlying loci explain nearly the entire additive contribution to heritable variation for these traits. Depending on the trait, the contribution to heritability of gene–gene interactions varies from near zero to 50%. This result implies that when a sufficiently powerful study is carried out, much of the 'missing' heritability is revealed and the remaining missing component arises primarily from many loci with small but not infinitesimal effects. For many traits, including susceptibility to common diseases in humans, causal loci uncovered by genetic-mapping studies explain only a minority of the heritable contribution to trait variation. Multiple explanations for this ‘missing heritability’ have been proposed 1 . Here we use a large cross between two yeast strains to accurately estimate different sources of heritable variation for 46 quantitative traits, and to detect underlying loci with high statistical power. We find that the detected loci explain nearly the entire additive contribution to heritable variation for the traits studied. We also show that the contribution to heritability of gene–gene interactions varies among traits, from near zero to approximately 50 per cent. Detected two-locus interactions explain only a minority of this contribution. These results substantially advance our understanding of the missing heritability problem and have important implications for future studies of complex and quantitative traits.