Quantitative trait loci (QTL) with small effects on phenotypic variation can be difficult to detect and analyze. Because of this a large fraction of the genetic architecture of many complex traits is not well understood. Here we use sporulation efficiency in Saccharomyces cerevisiae as a model complex trait to identify and study small-effect QTL. In crosses where the large-effect quantitative trait nucleotides (QTN) have been genetically fixed we identify small-effect QTL that explain approximately half of the remaining variation not explained by the major effects. We find that small-effect QTL are often physically linked to large-effect QTL and that there are extensive genetic interactions between small-and large-effect QTL. A more complete understanding of quantitative traits will require a better understanding of the numbers, effect sizes, and genetic interactions of small-effect QTL.
COMPLEX traits exhibit non-Mendelian inheritance patterns, which arise from the segregation of multiple quantitative trait loci (QTL) (Lander and Schork 1994). A QTL is a region of the genome containing an allelic difference that causes a change in phenotype. Many medically and agriculturally important traits exhibit complex genetic architecture, including phenotypes ranging from diabetes and cancer penetrance to meat quality and frost tolerance in crops (Glazier et al. 2002;Heuven et al. 2009;Dumont et al. 2009;Gaudet et al. 2010). QTL with relatively large effects are the easiest to identify and analyze, yet most QTL have small average effects on complex traits (Mackay 2001). Thus, while theory and experiment suggest that a large fraction of the variation of many phenotypes will be explained by QTL with smaller effect sizes (Fisher 1930;Lango Allen et al. 2010;Yang et al. 2011), our current understanding of complex traits is based primarily on analyses of QTL with the largest effect sizes. Because small-effect QTL are necessarily more difficult to detect and analyze, a large fraction of the genetic architecture of most complex traits is not well understood. A more complete model of complex traits should include an understanding of the numbers, effect sizes, and interactions of small-effect QTL.To identify and study small-effect QTL, we used sporulation efficiency in the yeast Saccharomyces cerevisiae as a model complex trait (Gerke et al. 2006). This system offers several advantages for the study of QTL with relatively small-effect sizes. Sporulation efficiency is a highly heritable trait in yeast (Gerke et al. 2006). The measurements of sporulation efficiency can be performed in controlled environments that provide the statistical power to detect QTL with small-effect sizes. With this system, we previously identified four quantitative trait nucleotides (QTN) that have large effects on sporulation efficiency (Gerke et al. 2009). Here we describe crosses designed to uncover additional QTL that account for phenotypic variation not explained by the major-effect QTN. For the purposes of this study we define these addition...