The complexity of heredity has been appreciated for decades: Many traits are controlled not by a single genetic locus but instead by polymorphisms throughout the genome. The importance of complex traits in biology and medicine has motivated diverse approaches to understanding their detailed genetic bases. Here, we focus on recent systematic studies, many in budding yeast, which have revealed that large numbers of all kinds of molecular variation, from noncoding to synonymous variants, can make significant contributions to phenotype. Variants can affect different traits in opposing directions, and their contributions can be modified by both the environment and the epigenetic state of the cell. The integration of prospective (synthesizing and analyzing variants) and retrospective (examining standing variation) approaches promises to reveal how natural selection shapes quantitative traits. Only by comprehensively understanding nature's genetic tool kit can we predict how phenotypes arise from the complex ensembles of genetic variants in living organisms.

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