Farm animal evolution demonstrates hidden molecular basis of human traits

Most human variants identified by genome-wide association studies are believed to affect traits by altering gene expression. This belief is supported by considerable circumstantial evidence, but statistical methods are unable to link most trait-associated variants to gene expression-a problem we refer to as "missing regulation." Many explanations have been proposed, including the possibility that natural selection on gene expression limits power. Here, we take a novel approach to the question of missing regulation, beginning with the observation that the majority of trait-associated variants alter gene expression in two non-human species: cattle and pigs. We explain this discrepancy by comparing the species' evolutionary histories. The observed differences in regulatory variants are consistent with selection on human gene regulation and increased genetic drift due to agricultural breeding. The differences are not limited to specific genes and reflect increased ascertainment of regulatory variants that are distal to genes. Additionally, we show that trait-associated gene regulation in cattle and pigs matches observed patterns from complex-trait genetics in humans, and may reflect currently unobserved trait-associated regulation in humans.