Adaptive eQTLs reveal the evolutionary impacts of pleiotropy and tissue-specificity, while contributing to health and disease in human populations

Regulatory DNA has the potential to be adaptive, and large numbers of expression quantitative trait loci (eQTLs) have recently been identified in humans. For the first time, a comprehensive study of adaptive eQTLs is possible. Many eQTLs have large allele frequency differences between populations, and these differences can be due to natural selection. Here, we combined population branch statistics with tissue-specific eQTL data to identify positively selected loci in human populations. Adaptive eQTLs tend to affect fewer tissues than non-adaptive eQTLs. Because the tissue breadth of an eQTL can be viewed as a measure of pleiotropy, these results suggest that pleiotropy can inhibit adaptation. The proportion of eQTLs that are adaptive varies by tissue, and we find that eQTLs that regulate expression in testis, thyroid, blood, or sun-exposed skin are enriched for adaptive outliers. By contrast, eQTLs that regulate expression in the cerebrum or female-specific tissues have a relative lack of adaptive outliers. These results reveal tissues that have been the targets of adaptation during the last 100,000 years of human evolution. The strongest adaptive signal in many regions of the human genome is an eQTL, including an eQTL associated with the Duffy blood group and malaria resistance. Scans of selection also reveal that many adaptive eQTLs are closely linked to disease-associated loci. Taken together, our results indicate that adaptive eQTLs have played an important role in human evolution.