Evidence for Positive Selection on a Number of MicroRNA Regulatory Interactions during Recent Human Evolution

Abstract

MicroRNA (miRNA)–mediated gene regulation is of critical functional importance in animals and is thought to be largely constrained during evolution. However, little is known regarding evolutionary changes of the miRNA network and their role in human evolution. Here we show that a number of miRNA binding sites display high levels of population differentiation in humans and thus are likely targets of local adaptation. In a subset we demonstrate that allelic differences modulate miRNA regulation in mammalian cells, including an interaction between miR-155 and TYRP1, an important melanosomal enzyme associated with human pigmentary differences. We identify alternate alleles of TYRP1 that induce or disrupt miR-155 regulation and demonstrate that these alleles are selected with different modes among human populations, causing a strong negative correlation between the frequency of miR-155 regulation of TYRP1 in human populations and their latitude of residence. We propose that local adaptation of microRNA regulation acts as a rheostat to optimize TYRP1 expression in response to differential UV radiation. Our findings illustrate the evolutionary plasticity of the microRNA regulatory network in recent human evolution.

Author Summary

MicroRNAs (miRNAs) are endogenous small RNAs that bind to their target mRNAs to post-transcriptionally repress protein production. miRNA–mediated gene regulation is usually considered to be strongly conserved among and within species, and thus alteration of such regulations is usually considered as detrimental. However, it is likely that evolutionary divergence of miRNA regulation may actually be selectively advantageous and could even serve as a genetic reservoir for innovation and adaptation. Towards this goal, we identified a number of polymorphic miRNA binding sites that display extreme population differentiation and show evidence of positive selection. We experimentally validated 3 regulations, including a regulation by miR-155 on TYRP1, a melanosomal enzyme associated with human pigmentation. We found that the two alternate alleles on the 3′ UTR of TYRP1, either inducing or disrupting repression by miR-155, are under opposite selections among human populations. This results in a strong negative correlation between the degree of fixation of miR-155–mediated repression of TYRP1 in a population and the population's latitude of residence. These observations collectively suggest miR-155 acts a rheostat to optimize TYRP1 expression for local adaptation to differential UV radiation along the latitudes. Our findings demonstrate the plasticity of miRNA regulation in recent human evolution.