Signatures of Genetic Variation in Human microRNAs Point to Processes of Positive Selection and Population-specific Disease Risks

Abstract The occurrence of natural variation in human microRNAs has been the focus of numerous studies during the last twenty years. Most of them have been centered on the role of specific mutations in disease, while a minor proportion seek to analyse microRNA diversity in the genomes of human populations. We investigate the latest human microRNA annotations in the light of the most updated catalog of genetic variation provided by the 1000 Genomes Project. By means of the in silico analysis of microRNA variants we show that the level of evolutionary constraint of these sequences is governed by the interplay of different factors, like their evolutionary age or genomic location. The role of mutations in the shaping of microRNA-driven regulatory interactions is emphasized with the acknowledgement that, while the whole microRNA sequence is highly conserved, the seed region shows a pattern of higher genetic diversity that appears to be caused by the dramatic frequency shifts of a fraction of human microRNAs. We highlight the participation of these microRNAs in population-specific processes by identifying that not only the seed, but also the loop, are particularly differentiated regions among human populations. The quantitative computational comparison of signatures of population differentiation showed that candidate microRNAs with the largest differences are enriched in variants related to gene expression levels (eQTLs), selective sweeps and pathological processes. We explore the implication of these evolutionary-driven microRNAs and their single nucleotide variants in human diseases, such as different types of cancer, and discuss their role in population-specific disease risk.