Abstract

Genetic variants in microRNA genes might be responsible for changes in their regulatory profile and, therefore, may generate functional adaptations underlying phenotypic diversity. We aim to study genetic variation and population-specific differentiation in 1918 human microRNA genes (miRBase v.22) taking into account their genomic context and evolutionary conservation. According to our analysis most human microRNAs, 51.7%, were primate-specific, versus 33.7% that were conserved beyond primates and 14.5% unclassified. We found 669 nucleotide variants (1KGP Phase-III, MAF>0.5%) in 504 microRNAs and, in contrast to previous reports, a higher nucleotide diversity was found in the seed microRNA region compared with the rest of the mature and hairpin sequences. These differences were particularly remarkable in the group of primate-specific microRNAs and were associated with a higher presence of transposable elements, in agreement with the explosion of microRNAs derived from transposable elements in primate lineages. Population-specific differences in variants located in either the seed or mature microRNA regions were analysed using the Hudson estimator of the Fst statistic across a global sample of 26 European, African and Asian human populations. Nineteen candidate microRNA variants to be highly differentiated were obtained by extracting the 1% most extreme values and considered for further investigation. Seven of them were associated with phenotypic differences in human populations, particularly with allele-specific differences in cancer risk. Evolutionary and functional studies of these candidate microRNA variants by considering allele-specific changes within regulatory networks will help to gain insight into the mechanisms underlying human phenotypic diversity and, eventually, to find signals of positive selection.