A map of human microRNA variation uncovers unexpectedly high levels of variability

Abstract

BackgroundMicroRNAs (miRNAs) are key components of the gene regulatory network in many species. During the past few years, these regulatory elements have been shown to be involved in an increasing number and range of diseases. Consequently, the compilation of a comprehensive map of natural variability in a healthy population seems an obvious requirement for future research on miRNA-related pathologies.MethodsData on 14 populations from the 1000 Genomes Project were analyzed, along with new data extracted from 60 exomes of healthy individuals from a population from southern Spain, sequenced in the context of the Medical Genome Project, to derive an accurate map of miRNA variability.ResultsDespite the common belief that miRNAs are highly conserved elements, analysis of the sequences of the 1,152 individuals indicated that the observed level of variability is double what was expected. A total of 527 variants were found. Among these, 45 variants affected the recognition region of the corresponding miRNA and were found in 43 different miRNAs, 26 of which are known to be involved in 57 diseases. Different parts of the mature structure of the miRNA were affected to different degrees by variants, which suggests the existence of a selective pressure related to the relative functional impact of the change. Moreover, 41 variants showed a significant deviation from the Hardy-Weinberg equilibrium, which supports the existence of a selective process against some alleles. The average number of variants per individual in miRNAs was 28.ConclusionsDespite an expectation that miRNAs would be highly conserved genomic elements, our study reports a level of variability comparable to that observed for coding genes.

Framework for microRNA variant annotation and prioritization using human population and disease datasets

“…); however, such prior efforts for noncoding RNAs have been challenging (Worth, Gong, & Blundell, ). We corroborated an earlier study of a smaller set of 729 miRNAs from 1000 Genomes Phase I dataset (Carbonell et al., ) and found that seed and mature domain variation is rare as compared to nearby regions (Figure b). Moreover, we report the largest catalog of seed and mature domain miRNA variation surpassing current datasets by many folds (Bhattacharya et al., ; Gong et al., ; Liu et al., ).…”

Unexpected findings of variability in microRNAs suggest roles in human genetics

“…[1] shows that we need to challenge some of the assumptions made about miRNAs, which would perhaps help us to understand better how miRNAs function. Certain questions arise from their results.…”

A selective screening platform reveals unique global expression patterns of microRNAs in a cohort of human soft-tissue sarcomas

“…11,12 Up until recently, most studies on miRNAs in sarcoma have utilized frozen specimens and have used tissue obtained from different patients as normal controls. Given the variability in miRNA expression between different individuals, [15][16][17] this methodology may lead to inaccurate results. The relative stability of miRNAs in formalin-fixed paraffin-embedded (FFPE) archival tissue has made them an attractive resource for miRNA profiling studies and indeed has been shown to be comparable to fresh frozen specimens.…”