Pervasive selection against microRNA target sites in human populations

Abstract

MicroRNA target sites are often conserved among related species. On the other hand, purifying selection against novel microRNA target sites can also exist. However, the relative impact of conservation versus selection against target sites is still unknown. We investigated these processes in human populations by focusing on polymorphic sites in which one allele is a target site and the other is not. Target allele frequencies were significantly lower than expected at these sites. The analysis of derived allele frequencies revealed that, when the non-target allele is ancestral, the proportion of non-target sites is higher than expected by chance. Conversely, when the target allele is ancestral, the proportion of non-target alleles is also significantly higher than expected. These analyses reveal a selective pressure against microRNA target alleles, which is more effective than selection to conserve target sites. Additionally, microRNA target sites show relatively low levels of population differentiation (Fst). However, when we analyse separately target sites in which the target allele is ancestral in the population, the proportion of SNPs with high Fst significantly increases. These findings support a scenario in which population differentiation (and possible local adaptation) is much more likely in target sites that are lost than in the gain of new target sites.Taking all the results together, we conclude that there is evidence of pervasive selection against microRNA target sites in human populations. The overall impact across untranslated regions is not negligible and should be taken into account when studying the evolution of genomic sequences.

The impact of population variation in the analysis of microRNA target sites

“…In microRNA target sites, some studies have shown that, as expected, functional target sites are often conserved in populations [19,20]. On the other hand, the creation of novel, potentially harmful, microRNA target sites, is selected against in populations [21,22]. In summary, the literature clearly shows evidence that nucleotide variation occurs at microRNA target sites.…”

“…We found 11 target sites with such a degree of variation across populations (Table 1) for highly expressed microRNAs. In general, these target sites are lost in Out-of-Africa populations, suggesting that losses rather than the gains of target sites are more likely to happen during differentiation between populations (see discussion in [22]). HM13 rs6059873 0.0000 0.1844 0.8275 0.1571 0.0378 0.7298 a SNP names are dbSNP accession numbers.…”

PopTargs: a database for studying population evolutionary genetics of human microRNA target sites

“…To explore variation at target sites in pre-computed lists, the ‘Browse’ form allows to study microRNAs with different levels of expression, expression breath, evolutionary conservation and even sub-population structure. For instance, we recently reported that in human populations there is detectable selection against microRNA target sites (6). We can explore some specific cases with PopTargs.…”

PopTargs: A database for studying population evolutionary genetics of human microRNA target sites

“…The fact that their targets can be predicted from their primary sequence has been exploited to study the potential impact of single-nucleotide polymorphisms at their target sites. Indeed, a number of studies have reported selective pressures at these target sites by investigating the variation in populations (3)(4)(5)(6).…”