| 其他摘要 | microRNAs (miRNAs) are a growing class of small noncoding RNAs(~22nt), present in most multicellular organisms and important for a diverse range of biological functions. These miRNA genes act post-transcriptionally to target 3’UTRs of mRNAs for translational repression, cleavage and destabilization. It is shown that one miRNA could regulate hundreds of target genes in animals. Most of the identified miRNAs are highly conserved among species, indicating strong functional constraint on miRNA evolution. However, non-conserved miRNAs may contribute to functional novelties during evolution. To address the question that how miRNAs originate and evolve, we studied two non-conserved miRNA families in primate species. The first family is located in X chromosome and has more miRNA copies in primates than do rodents and dog. We sequenced and compared this miRNA family in major primate lineages including human, great ape, lesser ape, Old World monkey, and New World monkey. Our data indicate rapid evolution of this family in primates including frequent tandem duplications and nucleotide substitutions. In addition, lineage-specific substitutions were observed in human and chimpanzee, leading to the emergence of potential novel mature miRNAs. The expression analysis in rhesus monkeys revealed a strong correlation between miRNA expression changes and male sexual maturation, suggesting regulatory roles of this miRNA family in testis development and spermatogenesis. We propose that, like protein-coding genes, miRNA genes involved in male reproduction are subject to rapid adaptive changes that may contribute to functional novelties during evolution. The second family is a primate-specific miRNA family located in chromosome 19. By sequencing and comparative analysis of this family in 9 diverse primate species, we report evidence of an Alu-mediated rapid expansion of miRNA genes in the family. Evolutionary analysis reveals similar divergence among miRNA copies whether they are within or between species, lineage-specific gain and loss of miRNAs, and gene pseudolization in multiple species. These observations support a birth-and-death process of miRNA genes in this family, implicating functional diversification during primate evolution. In addition, both secondary structure conservation and reduced SNP density attest to functional constraint of this family in primates. Finally, we observed preferential expression of miRNAs in human placenta and fetal brain, suggesting a functional importance of this family for primate development. In addition, we also address the question that whether miRNA regulation could have impact on the variability of gene expression. With the use of the genome-wide expression data in 193 human brain samples, we show that the increased variability of gene expression is concomitant with the increased number of the miRNA seeds interacting with the target genes, suggesting a direct influence of miRNA on gene expression variability. Compared with the non-miRNA-target genes, genes targeted by more than two miRNA seeds have increased expression variability, independent of the miRNA types. In addition, SNPs located in the miRNA binding sites could further increase the gene expression variability of the target genes. We propose that miRNAs are one of the driving forces causing expression variability in the human genome. |
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