Abstract
microRNAs are crucial post-transcriptional regulators of gene expression involved in a wide range of biological processes. Although microRNAs are highly conserved among species, the functional implications of existing lineage-specific changes and their role in determining differences between humans and other great apes have not been specifically addressed. We analyzed the recent evolutionary history of 1,595 human microRNAs by looking at their intra- and inter-species variation in great apes using high-coverage sequenced genomes of 82 individuals including gorillas, orangutans, bonobos, chimpanzees and humans. We explored the strength of purifying selection among microRNA regions and found that the seed and mature regions are under similar and stronger constraint than the precursor region. We further constructed a comprehensive catalogue of microRNA species-specific nucleotide substitutions among great apes and, for the first time, investigated the biological relevance that human-specific changes in microRNAs may have had in great ape evolution. Expression and functional analyses of four microRNAs (miR-299-3p, miR-503-3p, miR-508-3p and miR-541-3p) revealed that lineage-specific nucleotide substitutions and changes in the length of these microRNAs alter their expression as well as the repertoires of target genes and regulatory networks. We suggest that the studied molecular changes could have modified crucial microRNA functions shaping phenotypes that, ultimately, became human-specific. Our work provides a frame to study the impact that regulatory changes may have in the recent evolution of our species.
Highlights
Over the last years, attention has been focused on the role that regulatory elements may have played in shaping diversification among species and individuals that share extended genomic similarities
MiRNAs are initially transcribed by RNA polymerase II as primary miRNAs, from which Drosha-mediate cleavage gives a ~70 nt hairpin precursor miRNA, that is processed by Dicer in the cytoplasm into a miRNA duplex formed by two ~22 nt mature miRNA strands, 5p and 3p [6]
We first looked for differences in sequence conservation among miRNA functional domains by calculating single nucleotide variants density (SNV density) in 1,125 out of 1,595 human miRNAs for which we found an orthologous miRNA gene in all great ape species
Summary
Attention has been focused on the role that regulatory elements may have played in shaping diversification among species and individuals that share extended genomic similarities. Certain specific changes in transcription factors and non-coding RNAs have been shown to be under positive selection and to contribute to determine phenotypic differences between species such as humans and chimpanzees [1,2]. Among non-coding RNAs, microRNAs (miRNAs) are key post-transcriptional gene regulators with a clear role in evolution that are implicated in almost every biological function and in many types of diseases such as cancer and neurological disorders [3,4,5]. It was believed that only one of the two mature miRNA strands, named the major strand, played a significant role in gene regulation, while the other one was degraded. Stress out the biological importance of both mature strands in gene repression [8,10,11]
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