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Primate piRNA Cluster Evolution Suggests Limited Relevance of Pseudogenes in piRNA-Mediated Gene Regulation.

ABSTRACT: PIWI proteins and their guiding Piwi-interacting (pi-) RNAs direct the silencing of target nucleic acids in the animal germline and soma. Although in mammal testes fetal piRNAs are involved in extensive silencing of transposons, pachytene piRNAs have additionally been shown to act in post-transcriptional gene regulation. The bulk of pachytene piRNAs is produced from large genomic loci, named piRNA clusters. Recently, the presence of reversed pseudogenes within piRNA clusters prompted the idea that piRNAs derived from such sequences might direct regulation of their parent genes. Here, we examine primate piRNA clusters and integrated pseudogenes in a comparative approach to gain a deeper understanding about mammalian piRNA cluster evolution and the presumed gene-regulatory role of pseudogene-derived piRNAs. Initially, we provide a broad analysis of the evolutionary relationships of piRNA clusters and their differential activity among six primate species. Subsequently, we show that pseudogenes in reserve orientation relative to piRNA cluster transcription direction generally do not exhibit signs of selection pressure and cause weakly conserved targeting of homologous genes among species, suggesting a lack of functional constraints and thus only a minor significance for gene regulation in most cases. Finally, we report that piRNA-producing loci generally tend to be located in active genomic regions with elevated gene and pseudogene density. Thus, we conclude that the presence of most pseudogenes in piRNA clusters might be regarded as a byproduct of piRNA cluster generation, whereas this does not exclude that some pseudogenes nevertheless play critical roles in individual cases.

SUBMITTER: Gebert D

PROVIDER: S-EPMC6461890 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Project description:There is accumulating evidence that polymorphism in Toll-like receptor (TLR) genes might be associated with disease resistance or susceptibility traits in livestock. Polymorphic sites affecting TLR function should exhibit signatures of positive selection, identified as a high ratio of non-synonymous to synonymous nucleotide substitutions (omega). Phylogeny based models of codon substitution based on estimates of omega for each amino acid position can therefore offer a valuable tool to predict sites of functional relevance. We have used this approach to identify such polymorphic sites within the bovine TLR2 genes from ten Bos indicus and Bos taurus cattle breeds. By analysing TLR2 gene phylogeny in a set of mammalian species and a subset of ruminant species we have estimated the selective pressure on individual sites and domains and identified polymorphisms at sites of putative functional importance.The omega were highest in the mammalian TLR2 domains thought to be responsible for ligand binding and lowest in regions responsible for heterodimerisation with other TLR-related molecules. Several positively-selected sites were detected in or around ligand-binding domains. However a comparison of the ruminant subset of TLR2 sequences with the whole mammalian set of sequences revealed that there has been less selective pressure among ruminants than in mammals as a whole. This suggests that there have been functional changes during ruminant evolution. Twenty newly-discovered non-synonymous polymorphic sites were identified in cattle. Three of them were localised at positions shaped by positive selection in the ruminant dataset (Leu227Phe, His305Pro, His326Gln) and in domains involved in the recognition of ligands. His326Gln is of particular interest as it consists of an exchange of differentially-charged amino acids at a position which has previously been shown to be crucial for ligand binding in human TLR2.Within bovine TLR2, polymorphisms at amino acid positions 227, 305 and 326 map to functionally important sites of TLR2 and should be considered as candidate SNPs for immune related traits in cattle. A final proof of their functional relevance requires further studies to determine their functional effect on the immune response after stimulation with relevant ligands and/or their association with immune related traits in animals.

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Primate piRNA Cluster Evolution Suggests Limited Relevance of Pseudogenes in piRNA-Mediated Gene Regulation.

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