Evolutionary Nonindependence Between Human piRNAs and Their Potential Target Sites in Protein-Coding Genes.

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PIWI-interacting RNAs (piRNAs) are the most diverse small RNAs in animals. These small RNAs have been known to play an important role in the suppression of transposable elements (TEs). Protein-coding genes (PCGs) are the most well-recognized functional genes in genomes. In the present study, we designed and performed a set of statistics-based evolutionary analyses to reveal nonrandom phenomena in the evolution of human piRNA-PCG targeting relationships. Through analyzing the occurrence of single nucleotide variants (SNVs) in potential piRNA target sites in human PCGs, we provide evidence that there exists a mutational force biased to strengthen piRNA-PCG targeting relationships. Through analyzing the allele frequencies of SNVs in potential piRNA target sites in human PCGs, we provide evidence that there exists a piRNA-dependent selective force acting on potential piRNA target sites in human PCGs. Because of these nonrandom evolutionary forces, human piRNAs and their potential target sites in PCGs are not independent in evolution. Additionally, we found evidence that potential piRNA target sites in human PCGs are particularly likely to be present in regions derived from Alu elements. This finding suggests that the aforementioned evolutionary forces acting on piRNA-PCG targeting relationships could be particularly prone to affect Alu-derived regions in human PCGs. Collectively, our findings provide new insights into the evolutionary interplay between piRNAs, PCGs, and Alu elements in the evolution of the human genome.