Conserved Pool of piRNAs Function in Reproduction

Abstract

Piwi-interacting RNAs (piRNAs), small RNAs highly expressed in gonads, seem to evolve rapidly—even closely related species have distinct repertoires of these RNAs. However, a new study shows an exception to this pattern: a special set of piRNAs have deeply conserved expression patterns in eutherian mammals, which have placentas [1]. These conserved piRNAs seem to have key roles in reproduction. PiRNAs come in several flavors. Many piRNAs are encoded in large ‘‘intergenic’’ clusters of 10–100 kb. Some of these piRNAs repress transposons during gametogenesis, and others seem to regulate the activity of protein-coding genes, for instance—during spermatogenesis. In addition, a distinct set of ‘‘genic’’ piRNAs are found in the 3UTRs of many protein-coding genes (about 1700 in humans). The 3UTRs of these genes yield piRNAs that are active in gametogenesis and may have regulatory roles. In the new study, Nelson Lau and colleagues examined sequence data from piRNA loci in multiple animals. These included Drosophilids, chicken, and eleven mammals, from humans to horses. The researchers supplemented these data with their own analysis of piRNA loci from various species— for instance, assessing expression in testes. In sync with previous studies, the researchers found that most piRNA loci evolve rapidly (and they propose that this rapid evolution may largely be a result of genetic drift). They also found a set of piRNA loci that are deeply conserved in piRNA expression across eutherian mammals. This set comprised 21 intergenic and 56 genic piRNA loci that are highly expressed in humans, mice, and dogs—which share a common placental mammal ancestor about 100 million years ago. The conservation of piRNA expression occurred in orthologous loci even when the underlying sequence was not highly conserved. The researchers homed in on several of these genes—their analysis and previous studies suggest a key role in reproduction. For instance, two of the conserved genic loci are in widelydeployed genes (Cbl and Asb1) that also have mutants with male fertility defects. The researchers provide evidence that these fertility defects are due to loss of the genic piRNAs in the testes. Moreover, one of the conserved intergenic piRNA loci encodes a transcript antisense to STOX1, a gene implicated in pre-eclampsia in humans. Future studies should help reveal the function of these special piRNA loci, and further assess their role in reproduction and fertility.