What Drives Positive Selection in the Drosophila piRNA Machinery? The Genomic Autoimmunity Hypothesis

Abstract

In animals, PIWI-interacting RNAs (piRNAs) play a crucial role in genome defense. Moreover, because piRNAs can be maternally transmitted, they contribute to the epigenetic profile of inheritance. Multiple studies, especially in Drosophila, have demonstrated that the machinery of piRNA biogenesis is often the target of positive selection. Because transposable elements (TEs) are a form of genetic parasite, positive selection in the piRNA machinery is often explained by analogy to the signatures of positive selection commonly observed in genes that play a role in host-parasite dynamics. However, the precise mechanisms that drive positive selection in the piRNA machinery are not known. In this review, we outline several mechanistic models that might explain pervasive positive selection in the piRNA machinery of Drosophila species. We propose that recurrent positive selection in the piRNA machinery can be partly explained by an ongoing tension between selection for sensitivity required by genome defense and selection for specificity to avoid the off-target effects of maladaptive genic silencing by piRNA.

Keywords: Red Queen; host-parasite; piRNA; positive selection; selfish elements; transposable element.

Figure 1

The piRNA biogenesis and silencing pathway. dN/dS estimates, indicated with varying intensity of red, between D. melanogaster and D. simulans piRNA pathway components were obtained from the flyDIVaS web server [81], with the exception of estimates for ago3, deadlock, Yb, maelstrom, rhino, squash, vasa, and valois. dN/dS estimates for these missing genes were obtained by through our analysis.

Figure 2

Models for TE evasion of the piRNA machiney. A. General pathway for piRNA silencing with cluster insert that becomes source of anti-sense piRNA, followed by transcriptional and post-transcriptional gene silencing. B. Direct antagonism. A TE encoded antagonist of a piRNA effector. Here, a TE encoded protein (red) interferes with a PIWI protein (blue) directed slicing reaction. An evolutionary change in the PIWI protein (blue) allows it to silence the mRNA of the TE. C. Evasion. Specialized localization of the TE mRNA (either temporal or physical) allows the TE mRNA to avoid being a target. Separation in space or time is indicated with the green line. Adaptation in the PIWI protein (blue) allows it re-localize and silence the TE mRNA. D. Cluster evasion. A newly arriving TE proliferates within the genome, but avoids inserting into a cluster. A change in protein sequence (perhaps in rhino, as has been proposed [52]) facilitates TE insertion into the cluster, leading to subsequent piRNA silencing of the TE family.

Figure 3

Evolutionary Rate Covariation analysis of piRNA proteins across the Drosophila genus. Results were obtained from [84]. Proteins in the middle of the table share the greatest signature of co-evolution. Evolutionary Rate Covariation (ERC) analysis measures the degree to which changes in one protein (relative to background) are correlated with changes in another (also relative to background). The analysis is performed by estimating branch specific amino acid divergence across a phylogeny. Here, branch specific amino acid divergence was estimated for 12 sequenced species of the Drosophila genus. Significance is measured relative to the genomic background of all pairwise covariation estimates. Some proteins are not available due to lack of clear orthologs in divergent species. Above the diagonal: ERC values. Values range from -1 to 1, with values closer to 1 indicate higher levels of covariation. Red intensity above diagonal scales with strength of correlation. Below the diagonal: P values. P values were determined empirically relative to background. Red intensity below diagonal scales with degree of significance. Significant co-variation across the piRNA machinery is demonstrated by a Z-score of observed P values being equal to -15.4 (P << .001).