Regulatory logic of endogenous RNAi in silencing de novo genomic conflicts Journal Article
| Authors: | Vedanayagam, J.; Lin, C. J.; Papareddy, R.; Nodine, M.; Flynt, A. S.; Wen, J. Y.; Lai, E. C. |
| Article Title: | Regulatory logic of endogenous RNAi in silencing de novo genomic conflicts |
| Abstract: | Although the biological utilities of endogenous RNAi (endo-RNAi) have been largely elusive, recent studies reveal its critical role in the non-model fruitfly Drosophila simulans to suppress selfish genes, whose unchecked activities can severely impair spermatogenesis. In particular, hairpin RNA (hpRNA) loci generate endo-siRNAs that suppress evolutionary novel, X-linked, meiotic drive loci. The consequences of deleting even a single hpRNA (Nmy) in males are profound, as such individuals are nearly incapable of siring male progeny. Here, comparative genomic analyses of D. simulans and D. melanogaster mutants of the core RNAi factor dcr-2 reveal a substantially expanded network of recently-emerged hpRNA-target interactions in the former species. The de novo hpRNA regulatory network in D. simulans provides insight into molecular strategies that underlie hpRNA emergence and their potential roles in sex chromosome conflict. In particular, our data support the existence of ongoing rapid evolution of Nmy/Dox-related networks, and recurrent targeting of testis HMG Box loci by hpRNAs. Importantly, the impact of the endo-RNAi network on gene expression flips the convention for regulatory networks, since we observe strong derepression of targets of the youngest hpRNAs, but only mild effects on the targets of the oldest hpRNAs. These data suggest that endo-RNAi are especially critical during incipient stages of intrinsic sex chromosome conflicts, and that continual cycles of distortion and resolution may contribute to speciation. Author summarySelfish meiotic drive loci promote their own transmission at the cost of host reproductive fitness. Therefore, their existence and activity places strong pressure to innovate genetic suppressors that can return gametogenesis to a normal Mendelian state. Because such genetic battles are typically kept in a silenced, cryptic state, the identity of underlying meiotic drivers and suppressors is often hidden. We find that endo-siRNAs generated by the hairpin RNA (hpRNA) substrates of the RNA interference (RNAi) pathway evolve rapidly, and strongly repress specific genes in the male germline that exhibit signatures of genetic conflict. This indicates that genetic analysis of RNAi-suppressed target networks is a new forward strategy to uncover loci with candidate meiotic drivers. More generally, these data flip the convention for gene regulatory strategies for the paralogous miRNA pathway. Whereas only the oldest miRNAs typically have gained high expression levels and substantial target repression, it is the very youngest hpRNA-siRNA loci that exhibit highest expression and most overt effects on gene silencing. |
| Keywords: | evolution; gene-expression; pathway; duplication; expression analysis; y-chromosome; segregation distortion; drosophila-simulans; seq experiments; nhk-1 |
| Journal Title: | PLoS Genetics |
| Volume: | 19 |
| Issue: | 6 |
| ISSN: | 1553-7390 |
| Publisher: | Public Library of Science |
| Date Published: | 2023-06-01 |
| Start Page: | e1010787 |
| Language: | English |
| ACCESSION: | WOS:001012429500001 |
| DOI: | 10.1371/journal.pgen.1010787 |
| PROVIDER: | wos |
| PMCID: | PMC10317233 |
| PUBMED: | 37343034 |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding author is MSK author Eric C. Lai -- Source: Wos |
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