RNAi biology during intragenomic conflict and speciation

The Eric Lai lab at Sloan-Kettering Institute (NYC) has positions available under a newly funded NIH-R01 to address exciting and fundamental questions in small RNA biology, meiotic and chromosome conflicts, and ultimately the mechanisms of speciation.

What is endogenous RNAi utilized for? We earlier described a mysterious class of endo-RNAi substrates termed hpRNAs (Okamura Nature 2008), and later recognized these mediate adaptive gene regulation in testis (Wen Molecular Cell 2015). These data open a window on a vital biology of RNAi during spermatogenesis, and now lead us to explore the evolution and function of RNAi systems.

We discovered networks of rapidly evolving hpRNAs, and successfully used CRISPR/Cas9 in non-model fly species to test their functions (Lin Developmental Cell 2018). Amazingly, while RNAi mutants were historically thought to lack overt phenotypic impacts, we find that hpRNAs are responsible for silencing meiotic drive loci whose deleterious activities can paradoxically drive species extinction. We are excited to characterize more of these hpRNA loci, which unlock keys to genetic distorter loci that have been kept silent in a cryptic state (Vedanayagam, Nature Ecology & Evolution 2021). Reciprocally, we are fascinated to understand the novel molecular mechanisms by which these de novo selfish meiotic drivers act to bend Mendel’s laws. Overall, we find that endo-RNAi is used in parallel to the piRNA pathway, as two adaptive regulatory strategies that defend against distinct classes of invasive nucleic acid entities.

The ideal candidate will take advantage of our extensive unpublished genetic tools and genomic resources, and combine genome engineering, biochemistry, and/or bioinformatics to probe the evolution and function of RNAi to resolve intragenomic conflicts that deplete male progeny or induce male sterility. Although the entry point is RNAi biology, we anticipate these selfish factors will intersect with chromatin mechanisms. The candidate will integrate into a team engaged in diverse RNA topics (e.g. miRNAs, APA, m6A) in fly and mammalian models, and the Sloan-Kettering Institute provides a vibrant and inclusive research community.

We would love to talk to interested scientists at all levels (postdoc, postbac, staff), who share our excitement with RNA biology and meiotic drive. Please provide CV, motivation letter and references to Eric Lai, laie@mskcc.org.

Relevant recent papers on endogenous RNAi and meiotic drive:

Vedanayagam J., C.-J. Lin and E. C. Lai (2021). Rapid evolutionary dynamics of an expanding family of meiotic drive factors and their hpRNA suppressors. Nature Ecology & Evolution 5: 1613-1623. (Featured in NEE 5: 1574-1575).

Lin, C.-J., F. Hu, R. Dubruille, J. Wen, J. Vedanayagam, P. Smibert, B. Loppin and E. C. Lai (2018). The hpRNA/RNAi pathway is essential to resolve intragenomic conflict in the Drosophila male germline. Developmental Cell 46: 316-326. (Featured in Dev Cell 46: 251-253).

Kondo S., J. Vedanayagam, J. Mohammed, S. Eizadshenass, L. Kan, N. Pang, R. Aradhya, A. Siepel, J. Steinhauer and E. C. Lai (2017). New genes often acquire male-specific functions but rarely become essential in Drosophila. Genes and Development 31: 1841–1846. (Featured in G&D 31: 1825-1826.)

Wen, J., H. Duan, F. Bejarano, K. Okamura, L. Fabian, J. A. Brill, D. Bortolamiol-Becet, R. Martin, J. G. Ruby and E. C. Lai (2015). Adaptive regulation of testis gene expression and control of male fertility by the Drosophila hairpin RNA pathway. Molecular Cell 57: 165-78.