# Selfish meiotic drive and the role of RNAi in defending intragenomic conflict

> **NIH NIH K99** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $100,000

## Abstract

Project Summary/Abstract
 Selfish meiotic drive systems (SMDs) that cheat Mendel’s law of segregation during gametogenesis are
ubiquitous in nature. Paradoxically, the wildtype activities of such selfish genes, which permit their biased
transmission, have negative fitness costs, such as distortion of sex-ratio (SR) or sterility. Therefore, SMDs are
catalysts for intragenomic conflicts and place strong pressure to innovate host suppression mechanisms.
Despite their ubiquity and powerful effects on normal transmission, the molecular mechanisms by which SMDs
emerge, operate, and are silenced, generally remain poorly understood. My prior works on the evolutionary
genomics of simulans clade introduced me to the recently-emerged “cryptic” SMDs in D. simulans (Dsim) and
motivated me to study the molecular basis of meiotic drive for postdoctoral work. A significant contribution from
my postdoctoral work revealed a crucial role for hairpin RNA (hpRNA)-class siRNA loci in suppressing the
SMDs, Distorter on the X (Dox) and Mother of Dox (MDox) in Dsim. Furthermore, transcriptome profiling from
RNAi mutants (Ago2 and Dcr2) revealed an array of de novo hpRNAs that were born in the simulans clade and
preferentially target X-chromosome genes, suggesting sex chromosomes as a breeding ground for
intragenomic conflicts. I hypothesize that the surprising role(s) of RNAi in resolving intragenomic conflicts may
be widespread across taxa, and untamed meiotic drive can propel speciation. The proposed work expands on
my discoveries utilizing a multidisciplinary approach. First, in Specific Aim 1, using clues to the origin, and
their provocative similarity to sperm packaging proteins, I will study how Dox/MDox impair spermatogenesis,
employing cutting-edge molecular biology and genomics. The training component of SA1 includes learning the
state-of-the-art CRISPR-Cas9 gene editing techniques, and testis cytology. Based on conserved themes in
genetic conflicts, I suspect a role for RNAi in resolving intragenomic conflict in mice, analogous to flies, and in
Specific Aim 2, I will test this hypothesis with the proprietary Ago-2 catalytic dead (Ago2-CD) mutant mice
generated in Dr. Eric Lai’s lab. The proposed work in SA2 will be performed in collaboration with Dr. Scott
Keeney, an expert in mouse meiosis and spermatogenesis at Sloan-Kettering Institute. The training component
of SA2 includes learning microscopy, image analysis, and morphological characterization of Ago2-CD mutant
mice. Finally, in Specific Aim 3, I will build upon the exciting discovery in Dsim that several cryptic SMDs can
be uncovered by ablating the RNAi pathway. I propose to employ RNAi mutants as a versatile “tool” to unmask
cryptic SMDs in non-model insects, which otherwise take years of laborious genetics to identify and
characterize SMDs. The training component described in the proposed work will complement my previous
experience, and position me for a productive career as an independent investigator...

## Key facts

- **NIH application ID:** 10127378
- **Project number:** 1K99GM137077-01A1
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Jeffrey Vedanayagam
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $100,000
- **Award type:** 1
- **Project period:** 2021-09-08 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10127378

## Citation

> US National Institutes of Health, RePORTER application 10127378, Selfish meiotic drive and the role of RNAi in defending intragenomic conflict (1K99GM137077-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10127378. Licensed CC0.

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