Mechanisms of sperm dysfunction by meiotic drive

The National Institute of Child Health and Human Development awarded the University of Rochester $149,190 on February 1, 2026, under the Child Health and Human Development Extramural Research Projects program (CFDA 93.865) to investigate the molecular mechanisms of sperm dysfunction induced by meiotic drive.

The project combines gene editing, genetic, and cytological approaches to study segregation distorter (SD), a sperm-killing male meiotic driver found in natural populations of Drosophila melanogaster. The research has two specific aims: determining the role of responder (RSP) satellite-derived RNA in SD mechanisms and characterizing the timing and nature of the chromatin phenotype associated with sperm dysfunction. The work employs long-read-based epigenomic assays to study the dynamics of histone marks in driving testes and their controls, with the goal of elucidating how satellite DNA is regulated in the male germline and how chromatin states change during spermatogenesis.

Performance occurs at the University of Rochester in Rochester, New York, with a period of performance from February 1, 2026, through January 31, 2028.

Abstract

Meiosis ordinarily ensures the fair segregation of alleles to gametes. Meiotic drivers are selfish genetic elements that subvert this normally fair process and bias their transmission to the next generation, violating the principles of mendelian inheritance. Drivers are pervasive in sexually reproducing organisms and can spread in populations, even when they harm the host. We know little about the molecular mechanisms of drive but themes emerging from studies of sperm-killing male meiotic drivers implicate chromatin regulation and small rnas as important factors. This project proposes to study the molecular mechanism of drive in a powerful model system: segregation distorter (SD), a sperm killer found in natural populations of drosophila melanogaster. SD causes sperm dysfunction by inducing a chromatin defect in wild type spermatids containing a sensitive allele of its target-a large block of tandem satellite DNA repeats called responder (RSP)-through an unknown mechanism. This proposal studies the molecular basis of the SD- induced sperm chromatin defect and the role of the target in drive sensitivity. The project has two specific aims: 1) to determine the role of RSP satellite-derived RNA in the mechanism of SD; and 2) to determine the timing and nature of the chromatin phenotype associated with sperm dysfunction. The proposal combines gene editing techniques to manipulate RSP satellite-derived RNA, with genetic and cytological approaches to quantify the effects on drive strength and chromatin phenotypes. To study the chromatin defect in detail and pinpoint its timing, the proposal uses long-read-based epigenomic assays to study the dynamics of histone marks in driving testes and their controls. The fulfillment of these aims will shed light on mechanisms of drive, dynamic changes in chromatin states in testes, and how satellite dnas are regulated in the male germline. These insights have broad implications for our understanding of factors influencing male fertility in general and how spermatogenesis is vulnerable to selfish genetic elements.