Saturday, May 4, 2024
5/4/2024
Project Summary/Abstract Genomes are plagued by parasitic DNA sequences that do not promote health or fertility. Meiotic drive genes are one such class of genetic parasite that selfishly manipulate gametogenesis to increase their own transmission into the next generation. Rather than being passed to half of an individual’s offspring, like regular alleles, meiotic drivers manipulate gametogenesis to ensure their transmission to most, or even all, the offspring. Drivers are found throughout eukaryotes, including humans, but many more likely remain to be identified. Characterizing meiotic drivers is important because these parasites can have major impacts on fertility and health. Meiotic drivers can contribute to infertility directly by disrupting meiotic chromosome segregation or by destroying gametes that inherit the competing allele. Meiotic drivers can also cause infertility or other disease states indirectly by promoting the spread of linked deleterious (e.g., disease-associated) alleles. Despite their large impact, there is relatively little molecular understanding of meiotic drivers or their evolutionary impacts. However, there are emerging themes that unite many known drive systems, including the use of a poison/antidote mechanism and the association of meiotic drive genes with distributed DNA sequence repeats. This proposal exploits a highly tractable model, the wtf gene family found in fission yeasts, to investigate the molecular mechanisms and evolutionary impacts of drive systems. The wtf genes enact drive by destroying the wtf- gametes produced by wtf+/wtf- heterozygotes. Each wtf driver encodes both a poison protein and a separate antidote protein on overlapping coding sequences. All developing gametes are poisoned, but those that inherit the wtf+ allele are rescued by the antidote. This proposal aims to understand the mechanisms underlying the toxicity of Wtf poison proteins and how the Wtf antidote proteins rescue that toxicity. Analogous to other drive systems, the wtf genes are flanked by short repetitive DNA sequences (transposon-derived repeats or 5S rDNA genes). The proposed work will test the idea that the repeats flanking wtf genes affect their evolution by promoting non-allelic gene conversion. Finally, the proposed research program will explore the evolutionary impact of the wtf genes on the flanking 5S rDNA genes. Specifically, we will test the hypothesis that the wtf drivers have promoted the maintenance of deleterious versions of the 5S rDNA genes, which encode an essential component of ribosomes. This research program will greatly expand our understanding of the molecular mechanisms and molecular evolution of meiotic drive systems. This knowledge will help guide the search for and the molecular characterization of meiotic drivers in more complex systems, including humans. More broadly, this work will expand our understanding of DNA parasites and how they can directly and indirectly impact health, particularly infertility. This expanded understanding should ultimately lead to improved reproductive outcomes in humans.
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