Reconstructing Evolutionary Arms Races

Genes promoting their own transmission to the next generation are often in evolutionary arms races with other competing DNA sequences. The mouse X chromosome harbors a recently acquired gene family Slx and Slxl1, which is in an evolutionary arms race with a Y chromosome gene family Sly, to influence sperm fertilization success. A mechanistic understanding of how these two X- and Y-linked gene families compete will help address how evolutionary arms races evolve and how they influence sperm fertilization success. This proposal hypothesizes SLX and SLXL1 directly compete with SLY1 and SLY2 to influence sperm fertilization success. This hypothesis is based on preliminary data of the proteins interacting directly with specific domains of known and putative spindlin proteins. We will use a combination of novel in vitro genomic approaches (e.g. massively parallel sequencing screens and yeast three-hybrid competitions) to model how the X- and Y-linked gene families compete. The in vitro studies will inform in vivo transgenic studies to assess how the gene family variants influence sperm fertilization success. We will determine how the dosage of SLX and SLXL1 proteins influences the molecular competition with SLY1 and SLY2 in vitro. We will determine the most competitive alleles of SLXL1 and SLY2 via an in vitro saturation mutagenesis competition and comparative evolutionary analyses. Our understandings of the in vitro competitions will be translated into testing whether competitive SLXL1 and SLY2 alleles influence sperm fertilization success in mice. Collectively, our studies will deepen and expand our understanding of how proteins evolve to compete in evolutionary arms races and how the competitions can influence sperm reproductive success. This knowledge will provide new insights into the molecular basis of male infertility, sex ratio distortion, and the mechanics of how proteins compete. Project Number: 1R01GM158728-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Jacob Mueller | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $1,601,098 | Activity Code: R01 | Study Section: Genetic Variation and Evolution Study Section[GVE] View on NIH RePORTER: https://reporter.nih.gov/project-details/11294940