DESCRIPTION (provided by applicant): My research focus is to understand the molecular mechanisms of meiosis and infertility. I was trained as a geneticist, but I came to the Fred Hutchinson Cancer Research Center to expand my training in the lab of Dr. Harmit Malik. Dr. Malik is teaching me how to use an evolution-guided approach to explore the molecular causes of infertility. I hypothesized that selfish genetic parasites, such as transposable elements (TEs) and meiotic drive alleles may be significant contributors to infertility within natural populations including humans. These parasites persist in genomes because they act in the germline to promote their own transmission into gametes. TEs act by inserting copies of themselves into new genomic locations. Meiotic drive alleles bias their own transmission into functional gametes by altering meiotic chromosome segregation, or by killing gametes that do not inherit them. Differences between what is best for the parasite and what is best for the host sets up an `evolutionary arms race' where each side must rapidly evolve. This rapid evolution could contribute to the natural variation underlying differential health and fertility within a populatio. To test these ideas, I use S. pombe (Sp), its closely related sister species (99.5% sequence identity) S. kambucha (Sk), and Sk/Sp hybrids. I found that TEs and meiotic drive alleles each contributed to the rapid evolution of infertility between Sp and Sk. I also discovered significant functional divergence between Sp and Sk meiosis in that Sk is less able to ensure that meiosis generates haploid, as opposed to aneuploid gametes. My proposal expands my discoveries utilizing an interdisciplinary approach. First, I will use genetics and a novel genomics approach to map and identify the molecular mechanisms by which three meiotic drive loci within Sk act. Second, I will obtain training in confocal microscopy and utilize cytology and genetics to determine the mechanism and genetic determinants of the differential propensity of Sk and Sp to generate aneuploid gametes. Finally, my proposal further probes the functional consequences of rapid genome evolution, driven by genetic parasites and other factors, by using genetics and genomics to assess how the suite of genes essential for life and sexual reproduction differs between Sk and Sp. This will require me to learn computer programming and bioinformatics. Together, these aims will expand our understanding of the causes of infertility, congenital aneuploidy, and how rapid evolution can cause the functional divergence of genes essential for life and sexual reproduction. This award will allow me to obtain the training and resources I require to complete my research objectives. This training and the innovative research program it supports will help me reach my short-term goal of obtaining a junior faculty position. The award will also help me pursue my long-term career goal of uncovering causes of infertility within natural populations, including humans.

PUBLIC HEALTH RELEVANCE: Transposable elements and meiotic drive alleles are selfish genes found in humans that can cause rapid genome evolution, infertility, and contribute to the persistence of mal-adapted (e.g. disease-causing) alleles in a population. This proposal utilizes an innovative evolution-guided approach to uncover the mechanisms by which meiotic drive alleles can act and to address the functional consequences of rapid genome evolution on essential cellular processes. This work will provide novel insights into how selfish genes contribute to infertility, congenital aneuploidy, and differential penetrance of allele phenotypes n diverse individuals.