I am proposing a training program that will prepare me for an independent research career in the field of evolutionary genomics. I received my PhD from the Laboratory of Genetics at the University of Wisconsin- Madison for my work on the genetic and evolutionary basis of mammalian species differences in global recombination rate. I then completed a 2-year postdoc in the Department of Genome Sciences at the University of Washington where I acquired considerable experience and proficiency in the computational analysis of large genomic datasets. Through the proposed training program, I will expand my experimental skill set to include genomic library construction, diverse cytogenetic methods, and functional analyses of candidate genes in mammalian model systems. I propose a 5-year research program composed of a 2-year phase of organized mentorship and training in the Initiative for Biological Complexity at North Carolina State University (NCSU), followed by a 3-year research phase as an independent investigator. The proposed training program will leverage cutting-edge sequencing technologies and innovative methods for chromosome visualization to elucidate the mechanisms of recurrent degeneration and loss of the pseudoautosomal region (PAR) in voles (genus Microtus). This research will draw on diverse research fields, including genomics, evolutionary biology, and cytogenetics. Dr. Trudy Mackay, William Neal Reynolds and Distinguished University Professor of Genetics, will act as the primary mentor for my scientific development. Dr. Mackay is a world-renowned for her work in evolutionary and quantitative genetics, and has an impressive record of successful students and postdocs as a testament to her commitment and enthusiasm for training young investigators. Dr. David Threadgill, Professor and head of the Department of Genetics at NCSU, will provide specific instruction in mouse functional genetics. Dr. Matthew Breen and Dr. Lisa McGraw, both at NCSU, will provide focused mentoring in cytogenetics and vole genetics, respectively. The remarkable breadth of faculty research interests and their overlap with the intellectual and experimental foci of the proposed training program make NCSU the optimal place for conducting the mentored phase of this research. The mammalian PAR promotes pairing, synapsis, and recombination between the heterogametic sex chromosomes at meiosis. These processes are integral to proper sex chromosome segregation. Failure to initiate pairing or recombination in the PAR can lead to spermatogenic failure, infertility, and sex chromosome aneuploidy, including Turner and Kleinfelter Syndromes in humans. Despite its important meiotic function, the PAR is structurally dynamic, rapidly evolving, and has even been completely lost in several exceptional mammalian species. Voles (genus Microtus) display particularly exciting trends in recent PAR evolution. Across the vole phylogeny, there is evidence for ?3 parallel losses of X/Y chromosome pairing at meiosis, including multiple closely related species pairs with and without meiotic sex chromosome associations. I propose to study these recurrent evolutionary episodes to address 3 specific questions: 1. What structural and sequence-level changes precipitated the degeneration and loss of the PAR along these vole lineages? I propose cytogenetic assays and genome sequence comparisons between closely related vole species with and without meiotic X/Y pairing and recombination to answer this question. 2. How do unpaired, achiasmate sex chromosomes reliably segregate at meiosis? I propose cytological studies linking sex chromosome dynamics with the localization patterns of meiotic proteins to identify candidate achiasmate segregation genes. 3. Do candidate X/Y segregation genes identified in voles rescue sex chromosome segregation defects in organisms with obligate requirements for PAR pairing that harbor disruptive mutations across the region? I will carry out these functional tests using a mouse model with a high frequency of sex chromosome aneuploidy. The availability of multiple, independent episodes of PAR loss across the vole phylogeny presents a logical transition between a mentored phase focused on dissecting the basis of X/Y pairing loss in one species set, and an independent investigator phase that builds on this training to determine the mechanisms of PAR degradation and sex chromosome segregation in other vole species. The proposed research program will provide key insights into the mechanisms of PAR evolution and sex chromosome segregation at meiosis, with potential clinical consequences for understanding the genesis of sex chromosome aneuploidies in humans.

Public Health Relevance

Errors in sex chromosome segregation at meiosis can lead to sex chromosome aneuploidies such as Turner Syndrome and Kleinfelter Syndrome in humans. The proposed research will capitalize on remarkable trends in recent sex chromosome evolution in voles to determine how proper sex chromosome segregation is achieved in closely related species with diverse sex chromosome architectures. The proposed research program will provide significant insights into the mechanisms of sex chromosome evolution and sex chromosome segregation at meiosis, and will advance our understanding of the genetic etiology of human aneuploidy.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Melillo, Amanda A
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Jackson Laboratory
Bar Harbor
United States
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