Factors Shaping the Genomic Spectrum of Structural Variants - Despite decades of research into mechanisms of double-strand break (DSB) repair, factors shaping the outcomes of defective repair remain poorly understood. DSB repair plays a central role in the maintenance of genome integrity, and is relevant for a variety of congenital diseases, cancer, and infertility. DSBs are repaired by a range of mechanisms that utilize varying lengths of homologous sequence to form repair intermediates. The mutations that occur when DSBs are joined to incorrect regions of the genome are termed structural variants (SVs). I hypothesize that factors guiding SV formation and genomic patterns of SVs can be revealed by studying features of SVs such as imperfect sequence homology, span, and SV type (ie deletion, translocation, etc). Using innovative computational methods and experimentation in yeast and human cells, I will test the following hypotheses: Aim 1: Homology-mediated DSB repair uses imperfect homology to repair DSBs. My previous results suggest that imperfect homology, or microhomeology (MHe) likely plays a role in homologous recombination (HR). I will use computational methods to determine if HR status is associated with MHe prevalence across thousands of genomes. I will then create DSBs in yeast and human cell lines to determine if DSBs are preferentially repaired to regions with more homeology. Finally, I will analyze new datasets to determine if MHe can be used as a tool to predict tumor response to drugs that target HR or cause DSBs. Aim 2: Germline alterations in DSB repair genes associate with germline genomic signatures of SVs. Using previously-established computational methods, I will discover patterns, or signatures, of SVs in large databases of germline genomes. By comparing SV signatures between individuals with vs. without loss-of-function mutations in DSB repair genes, I will determine the effect of DSB repair defects on genomic structure. Finally, given recent surprising findings indicating a role for SVs in neurodegenerative disorders, I will assess the role of SV signatures in heart and lung diseases. This work will enable greater understanding of DSB repair, an essential aspect of cellular biology that plays a role in many areas of human health. I plan to lead a lab leveraging wet and dry methods to study DSB repair, genomic signatures of SVs, and their role in human disease. In my lab I will mentor young scientists. My career development plan includes training in software development, genomics tools, and yeast experimentation, as well as scientific communication, lab management, and scientific writing. My institutions provide a rich environment replete with ample seminars, cutting-edge technologies, and expert collaborators.
