Funded Projects

Variation in short tandem repeats in human genomes can have profound influences on human health and evolution. However, the technical limitations in documenting this variation have prevented investigating the full extent of their functional effects. Recent advances in sequencing technologies now allow us to discover and genotype such repeats. We have now assembled a multidisciplinary team to investigate the functional and evolutionary effect of such repeats. Specifically, we will focus, mucin genes defined by highly glycosylated repeat sequences that show biomedically relevant copy number variation among humans. Mucins are critical for mucus generation, cellular signaling, and microbial interactions on epithelial surfaces. The evolution and functional effects of variation in mucin repeats are not well understood but were associated with several immune-mediated disorders and cancer progression. Here, we propose to i) bioinformatically infer the repeat variations among dozens of mucin genes in the human genome using recently available long-read genome databases (Gokcumen). Next,  we will confirm that this genetic translates into higher glycosylation potential at the protein level (Ruhl). Last, we will conduct proof-of-concept experiments to investigate the functional effects of mucin repeat copy number variation in yeast models (Cullen). Our results have broad implications for understanding the evolution of gene families coding for O-glycosylated secreted multiple-repeat-domain proteins. They will also provide the necessary preliminary data for federal grant proposals.