Evolutionary and functional impact of common genomic structural variations

SUMMARY The long-term goal of our laboratory is to elucidate the evolutionary, biomedical, and functional impact of genomic structural variation. Genomic structural variants (SVs), which are deletions, duplications, inversions, and translocations of large segments of DNA, were recently appreciated as a primary contributor to biomedically and evolutionarily relevant phenotypic diversity. My group has led several studies integrating evolutionary genomics with in vivo models to provide a theoretical and methodological framework for studying SVs. We identified hundreds of candidate SVs evolving under selective constraint and enriched for metabolic and immune functions. Recent advances in long-read sequencing, along with the advent of various functional genomics datasets, enabled the systematic study of the evolution and function of SVs. In the next five years, we will address specific hypotheses that we constructed based on our preliminary data: Research Area 1: What mutational mechanisms shape the size, functional impact, and genomic distribution of different types of SVs? We will test the hypothesis that both replication slippage and non-homologous recombination-based mechanisms underlie exonic copy number variation in humans, where negative selection eliminates frame-shift mutations and maintains the integrity of sequence motifs essential for biological function, such as glycosylation binding sites. Our insights from this research will unveil new insights into genetic stability and the mutational basis of biomedically relevant variation. Research Area 2: What evolutionary processes maintain functional SVs in the human population? We will test the hypothesis that structural variation in gene families that encode digestive enzymes linked to metabolic disease has evolved under geography-specific selection on standing variation. This research explores how different types of structural variation in larger gene families are evolving rapidly in a population-specific manner and delves into the potential effects of these variations on metabolic health. Research Area 3: How do different types of SVs affect biological function at the genetic, transcriptomic, cellular, and organismal levels? In this broad context, we will test the hypothesis using an in vivo model that a common deletion involving the growth hormone receptor gene has broad but sex- and environment-dependent effects on metabolic and immunity traits, which underlies susceptibility to obesity. This research will establish a common structural variant as a key driver of metabolic traits and provide mechanistic insights into how this variant affects growth signaling pathway function. Significance and impact: Our integrative research program will determine novel ways SVs influence chromosomal stability and affect biological function in an evolutionary framework. The overall vision of the research program is to understand the mechanistic basis through which SVs are linked to biological function to provide a more accurate picture of the expected impact of structural variation on disease risk.