Evolution and Biomedical Implications of Structural Variants in Human Populations

PingHsun (Benson) Hsieh, Ph.D.
Department of Genome Sciences
University of Washington

BlueJeans Livestream

ABSTRACT
Evolutionary theory provides a critical framework for studying human biology and health, from identifying variants that could lead to genetic novelties through evolutionary processes, such as hybridization and selection, to understanding the genetic basis of adaptive traits and disease risk in populations. With the recent long-read sequencing technologies, we are now able to study previously inaccessible DNA and RNA variants in some of the most challenging regions in the human genome and discover disease mechanisms. In this talk, I will focus on the evolution and fitness implications of structural variants (SVs, e.g., deletions, duplications, inversions)—an important but understudied genomic variation that affects many more bases than single-nucleotide variants in the genome. Using evolutionary theory and long-read sequencing, I will first provide evidence for hybridization and adaptation events in the evolution of humans, including a large (>380,000 bp), complex duplication in an Oceanic population that has an origin from a now-extinct human species. I will then delineate the structure of this duplication, including its novel protein-coding gene content, and hypothesize its biomedical implication in the population. In addition, I will discuss unique insights of SVs for biologically important traits, such as dietary and cold adaptations in humans. Finally, I will show evidence for recurrent SVs in the human genome and their implications in predispositions to recurrent disease-causing rearrangements in humans. Together, these works demonstrate the untapped diversity and fitness effect of uncharacterized SVs in humans and how evolutionary inferences help improve our understanding of human biology and health.