Characterizing the full spectrum of genomic variation in biomedically-relevant primates

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PROJECT SUMMARY Gaining a better understanding of the population genomic processes that shape observed genetic variation is at the heart of evolutionary biology. Over the past decades, much previous genomics work has focused on studying the causes and consequences of point mutations, utilizing single nucleotide variation to infer rates and patterns of recombination, population demographic history (modulating genetic drift), and natural selection. However, by failing to incorporate structural variants (insertions, deletions, duplications, translocations, and inversions with a length of ≥ 50 bp), the greatest source of heritable variation was often neglected, contributing to the 'missing heritability' problem faced in many studies of complex phenotypes. Owing to their size, structural variants frequently disrupt protein-coding genes and/or modify gene expression, thus their characterization is crucially important to elucidate factors related to health and disease. Several population- specific structural variant catalogues have recently started to emerge for human populations; yet, similar datasets remain limited for most non-human primates, despite their importance to evolutionary research (as outgroups to the human lineage) and extensive usage in biomedical and behavioral research. This neglect is largely owing to historical reasons, as short-read sequencing and limited sampling previously made a comprehensive quantification of genome-wide structural variation impossible. However, cutting-edge single- molecule long-read sequencing technologies now allow us to investigate the topic with considerable resolution. Over the next five years, the Pfeifer lab will combine the development of novel long-read genomics datasets with computational methods for evolutionary inference to: (i) comprehensively characterize the full spectrum of genomic variation (including the relative frequencies of different types of structural variants) in three biomedically-relevant primate species, (ii) conduct genomic-wide comparisons with hominoids to gain a better understanding of the diversity within and divergence between species, (iii) characterize the molecular and evolutionary processes determining the accrual, and dictating the fate, of structural variants, (iv) determine associations with previously characterized clinical phenotypes, as well as (v) investigate the interplay of (structural) mutation with another population genetic process that shapes genome structure, recombination. Taken together, this research will improve the utility of these species as models in biomedical research, provide new insights into the etiology of disease, and allow for a deeper understanding of the mode and tempo of evolutionary changes across the primate clade.