A key question in biology is why genomic variation persists in a population for extended periods. Recent studies have identified examples of genomic deletions that have remained polymorphic in the human lineage for hundreds of millennia, ostensibly owing to balancing selection. Nevertheless, genome-wide investigation of ancient and possibly adaptive deletions remains imperative. Here, we demonstrate an excess of polymorphisms in present-day humans that predate the modern human-Neanderthal split (ancient polymorphisms), which cannot be explained solely by selectively neutral scenarios. We analyze the adaptive mechanisms that underlie this excess in deletion polymorphisms. Using a previously published measure of balancing selection, we show that this excess of ancient deletions is largely owing to balancing selection. Based on the absence of signatures of overdominance, we conclude that it is a rare mode of balancing selection among ancient deletions. Instead, more complex scenarios involving spatially and temporally variable selective pressures are likely more common mechanisms. Our results suggest that balancing selection resulted in ancient deletions harboring disproportionately more exonic variants with GWAS associations. We further found that ancient deletions are significantly enriched for traits related to metabolism and immunity. As a by-product of our analysis, we show that deletions are, on average, more deleterious than single-nucleotide variants. We can now argue that not only is a vast majority of common variants shared among human populations, but a considerable portion of biologically relevant variants has been segregating among our ancestors for hundreds of thousands, if not millions, of years.
All data that are used in the study can be found publically. The references and databases are provided in the manuscript. The code and resulting datasets are all provided either through our laboratory's GitHub page, FigShare, or as supplementary tables.
Curated UK Biobank traitsFigShare, 19606192.
An integrated map of structural variation in 2,504 human genomesDatabase of Genomic variants: estd219.
UK Biobank - Curatedhttps://docs.google.com/spreadsheets/d/1kvPoupSzsSFBNSztMzl04xMoSC3Kcx3CrjVf4yBmESU/edit#gid=227859291.
GTEXdbGaP accession number phs000424.vN.pN.
- Omer Gokcumen
- Leo Speidel
- Leo Speidel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Human subjects: This study investigated variation in previously published anonymized genome data from the 1000 Genomes Project.
- Philipp W Messer, Cornell University, United States
© 2023, Aqil et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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