Balancing selection on genomic deletion polymorphisms in humans
- University at Buffalo, State University of New York, United States
- University College London, United Kingdom
- Foundation for Research and Technology Hellas, Greece
Abstract
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.
Data availability
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.
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An integrated map of structural variation in 2,504 human genomesDatabase of Genomic variants: estd219.
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UK Biobank - Curatedhttps://docs.google.com/spreadsheets/d/1kvPoupSzsSFBNSztMzl04xMoSC3Kcx3CrjVf4yBmESU/edit#gid=227859291.
Article and author information
Author details
Funding
National Science Foundation (2123284)
- Omer Gokcumen
Sir Henry Wellcome Fellowship (220457/Z/20/Z)
- Leo Speidel
Wellcome Trust
- Leo Speidel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: This study investigated variation in previously published anonymized genome data from the 1000 Genomes Project.
Copyright
© 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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Balancing selection on genomic deletion polymorphisms in humans
eLife 12:e79111.
https://doi.org/10.7554/eLife.79111
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- Evolutionary Biology
The majority of highly polymorphic genes are related to immune functions and with over 100 alleles within a population, genes of the major histocompatibility complex (MHC) are the most polymorphic loci in vertebrates. How such extraordinary polymorphism arose and is maintained is controversial. One possibility is heterozygote advantage (HA), which can in principle maintain any number of alleles, but biologically explicit models based on this mechanism have so far failed to reliably predict the coexistence of significantly more than ten alleles. We here present an eco-evolutionary model showing that evolution can result in the emergence and maintenance of more than 100 alleles under HA if the following two assumptions are fulfilled: first, pathogens are lethal in the absence of an appropriate immune defence; second, the effect of pathogens depends on host condition, with hosts in poorer condition being affected more strongly. Thus, our results show that HA can be a more potent force in explaining the extraordinary polymorphism found at MHC loci than currently recognized.
