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.
-
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.
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.
Metrics
-
- 4,105
- views
-
- 503
- downloads
-
- 15
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Balancing selection on genomic deletion polymorphisms in humans
eLife 12:e79111.
https://doi.org/10.7554/eLife.79111
Further reading
-
- Evolutionary Biology
Gene duplication drives evolution by providing raw material for proteins with novel functions. An influential hypothesis by Ohno (1970) posits that gene duplication helps genes tolerate new mutations and thus facilitates the evolution of new phenotypes. Competing hypotheses argue that deleterious mutations will usually inactivate gene duplicates too rapidly for Ohno’s hypothesis to work. We experimentally tested Ohno’s hypothesis by evolving one or exactly two copies of a gene encoding a fluorescent protein in Escherichia coli through several rounds of mutation and selection. We analyzed the genotypic and phenotypic evolutionary dynamics of the evolving populations through high-throughput DNA sequencing, biochemical assays, and engineering of selected variants. In support of Ohno’s hypothesis, populations carrying two gene copies displayed higher mutational robustness than those carrying a single gene copy. Consequently, the double-copy populations experienced relaxed purifying selection, evolved higher phenotypic and genetic diversity, carried more mutations and accumulated combinations of key beneficial mutations earlier. However, their phenotypic evolution was not accelerated, possibly because one gene copy rapidly became inactivated by deleterious mutations. Our work provides an experimental platform to test models of evolution by gene duplication, and it supports alternatives to Ohno’s hypothesis that point to the importance of gene dosage.
-
- Cell Biology
- Evolutionary Biology
Maintenance of rod-shape in bacterial cells depends on the actin-like protein MreB. Deletion of mreB from Pseudomonas fluorescens SBW25 results in viable spherical cells of variable volume and reduced fitness. Using a combination of time-resolved microscopy and biochemical assay of peptidoglycan synthesis, we show that reduced fitness is a consequence of perturbed cell size homeostasis that arises primarily from differential growth of daughter cells. A 1000-generation selection experiment resulted in rapid restoration of fitness with derived cells retaining spherical shape. Mutations in the peptidoglycan synthesis protein Pbp1A were identified as the main route for evolutionary rescue with genetic reconstructions demonstrating causality. Compensatory pbp1A mutations that targeted transpeptidase activity enhanced homogeneity of cell wall synthesis on lateral surfaces and restored cell size homeostasis. Mechanistic explanations require enhanced understanding of why deletion of mreB causes heterogeneity in cell wall synthesis. We conclude by presenting two testable hypotheses, one of which posits that heterogeneity stems from non-functional cell wall synthesis machinery, while the second posits that the machinery is functional, albeit stalled. Overall, our data provide support for the second hypothesis and draw attention to the importance of balance between transpeptidase and glycosyltransferase functions of peptidoglycan building enzymes for cell shape determination.
