Broad-scale variation in human genetic diversity levels is predicted by purifying selection on coding and non-coding elements
- Oklahoma Medical Research Foundation, United States
- Columbia University, United States
Abstract
Analyses of genetic variation in many taxa have established that neutral genetic diversity is shaped by natural selection at linked sites. Whether the mode of selection is primarily the fixation of strongly beneficial alleles (selective sweeps) or purifying selection on deleterious mutations (background selection) remains unknown, however. We address this question in humans by fitting a model of the joint effects of selective sweeps and background selection to autosomal polymorphism data from the 1000 Genomes Project. After controlling for variation in mutation rates along the genome, a model of background selection alone explains ~60% of the variance in diversity levels at the megabase scale. Adding the effects of selective sweeps driven by adaptive substitutions to the model does not improve the fit, and when both modes of selection are considered jointly, selective sweeps are estimated to have had little or no effect on linked neutral diversity. The regions under purifying selection are best predicted by phylogenetic conservation, with ~80% of the deleterious mutations affecting neutral diversity occurring in non-exonic regions. Thus, background selection is the dominant mode of linked selection in humans, with marked effects on diversity levels throughout autosomes.
Data availability
Shared data can be found at github.com/sellalab/HumanLinkedSelectionMaps. This repository includes fully documented code for: downloading and processing public datasets used, running inferences, analyzing results, and generating all figures from the manuscript. This repository also includes B-maps for all "best-fitting" models described in the manuscript. Customized CADD scores with bStatistic removed are available on Data Dryad at https://doi.org/10.5061/dryad.n8pk0p2x0.
-
data from: Broad-scale variation in human genetic diversity levels is predicted by purifying selection on coding and non-coding elementsDryad Digital Repository, doi:10.5061/dryad.n8pk0p2x0.
-
Data from: A global reference for human genetic variationdoi:10.1038/nature15393.
-
Data from: The UCSC Table Browser data retrieval tooldoi:10.1093/nar/gkh103.
-
Data from: The landscape of recombination in African Americansdoi:10.1038/nature10336.
-
Data from: Expanded encyclopaedias of DNA elements in the human and mouse genomesdoi:10.1038/s41586-020-2493-4.
Article and author information
Author details
Funding
NIH (GM115889)
- Guy Sella
NIH (T32GM008798)
- David A Murphy
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Magnus Nordborg, Gregor Mendel Institute, Austria
Version history
- Preprint posted: July 2, 2021 (view preprint)
- Received: December 3, 2021
- Accepted: August 22, 2022
- Accepted Manuscript published: October 5, 2022 (version 1)
- Version of Record published: June 23, 2023 (version 2)
Copyright
© 2022, Murphy 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
-
- 1,485
- views
-
- 300
- downloads
-
- 22
- 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)
Broad-scale variation in human genetic diversity levels is predicted by purifying selection on coding and non-coding elements
eLife 11:e76065.
https://doi.org/10.7554/eLife.76065
Further reading
-
- Evolutionary Biology
Extant ecdysozoans (moulting animals) are represented by a great variety of soft-bodied or articulated organisms that may or may not have appendages. However, controversies remain about the vermiform nature (i.e. elongated and tubular) of their ancestral body plan. We describe here Beretella spinosa gen. et sp. nov. a tiny (maximal length 3 mm) ecdysozoan from the lowermost Cambrian, Yanjiahe Formation, South China, characterized by an unusual sack-like appearance, single opening, and spiny ornament. Beretella spinosa gen. et sp. nov has no equivalent among animals, except Saccorhytus coronarius, also from the basal Cambrian. Phylogenetic analyses resolve both fossil species as a sister group (Saccorhytida) to all known Ecdysozoa, thus suggesting that ancestral ecdysozoans may have been non-vermiform animals. Saccorhytids are likely to represent an early off-shot along the stem-line Ecdysozoa. Although it became extinct during the Cambrian, this animal lineage provides precious insight into the early evolution of Ecdysozoa and the nature of the earliest representatives of the group.
-
- Biochemistry and Chemical Biology
- Evolutionary Biology
The emergence of new protein functions is crucial for the evolution of organisms. This process has been extensively researched for soluble enzymes, but it is largely unexplored for membrane transporters, even though the ability to acquire new nutrients from a changing environment requires evolvability of transport functions. Here, we demonstrate the importance of environmental pressure in obtaining a new activity or altering a promiscuous activity in members of the amino acid-polyamine-organocation (APC)-type yeast amino acid transporters family. We identify APC members that have broader substrate spectra than previously described. Using in vivo experimental evolution, we evolve two of these transporter genes, AGP1 and PUT4, toward new substrate specificities. Single mutations on these transporters are found to be sufficient for expanding the substrate range of the proteins, while retaining the capacity to transport all original substrates. Nonetheless, each adaptive mutation comes with a distinct effect on the fitness for each of the original substrates, illustrating a trade-off between the ancestral and evolved functions. Collectively, our findings reveal how substrate-adaptive mutations in membrane transporters contribute to fitness and provide insights into how organisms can use transporter evolution to explore new ecological niches.
