The lingering effects of Neanderthal introgression on human complex traits
- Cornell University, United States
- University of California, Los Angeles, United States
- Broad Institute, United States
- Harvard University, United States
- University of Southern California, United States
Abstract
The genetic variants introduced into the ancestors of modern humans from interbreeding with Neanderthals have been suggested to contribute an unexpected extent to complex human traits. However, testing this hypothesis has been challenging due to the idiosyncratic population genetic properties of introgressed variants. We developed rigorous methods to assess the contribution of introgressed Neanderthal variants to heritable trait variation relative to that of modern human variants. We applied these methods to analyze 235,592 introgressed Neanderthal variants and 96 distinct phenotypes measured in about 300,000 unrelated white British individuals in the UK Biobank. Introgressed Neanderthal variants have a significant contribution to trait variation consistent with the polygenic architecture of complex phenotypes (contributing 0.12% of heritable variation averaged across phenotypes). However, the contribution of introgressed variants tends to be significantly depleted relative to modern human variants matched for allele frequency and linkage disequilibrium (about 59% depletion on average), consistent with purifying selection on introgressed variants. Different from previous studies (McArthur 2021), we find no evidence for elevated heritability across the phenotypes examined. We identified 348 independent significant associations of introgressed Neanderthal variants with 64 phenotypes . Previous work (Skov 2020) has suggested that a majority of such associations are likely driven by statistical association with nearby modern human variants that are the true causal variants. We therefore developed a customized statistical fine-mapping methodology for introgressed variants that led us to identify 112 regions (at a false discovery proportion of 16%) across 47 phenotypes containing 4,303 unique genetic variants where introgressed variants are highly likely to have a phenotypic effect. Examination of these variants reveal their substantial impact on genes that are important for the immune system, development, and metabolism. Our results provide the first rigorous basis for understanding how Neanderthal introgression modulates complex trait variation in present-day humans.
Data availability
New software is deposited on GitHub: https://github.com/alipazokit/RHEmc-coeffData for figures (and supplement data) are deposited on GitHub: https://github.com/AprilWei001/NIM
Article and author information
Author details
Christopher R Robles
Sriram Sankararaman
Funding
National Institutes of Health (GM100233)
- David Reich
Alfred P. Sloan Foundation
- Sriram Sankararaman
Okawa Foundation
- Sriram Sankararaman
Burroughs Wellcome Fund
- Po-Ru Loh
Next Generation Fund at the Broad Institute of MIT and Harvard
- Po-Ru Loh
National Science Foundation (BCS1032255)
- David Reich
National Institutes of Health (HG006399)
- David Reich
Paul G. Allen Frontiers Group (Allen Discovery Center Grant on Brain Evolution)
- David Reich
John Templeton Foundation (61220)
- David Reich
Howard Hughes Medical Institute
- David Reich
National Institutes of Health (R35GM125055)
- Sriram Sankararaman
National Science Foundation (III1705121)
- Sriram Sankararaman
National Science Foundation (CAREER1943497)
- Sriram Sankararaman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Wei 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
-
- 11,609
- views
-
- 884
- downloads
-
- 17
- 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)
The lingering effects of Neanderthal introgression on human complex traits
eLife 12:e80757.
https://doi.org/10.7554/eLife.80757
Further reading
-
- Evolutionary Biology
Spatial patterns in genetic diversity are shaped by individuals dispersing from their parents and larger-scale population movements. It has long been appreciated that these patterns of movement shape the underlying genealogies along the genome leading to geographic patterns of isolation by distance in contemporary population genetic data. However, extracting the enormous amount of information contained in genealogies along recombining sequences has, until recently, not been computationally feasible. Here we capitalize on important recent advances in genome-wide gene-genealogy reconstruction and develop methods to use thousands of trees to estimate per-generation dispersal rates and to locate the genetic ancestors of a sample back through time. We take a likelihood approach in continuous space using a simple approximate model (branching Brownian motion) as our prior distribution of spatial genealogies. After testing our method with simulations we apply it to Arabidopsis thaliana. We estimate a dispersal rate of roughly 60km2 per generation, slightly higher across latitude than across longitude, potentially reflecting a northward post-glacial expansion. Locating ancestors allows us to visualize major geographic movements, alternative geographic histories, and admixture. Our method highlights the huge amount of information about past dispersal events and population movements contained in genome-wide genealogies.
-
- 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.
