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The lingering effects of Neanderthal introgression on human complex traits
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 int...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10076017/ https://www.ncbi.nlm.nih.gov/pubmed/36939312 http://dx.doi.org/10.7554/eLife.80757 |
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author | Wei, Xinzhu Robles, Christopher R Pazokitoroudi, Ali Ganna, Andrea Gusev, Alexander Durvasula, Arun Gazal, Steven Loh, Po-Ru Reich, David Sankararaman, Sriram |
author_facet | Wei, Xinzhu Robles, Christopher R Pazokitoroudi, Ali Ganna, Andrea Gusev, Alexander Durvasula, Arun Gazal, Steven Loh, Po-Ru Reich, David Sankararaman, Sriram |
author_sort | Wei, Xinzhu |
collection | PubMed |
description | 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 and 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 make a significant contribution to trait variation (explaining 0.12% of trait variation on average). 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 et al., 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 et al., 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. Applying a customized fine-mapping led us to identify 112 regions across 47 phenotypes containing 4303 unique genetic variants where introgressed variants are highly likely to have a phenotypic effect. Examination of these variants reveals their substantial impact on genes that are important for the immune system, development, and metabolism. |
format | Online Article Text |
id | pubmed-10076017 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-100760172023-04-06 The lingering effects of Neanderthal introgression on human complex traits Wei, Xinzhu Robles, Christopher R Pazokitoroudi, Ali Ganna, Andrea Gusev, Alexander Durvasula, Arun Gazal, Steven Loh, Po-Ru Reich, David Sankararaman, Sriram eLife Evolutionary Biology 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 and 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 make a significant contribution to trait variation (explaining 0.12% of trait variation on average). 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 et al., 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 et al., 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. Applying a customized fine-mapping led us to identify 112 regions across 47 phenotypes containing 4303 unique genetic variants where introgressed variants are highly likely to have a phenotypic effect. Examination of these variants reveals their substantial impact on genes that are important for the immune system, development, and metabolism. eLife Sciences Publications, Ltd 2023-03-20 /pmc/articles/PMC10076017/ /pubmed/36939312 http://dx.doi.org/10.7554/eLife.80757 Text en © 2023, Wei, Robles et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Evolutionary Biology Wei, Xinzhu Robles, Christopher R Pazokitoroudi, Ali Ganna, Andrea Gusev, Alexander Durvasula, Arun Gazal, Steven Loh, Po-Ru Reich, David Sankararaman, Sriram The lingering effects of Neanderthal introgression on human complex traits |
title | The lingering effects of Neanderthal introgression on human complex traits |
title_full | The lingering effects of Neanderthal introgression on human complex traits |
title_fullStr | The lingering effects of Neanderthal introgression on human complex traits |
title_full_unstemmed | The lingering effects of Neanderthal introgression on human complex traits |
title_short | The lingering effects of Neanderthal introgression on human complex traits |
title_sort | lingering effects of neanderthal introgression on human complex traits |
topic | Evolutionary Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10076017/ https://www.ncbi.nlm.nih.gov/pubmed/36939312 http://dx.doi.org/10.7554/eLife.80757 |
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