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Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome

Evolutionary forces like Hill-Robertson interference and negative epistasis can lead to deleterious mutations being found on distinct haplotypes. However, the extent to which these forces depend on the selection and dominance coefficients of deleterious mutations and shape genome-wide patterns of li...

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Autores principales: Garcia, Jesse A., Lohmueller, Kirk E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351996/
https://www.ncbi.nlm.nih.gov/pubmed/34319975
http://dx.doi.org/10.1371/journal.pgen.1009676
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author Garcia, Jesse A.
Lohmueller, Kirk E.
author_facet Garcia, Jesse A.
Lohmueller, Kirk E.
author_sort Garcia, Jesse A.
collection PubMed
description Evolutionary forces like Hill-Robertson interference and negative epistasis can lead to deleterious mutations being found on distinct haplotypes. However, the extent to which these forces depend on the selection and dominance coefficients of deleterious mutations and shape genome-wide patterns of linkage disequilibrium (LD) in natural populations with complex demographic histories has not been tested. In this study, we first used forward-in-time simulations to predict how negative selection impacts LD. Under models where deleterious mutations have additive effects on fitness, deleterious variants less than 10 kb apart tend to be carried on different haplotypes relative to pairs of synonymous SNPs. In contrast, for recessive mutations, there is no consistent ordering of how selection coefficients affect LD decay, due to the complex interplay of different evolutionary effects. We then examined empirical data of modern humans from the 1000 Genomes Project. LD between derived alleles at nonsynonymous SNPs is lower compared to pairs of derived synonymous variants, suggesting that nonsynonymous derived alleles tend to occur on different haplotypes more than synonymous variants. This result holds when controlling for potential confounding factors by matching SNPs for frequency in the sample (allele count), physical distance, magnitude of background selection, and genetic distance between pairs of variants. Lastly, we introduce a new statistic H(R)((j)) which allows us to detect interference using unphased genotypes. Application of this approach to high-coverage human genome sequences confirms our finding that nonsynonymous derived alleles tend to be located on different haplotypes more often than are synonymous derived alleles. Our findings suggest that interference may play a pervasive role in shaping patterns of LD between deleterious variants in the human genome, and consequently influences genome-wide patterns of LD.
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spelling pubmed-83519962021-08-10 Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome Garcia, Jesse A. Lohmueller, Kirk E. PLoS Genet Research Article Evolutionary forces like Hill-Robertson interference and negative epistasis can lead to deleterious mutations being found on distinct haplotypes. However, the extent to which these forces depend on the selection and dominance coefficients of deleterious mutations and shape genome-wide patterns of linkage disequilibrium (LD) in natural populations with complex demographic histories has not been tested. In this study, we first used forward-in-time simulations to predict how negative selection impacts LD. Under models where deleterious mutations have additive effects on fitness, deleterious variants less than 10 kb apart tend to be carried on different haplotypes relative to pairs of synonymous SNPs. In contrast, for recessive mutations, there is no consistent ordering of how selection coefficients affect LD decay, due to the complex interplay of different evolutionary effects. We then examined empirical data of modern humans from the 1000 Genomes Project. LD between derived alleles at nonsynonymous SNPs is lower compared to pairs of derived synonymous variants, suggesting that nonsynonymous derived alleles tend to occur on different haplotypes more than synonymous variants. This result holds when controlling for potential confounding factors by matching SNPs for frequency in the sample (allele count), physical distance, magnitude of background selection, and genetic distance between pairs of variants. Lastly, we introduce a new statistic H(R)((j)) which allows us to detect interference using unphased genotypes. Application of this approach to high-coverage human genome sequences confirms our finding that nonsynonymous derived alleles tend to be located on different haplotypes more often than are synonymous derived alleles. Our findings suggest that interference may play a pervasive role in shaping patterns of LD between deleterious variants in the human genome, and consequently influences genome-wide patterns of LD. Public Library of Science 2021-07-28 /pmc/articles/PMC8351996/ /pubmed/34319975 http://dx.doi.org/10.1371/journal.pgen.1009676 Text en © 2021 Garcia, Lohmueller https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Garcia, Jesse A.
Lohmueller, Kirk E.
Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome
title Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome
title_full Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome
title_fullStr Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome
title_full_unstemmed Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome
title_short Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome
title_sort negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351996/
https://www.ncbi.nlm.nih.gov/pubmed/34319975
http://dx.doi.org/10.1371/journal.pgen.1009676
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