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:	Jesse A Garcia, Kirk E Lohmueller
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/fdc20550f1474d898c3d0170407f140c
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spelling	oai:doaj.org-article:fdc20550f1474d898c3d0170407f140c2021-12-02T20:02:54ZNegative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome.1553-73901553-740410.1371/journal.pgen.1009676https://doaj.org/article/fdc20550f1474d898c3d0170407f140c2021-07-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009676https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Evolutionary 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 HR(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.Jesse A GarciaKirk E LohmuellerPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 7, p e1009676 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Jesse A Garcia Kirk E Lohmueller Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome.
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 HR(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.
format	article
author	Jesse A Garcia Kirk E Lohmueller
author_facet	Jesse A Garcia Kirk E Lohmueller
author_sort	Jesse A Garcia
title	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_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_sort	negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/fdc20550f1474d898c3d0170407f140c
work_keys_str_mv	AT jesseagarcia negativelinkagedisequilibriumbetweenaminoacidchangingvariantsrevealsinterferenceamongdeleteriousmutationsinthehumangenome AT kirkelohmueller negativelinkagedisequilibriumbetweenaminoacidchangingvariantsrevealsinterferenceamongdeleteriousmutationsinthehumangenome
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Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome.

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