Negative selection in humans and fruit flies involves synergistic epistasis

Mashaal Sohail; Olga A Vakhrusheva; Jae Hoon Sul; Sara L Pulit; Laurent C Francioli; Leonard H van den Berg; Jan H Veldink; Paul I W de Bakker; Georgii A Bazykin; Alexey S Kondrashov; Shamil R Sunyaev; Genome of the Netherlands Consortium; A. Abdellaoui; J.J. Hottenga; Gonneke Willemsen; D.I. Boomsma

doi:10.1126/science.aah5238

Negative selection in humans and fruit flies involves synergistic epistasis

Mashaal Sohail, Olga A Vakhrusheva, Jae Hoon Sul, Sara L Pulit, Laurent C Francioli, Leonard H van den Berg, Jan H Veldink, Paul I W de Bakker, Georgii A Bazykin, Alexey S Kondrashov, Shamil R Sunyaev, Genome of the Netherlands Consortium, A. Abdellaoui, J.J. Hottenga, Gonneke Willemsen, D.I. Boomsma

Research output: Contribution to Journal › Article › Academic › peer-review

14 Downloads (Pure)

Abstract

Negative selection against deleterious alleles produced by mutation influences within-population variation as the most pervasive form of natural selection. However, it is not known whether deleterious alleles affect fitness independently, so that cumulative fitness loss depends exponentially on the number of deleterious alleles, or synergistically, so that each additional deleterious allele results in a larger decrease in relative fitness. Negative selection with synergistic epistasis should produce negative linkage disequilibrium between deleterious alleles and, therefore, an underdispersed distribution of the number of deleterious alleles in the genome. Indeed, we detected underdispersion of the number of rare loss-of-function alleles in eight independent data sets from human and fly populations. Thus, selection against rare protein-disrupting alleles is characterized by synergistic epistasis, which may explain how human and fly populations persist despite high genomic mutation rates.

Original language	English
Pages (from-to)	539-542
Number of pages	4
Journal	Science
Volume	356
Issue number	6337
Early online date	5 May 2017
DOIs	https://doi.org/10.1126/science.aah5238
Publication status	Published - 5 May 2017

Funding

We are grateful to L. Mirny, G. McVean, and I. Adzhubey for scientific discussions; all members of the Sunyaev lab and two anonymous reviewers for comments that improved the manuscript; D. Jordan for providing SLiM 2.0 simulation runs; C. Cassa, D. Jordan, D. Weghorn, and D. Balick for providing genic selection estimates for humans; J. Fan for helping with analyses as a summer student; and J. Lack for help with D. melanogaster inversion data. This project was supported by NIH grants R01GM078598, R01GM105857, R01MH101244, and U01HG009088. Analysis of fruit fly data was performed at IITP RAS and supported by the Russian Science Foundation (grant no. 14-50-00150). Data sets used in this study can be accessed as follows: GoNL: www.nlgenome.nl/; ADNI: http://adni.loni.usc.edu/; Project MinE: www.projectmine.com; The 1000 Genomes Phase I Project: ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp/; DGRP and DPGP3: www.johnpool.net/genomes.html.

Funders	Funder number
National Institutes of Health	R01GM078598, R01GM105857, U01HG009088
National Institute of Mental Health	R01MH101244
Alzheimer's Disease Neuroimaging Initiative
Russian Science Foundation	14-50-00150

Keywords

Journal Article

Cohort Studies

Netherlands Twin Register (NTR)

Access to Document

10.1126/science.aah5238

Negative selection in humans and fruit flies involves synergistic epistasisFinal published version, 348 KBLicence: Article 25fa Dutch Copyright Act

Persistent URL (handle)

Persistent link

Cite this

Sohail, M., Vakhrusheva, O. A., Sul, J. H., Pulit, S. L., Francioli, L. C., van den Berg, L. H., Veldink, J. H., de Bakker, P. I. W., Bazykin, G. A., Kondrashov, A. S., Sunyaev, S. R., Genome of the Netherlands Consortium, Abdellaoui, A., Hottenga, J. J., Willemsen, G., & Boomsma, D. I. (2017). Negative selection in humans and fruit flies involves synergistic epistasis. Science, 356(6337), 539-542. https://doi.org/10.1126/science.aah5238

@article{e374409cba514e0b9a4be139ee1b6070,

title = "Negative selection in humans and fruit flies involves synergistic epistasis",

abstract = "Negative selection against deleterious alleles produced by mutation influences within-population variation as the most pervasive form of natural selection. However, it is not known whether deleterious alleles affect fitness independently, so that cumulative fitness loss depends exponentially on the number of deleterious alleles, or synergistically, so that each additional deleterious allele results in a larger decrease in relative fitness. Negative selection with synergistic epistasis should produce negative linkage disequilibrium between deleterious alleles and, therefore, an underdispersed distribution of the number of deleterious alleles in the genome. Indeed, we detected underdispersion of the number of rare loss-of-function alleles in eight independent data sets from human and fly populations. Thus, selection against rare protein-disrupting alleles is characterized by synergistic epistasis, which may explain how human and fly populations persist despite high genomic mutation rates.",

keywords = "Journal Article",

author = "Mashaal Sohail and Vakhrusheva, {Olga A} and Sul, {Jae Hoon} and Pulit, {Sara L} and Francioli, {Laurent C} and {van den Berg}, {Leonard H} and Veldink, {Jan H} and {de Bakker}, {Paul I W} and Bazykin, {Georgii A} and Kondrashov, {Alexey S} and Sunyaev, {Shamil R} and {Genome of the Netherlands Consortium} and A. Abdellaoui and J.J. Hottenga and Gonneke Willemsen and D.I. Boomsma",

note = "Copyright {\textcopyright} 2017, American Association for the Advancement of Science.",

year = "2017",

month = may,

day = "5",

doi = "10.1126/science.aah5238",

language = "English",

volume = "356",

pages = "539--542",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6337",

}

Sohail, M, Vakhrusheva, OA, Sul, JH, Pulit, SL, Francioli, LC, van den Berg, LH, Veldink, JH, de Bakker, PIW, Bazykin, GA, Kondrashov, AS, Sunyaev, SR, Genome of the Netherlands Consortium, Abdellaoui, A, Hottenga, JJ, Willemsen, G & Boomsma, DI 2017, 'Negative selection in humans and fruit flies involves synergistic epistasis', Science, vol. 356, no. 6337, pp. 539-542. https://doi.org/10.1126/science.aah5238

TY - JOUR

T1 - Negative selection in humans and fruit flies involves synergistic epistasis

AU - Sohail, Mashaal

AU - Vakhrusheva, Olga A

AU - Sul, Jae Hoon

AU - Pulit, Sara L

AU - Francioli, Laurent C

AU - van den Berg, Leonard H

AU - Veldink, Jan H

AU - de Bakker, Paul I W

AU - Bazykin, Georgii A

AU - Kondrashov, Alexey S

AU - Sunyaev, Shamil R

AU - Genome of the Netherlands Consortium

AU - Abdellaoui, A.

AU - Hottenga, J.J.

AU - Willemsen, Gonneke

AU - Boomsma, D.I.

PY - 2017/5/5

Y1 - 2017/5/5

N2 - Negative selection against deleterious alleles produced by mutation influences within-population variation as the most pervasive form of natural selection. However, it is not known whether deleterious alleles affect fitness independently, so that cumulative fitness loss depends exponentially on the number of deleterious alleles, or synergistically, so that each additional deleterious allele results in a larger decrease in relative fitness. Negative selection with synergistic epistasis should produce negative linkage disequilibrium between deleterious alleles and, therefore, an underdispersed distribution of the number of deleterious alleles in the genome. Indeed, we detected underdispersion of the number of rare loss-of-function alleles in eight independent data sets from human and fly populations. Thus, selection against rare protein-disrupting alleles is characterized by synergistic epistasis, which may explain how human and fly populations persist despite high genomic mutation rates.

AB - Negative selection against deleterious alleles produced by mutation influences within-population variation as the most pervasive form of natural selection. However, it is not known whether deleterious alleles affect fitness independently, so that cumulative fitness loss depends exponentially on the number of deleterious alleles, or synergistically, so that each additional deleterious allele results in a larger decrease in relative fitness. Negative selection with synergistic epistasis should produce negative linkage disequilibrium between deleterious alleles and, therefore, an underdispersed distribution of the number of deleterious alleles in the genome. Indeed, we detected underdispersion of the number of rare loss-of-function alleles in eight independent data sets from human and fly populations. Thus, selection against rare protein-disrupting alleles is characterized by synergistic epistasis, which may explain how human and fly populations persist despite high genomic mutation rates.

KW - Journal Article

UR - http://www.scopus.com/inward/record.url?scp=85018792261&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85018792261&partnerID=8YFLogxK

U2 - 10.1126/science.aah5238

DO - 10.1126/science.aah5238

M3 - Article

C2 - 28473589

SN - 0036-8075

VL - 356

SP - 539

EP - 542

JO - Science

JF - Science

IS - 6337

ER -

Negative selection in humans and fruit flies involves synergistic epistasis

Abstract

Funding

Keywords

Cohort Studies

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this