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Title: Most of rare missense alleles in humans are deleterious:implications for evolution of complex disease and associationstudies

Abstract

The accumulation of mildly deleterious missense mutations inindividual human genomes has been proposed to be a genetic basis forcomplex diseases. The plausibility of this hypothesis depends onquantitative estimates of the prevalence of mildly deleterious de novomutations and polymorphic variants in humans and on the intensity ofselective pressure against them. We combined analysis of mutationscausing human Mendelian diseases, human-chimpanzee divergence andsystematic data on human SNPs and found that about 20 percent of newmissense mutations in humans result in a loss of function, while about 27percent are effectively neutral. Thus, more than half of new missensemutations have mildly deleterious effects. These mutations give rise tomany low frequency deleterious allelic variants in the human populationas evident from a new dataset of 37 genes sequenced in over 1,500individual human chromosomes. Surprisingly, up to 70 percent of lowfrequency missense alleles are mildly deleterious and associated with aheterozygous fitness loss in the range 0.001-0.003. Thus, the low allelefrequency of an amino acid variant can by itself serve as a predictor ofits functional significance. Several recent studies have reported asignificant excess of rare missense variants in disease populationscompared to controls in candidate genes or pathways. These studies wouldbe unlikely to work if most rare variants were neutralmore » or if rarevariants were not a significant contributor to the genetic component ofphenotypic inheritance. Our results provide a justification for thesetypes of candidate gene (pathway) association studies and imply thatmutation-selection balance may be a feasible mechanism for evolution ofsome common diseases.« less

Authors:
; ;
Publication Date:
Research Org.:
COLLABORATION - Brigham and Women'sHospital
OSTI Identifier:
910227
Report Number(s):
LBNL-62805
Journal ID: ISSN 0002-9297; AJHGAG; R&D Project: Y0007; TRN: US200723%%569
DOE Contract Number:  
DE-AC02-05CH11231
Resource Type:
Journal Article
Journal Name:
American Journal of Human Genetics
Additional Journal Information:
Journal Volume: 80; Related Information: Journal Publication Date: 03/08/2007; Journal ID: ISSN 0002-9297
Country of Publication:
United States
Language:
English
Subject:
60; AMINO ACIDS; DISEASES; FUNCTIONALS; GENES; GENETICS; HUMAN CHROMOSOMES; HUMAN POPULATIONS; HYPOTHESIS; MUTATIONS

Citation Formats

Kryukov, Gregory V, Pennacchio, Len A, and Sunyaev, Shamil R. Most of rare missense alleles in humans are deleterious:implications for evolution of complex disease and associationstudies. United States: N. p., 2006. Web.
Kryukov, Gregory V, Pennacchio, Len A, & Sunyaev, Shamil R. Most of rare missense alleles in humans are deleterious:implications for evolution of complex disease and associationstudies. United States.
Kryukov, Gregory V, Pennacchio, Len A, and Sunyaev, Shamil R. 2006. "Most of rare missense alleles in humans are deleterious:implications for evolution of complex disease and associationstudies". United States. https://www.osti.gov/servlets/purl/910227.
@article{osti_910227,
title = {Most of rare missense alleles in humans are deleterious:implications for evolution of complex disease and associationstudies},
author = {Kryukov, Gregory V and Pennacchio, Len A and Sunyaev, Shamil R},
abstractNote = {The accumulation of mildly deleterious missense mutations inindividual human genomes has been proposed to be a genetic basis forcomplex diseases. The plausibility of this hypothesis depends onquantitative estimates of the prevalence of mildly deleterious de novomutations and polymorphic variants in humans and on the intensity ofselective pressure against them. We combined analysis of mutationscausing human Mendelian diseases, human-chimpanzee divergence andsystematic data on human SNPs and found that about 20 percent of newmissense mutations in humans result in a loss of function, while about 27percent are effectively neutral. Thus, more than half of new missensemutations have mildly deleterious effects. These mutations give rise tomany low frequency deleterious allelic variants in the human populationas evident from a new dataset of 37 genes sequenced in over 1,500individual human chromosomes. Surprisingly, up to 70 percent of lowfrequency missense alleles are mildly deleterious and associated with aheterozygous fitness loss in the range 0.001-0.003. Thus, the low allelefrequency of an amino acid variant can by itself serve as a predictor ofits functional significance. Several recent studies have reported asignificant excess of rare missense variants in disease populationscompared to controls in candidate genes or pathways. These studies wouldbe unlikely to work if most rare variants were neutral or if rarevariants were not a significant contributor to the genetic component ofphenotypic inheritance. Our results provide a justification for thesetypes of candidate gene (pathway) association studies and imply thatmutation-selection balance may be a feasible mechanism for evolution ofsome common diseases.},
doi = {},
url = {https://www.osti.gov/biblio/910227}, journal = {American Journal of Human Genetics},
issn = {0002-9297},
number = ,
volume = 80,
place = {United States},
year = {2006},
month = {10}
}