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

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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 ... continued below

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Kryukov, Gregory V.; Pennacchio, Len A. & Sunyaev, Shamil R. October 24, 2006.

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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.

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  • Journal Name: American Journal of Human Genetics; Journal Volume: 80; Related Information: Journal Publication Date: 03/08/2007

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  • Report No.: LBNL--62805
  • Grant Number: DE-AC02-05CH11231
  • Office of Scientific & Technical Information Report Number: 910227
  • Archival Resource Key: ark:/67531/metadc885450

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  • October 24, 2006

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  • Sept. 22, 2016, 2:13 a.m.

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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, article, October 24, 2006; United States. (digital.library.unt.edu/ark:/67531/metadc885450/: accessed August 21, 2017), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.