Proportionally more deleterious genetic variation in European than in African populations

被引:295
作者
Lohmueller, Kirk E. [1 ,2 ]
Indap, Amit R. [1 ]
Schmidt, Steffen [3 ]
Boyko, Adam R. [1 ,2 ]
Hernandez, Ryan D. [1 ]
Hubisz, Melissa J. [4 ]
Sninsky, John J. [5 ]
White, Thomas J. [5 ]
Sunyaev, Shamil R. [6 ,7 ]
Nielsen, Rasmus [8 ]
Clark, Andrew G. [2 ]
Bustamante, Carlos D. [1 ]
机构
[1] Cornell Univ, Dept Biol Stat & Computat Biol, Ithaca, NY 14853 USA
[2] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA
[3] Max Planck Inst Dev Biol, Dept Biochem, D-72076 Tubingen, Germany
[4] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA
[5] Celera Diagnost, Alameda, CA 94592 USA
[6] Brigham & Womens Hosp, Div Genet, Dept Med, Boston, MA 02115 USA
[7] Harvard Univ, Sch Med, Boston, MA 02115 USA
[8] Univ Copenhagen, Ctr Comparat Genom, Dept Biol, DK-2100 Copenhagen O, Denmark
关键词
D O I
10.1038/nature06611
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Quantifying the number of deleterious mutations per diploid human genome is of crucial concern to both evolutionary and medical geneticists(1-3). Here we combine genome- wide polymorphism data from PCR- based exon resequencing, comparative genomic data across mammalian species, and protein structure predictions to estimate the number of functionally consequential singlenucleotide polymorphisms (SNPs) carried by each of 15 African American (AA) and 20 European American (EA) individuals. We find that AAs show significantly higher levels of nucleotide heterozygosity than do EAs for all categories of functional SNPs considered, including synonymous, non- synonymous, predicted 'benign', predicted 'possibly damaging' and predicted 'probably damaging' SNPs. This result is wholly consistent with previous work showing higher overall levels of nucleotide variation in African populations than in Europeans(4). EA individuals, in contrast, have significantly more genotypes homozygous for the derived allele at synonymous and non- synonymous SNPs and for the damaging allele at ` probably damaging' SNPs than AAs do. For SNPs segregating only in one population or the other, the proportion of non-synonymous SNPs is significantly higher in the EA sample (55.4%) than in the AA sample (47.0%; P < 2.33 X 10(-37)). We observe a similar proportional excess of SNPs that are inferred to be 'probably damaging' (15.9% in EA; 12.1% in AA; P < 3.33 X 10(-11)). Using extensive simulations, we show that this excess proportion of segregating damaging alleles in Europeans is probably a consequence of a bottleneck that Europeans experienced at about the time of the migration out of Africa.
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收藏
页码:994 / U5
页数:5
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