Journal
NATURE
Volume 451, Issue 7181, Pages 994-U5Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature06611
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Funding
- NHGRI NIH HHS [R01 HG003229-03, R01 HG003229] Funding Source: Medline
- NHLBI NIH HHS [R01 HL072904] Funding Source: Medline
- NIGMS NIH HHS [P50 GM065509, P50 GM065509-070006] Funding Source: Medline
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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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