Proportionally More Deleterious Genetic Variation In European than in African Populations

摘要

Quantifying the number of deleterious mutations per diploid human genome is of critical concern to both evolutionary and medical geneticists^–. Here, we combine genome-wide polymorphism data from PCR-based exon re-sequencing, comparative genomic data across mammalian species, and protein structure predictions to estimate the number of functionally consequential mutations 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 mutations considered including synonymous, nonsynonymous, predicted “benign”, predicted “possibly damaging” and predicted “probably damaging” mutations. This result is wholly consistent with previous work showing higher overall levels of nucleotide variation in African populations as compared to Europeans. EA individuals, on the other hand, have significantly more genotypes homozygous for the derived allele at synonymous and nonsynonymous SNPs and for the damaging allele at “probably damaging” SNPs than AAs do. Surprisingly, for SNPs segregating only in one population or the other, the proportion of nonsynonymous SNPs is significantly higher in the EA sample (55.4%) than in the AA sample (47.0%; P<2.3 ×10⁻³⁷). We observe a similar proportional excess of SNPs that are inferred to be “probably damaging” (15.9% EA; 12.1% AA; P<3.3 ×10⁻¹¹). Using extensive simulations, we show that this excess proportion of segregating damaging alleles in Europeans is likely a consequence of a bottleneck that Europeans experienced around the time of the migration out of Africa.