1. Department of Molecular Biology and Genetics,
2. Department of Biological Statistics and Computational Biology, Biotechnology Building, Cornell University, Ithaca, New York 14853, USA
3. Department of Biochemistry, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany
4. Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA
5. Celera Diagnostics, Alameda, California 94592, USA
6. Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
7. Center for Comparative Genomics, Department of Biology, University of Copenhagen, Universitetsparken 15, 2100, KBH Ø, Denmark

Correspondence to: Carlos D. Bustamante² Correspondence and requests for materials should be addressed to C.D.B. (Email: cdb28@cornell.edu).

Quantifying the number of deleterious mutations per diploid human genome is of crucial concern to both evolutionary and medical geneticists^{1, 2, 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 single-nucleotide 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 Europeans⁴. 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 < 2.3  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 < 3.3  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.

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.