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Determination of ancestral alleles for human single-nucleotide polymorphisms using high-density oligonucleotide arrays

Abstract

Here we report the application of high-density oligonucleotide array (DNA chip)-based analysis to determine the distant history of single nucleotide polymorphisms (SNPs) in current human populations. We analysed orthologues for 397 human SNP sites (identified in CEPH pedigrees from Amish, Venezuelan and Utah populations1) from 23 common chimpanzee, 19 pygmy chimpanzee and 11 gorilla genomic DNA samples. From this data we determined 214 proposed ancestral alleles (the sequence found in the last common ancestor of humans and chimpanzees). In a diverse human population set, we found that SNP alleles with higher frequencies were more likely to be ancestral than less frequently occurring alleles. There were, however, exceptions. We also found three shared human/pygmy chimpanzee polymorphisms, all involving CpG dinucleotides, and two shared human/gorilla polymorphisms, one involving a CpG dinucleotide. We demonstrate that microarray-based assays allow rapid comparative sequence analysis of intra- and interspecies genetic variation.

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Figure 1: Flowchart of SNP genotype analysis in higher primates.
Figure 2: Nucleotide composition effects.
Figure 3: 5´-nearest neighbour effects.
Figure 4: 3´-nearest neighbour effects.
Figure 5: Correlations between human allele frequencies and ancestral states.

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References

  1. Wang, D.G. et al. Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science 280, 1077–1082 (1998).

    Article  CAS  Google Scholar 

  2. Ruvolo, M. A new approach to studying modern human origins: hypothesis testing with coalescence time distributions. Mol. Phylogenet. Evol. 5, 202–219 (1996).

    Article  CAS  Google Scholar 

  3. Goodman, M. et al. Toward a phylogenetic classification of primates based on DNA evidence complemented by fossil evidence. Mol. Phylogenet. Evol. 9, 585–598 ( 1998).

    Article  CAS  Google Scholar 

  4. Hacia, J.G. et al. Evolutionary sequence comparisons using high-density oligonucleotide arrays. Nature Genet. 18, 155– 158 (1998).

    Article  CAS  Google Scholar 

  5. Savatier, P. et al. Evolution of the primate β-globin gene region. High rate of variation in CpG dinucleotides and in short repeated sequences between man and chimpanzee. J. Mol. Biol. 182, 21 –29 (1985).

    Article  CAS  Google Scholar 

  6. Sved, J. & Bird, A. The expected equilibrium of the CpG dinucleotide in vertebrate genomes under a mutation model. Proc. Natl Acad. Sci. USA 12, 4692–4696 (1990).

    Article  Google Scholar 

  7. Yang, A.S. et al. The rate of CpG mutation in Alu repetitive elements within the p53 tumor suppressor gene in the primate germline. J. Mol. Biol. 258, 240–250 ( 1996).

    Article  CAS  Google Scholar 

  8. Watterson, G.A. & Guess, H.A. Is the most frequent allele the oldest? Theor. Popul. Biol. 11, 141–160 (1977).

    Article  CAS  Google Scholar 

  9. Watkins, D.I. The evolution of major histocompatibility class I genes in primates. Crit. Rev. Immunol. 15, 1–29 (1995).

    Article  CAS  Google Scholar 

  10. Brown, W.M., Prager, E.M., Wang, A. & Wilson, A.C. Mitochondrial DNA sequences of primates: tempo and mode of evolution. J. Mol. Evol. 18, 225–239 ( 1982).

    Article  CAS  Google Scholar 

  11. Garner, K.J. & Ryder, O.A. Mitochondrial DNA diversity in gorillas. Mol. Phylogenet. Evol. 6, 39– 48 (1996).

    Article  CAS  Google Scholar 

  12. Crouau-Roy, B., Service, S., Slatkin, M. & Freimer, N. A fine-scale comparison of the human and chimpanzee genomes: linkage, linkage disequilibrium and sequence analysis. Hum. Mol. Genet. 5, 1131– 1137 (1996).

    Article  CAS  Google Scholar 

  13. Wise, C.A., Sraml, M., Rubinsztein, D.C. & Easteal, S. Comparative nuclear and mitochondrial genome diversity in humans and chimpanzees. Mol. Biol. Evol. 14, 707– 716 (1997).

    Article  CAS  Google Scholar 

  14. Cooper, G., Rubinsztein, D.C. & Amos, W. Ascertainment bias cannot entirely account for human microsatellites being longer than their chimpanzee homologues. Hum. Mol. Genet. 7, 1425–1429 (1998).

    Article  CAS  Google Scholar 

  15. Mountain, J.L. & Cavalli-Sforza, L.L. Inference of human evolution through cladistic analysis of nuclear DNA restriction polymorphisms. Proc. Natl Acad. Sci. USA 91, 6515– 6519 (1994).

    Article  CAS  Google Scholar 

  16. Martinko, J.M., Vincek, V., Klein, D. & Klein, J. Primate ABO glycotransferases: evidence for trans-species evolution. Immunogenetics 37, 274–278 (1993).

    Article  CAS  Google Scholar 

  17. Deeb, S.S., Jorgensen, A.L., Battisti, L., Iwasaki, L. & Motulsky, A.G. Sequence divergence of the red and green visual pigments in great apes and humans. Proc. Natl Acad. Sci. USA 91, 7262–7266 (1994).

    Article  CAS  Google Scholar 

  18. Jaeger, E.E.M. et al. Characterization of chimpanzee TCRV gene polymorphism: how old are human TCRV alleles? Immunogenetics 47, 115–123 (1998).

    Article  CAS  Google Scholar 

  19. Kimura, M. The Neutral Theory of Molecular Evolution (Cambridge University Press, Cambridge, 1983).

    Book  Google Scholar 

  20. Bergstrom, T.F., Josefsson, A., Erlich, H.A. & Gyllensten, U. Recent origin of HLA-DRB1 alleles and implications for human evolution. Nature Genet. 18, 237– 242 (1998).

    Article  CAS  Google Scholar 

  21. Clark, A.G. Neutral behavior of shared polymorphism. Proc. Natl Acad. Sci. USA 94, 7730–7734 ( 1997).

    Article  CAS  Google Scholar 

  22. Chee, M.S. et al. Accessing genetic information with high-density DNA arrays. Science 274, 610–614 (1996).

    Article  CAS  Google Scholar 

  23. Hacia, J.G. et al. Detection of heterozygous mutations in BRCA1 using high density oligonucleotide arrays and two-colour fluorescence analysis. Nature Genet. 14, 441– 447 (1996).

    Article  CAS  Google Scholar 

  24. Morin, P.A. et al. Kin selection, social structure, gene flow, and the evolution of chimpanzees. Science 265, 1193– 1201 (1994).

    Article  CAS  Google Scholar 

  25. Collins, F.S., Guyer, M.S. & Chakravarti, A. Variations on a theme: cataloging human DNA sequence variation. Science 278, 1580– 1581 (1997).

    Article  CAS  Google Scholar 

  26. Kruglyak, L. The use of a genetic map of biallelic markers in linkage studies. Nature Genet. 17, 21–24 (1997).

    Article  CAS  Google Scholar 

  27. Nickerson D.A. et al. DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nature Genet. 19, 233– 240 (1998).

    Article  CAS  Google Scholar 

  28. Lai, E., Riley, J., Purvis, I. & Roses, A. A 4-Mb high-density single nucleotide polymorphism-based map around human APOE. Genomics 54, 31–38 ( 1998).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank P.A. Morin for assistance in obtaining chimpanzee DNA samples. Partial support for this work was provided by 5POLHGO1323-03 (S.P.A.F.).

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Correspondence to Francis S. Collins.

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Hacia, J., Fan, JB., Ryder, O. et al. Determination of ancestral alleles for human single-nucleotide polymorphisms using high-density oligonucleotide arrays. Nat Genet 22, 164–167 (1999). https://doi.org/10.1038/9674

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