Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis

Nature Genetics volume 22, pages 239–247 (1999)Cite this article

Abstract

Sequence variation in human genes is largely confined to single-nucleotide polymorphisms (SNPs) and is valuable in tests of association with common diseases and pharmacogenetic traits. We performed a systematic and comprehensive survey of molecular variation to assess the nature, pattern and frequency of SNPs in 75 candidate human genes for blood-pressure homeostasis and hypertension. We assayed 28 Mb (190 kb in 148 alleles) of genomic sequence, comprising the 5´ and 3´ untranslated regions (UTRs), introns and coding sequence of these genes, for sequence differences in individuals of African and Northern European descent using high-density variant detection arrays (VDAs). We identified 874 candidate human SNPs, of which 22% were confirmed by DNA sequencing to reveal a discordancy rate of 21% for VDA detection. The SNPs detected have an average minor allele frequency of 11%, and 387 are within the coding sequence (cSNPs). Of all cSNPs, 54% lead to a predicted change in the protein sequence, implying a high level of human protein diversity. These protein-altering SNPs are 38% of the total number of such SNPs expected, are more likely to be population-specific and are rarer in the human population, directly demonstrating the effects of natural selection on human genes. Overall, the degree of nucleotide polymorphism across these human genes, and orthologous great ape sequences, is highly variable and is correlated with the effects of functional conservation on gene sequences.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Distribution of nucleotide diversity in human genes in coding and non-coding segments.
Figure 2: Distribution of minor allele frequency of SNPs classified by their occurrence among individuals of either African or European descent (population specific) or their presence in both (shared).
Figure 3: Schematic summary of all sequence changes between 75 human and 3 chimpanzee samples.

Similar content being viewed by others

References

  1. Jeffreys, A.J. DNA sequence variants in the G γ-, A γ-, δ- and β-globin genes of man. Cell 18, 1– 10 (1979).

    Article  CAS  PubMed  Google Scholar 

  2. Chakravarti, A. et al. Nonuniform recombination within the human β-globin gene cluster. Am. J. Hum. Genet. 36, 1239– 1258 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Chakravarti, A., Phillips, J.A. 3d, Mellits, K.H., Buetow, K.H. & Seeburg, P.H. Patterns of polymorphism and linkage disequilibrium suggest independent origins of the human growth hormone gene cluster. Proc. Natl Acad. Sci. USA 81, 6085 –6089 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jorde, L. et al. Linkage disequilibrium predicts physical distance in the adenomatous polyposis coli region. Am. J. Hum. Genet. 54, 884–898 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Li, W.H. & Sadler, L.A. Low nucleotide diversity in man. Genetics 129, 513–523 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 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  PubMed  Google Scholar 

  7. Harding, R.M. et al. Archaic African and Asian lineages in the genetic ancestry of modern humans. Am. J. Hum. Genet. 60, 772–789 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Chakravarti, A. Population genetics—making sense out of sequence. Nature Genet. 21, 56–60 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  9. Lipshutz, R.J., Fodor, S.P., Gingeras, T.R. & Lockhart, D.J. High density synthetic oligonucleotide arrays. Nature Genet. 21, 20–24 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Cargill, M. et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nature Genet. 22, 231–238 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Chakravarti, A. It's raining SNPs, hallelujah? Nature Genet. 19, 216–217 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Lander, E.S. The new genomics: global views of biology. Science 274, 536–539 (1996).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Housman, D. & Ledley, F.D. Why pharmacogenomics? Why now? Nature Biotechnol. 16, 492– 493 (1998).

    Article  CAS  Google Scholar 

  19. Ward, R. in Hypertension: Pathophysiology, Diagnosis, and Management (eds Laragh, J.H. & Brenner, B.M.) 81–100 (Raven Press, New York, 1990).

    Google Scholar 

  20. Kurtz, T.W. & Spence, M.A. Genetics of essential hypertension. Am. J. Med. 94, 77–84 (1993).

    Article  CAS  PubMed  Google Scholar 

  21. Kaplan, N.M. Clinical Hypertension (Williams and Wilkins, Baltimore, 1994).

    Google Scholar 

  22. Jeunemaitre, X. et al. Molecular basis of human hypertension: role of angiotensinogen. Cell 71, 169–180 (1992).

    Article  CAS  PubMed  Google Scholar 

  23. Smithies, O. & Maeda, N. Gene targeting approaches to complex genetic diseases: atherosclerosis and essential hypertension. Proc. Natl Acad. Sci. USA 92, 5266– 5272 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mockrin, S.C. Molecular Genetics and Gene Therapy of Cardiovascular Diseases (Marcel Dekker, New York, 1996).

    Book  Google Scholar 

  25. Lifton, R.P. Molecular genetics of human blood pressure variation. Science 272, 676–680 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. The History and Geography of Human Genes (eds Cavalli-Sforza, L.L., Menozzi, P. & Piazza, A.) (Princeton University Press, Princeton, 1994).

  27. Bird, A.P. CpG-rich islands and the function of DNA methylation. Nature 321, 209–213 (1986).

    Article  CAS  PubMed  Google Scholar 

  28. Nei, M. Molecular Evolutionary Genetics (Columbia University Press, New York, 1987).

    Google Scholar 

  29. Li, W.H. Molecular Evolution (Sinauer Associates, Sunderland, 1997).

    Google Scholar 

  30. Charlesworth, B., Moran, M. & Charlesworth, D. The effect of deleterious mutations on neutral molecular variation. Genetics 134, 1289– 1303 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Nachman, M.W., Bauer, V.L., Crowell, S.L. & Aquadro, C.F. DNA variability and recombination rates at X-linked loci in humans. Genetics 150, 1133–1141 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Collins, F.S., Brooks, L.D. & Chakravarti, A. A DNA polymorphism discovery resource for research on human genetic variation. Genome Res. 8, 1229–1231 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  34. Venter, J.C. et al. Shotgun sequencing of the human genome. Science 280, 1540–1542 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  35. Harpending, H.C. et al. Genetic traces of ancient demography. Proc. Natl Acad. Sci. USA 95, 1961–1967 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Eyre-Walker, A. & Keightley, P.D. High genomic deleterious mutation rates in hominids. Nature 397, 344–347 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. Wolfsberg, T.G. & Landsman, D. A comparison of expressed sequence tags (ESTs) to human genomic sequences. Nucleic Acids Res. 26, 1626–1632 (1997).

    Article  Google Scholar 

  38. Gerhold, D. & Caskey C.T. It's the genes! EST access to human genome content. Bioessays 18, 973– 981 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Collins, F.S. et al. New goals for the U.S. Human Genome Project: 1998–2003. Science 282, 682–689 (1998).

    Article  CAS  PubMed  Google Scholar 

  40. Harris, H. Enzyme polymorphisms in man. Proc. R. Soc. Lond. B. Biol. Sci. 164, 298–310 ( 1966).

    Article  CAS  PubMed  Google Scholar 

  41. Harris, H. & Hopkinson, D.A. Average heterozygosity per locus in man: an estimate based on the incidence of enzyme polymorphisms. Ann. Hum. Genet. 36, 9–20 (1972).

    Article  CAS  PubMed  Google Scholar 

  42. King, M.C. & Wilson, A.C. Evolution at two levels in humans and chimpanzees. Science 188, 107– 116 (1975).

    Article  CAS  PubMed  Google Scholar 

  43. Angrist, M. et al. Human GFRA1: cloning, mapping, genomic structure, and evaluation as a candidate gene for Hirschsprung disease susceptibility. Genomics 48, 354–362 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  44. Gordon, D., Abajian, C. & Green, P. Consed: a graphical tool for sequence finishing. Genome Res. 8, 195 (1998).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge the assistance of N. Bringht-Twumasi and R. Keefer for technical assistance in sample preparation, PCR analyses and sequencing; M. Mittmann and E. Hubbell for chip design; A. Berno for chip data analyses; N. Patil and C. Marjoribanks for cDNA samples; M. Zwick, H. Willard, C. Langley, E. Eichler and anonymous reviewers for comments on the manuscript; and M. Chee for his efforts at the initiation of this gene screening project. This study was supported by research funds from Case Western Reserve University, University Hospitals of Cleveland, National Heart, Lung & Blood Institute (U10 HL54466) and National Human Genome Research Institute (RO1 HG01847) to A.C. This study is a component of the GenNet network of the NHLBI Family Blood Pressure Program.

Author information

Authors and Affiliations

  1. Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, 44106, Ohio, USA

    Marc K. Halushka, Kimberly Bentley & Aravinda Chakravarti

  2. Affymetrix, Inc., 3380 Central Expressway , Santa Clara, 95051, California, USA

    Jian-Bing Fan, Linda Hsie, Naiping Shen & Robert Lipshutz

  3. Department of Medicine, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Alan Weder

  4. Department of Epidemiology, Loyola University Medical Center, Maywood, 60153, Illinois, USA

    Richard Cooper

Authors
  1. Marc K. Halushka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jian-Bing Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kimberly Bentley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Linda Hsie
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Naiping Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alan Weder
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Richard Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Robert Lipshutz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Aravinda Chakravarti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aravinda Chakravarti.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Halushka, M., Fan, JB., Bentley, K. et al. Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nat Genet 22, 239–247 (1999). https://doi.org/10.1038/10297

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/10297

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing