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.

  • Letter
  • Published:

Experimentally-derived haplotypes substantially increase the efficiency of linkage disequilibrium studies

Nature Genetics volume 28, pages 361–364 (2001)Cite this article

Abstract

The study of complex genetic traits in humans is limited by the expense and difficulty of ascertaining populations of sufficient sample size to detect subtle genetic contributions to disease. Here we introduce an application of a somatic cell hybrid construction strategy called conversion1,2,3,4 that maximizes the genotypic information from each sampled individual. The approach permits direct observation of individual haplotypes, thereby eliminating the need for collecting and genotyping DNA from family members for haplotype-based analyses. We describe experimental data that validate the use of conversion as a whole-genome haplotyping tool and evaluate the theoretical efficiency of using conversion-derived haplotypes instead of conventional genotypes in the context of haplotype-frequency estimation. We show that, particularly when phenotyping is expensive, conversion-based haplotyping can be more efficient and cost-effective than standard genotyping.

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: Human chromosomal composition of mouse-human somatic cell hybrids.
Figure 2: Select haplotype-frequency information ratios.

Similar content being viewed by others

References

  1. Papadopolous, N., Leach, F.S., Kinzler, K.W. & Vogelstein, B. Monoallelic mutation analysis (MAMA) for identifying germline mutations. Nature Genet. 11, 99–102 (1995).

    Article  Google Scholar 

  2. Laken, S.J. et al. Analysis of masked mutations in familial adenomatous polyposis. Proc. Natl. Acad. Sci. USA 96, 2322–2326 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yan, H. et al. Conversion of diploidy to haploidy. Nature 403, 723–724 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Yan, H., Kinzler, K.W. & Vogelstein, B. Genetic testing—present and future. Science 289, 1890–1892 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. MacLean, C.J. & Morton, N.E. Estimation of myriad haplotype frequencies. Genet. Epidemiol. 2, 263–272 (1985).

    Article  CAS  PubMed  Google Scholar 

  6. Excoffier, L. & Slatkin, M. Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol. Biol. Evol. 12, 921–927 (1995).

    CAS  PubMed  Google Scholar 

  7. Hawley, M.E. & Kidd, K.K. HAPLO: a program using the EM algorithm to estimate the frequencies of multi-site haplotypes. J. Hered. 86, 409–411 (1995).

    Article  CAS  PubMed  Google Scholar 

  8. Long, J.C., Williams, R.C. & Urbanek, M. An E-M algorithm and testing strategy for multiple-locus haplotypes. Am. J. Hum. Genet. 56, 799–810 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Michalatos-Beloin, S., Tishkoff, S.A., Bentley, K.L., Kidd, K.K. & Ruano, G. Molecular haplotyping of genetic markers 10 kb apart by allele-specific long-range PCR. Nucleic Acids Res. 24, 4841–4843 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hodge, S.E., Boehnke, M. & Spence, M.A. Loss of information due to ambiguous haplotyping of SNPs. Nature Genet. 21, 360–361 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Weiss, M.C. & Green, H. Human-mouse hybrid cell lines containing partial complements of human chromosomes and functioning human genes. Proc. Natl. Acad. Sci. USA 58, 1104–1111 (1967).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Nishimura, D.Y. et al. The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nature Genet. 19, 140–147 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Glaser, T. et al. The beta-subunit of follicle-stimulating hormone is deleted in patients with aniridia and Wilms' tumour, allowing a further definition of the WAGR locus. Nature 321, 882–887 (1986).

    Article  CAS  PubMed  Google Scholar 

  14. Tishkoff, S.A., Pakstis, A.J., Ruano, G. & Kidd, K.K. The accuracy of statistical methods for estimation of haplotype frequencies: an example from the CD4 locus. Am. J. Hum. Genet. 67, 518–522 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hill, W.G. Estimation of linkage disequilibrium in randomly mating populations. Heredity 33, 229–239 (1974).

    Article  CAS  PubMed  Google Scholar 

  16. McKeigue, P.M. Efficiency of estimation of haplotype frequencies: use of marker phenotypes of unrelated individuals versus gene counting of phase known gametes. Am. J. Hum. Genet. 67, 1626–1627 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Veldman, T., Vignon, C., Schrock, E., Rowley, J.D. & Ried, T. Hidden chromosome abnormalities in haematological malignancies detected by multicolour spectral karyotyping. Nature Genet. 15, 406–410 (1997).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank B. Vogelstein and H. Yan of Johns Hopkins University for generously donating the somatic cell hybrids. We would also like to acknowledge the technical assistance of T. Dennis and A. Dutra of the National Human Genome Research Institute Cytogenetic and Confocal Microscopy Core. This work was supported in part by a University of Michigan Predoctoral Fellowship to J.A.D. and by National Institutes of Health grants to M.B. (R01 HG00376) and S.B.G. (R01 CA81488).

Author information

Authors and Affiliations

  1. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA

    Julie A. Douglas

  2. Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA

    Michael Boehnke

  3. Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, USA

    Stephen B. Gruber

  4. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Stephen B. Gruber

  5. Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA

    Julie A. Douglas, Michael Boehnke & Stephen B. Gruber

  6. National Human Genome Research Institute, Bethesda, Maryland, USA

    Elizabeth Gillanders & Jeffrey M. Trent

Authors
  1. Julie A. Douglas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Boehnke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elizabeth Gillanders
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeffrey M. Trent
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephen B. Gruber
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Boehnke.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Douglas, J., Boehnke, M., Gillanders, E. et al. Experimentally-derived haplotypes substantially increase the efficiency of linkage disequilibrium studies. Nat Genet 28, 361–364 (2001). https://doi.org/10.1038/ng582

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng582

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