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:

Dissecting the loci controlling fetal haemoglobin production on chromosomes 11p and 6q by the regressive approach

Nature Genetics volume 12, pages 58–64 (1996)Cite this article

Abstract

The Changes in the type of haemoglobin (Hb) produced during embryonic, fetal and adult life, have served as a paradigm for understanding the developmental regulation of human genes. A genetically determined persistence of fetal Hb synthesis has an ameliorating effect on β thalassaemia and sickle cell anaemia, globally the commonest single gene disorders. The search for the putative gene(s) controlling the level of fetal Hb production has been extremely difficult because this trait may be influenced by several factors. We have studied a large kindred with hereditary persistence of fetal haemoglobin (HPFH). Using a genetic mapping strategy and statistical methods that account simultaneously for the effects of several genetic factors, we have demonstrated that in addition to the two factors (β thalassaemia and Xmn l-Gγ site) on chromosome 11 p, there is a third major genetic determinant for fetal Hb production localized on chromosome 6q.

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

Similar content being viewed by others

References

  1. Stamatoyannopoulos, G. & Nienhuis, A.W. Hemoglobin switching. in The molecular basis of blood diseases (2nd Edition) (eds Stamatoyannopoulos, G., Nienhuis, A.W., Majerus, P.W. & Varmus, H.) 107–155 (W.B. Saunders and Co., Philadelphia, 1994).

    Google Scholar 

  2. Grosveld, F., van Assendelft, G.B., Breaves, D.R. & Kollias, G. Position-independent, high-level expression of the human γ-globin gene in transgenic mice. Cell 51, 975–985 (1987).

    Article  CAS  Google Scholar 

  3. Sampietro, M., Thein, S.L., Contreras, M. & Pazmany, L. Variation of HPF and F-cell number with the G-γXmn I (C-T) polymorphism in normal individuals. Blood 79, 832–833 (1992).

    CAS  PubMed  Google Scholar 

  4. Zago, M.A. et al. Genetic control of F cells in human adults. Blood 53, 977–986 (1979).

    CAS  PubMed  Google Scholar 

  5. Miyoshi, K. et al. X-linked dominant control of F-cells in normal adult life: Characterization of the Swiss type as hereditary persistence of fetal hemoglobin regulated dominantly by gene(s) on X chromosome. Blood 72, 1854–1860 (1988).

    CAS  PubMed  Google Scholar 

  6. Gianni, A.M. et al. A gene controlling fetal hemoglobin expression in adults is not linked to the non−a globin cluster. EMBO J. 2, 921–925 (1983).

    Article  CAS  Google Scholar 

  7. Martinez, G., Novelletto, A., Di Rienzo, A., Felicetti, L. & Colombo, B. A case of hereditary persistence of fetal hemoglobin caused by a gene not linked to the β-globin cluster. Hum. Genet. 82, 335–337 (1989).

    Article  CAS  Google Scholar 

  8. Thein, S.L. & Weatherall, D.J. A non-deletion hereditary persistance of fetal hemoglobin (HPFH) determinant not linked to the β-globin gene complex. in Hemoglobin Switching, Part B: Cellular and Molecular Mechanisms (eds Stamatoyannopoulos, G. & Nienhuis, A.W.) 97–111 (Alan R. Liss, Inc., New York, 1989).

    Google Scholar 

  9. Giampaolo, A. et al. Heterocellular HPFH: molecular mechanisms of abnormal γ gene expression in association with β-thalassemia and linkage relationship with the β-globin gene cluster. Hum. Genet. 66, 151–156 (1984).

    Article  CAS  Google Scholar 

  10. Dover, G.J. et al. Fetal hemoglobin levels in sickle cell disease and normal individuals are partially controlled by an X−linked gene located at Xp22.2. Blood 80, 816–824 (1992).

    CAS  PubMed  Google Scholar 

  11. Chang, Y.C., Smith, K.D., Moore, R.D., Serjeant, G.R. & Dover, G.J. An analysis of fetal hemoglobin variation in sickle cell disease: the relative contributions of the X-linked factor, β-globin haplotypes, α-globin gene number, gender and age. Blood 85, 1111–1117 (1995).

    CAS  PubMed  Google Scholar 

  12. Cappellini, M.D., Fiorelli, G. & Berini, L.F. Interaction between homozygous β° thalassaemia and the Swiss type of hereditary persistence of fetal haemoglobin. Br. J. Haem. 48, 561–572 (1981).

    Article  CAS  Google Scholar 

  13. Perrine, S.P., Brown, M.J., Clegg, J.B., Weatherall, D.J. & May, A. Benign sickle-cell anaemia. Lancet 2, 1163 (1972).

    Article  CAS  Google Scholar 

  14. Rutland, P.C., Pembrey, M.E. & Davies, T. The estimation of fetal haemoglobin in healthy adults by radioimmunoassay. Br. J. Haem. 53, 673–682 (1983).

    Article  CAS  Google Scholar 

  15. Stamatoyannopoulos, G., Wood, W.G. & Papayannopoulou, T. A new form of hereditary persistence of fetal hemoglobin in blacks and its association with sickle cell trait. Blood 46, 683–692 (1975).

    CAS  PubMed  Google Scholar 

  16. Rochette, J., Dode, C., Leturcq, F. & Krishnamoorthy, R. Level and composition of fetal hemoglobin expression in normal newborn babies are not dependent on β cluster DNA haplotype. Am. J. Hem. 34, 223–224 (1990).

    Article  CAS  Google Scholar 

  17. Gilman, J.G. & Huisman, T.H.J. DNA sequence variation associated with elevated fetal Gγ globin production. Blood 66, 783–787 (1985).

    CAS  PubMed  Google Scholar 

  18. Bonney, G.E. On the statistical determination of major gene mechanisms in continuous human traits: regressive models. Am. J. Med. Genet. 18, 731–749 (1984).

    Article  CAS  Google Scholar 

  19. Bonney, G.E., Lathrop, G.M. & Lalouel, J.-M. Combined linkage and segregation analysis using regressive models. Am. J. Hum. Genet. 43, 29–37 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Thein, S.L. et al. Detection of a major gene for heterocellular hereditary persistence of fetal hemoglobin after accounting for genetic modifiers. Am. J. Hum. Genet. 54, 214–228 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Demenais, F.M., Murigande, C. & Bonney, G.E. Search for faster methods of fitting the regressive models to quantitative traits. Genet. Epidemiol. 7, 319–334 (1990).

    Article  CAS  Google Scholar 

  22. Weissenbach, J. et al. A second-generation linkage map of the human genome. Nature. 359, 794–801 (1992).

    Article  CAS  Google Scholar 

  23. Gyapay, G. et al. The 1993–94 Généthon human genetic linkage map. Nature Genetics 7, 246–339 (1994).

    Article  CAS  Google Scholar 

  24. Morton, I.N. The detection and estimation of linkage between the genes for elliptocytes and Rh phenotype. Am. J. Hum. Genet. 8, 80–96 (1956).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Ott, J. Analysis of Human Genetic Linkage (Johns Hopkins University Press, Baltimore, 1991).

    Google Scholar 

  26. Lander, E.S. & Schork, N.J. Genetic dissection of complex traits. Science 265, 2037–2048 (1994).

    Article  CAS  Google Scholar 

  27. Hashimoto, L. et al. Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome 11q. Nature 371, 161–164 (1994).

    Article  CAS  Google Scholar 

  28. Davies, J.L. et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature 371, 130–136 (1994).

    Article  CAS  Google Scholar 

  29. Marsh, D.G. et al. Linkage analysis of IL4 and other chromosomes 5q31.1 markers and total serum immunoglobulin E concentrations. Science 264, 1152–1156 (1994).

    Article  CAS  Google Scholar 

  30. Suarez, B.K., Hampe, C.L. & Van Eerdewegh, P. in Genetic Approaches to Mental Disorders (eds Gershon, E.S. & Cloninger, C.R.) 23–46 (American Psychiatric Press, Washington DC, 1994).

    Google Scholar 

  31. Martinez, M., Abel, L. & Demenais, F. How can maximum likelihood methods reveal candidate genes in a quantitative trait? Genet. Epidemiol. (in the press).

  32. Crossley, M. & Orkin, S.H. Regulation of the β-globin locus. Curr. Opin. Genet. Devel. 3, 232–237 (1993).

    Article  CAS  Google Scholar 

  33. Grosveld, F, Dillon, N. & Higgs, D. The regulation of human globin gene expression. in Baillière's Clinical Haematology (eds Higgs, D.R. & Weatherall, D.J.) 31–55 (BaillièreTindall, London, 1993).

    Google Scholar 

  34. Collins, F.S. Positional cloning: Let's not call it reverse anymore. Nature Genet. 1, 3–6 (1992).

    Article  CAS  Google Scholar 

  35. DeSimone, J., Heller, R., Biel, M. & Zwiers, D. Genetic relationship between fetal Hb levels in normal and erythropoietically stressed baboons. Br. J. Haem. 49, 175–183 (1981).

    Article  CAS  Google Scholar 

  36. Volz, A. et al. Report of the Second International Workshop on Human Chromosome 6. Genomics 21, 464–472 (1994).

    Article  CAS  Google Scholar 

  37. Sparkes, R.S. et al. The gene for human liver arginase (ARG1) is assigned to chromosome band 6q23. Am. J. hum. Genet. 39, 186–193 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Meloni, R., Fougerousse, F., Roudaut, C. & Beckmann, J.S. Dinucleotide repeat polymorphism at the human liver arginase gene (ARG1). Nucl. Acids Res. 20, 1166 (1993).

    Article  Google Scholar 

  39. Higgs, D.R. α-thalassaemia. in Baillière's Clinical Haematology. International Practice and Research: The Haemogtobinopathies (eds Higgs, D.R. & Weatherall, DJ.) 117–150 (Baillière Tindall, London, 1993).

    Google Scholar 

  40. Gibbons, R.J., Picketts, D.J., Vlllard, L. & Higgs, D.R X-linked mental retardation associated with α thalassaemia (ATR-X syndrome) results from mutations in a putative global transcriptional regulator. Cell 80, 837–845 (1995).

    Article  CAS  Google Scholar 

  41. Thein, S.L., Wood, W.G., Wickramasinghe, S.N. & Galvin, M.C., Galvin, M.C. β-thalassemia unlinked to the β-globin gene in an English family. Blood 82, 961–967 (1993).

    CAS  PubMed  Google Scholar 

  42. Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am. J. Hum. Genet. 37, 482–498 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Elston, R.C. & Stewart, J. A general model for the genetic anlaysis of pedigree data. Hum. Hered. 21, 523–542 (1971).

    Article  CAS  Google Scholar 

  44. Demenais, F. & Lathrop, G.M. REGRESS: A computer program including the regression approach into the linkage package. Genet. Epidemiol. 11, 291 (1994).

    Google Scholar 

Download references

Author information

Author notes

  1. SweeLay Thein: Correspondence should be addressed to S.L.T.

Authors and Affiliations

  1. MRC Molecular Haematology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DU, UK

    Jamie E. Craig, Jacques Rochette, Chris A. Fisher, David J. Weatherall & SweeLay Thein

  2. Généthon, 1, rue de l'internationale, 91000, Evry, France

    Sophie Marc

  3. Wellcome Trust Centre for Human Genetics, Windmill Road, Oxford, UK

    G. Mark Lathrop

  4. INSERM U358, Hospital Saint-Louis, Paris, 75010, France

    G. Mark Lathrop & Florence Demenais

Authors
  1. Jamie E. Craig
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jacques Rochette
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chris A. Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David J. Weatherall
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sophie Marc
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G. Mark Lathrop
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Florence Demenais
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. SweeLay Thein
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Craig, J., Rochette, J., Fisher, C. et al. Dissecting the loci controlling fetal haemoglobin production on chromosomes 11p and 6q by the regressive approach. Nat Genet 12, 58–64 (1996). https://doi.org/10.1038/ng0196-58

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0196-58

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