Skip to main content
SpringerLink
Log in

The evolution of the α- and β-globin gene clusters in human populations

  • Review Articles
  • Published:
Human Genetics Aims and scope Submit manuscript

Summary

DNA analysis of the α- and β-globin gene clusters has revealed substantial variability between individuals and populations. As well as restriction enzyme site and length polymorphisms, variation in gene copy number and type is observed. Because of this extensive polymorphism DNA analysis offers a highly informative method of studying genetic affinities between human populations. Haplotypes, consisting of a set of restriction enzyme polymorphisms distributed along the cluster, have been developed for both loci. Analysis of the molecular basis of numerous β-thalassaemia alleles has revealed, in general, different sets of mutations in different populations, indicating that these postdate the racial divergence. Recent microepidemiological studies on the distribution of α-thalassaemia support the hypothesis that this condition, like the {ie16-1}, has been selected because it confers protection against malaria. Population-specific DNA polymorphisms at these and other loci promise to be of considerable value to genetic anthropology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Antonarakis SE, Boehm CD, Giardina PJV, Kazazian HH Jr (1982a) Nonrandom association of polymorphic restriction sites in the β-globin gene cluster. Proc Natl Acad Sci USA 79:137–141

    Google Scholar 

  • Antonarakis SE, Orkin SH, Kazazian HH Jr, Goff SC, Boehm CD, Waber PG, Sexton JP, Ostrer H, Fairbanks VF, Charkravarti A (1982) Evidence for multiple origins of the 22-1 gene in Southeast Asia. Proc Natl Acad Sci USA 79:6608–6611

    Google Scholar 

  • Antonarakis SE, Boehm CD, Serjeant GR, Theisen CE, Dover GJ, Kazazian HH Jr (1984a) Origin of the 22-2 globin gene in Blacks: the contribution of recurrent mutation or gene conversion or both. Proc Natl Acad Sci USA 81:853–856

    Google Scholar 

  • Antonarakis SE, Orkin SH, Cheng T-c, Scott AF, Sexton JF, Trusco S., Charache S, Kazazian HH Jr (1984b) β-thalassemia in American Blacks: novel mutations in the TATA box and IVS-2 acceptor splice site. Proc Natl Acad Sci USA 81:1154–1158

    Google Scholar 

  • Antonarakis SE, Kazazian HH, Orkin SH (1985) DNA polymorphism and molecular pathology of the human globin gene clusters. Hum Genet 69:1–14

    Google Scholar 

  • Baltimore D (1981) Gene conversion: some implications for immunoglobulin genes. Cell 24:592–594

    Google Scholar 

  • Black RH (1955) The geographical distribution of malaria in the south-west Pacific. Aust Geographer 6:32–36

    Google Scholar 

  • Boehm CD, Dowling CE, Antonarakis SE, Honig GR, Kazazian HH (1985) Evidence supporting a single origin of the 22-3 gene in Blacks. Am J Hum Genet 37:771–777

    Google Scholar 

  • Cavalli-Sforza LL, Bodmer WG (1971) The genetics of human populations. Freeman, San Francisco

    Google Scholar 

  • Cavalli-Sforza LL (1985) Current knowledge of the human genome and outlook for the future (abstr). Paris meeting (in press)

  • Chakravarti A, Buetow KH, Antonarakis SE, Waber PG, Boehm CD, Kazazian HH Jr (1984) Nonuniform recombination within the human β-globin gene cluster. Am J Hum Genet 36:1239–1258

    Google Scholar 

  • Chehab FF, Honig GR, Kan YW (1986) Spontaneous mutation in β-thalassaemia producing the same nucleotide substitution as that in a common hereditary form. Lancet I:3–5

    Google Scholar 

  • Cheng T-c, Orkin SH, Antonarakis SE, Potter MJ, Sexton JP, Markham AF, Giardina PVJ, Li A, Kazazian HH Jr (1984) β-thalassemia in Chinese: use of in vivo RNA analysis and oligonucleotide hybridization in systematic characterization of molecular defects. Proc Natl Acad Sci USA 81:2821–2825

    Google Scholar 

  • Collins FS, Weissman SM (1984) The molecular genetics of human hemoglobin. Prog Nucleic Acid Res Mol Biol 3:315–462

    Google Scholar 

  • Collins FS, Boehm CD, Waber PG, Stoeckert CJ, Weissman SM, Forget BG, Kazazian HH (1984) Concordance of a point mutation 5′ to the GJ globin gene with 22-4 hereditary persistence of fetal hemoglobin in the black population. Blood 64:1292–1296

    Google Scholar 

  • Cooper DN, Schmidtke J (1984) DNA restriction fragment length polymorphisms and heterozygosity in the human genome. Hum Genet 66:1–17

    Google Scholar 

  • Deisseroth A, Nienhuis A, Turner P, Velez R, Anderson WF, Ruddle F, Lawrence J, Creagan R, Kucherlapati R (1977) Localization of the human α-globin structural gene to chromosome 16 in somatic cell hybrids by molecular hybridization asay. Cell 12:205–218

    Google Scholar 

  • Deisseroth A, Nienhuis A, Lawrence J, Giles R, Turner P, Ruddle FH (1978) Chromosomal localization of human β-globin gene on human chromosome 11 in somatic cell hybrids. Proc Natl Acad Sci USA 75:1456–1460

    Google Scholar 

  • Flint J, Hill AVS, Bowden DK, Oppenheimer SJ, Sill PR, Serjeartson SW, Banakoiri J, Bhatia K, Alpers MP, Boyce AJ, Weatherall OJ, Clegg JB (1986) High frequencies of α thalassaemia are the result of natural selection by malaria. Nature 321:744–750

    Google Scholar 

  • Friedman MJ (1978) Erythrocytic mechanisms of sickle resistance to malaria. Proc Natl Acad Sci USA 75:1994–1997

    Google Scholar 

  • Gerhard DS, Kidd KK, Kidd JR, Egeland JA, Housman DE (1984) Identification of a recent recombination event within the human β-globin gene cluster. Proc Natl Acad Sci USA 81:7875–7879

    Google Scholar 

  • Giles RE, Blanc H, Cann HM, Wallace DC (1980) Maternal inheritance of human mitochondrial DNA. Proc Natl Acad Sci USA 77:6715–6719

    Google Scholar 

  • Gilman JB, Huisman THJ (1985) DNA sequence variation associated with elevated fetal 22-5 globin production. Blood 66:783–787

    Google Scholar 

  • Goodbourn SEY, Higgs DR, Clegg JB, Weatherall DJ (1983) Molecular basis of length polymorphism in the human α-globin gene complex. Proc Natl Acad Sci USA 80:5022–5026

    Google Scholar 

  • Goodbourn SEY, Higgs DR, Clegg JB, Weatherall DJ (1984) Allelic variation and linkage properties of a highly polymorphic restriction fragment in humans. Mol Biol Med 2:223–238

    Google Scholar 

  • Goosens M, Dozy AN, Embury SH, Zachariades Z, Hadjimias MG, Stamatoyannopoulos G, Kan YW (1980) Triplicated α-globin loci in humans. Proc Natl Acad Sci USA 77:518–521

    Google Scholar 

  • Haldane JBS (1949) The rate of mutation of human genes. Proceedings of 8th International Congress on Genetics, pp 267–273

  • Harano K, Harano T, Kutlar F, Huisman THJ (1985) γ-globin triplication and quadruplication in Japanese newborns. FEBS Lett 190:45–49

    Google Scholar 

  • Hardison RC, Sanvada I, Cheng J-F, Shen C-KJ, Schmid CW (1986) A previously undetected pseudogene in the human alpha globin gene cluster. Nucleic Acids Res 14:1903–1911

    Google Scholar 

  • Harris S, Barrie PA, Weiss ML, Jeffreys AJ (1984) The primate ψβ1 gene. J Mol Biol 180:785–801

    Google Scholar 

  • Heyerdahl T (1950) Kon-Tiki: across the Pacific by raft. McNally, New York

    Google Scholar 

  • Higgs DR, Old JM, Pressley L, Clegg JB, Weatherall DJ (1980) A novel globin gene arrangement in man. Nature 284:632–635

    Google Scholar 

  • Higgs DR, Goodbourn SEY, Wainscoat JS, Clegg JB, Weatherall DJ (1981) Highly variable regions of DNA flank the human α-globin genes. Nucleic Acids Res 9:4213–4224

    Google Scholar 

  • Higgs DR, Weatherall DJ (1983) Alpha-thalassaemia. Curr Top Hematol 4:37–97

    Google Scholar 

  • Higgs DR, Wainscoat JS, Flint J, Hill AVS, Thein SL, Nicholls RD, Teal H, Ayyub H, Peto TEA, Jarman AP, Clegg JB, Weatherall DJ (1986) Analysis of the human α-globin gene cluster reveals a highly informative genetic locus. Proc Natl Acad Sci USA (in press)

  • Hill AVS (1986) The population genetics of α thalassaemia and the malaria hypothesis. Cold Spring Harbor Symp Quant Biol, vol 51 (in press)

  • Hill AVS, Bowden DK, Trent RJ, Higgs DR, Oppenheimer SJ, Thein SL, Mickleson KNP, Weatherall DJ, Clegg JB (1985a) Melanesians and Polynesians share a unique α-thalassaemia mutation. Am J Hum Genet 37:571–580

    Google Scholar 

  • Hill AVS, Nicholls RD, Thein SL, Higgs DR (1985b) Recombination within the human embryonic χ-globin locus: a common χ-χ chromosome produced by gene conversion of the ψχ gene. Cell 42:809–819

    Google Scholar 

  • Hill AVS, Bowden DK, Weatherall DJ, Clegg JB (1986) Chromosomes with one, two, three and four fetal globin genes: molecular and hematological analysis. Blood (in press)

  • Huisman THJ, Kutlar F, Nakatsuji T, Bruce Tagoe A, Kilinc Y, Canchi MN, Romero Garcia C (1985) The frequency of the γ chain variant 22-6 in different populations, and its use in evaluating γ gene expression in association with thalassaemia. Hum Genet 71:127–133

    Google Scholar 

  • Ifediba TC, Stern A, Ibrahim A, Rieder RF (1985) Plasmodium falciparum in vitro: diminished growth in hemoglobin H disease erythrocytes. Blood 65:452–455

    Google Scholar 

  • Jarman AP, Nicholls DR, Weatherall DJ, Clegg JB, Higgs DR (1986) Molecular characterisation of a hypervariable region downstream of the human α-blobin gene cluster. EMBO J (in press)

  • Jeffereys AJ (1979) DNA sequence variants in the 22-7, 22-8, δ and β globin genes of man. Cell 18:1–10

    Google Scholar 

  • Jeffreys AJ (1982) Evolution of globin genes In: Genome evolution. Academic Press, New York London, pp 157–176

    Google Scholar 

  • Johnson JM, Wallace DC, Ferris SD, Ratlazzi MC, Cavalli-Sforza LL (1983) Radiation of human mitochondrial DNA types analyzed by restriction endonuclease cleavage patterns. J Mol Evol 19:255–271

    Google Scholar 

  • Jones JS, Rouhani S (1986) Human vvolution: how small was the bottleneck. Nature 319:449–450

    Google Scholar 

  • Jorde LB (1985) Human genetic distance studies: present status and future prospects. Annu Rev Anthropol 14:343–373

    Google Scholar 

  • Kan YW, Dozy AM (1978) Polymorphism of DNA sequence adjacent to the human β-globin structural gene: relationship to sickle mutation. Proc Natl Acad Sci USA 75:5631–5635

    Google Scholar 

  • Kan YW, Dozy AM (1980) Evolution of the hemoglobin S and C genes in world populations. Science 209:492–493

    Google Scholar 

  • Kazazian HH Jr, Orkin SH, Antonarakis SE, Sexton JP, Boehm CD, Goff SC, Waber PG (1984a) Molecular characterization of seven β-thalassaemia mutations in Asian Indians. EMBO J 3:593–596

    Google Scholar 

  • Kazazian HH Jr, Orkin SH, Markham AF, Chapman CR, Youssoufian HA, Waber PG (1984b) Quantitation of the close association between DNA haplotypes and specific β-thalassaemia mutations in Mediterraneans. Nature 300:152–154

    Google Scholar 

  • Kazazian HH Jr, Waber PG, Boehm CD, Lee JI, Antonarakis SE, Fairbank VF (1984c) Hemoglobin E in Europeans: further evidence for multiple origins of the 23-1 gene. Am J Hum Genet 36:212–217

    Google Scholar 

  • Klein HL, Petes TD (1981) Intrachromosomal gene conversion in yeast. Nature 289:144–148

    Google Scholar 

  • Koop BF, Goodman M, Xa P, Chan K, Slightom JL (1986) Primate η-globin DNA sequences and man's place among the great apes. Nature 319:234–237

    Google Scholar 

  • Kulozik AE, Wainscoat JS, Scrjeant GR, Al-Awamy B, Essan F, Falusi Y, Hague SK, Hilali AM, Kate S, Ranasinghe WACP. Weatherall DJ (1986) Geographical survey of {ie23-2} globin gene haplotypes: evidence for an independent Asian origin of the sicklecell mutation. Am J Hum Genet (in press)

  • Lauer J, Shen C-KJ, Maniatis T (1980) The chromosomal arrangement of human α-like globin genes. Sequence homology and α-globin gene deletions. Cell 20:119–130

    Google Scholar 

  • Liebhaber SA, Rappaport EF, Cash FE, Ballas SK, Schwartz E, Surrey S (1984) Hemoglobin I mutation encoded at both alpha-globin loci on the same chromosome: concerted evolution in the human genome. Science 226:1449–1451

    Google Scholar 

  • Livingstone FB (1983) The malaria hypothesis. In: Bowman J (ed) The distribution and evolution of the hemoglobin and globin gene loci. Elsevier, New York, pp 15–44

    Google Scholar 

  • Maeda N, Bliska JB, Smithies O (1983) Recombination and balanced chromosome polymorphism suggested by DNA sequences 5′ to the human δ-globin gene. Proc Natl Acad Sci USA 80:5012–5016

    Google Scholar 

  • Marks J, Show J-P, Shen C-KJ (1983) Sequence organisation and complexity of the primate δ1 globin gene, a novel α-globin like gene. Nature (in press)

  • Molineaux L, Gramiccia G (1980) The Garki project: research on the epidemiology and control of malaria in the Sudan Savanna of West Africa. WHO, Geneva, pp 213–229

    Google Scholar 

  • Motulsky AG (1964) Hereditary red cell traits and malaria. Am J Trop Hyg 13:147–156

    Google Scholar 

  • Nagel RL (1984) The origin of the hemoglobin S gene: clinical, genetic, and anthropological consequences. The Einstein Quarterly J Med 2:53–62

    Google Scholar 

  • Nei M, Roychoudbury AK (1982) Genetic relationship and evolution of human races. In: Krecht MK, Wallace B, Prance GT (eds) Evolutionary biology, vol 14. Plenum Press, New York, pp 1–59

    Google Scholar 

  • Old JM, Heath C, Fitches A, Thein SL, Jeffreys AJ, Petrou M, Modell B, Weatherall DJ (1986) Meiotic recombination between two polymorphic restriction sites within the β-globin gene cluster. J Med Genet 23:14–18

    Google Scholar 

  • Oppenheimer SJ, Higgs DR, Weatherall DJ, Barker J, Spark RA (1984) α-thalassaemia in Papua New Guinea. Lancet I:424–426

    Google Scholar 

  • Orkin SH, Kazazian HH Jr, Antonarakis SE, Goff SC, Boehm CD, Sexton JP, Waber PG, Giardina PVJ (1982) Linkage of β-thalassaemia mutations and β-globin gene polymorphisms with DNA polymorphic in the human β-globin gene cluster. Nature 296:627–631

    Google Scholar 

  • Pagnier J, Mears JG, Dunda-Belkhodja O, Schaefer-Rego KE, Beldjord C, Nagel RL, Labie D (1984) Evidence for the multicentric origin of the sickle cell hemoglobin gene in Africa. Proc Natl Acad Sci USA 81:1771–1773

    Google Scholar 

  • Pasvol G, Weatherall DJ, Wilson RJM (1978) Cellular mechanism for the protective effect of haemoglobin S against P. falciparum malaria. Nature 274:701–703

    Google Scholar 

  • Powars PA, Smithies O (1986) Short gene conversions in the human fetal globin gene region: a by-product of chromosomal pairing during meiosis? Genetics 112:343–358

    Google Scholar 

  • Proudfoot NJ, Maniatis T (1980) The structure of a human α-globin pseudogene and its relationship to α-globin gene duplication. Cell 21:537–544

    Google Scholar 

  • Proudfoot NJ, Gil A, Maniatis T (1982) The structure of the human zeta-globin gene and a closely linked, nearly identical pseudogene. Cell 31:553–563

    Google Scholar 

  • Reeders ST, Breuning MH, Davies KE, Nicholls RD, Jarman AP, Higgs DR, Pearson PL, Weatherall DJ (1985) A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16. Nature 317:542–544

    Google Scholar 

  • Rosatelli C, Falchi AM, Tuveri T, Scalas MT, DiTucci A, Monni G, Cao A (1985) Prenatal diagnosis of beta-thalassaemia with the synthetic-oligomer technique. Lancet I:241–243

    Google Scholar 

  • Scott AF, Health P, Trusko S, Boyer SH, Prass W, Goodman M, Czelusniak J, Chang L-YE, Slightom JL (1984) The sequence of the gorilla fetal globin genes: evidence for multiple gene conversions in human evolution. Mol Biol Evol 1:371–389

    Google Scholar 

  • Shimasaki S, Iuchi I (1986) Diversity of human γ-globin gene loci including a quadruplicated arrangement. Blood 67:784–788

    Google Scholar 

  • Slightom JL, Blechl AE, Smithies O (1980) Human fetal 23-3 and 23-4 globin genes: complete nucleotide sequences suggest that DNA can be exchanged between these duplicated genes. Cell 21:627–638

    Google Scholar 

  • Sukumaran PK, Wakatsuji T, Gardiner MB, Gilman JG, Huisman THJ (1983) Gamma thalassaemia resulting from deletion of a γ-globin gene. Nucleic Acids Res 11:4635–4643

    Google Scholar 

  • Thein SL, Old JM, Wainscoat JS, Petrou M, Modell B, Weatherall DJ (1984) Population and genetic studies suggest a single origin for the Indian deletion 23-5 thalassaemia. Br J Hacmatol 57:271–278

    Google Scholar 

  • Thein SL, Wainscoat JS, Old JM, Wallace RB, Weatherall DJ (1985) The AvaII ψβ polymorphism is linked to the common Mediterranean 23-6 thalassaemia mutation. Br J Haematol 61:747–748

    Google Scholar 

  • Trent RJ, Bowden DK, Old JM, Wainscoat JS, Clegg JB, Weatherall DJ (1981) A novel rearrangement of the human β-like globin gene cluster. Nucleic Acids Res 9:6723–6733

    Google Scholar 

  • Vogel F, Motulsky AG (1982) Human Genetics: problems and approaches. Springer, New York Berlin Heidelberg, pp 399–404

    Google Scholar 

  • Wainscoat JS, Bell JI, Thein SL, Higgs DR, Serjeant GR, Peto TEA, Weatherall DJ (1983) Multiple origins of the sickle mutation: evidence from 23-7 globin gene cluster polymorphisms. Mol Biol Med 1:191–197

    Google Scholar 

  • Wainscoat JS, Old JM, Thein SL, Weatherall DJ (1984) A new DNA polymorphism for prenatal diagnosis of β-thalassaemia in Mediterranean populations. Lancet II:1299–1301

    Google Scholar 

  • Wainscoat JS, Thein SL, Higgs DR, Bell JI, Weatherall DJ, Al-Awamy B, Serjeant GR (1985) A genetic marker for elevated levels of haemoglobin F in sickle cell disease? Br J Haematol 60:261–268

    Google Scholar 

  • Wainscoat JS, Hill AVS, Boyce AL, Flint J, Hernandez M, Thein SL, Old JM, Lynch JR, Falusi AG, Weatherall DJ, Clegg JB (1986) Evolutionary relationships of human populations from an analysis of nuclear DNA polymorphisms. Nature 319:491–493

    Google Scholar 

  • Wainscoat JS, Kulozik AE, Ramsay M, Falusi AG, Weatherall DJ (1986) A Taq-1 γ-globin gene polymorphism: an African specific marker. Hum Genet (in press)

  • Willcox M (1982) Beta thalassaemia and the malaria hypothesis. A study in Liberia. M.D. Thesis, University of Stockholm

  • Wilson AC, Carlson SS, Whie TJ (1977) Biochemical evolution. Annu Rev Biochem 46:573–639

    Google Scholar 

  • Winichagoon P, Higgs DR, Goodbourn SEY, Lamb J, Clegg JB, Weatherall DJ (1982) Multiple arrangements of the human embryonic zeta globin genes. Nucleic Acids Res 10:5853–5868

    Google Scholar 

  • Winichagoon P, Higgs DR, Goodbourn SEY, Clegg JB, Weatherall DJ, Wasi P (1984) The molecular basis of α-thalassaemia in Thailand. EMBO J 3:1813–1818

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. MRC Molecular Haematology Unit, Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, OX3 9DU, Oxford, UK

    A. V. S. Hill & J. S. Wainscoat

Authors
  1. A. V. S. Hill
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. S. Wainscoat
    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

Hill, A.V.S., Wainscoat, J.S. The evolution of the α- and β-globin gene clusters in human populations. Hum Genet 74, 16–23 (1986). https://doi.org/10.1007/BF00278779

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00278779

Keywords

Search

Navigation