Human Genetics

, Volume 90, Issue 4, pp 443–449 | Cite as

Analysis of β-globin gene haplotypes in Asian Indians: origin and spread of β-thalassaemia on the Indian subcontinent

  • Nermeen Y. Varawalla
  • Alison C. Fitches
  • John M. Old
Original Investigations


β-globin gene haplotypes were determined for 196 normal (β-A) and 419 thalassaemia (β-Th) chromosomes of individuals from four different regions of the Indian subcontinent; North-west Pakistan, Gujarat, Punjab and Sindh. Analysis of β-A and β-Th haplotypes and haplotype-mutation associations in each regional group along with a consideration of Indian history provided information about the origin and spread of β-thalassaemia mutations on the Indian subcontinent. The data are consistent with relatively recent and local origins for most β-thalassaemia mutations. The frequencies of particular alleles differ markedly in various regions and these may be useful population markers. Of the high frequency alleles, intervening sequence 1 (IVS-1) nucleotide 5 (G-C) and codons 41/42 (-CTTT) appear to be older as suggested by multiple haplotype associations and a widespread geographical distribution. The microepidemiology of β-thalassaemia in this region reflects considerable ethnic diversity, gene flow from population migration and natural selection by malaria infection.


Codon Frequency Allele Malaria Gene Flow Natural Selection 
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  1. Antonarakis SE, Boehm CD, Giardina PJ, Kazazian HH (1982) Nonrandom association of polymorphic restriction sites in the beta globin cluster. Proc Natl Acad Sci USA 79:137–141Google Scholar
  2. Brittenham GM (1983) The geographic and ethnographic distribution of haemoglobinopathies in India. In: Bowman JE (eds) Distribution and evolution of haemoglobin and globin loci. Elsevier, Amsterdam, pp 169–178Google Scholar
  3. Brown JM, Thein SL, Weatherall DJ, Mar KM (1992) The spectrum of β-thalassaemia in Burma. Br J Haematol 81:574–578Google Scholar
  4. Chebloune Y, Pagnier J, Trabuchet G, Faure C, Verdier G, Labie D, Nignon V (1988) Structural analysis of the 5′ flanking region of the β-globin gene in African sickle cell anemia patients: further evidence for three origins of the sickle cell mutation in Africa. Proc Natl Acad Sci USA 85:4431–4435Google Scholar
  5. Chehbab FF, Der Kaloustian V, Khouri FP, Deeb SS, Kan YW (1987) The molecular basis of β-thalassemia in Lebanon: application to prenatal diagnosis. Blood 69:1141–1145Google Scholar
  6. Diaz-Chico JC, Yang KG, Stoming TA, Efremov DG, Kutlar A, Kutlar F, Aksoy M, Altay C, Gurgey A, Kininc Y, Huisman THJ (1988) Mild and severe β-thalassemia among homozygotes from Turkey: identification of the types by hybridisation of amplified DNA with synthetic probes. Blood 71:248–251Google Scholar
  7. Hill AVS, Bowden DK, O'Shaughnessy DF, Weatherall DJ, Clegg JB (1988) β-Thalassemiain Melanesia: association with malaria and characterization of a common variant (IVS-1 nt 5 G-C), Blood 72:9–14Google Scholar
  8. Hill AVS, O'Shaughnessy DF, Clegg JB (1989) Haemoglobin and globin gene variants in the Pacific. In: Hill AVS, Serjeantson SW (eds) The colonization of the Pacific: a genetic trail. Clarendon Press, Oxford, pp 246–285Google Scholar
  9. Kazazian HH, Dowling CE, Waber PG, Huang S, Wilson HYL (1986) The spectrum of β-thalassemia genes in China and Southeast Asia. Blood 68:964–966Google Scholar
  10. Kollia P, Gonzalez-Redondo JM, Stoming TA, Loukopoulos D, Politis C, Huisman THJ (1989) Frameshift codon 5 [FSC-5(-CT)] thalassemia: a novel mutation detected in a Greek patient. Hemoglobin 13:597–604Google Scholar
  11. Laig M, Sanguansermsri T, Wiangnon S, Hundrieser J, Pape M, Flatz G (1989) The spectrum of β-thalassaemia mutations in northern and northeastern Thailand. Hum Genet 84:47–50Google Scholar
  12. Lie-Injo LE, Cai SP, Wahidijat S, Moeslichan S, Lim ML, Evan-galista L, Doherty M, Kan YW (1989) β-Thalassemia mutations in Indonesia and their linkage to β haplotypes. Am J Hum Genet 45:971–975Google Scholar
  13. Mourant AE (1983) Asia. In: Mourant AE (eds) Blood relations, blood groups and anthropology. Oxford University Press, Oxford, pp 57–72Google Scholar
  14. Old JM, Higgs DR (1983) Gene analysis. In: Weatherall DJ (eds) Methods in haematology: the thalassaemias. Churchill Living-stone, Edinburgh, pp 74–96Google Scholar
  15. Orkin SH, Kazazian HH, Antonarakis SE, Goff SC, Boehm CD, Sexton JP, Waber PG, Giardina PJV (1982) Linkage of β-thalassaemia mutations and β-globin gene polymorphisms with DNA polymorphisms in the human β-globin gene cluster. Nature 296:627–631Google Scholar
  16. Pirastu M, Galanello R, Doherty MA, Tuveri T, Cao A, Kan YW (1987) The same β-globin gene mutation is present on nine different β-thalassemia chromosomes in a Sardinian population. Proc Natl Acad Sci USA 84:2882–2885Google Scholar
  17. Semenza GL, Dowling CE, Kazazian HH (1989) HinfI polymorphism 3′ to the human β-globin gene detected by the polymerase chain reaction (PCR). Nucleic Acids Res 17:2376Google Scholar
  18. Slightom JL, Blechl AE, Smithies O (1980) Human fetal Gγ- and Aγ- globin genes: complete nucleotide sequences suggest that DNA can be exchanged between these duplicated genes. Cell 21:627–638Google Scholar
  19. Sukumaran PK (1974) Abnormal haemoglobins in India. In: Sen NN (eds) Trends in haematology. Calcutta, pp 225–261Google Scholar
  20. Thapar R (1966) A history of India, vol 1. Penguin, Harmonds-worthGoogle Scholar
  21. Thein SL, Wainscoat JS, Sampietro M, Old JM, Cappellini D, Florelli G, Modell B, Weatherall DJ (1987) Association of thalassaemia intermedia with a beta-globin gene haplotype. Br J Haematol 65:367–373Google Scholar
  22. Varawalla NY, Old JM, Sarkar R, Venkatesan R, Weatherall DJ (1991a) The spectrum of β-thalassaemia mutations on the Indian subcontinent: the basis for prenatal diagnosis. Br J Haematol 78:242–247PubMedGoogle Scholar
  23. Varawalla NY, Old JM, Weatherall DJ (1991b) Rare β-thalassaemia mutations in Asian Indians. Br J Haematol 79:640–644PubMedGoogle Scholar
  24. 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 319:491–493Google Scholar
  25. Yang KG, Kutlar F, George E, Wilson JB, Kutlar A, Stoming TA, Gonzalez-Redondon JM, Huisman THJ (1989) Molecular characterization of β-globin gene mutations in Malay patients with HbE-β-thalassaemia and thalassaemia major. Br J Haematol 72:73–80Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Nermeen Y. Varawalla
    • 1
  • Alison C. Fitches
    • 1
  • John M. Old
    • 1
  1. 1.Institute of Molecular Medicine, John Radcliffe HospitalOxfordUK

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