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. 1994 Mar 1;91(5):1805–1809. doi: 10.1073/pnas.91.5.1805

Molecular and population genetic analysis of allelic sequence diversity at the human beta-globin locus.

S M Fullerton 1, R M Harding 1, A J Boyce 1, J B Clegg 1
PMCID: PMC43252  PMID: 7907422

Abstract

Allelic sequence polymorphism at the beta-globin locus was investigated in a group of 36 Melanesians. A 3-kilobase fragment containing the gene and its flanking regions was sequenced in 60 normal (beta A) and 12 thalassemic (intron 1, position 5, G-->C) chromosomes. Haplotype relationships between linked polymorphisms were derived by allele-specific PCR amplification and sequencing. Seventeen nucleotide polymorphisms and 2 length variants were identified, and these sites segregated as 17 sequence haplotypes in the normal chromosomes. This haplotype diversity is higher than that expected on the basis of the nucleotide polymorphism observed and is probably due to recombination and gene conversion. Nucleotide diversity at synonymous sites in the sample is 0.14%, suggesting an average age of sequence divergence of approximately 450,000 years, consistent with that expected for a neutrally evolving human nuclear locus.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Antonarakis S. E., Boehm C. D., Giardina P. J., Kazazian H. H., Jr Nonrandom association of polymorphic restriction sites in the beta-globin gene cluster. Proc Natl Acad Sci U S A. 1982 Jan;79(1):137–141. doi: 10.1073/pnas.79.1.137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Antonarakis S. E., Kazazian H. H., Jr, Orkin S. H. DNA polymorphism and molecular pathology of the human globin gene clusters. Hum Genet. 1985;69(1):1–14. doi: 10.1007/BF00295521. [DOI] [PubMed] [Google Scholar]
  3. Bowcock A. M., Kidd J. R., Mountain J. L., Hebert J. M., Carotenuto L., Kidd K. K., Cavalli-Sforza L. L. Drift, admixture, and selection in human evolution: a study with DNA polymorphisms. Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):839–843. doi: 10.1073/pnas.88.3.839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cann R. L., Stoneking M., Wilson A. C. Mitochondrial DNA and human evolution. Nature. 1987 Jan 1;325(6099):31–36. doi: 10.1038/325031a0. [DOI] [PubMed] [Google Scholar]
  5. Chakravarti A., Buetow K. H., Antonarakis S. E., Waber P. G., Boehm C. D., Kazazian H. H. Nonuniform recombination within the human beta-globin gene cluster. Am J Hum Genet. 1984 Nov;36(6):1239–1258. [PMC free article] [PubMed] [Google Scholar]
  6. Chebloune Y., Pagnier J., Trabuchet G., Faure C., Verdier G., Labie D., Nigon V. Structural analysis of the 5' flanking region of the beta-globin gene in African sickle cell anemia patients: further evidence for three origins of the sickle cell mutation in Africa. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4431–4435. doi: 10.1073/pnas.85.12.4431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Flint J., Harding R. M., Clegg J. B., Boyce A. J. Why are some genetic diseases common? Distinguishing selection from other processes by molecular analysis of globin gene variants. Hum Genet. 1993 Mar;91(2):91–117. doi: 10.1007/BF00222709. [DOI] [PubMed] [Google Scholar]
  8. Hill A. V., Bowden D. K., O'Shaughnessy D. F., Weatherall D. J., Clegg J. B. Beta thalassemia in Melanesia: association with malaria and characterization of a common variant (IVS-1 nt 5 G----C). Blood. 1988 Jul;72(1):9–14. [PubMed] [Google Scholar]
  9. Horai S., Satta Y., Hayasaka K., Kondo R., Inoue T., Ishida T., Hayashi S., Takahata N. Man's place in Hominoidea revealed by mitochondrial DNA genealogy. J Mol Evol. 1992 Jul;35(1):32–43. doi: 10.1007/BF00160258. [DOI] [PubMed] [Google Scholar]
  10. Hudson R. R., Kreitman M., Aguadé M. A test of neutral molecular evolution based on nucleotide data. Genetics. 1987 May;116(1):153–159. doi: 10.1093/genetics/116.1.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kohen G., Philippe N., Godet J. Polymorphism of the Hinf I restriction site located 1 Kb 5' to the human beta-globin gene. Hum Genet. 1982;62(2):121–123. doi: 10.1007/BF00282298. [DOI] [PubMed] [Google Scholar]
  12. Kreitman M. Nucleotide polymorphism at the alcohol dehydrogenase locus of Drosophila melanogaster. Nature. 1983 Aug 4;304(5925):412–417. doi: 10.1038/304412a0. [DOI] [PubMed] [Google Scholar]
  13. Kwok S., Kellogg D. E., McKinney N., Spasic D., Goda L., Levenson C., Sninsky J. J. Effects of primer-template mismatches on the polymerase chain reaction: human immunodeficiency virus type 1 model studies. Nucleic Acids Res. 1990 Feb 25;18(4):999–1005. doi: 10.1093/nar/18.4.999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lapouméroulie C., Dunda O., Ducrocq R., Trabuchet G., Mony-Lobé M., Bodo J. M., Carnevale P., Labie D., Elion J., Krishnamoorthy R. A novel sickle cell mutation of yet another origin in Africa: the Cameroon type. Hum Genet. 1992 May;89(3):333–337. doi: 10.1007/BF00220553. [DOI] [PubMed] [Google Scholar]
  15. Li W. H., Sadler L. A. Low nucleotide diversity in man. Genetics. 1991 Oct;129(2):513–523. doi: 10.1093/genetics/129.2.513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Matsuno Y., Yamashiro Y., Yamamoto K., Hattori Y., Yamamoto K., Ohba Y., Miyaji T. A possible example of gene conversion with a common beta-thalassemia mutation and Chi sequence present in the beta-globin gene. Hum Genet. 1992 Jan;88(3):357–358. doi: 10.1007/BF00197277. [DOI] [PubMed] [Google Scholar]
  17. Moschonas N., de Boer E., Flavell R. A. The DNA sequence of the 5' flanking region of the human beta-globin gene: evolutionary conservation and polymorphic differences. Nucleic Acids Res. 1982 Mar 25;10(6):2109–2120. doi: 10.1093/nar/10.6.2109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Newton C. R., Graham A., Heptinstall L. E., Powell S. J., Summers C., Kalsheker N., Smith J. C., Markham A. F. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res. 1989 Apr 11;17(7):2503–2516. doi: 10.1093/nar/17.7.2503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Orkin S. H., Kazazian H. H., Jr, Antonarakis S. E., Goff S. C., Boehm C. D., Sexton J. P., Waber P. G., Giardina P. J. Linkage of beta-thalassaemia mutations and beta-globin gene polymorphisms with DNA polymorphisms in human beta-globin gene cluster. Nature. 1982 Apr 15;296(5858):627–631. doi: 10.1038/296627a0. [DOI] [PubMed] [Google Scholar]
  20. Poncz M., Schwartz E., Ballantine M., Surrey S. Nucleotide sequence analysis of the delta beta-globin gene region in humans. J Biol Chem. 1983 Oct 10;258(19):11599–11609. [PubMed] [Google Scholar]
  21. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  22. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Savatier P., Trabuchet G., Faure C., Chebloune Y., Gouy M., Verdier G., Nigon V. M. Evolution of the primate beta-globin gene region. High rate of variation in CpG dinucleotides and in short repeated sequences between man and chimpanzee. J Mol Biol. 1985 Mar 5;182(1):21–29. doi: 10.1016/0022-2836(85)90024-5. [DOI] [PubMed] [Google Scholar]
  24. Schwarz K., Hansen-Hagge T., Bartram C. Improved yields of long PCR products using gene 32 protein. Nucleic Acids Res. 1990 Feb 25;18(4):1079–1079. doi: 10.1093/nar/18.4.1079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Semenza G. L., Delgrosso K., Poncz M., Malladi P., Schwartz E., Surrey S. The silent carrier allele: beta thalassemia without a mutation in the beta-globin gene or its immediate flanking regions. Cell. 1984 Nov;39(1):123–128. doi: 10.1016/0092-8674(84)90197-1. [DOI] [PubMed] [Google Scholar]
  26. Semenza G. L., Malladi P., Surrey S., Delgrosso K., Poncz M., Schwartz E. Detection of a novel DNA polymorphism in the beta-globin gene cluster. J Biol Chem. 1984 May 25;259(10):6045–6048. [PubMed] [Google Scholar]
  27. Stephens J. C., Nei M. Phylogenetic analysis of polymorphic DNA sequences at the Adh locus in Drosophila melanogaster and its sibling species. J Mol Evol. 1985;22(4):289–300. doi: 10.1007/BF02115684. [DOI] [PubMed] [Google Scholar]
  28. Strobeck C. Average number of nucleotide differences in a sample from a single subpopulation: a test for population subdivision. Genetics. 1987 Sep;117(1):149–153. doi: 10.1093/genetics/117.1.149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Strobeck C., Morgan K. The effect of intragenic recombination on the number of alleles in a finite population. Genetics. 1978 Apr;88(4):829–844. doi: 10.1093/genetics/88.4.829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sutton M., Bouhassira E. E., Nagel R. L. Polymerase chain reaction amplification applied to the determination of beta-like globin gene cluster haplotypes. Am J Hematol. 1989 Sep;32(1):66–69. doi: 10.1002/ajh.2830320113. [DOI] [PubMed] [Google Scholar]
  31. Symington L. S., Brown A., Oliver S. G., Greenwell P., Petes T. D. Genetic analysis of a meiotic recombination hotspot on chromosome III of Saccharomyces cerevisiae. Genetics. 1991 Aug;128(4):717–727. doi: 10.1093/genetics/128.4.717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Takahata N. Allelic genealogy and human evolution. Mol Biol Evol. 1993 Jan;10(1):2–22. doi: 10.1093/oxfordjournals.molbev.a039995. [DOI] [PubMed] [Google Scholar]
  33. Trabuchet G., Elion J., Baudot G., Pagnier J., Bouhass R., Nigon V. M., Labie D., Krishnamoorthy R. Origin and spread of beta-globin gene mutations in India, Africa, and Mediterranea: analysis of the 5' flanking and intragenic sequences of beta S and beta C genes. Hum Biol. 1991 Jun;63(3):241–252. [PubMed] [Google Scholar]
  34. Wahls W. P., Wallace L. J., Moore P. D. The Z-DNA motif d(TG)30 promotes reception of information during gene conversion events while stimulating homologous recombination in human cells in culture. Mol Cell Biol. 1990 Feb;10(2):785–793. doi: 10.1128/mcb.10.2.785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wainscoat J. S., Hill A. V., Boyce A. L., Flint J., Hernandez M., Thein S. L., Old J. M., Lynch J. R., Falusi A. G., Weatherall D. J. Evolutionary relationships of human populations from an analysis of nuclear DNA polymorphisms. Nature. 1986 Feb 6;319(6053):491–493. doi: 10.1038/319491a0. [DOI] [PubMed] [Google Scholar]
  36. Watterson G. A. On the number of segregating sites in genetical models without recombination. Theor Popul Biol. 1975 Apr;7(2):256–276. doi: 10.1016/0040-5809(75)90020-9. [DOI] [PubMed] [Google Scholar]

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