Skip to main content
NCBI home page
Genetics logoLink to Genetics
. 2004 May;167(1):423–437. doi: 10.1534/genetics.167.1.423

Nucleotide variation at Msn and Alas2, two genes flanking the centromere of the X chromosome in humans.

Michael W Nachman 1, Susan L D'Agostino 1, Christopher R Tillquist 1, Zahra Mobasher 1, Michael F Hammer 1
PMCID: PMC1470878  PMID: 15166166

Abstract

The centromeric region of the X chromosome in humans experiences low rates of recombination over a considerable physical distance. In such a region, the effects of selection may extend to linked sites that are far away. To investigate the effects of this recombinational environment on patterns of nucleotide variability, we sequenced 4581 bp at Msn and 4697 bp at Alas2, two genes situated on either side of the X chromosome centromere, in a worldwide sample of 41 men, as well as in one common chimpanzee and one orangutan. To investigate patterns of linkage disequilibrium (LD) across the centromere, we also genotyped several informative sites from each gene in 120 men from sub-Saharan Africa. By studying X-linked loci in males, we were able to recover haplotypes and study long-range patterns of LD directly. Overall patterns of variability were remarkably similar at these two loci. Both loci exhibited (i) very low levels of nucleotide diversity (among the lowest seen in the human genome); (ii) a strong skew in the distribution of allele frequencies, with an excess of both very-low and very-high-frequency derived alleles in non-African populations; (iii) much less variation in the non-African than in the African samples; (iv) very high levels of population differentiation; and (v) complete LD among all sites within loci. We also observed significant LD between Msn and Alas2 in Africa, despite the fact that they are separated by approximately 10 Mb. These observations are difficult to reconcile with a simple demographic model but may be consistent with positive and/or purifying selection acting on loci within this large region of low recombination.

Full Text

The Full Text of this article is available as a PDF (239.2 KB).

Selected References

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

  1. Akey Joshua M., Zhang Ge, Zhang Kun, Jin Li, Shriver Mark D. Interrogating a high-density SNP map for signatures of natural selection. Genome Res. 2002 Dec;12(12):1805–1814. doi: 10.1101/gr.631202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alonso S., Armour J. A. A highly variable segment of human subterminal 16p reveals a history of population growth for modern humans outstide Africa. Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):864–869. doi: 10.1073/pnas.98.3.864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bahlo M., Griffiths R. C. Inference from gene trees in a subdivided population. Theor Popul Biol. 2000 Mar;57(2):79–95. doi: 10.1006/tpbi.1999.1447. [DOI] [PubMed] [Google Scholar]
  4. Bamshad Michael J., Mummidi Srinivas, Gonzalez Enrique, Ahuja Seema S., Dunn Diane M., Watkins W. Scott, Wooding Stephen, Stone Anne C., Jorde Lynn B., Weiss Robert B. A strong signature of balancing selection in the 5' cis-regulatory region of CCR5. Proc Natl Acad Sci U S A. 2002 Jul 29;99(16):10539–10544. doi: 10.1073/pnas.162046399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Braverman J. M., Hudson R. R., Kaplan N. L., Langley C. H., Stephan W. The hitchhiking effect on the site frequency spectrum of DNA polymorphisms. Genetics. 1995 Jun;140(2):783–796. doi: 10.1093/genetics/140.2.783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Charlesworth B., Morgan M. T., Charlesworth D. The effect of deleterious mutations on neutral molecular variation. Genetics. 1993 Aug;134(4):1289–1303. doi: 10.1093/genetics/134.4.1289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Clark A. G., Weiss K. M., Nickerson D. A., Taylor S. L., Buchanan A., Stengård J., Salomaa V., Vartiainen E., Perola M., Boerwinkle E. Haplotype structure and population genetic inferences from nucleotide-sequence variation in human lipoprotein lipase. Am J Hum Genet. 1998 Aug;63(2):595–612. doi: 10.1086/301977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Enard Wolfgang, Przeworski Molly, Fisher Simon E., Lai Cecilia S. L., Wiebe Victor, Kitano Takashi, Monaco Anthony P., Päbo Svante. Molecular evolution of FOXP2, a gene involved in speech and language. Nature. 2002 Aug 14;418(6900):869–872. doi: 10.1038/nature01025. [DOI] [PubMed] [Google Scholar]
  9. Excoffier L., Smouse P. E., Quattro J. M. Analysis of molecular variance inferred from metric distances among DNA haplotypes: application to human mitochondrial DNA restriction data. Genetics. 1992 Jun;131(2):479–491. doi: 10.1093/genetics/131.2.479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fay J. C., Wu C. I. Hitchhiking under positive Darwinian selection. Genetics. 2000 Jul;155(3):1405–1413. doi: 10.1093/genetics/155.3.1405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Frisse L., Hudson R. R., Bartoszewicz A., Wall J. D., Donfack J., Di Rienzo A. Gene conversion and different population histories may explain the contrast between polymorphism and linkage disequilibrium levels. Am J Hum Genet. 2001 Aug 29;69(4):831–843. doi: 10.1086/323612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fu Y. X., Li W. H. Statistical tests of neutrality of mutations. Genetics. 1993 Mar;133(3):693–709. doi: 10.1093/genetics/133.3.693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fullerton S. M., Clark A. G., Weiss K. M., Nickerson D. A., Taylor S. L., Stengârd J. H., Salomaa V., Vartiainen E., Perola M., Boerwinkle E. Apolipoprotein E variation at the sequence haplotype level: implications for the origin and maintenance of a major human polymorphism. Am J Hum Genet. 2000 Sep 13;67(4):881–900. doi: 10.1086/303070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gilad Yoav, Rosenberg Shai, Przeworski Molly, Lancet Doron, Skorecki Karl. Evidence for positive selection and population structure at the human MAO-A gene. Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):862–867. doi: 10.1073/pnas.022614799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hamblin M. T., Di Rienzo A. Detection of the signature of natural selection in humans: evidence from the Duffy blood group locus. Am J Hum Genet. 2000 Apr 12;66(5):1669–1679. doi: 10.1086/302879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hammer M. F. A recent common ancestry for human Y chromosomes. Nature. 1995 Nov 23;378(6555):376–378. doi: 10.1038/378376a0. [DOI] [PubMed] [Google Scholar]
  17. Hammer Michael F., Blackmer Felisa, Garrigan Dan, Nachman Michael W., Wilder Jason A. Human population structure and its effects on sampling Y chromosome sequence variation. Genetics. 2003 Aug;164(4):1495–1509. doi: 10.1093/genetics/164.4.1495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Harding R. M., Fullerton S. M., Griffiths R. C., Bond J., Cox M. J., Schneider J. A., Moulin D. S., Clegg J. B. Archaic African and Asian lineages in the genetic ancestry of modern humans. Am J Hum Genet. 1997 Apr;60(4):772–789. [PMC free article] [PubMed] [Google Scholar]
  19. Harding R. M., Healy E., Ray A. J., Ellis N. S., Flanagan N., Todd C., Dixon C., Sajantila A., Jackson I. J., Birch-Machin M. A. Evidence for variable selective pressures at MC1R. Am J Hum Genet. 2000 Mar 24;66(4):1351–1361. doi: 10.1086/302863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hardison Ross C., Roskin Krishna M., Yang Shan, Diekhans Mark, Kent W. James, Weber Ryan, Elnitski Laura, Li Jia, O'Connor Michael, Kolbe Diana. Covariation in frequencies of substitution, deletion, transposition, and recombination during eutherian evolution. Genome Res. 2003 Jan;13(1):13–26. doi: 10.1101/gr.844103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Harris E. E., Hey J. Human populations show reduced DNA sequence variation at the factor IX locus. Curr Biol. 2001 May 15;11(10):774–778. doi: 10.1016/s0960-9822(01)00223-8. [DOI] [PubMed] [Google Scholar]
  22. Harris E. E., Hey J. X chromosome evidence for ancient human histories. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3320–3324. doi: 10.1073/pnas.96.6.3320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hellmann Ines, Ebersberger Ingo, Ptak Susan E., Päbo Svante, Przeworski Molly. A neutral explanation for the correlation of diversity with recombination rates in humans. Am J Hum Genet. 2003 May 8;72(6):1527–1535. doi: 10.1086/375657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hey J. Mitochondrial and nuclear genes present conflicting portraits of human origins. Mol Biol Evol. 1997 Feb;14(2):166–172. doi: 10.1093/oxfordjournals.molbev.a025749. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Kaessmann H., Heissig F., von Haeseler A., Päbo S. DNA sequence variation in a non-coding region of low recombination on the human X chromosome. Nat Genet. 1999 May;22(1):78–81. doi: 10.1038/8785. [DOI] [PubMed] [Google Scholar]
  27. Kitano Takashi, Schwarz Carsten, Nickel Birgit, Päbo Svante. Gene diversity patterns at 10 X-chromosomal loci in humans and chimpanzees. Mol Biol Evol. 2003 May 30;20(8):1281–1289. doi: 10.1093/molbev/msg134. [DOI] [PubMed] [Google Scholar]
  28. Kong Augustine, Gudbjartsson Daniel F., Sainz Jesus, Jonsdottir Gudrun M., Gudjonsson Sigurjon A., Richardsson Bjorgvin, Sigurdardottir Sigrun, Barnard John, Hallbeck Bjorn, Masson Gisli. A high-resolution recombination map of the human genome. Nat Genet. 2002 Jun 10;31(3):241–247. doi: 10.1038/ng917. [DOI] [PubMed] [Google Scholar]
  29. Lander E. S., Linton L. M., Birren B., Nusbaum C., Zody M. C., Baldwin J., Devon K., Dewar K., Doyle M., FitzHugh W. Initial sequencing and analysis of the human genome. Nature. 2001 Feb 15;409(6822):860–921. doi: 10.1038/35057062. [DOI] [PubMed] [Google Scholar]
  30. Lercher Martin J., Hurst Laurence D. Human SNP variability and mutation rate are higher in regions of high recombination. Trends Genet. 2002 Jul;18(7):337–340. doi: 10.1016/s0168-9525(02)02669-0. [DOI] [PubMed] [Google Scholar]
  31. Lewontin R. C. The detection of linkage disequilibrium in molecular sequence data. Genetics. 1995 May;140(1):377–388. doi: 10.1093/genetics/140.1.377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. 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]
  33. Mouse Genome Sequencing Consortium. Waterston Robert H., Lindblad-Toh Kerstin, Birney Ewan, Rogers Jane, Abril Josep F., Agarwal Pankaj, Agarwala Richa, Ainscough Rachel, Alexandersson Marina. Initial sequencing and comparative analysis of the mouse genome. Nature. 2002 Dec 5;420(6915):520–562. doi: 10.1038/nature01262. [DOI] [PubMed] [Google Scholar]
  34. Nachman M. W., Bauer V. L., Crowell S. L., Aquadro C. F. DNA variability and recombination rates at X-linked loci in humans. Genetics. 1998 Nov;150(3):1133–1141. doi: 10.1093/genetics/150.3.1133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Nachman M. W., Crowell S. L. Contrasting evolutionary histories of two introns of the duchenne muscular dystrophy gene, Dmd, in humans. Genetics. 2000 Aug;155(4):1855–1864. doi: 10.1093/genetics/155.4.1855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Nachman M. W., Crowell S. L. Estimate of the mutation rate per nucleotide in humans. Genetics. 2000 Sep;156(1):297–304. doi: 10.1093/genetics/156.1.297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Nachman M. W. Single nucleotide polymorphisms and recombination rate in humans. Trends Genet. 2001 Sep;17(9):481–485. doi: 10.1016/s0168-9525(01)02409-x. [DOI] [PubMed] [Google Scholar]
  38. Patil N., Berno A. J., Hinds D. A., Barrett W. A., Doshi J. M., Hacker C. R., Kautzer C. R., Lee D. H., Marjoribanks C., McDonough D. P. Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21. Science. 2001 Nov 23;294(5547):1719–1723. doi: 10.1126/science.1065573. [DOI] [PubMed] [Google Scholar]
  39. Payseur B. A., Nachman M. W. Microsatellite variation and recombination rate in the human genome. Genetics. 2000 Nov;156(3):1285–1298. doi: 10.1093/genetics/156.3.1285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Payseur Bret A., Nachman Michael W. Gene density and human nucleotide polymorphism. Mol Biol Evol. 2002 Mar;19(3):336–340. doi: 10.1093/oxfordjournals.molbev.a004086. [DOI] [PubMed] [Google Scholar]
  41. Przeworski M., Hudson R. R., Di Rienzo A. Adjusting the focus on human variation. Trends Genet. 2000 Jul;16(7):296–302. doi: 10.1016/s0168-9525(00)02030-8. [DOI] [PubMed] [Google Scholar]
  42. Reich D. E., Cargill M., Bolk S., Ireland J., Sabeti P. C., Richter D. J., Lavery T., Kouyoumjian R., Farhadian S. F., Ward R. Linkage disequilibrium in the human genome. Nature. 2001 May 10;411(6834):199–204. doi: 10.1038/35075590. [DOI] [PubMed] [Google Scholar]
  43. Rieder M. J., Taylor S. L., Clark A. G., Nickerson D. A. Sequence variation in the human angiotensin converting enzyme. Nat Genet. 1999 May;22(1):59–62. doi: 10.1038/8760. [DOI] [PubMed] [Google Scholar]
  44. Sabeti Pardis C., Reich David E., Higgins John M., Levine Haninah Z. P., Richter Daniel J., Schaffner Stephen F., Gabriel Stacey B., Platko Jill V., Patterson Nick J., McDonald Gavin J. Detecting recent positive selection in the human genome from haplotype structure. Nature. 2002 Oct 9;419(6909):832–837. doi: 10.1038/nature01140. [DOI] [PubMed] [Google Scholar]
  45. Saunders Matthew A., Hammer Michael F., Nachman Michael W. Nucleotide variability at G6pd and the signature of malarial selection in humans. Genetics. 2002 Dec;162(4):1849–1861. doi: 10.1093/genetics/162.4.1849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Slatkin M. Hitchhiking and associative overdominance at a microsatellite locus. Mol Biol Evol. 1995 May;12(3):473–480. doi: 10.1093/oxfordjournals.molbev.a040222. [DOI] [PubMed] [Google Scholar]
  47. Slatkin M., Wiehe T. Genetic hitch-hiking in a subdivided population. Genet Res. 1998 Apr;71(2):155–160. doi: 10.1017/s001667239800319x. [DOI] [PubMed] [Google Scholar]
  48. Smith J. M., Haigh J. The hitch-hiking effect of a favourable gene. Genet Res. 1974 Feb;23(1):23–35. [PubMed] [Google Scholar]
  49. Stephens J. C., Schneider J. A., Tanguay D. A., Choi J., Acharya T., Stanley S. E., Jiang R., Messer C. J., Chew A., Han J. H. Haplotype variation and linkage disequilibrium in 313 human genes. Science. 2001 Jul 12;293(5529):489–493. doi: 10.1126/science.1059431. [DOI] [PubMed] [Google Scholar]
  50. Tajima F. Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics. 1989 Nov;123(3):585–595. doi: 10.1093/genetics/123.3.585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Tishkoff S. A., Dietzsch E., Speed W., Pakstis A. J., Kidd J. R., Cheung K., Bonné-Tamir B., Santachiara-Benerecetti A. S., Moral P., Krings M. Global patterns of linkage disequilibrium at the CD4 locus and modern human origins. Science. 1996 Mar 8;271(5254):1380–1387. doi: 10.1126/science.271.5254.1380. [DOI] [PubMed] [Google Scholar]
  52. Underhill P. A., Shen P., Lin A. A., Jin L., Passarino G., Yang W. H., Kauffman E., Bonné-Tamir B., Bertranpetit J., Francalacci P. Y chromosome sequence variation and the history of human populations. Nat Genet. 2000 Nov;26(3):358–361. doi: 10.1038/81685. [DOI] [PubMed] [Google Scholar]
  53. Venter J. C., Adams M. D., Myers E. W., Li P. W., Mural R. J., Sutton G. G., Smith H. O., Yandell M., Evans C. A., Holt R. A. The sequence of the human genome. Science. 2001 Feb 16;291(5507):1304–1351. doi: 10.1126/science.1058040. [DOI] [PubMed] [Google Scholar]
  54. Verrelli Brian C., McDonald John H., Argyropoulos George, Destro-Bisol Giovanni, Froment Alain, Drousiotou Anthi, Lefranc Gerard, Helal Ahmed N., Loiselet Jacques, Tishkoff Sarah A. Evidence for balancing selection from nucleotide sequence analyses of human G6PD. Am J Hum Genet. 2002 Oct 11;71(5):1112–1128. doi: 10.1086/344345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Vigilant L., Stoneking M., Harpending H., Hawkes K., Wilson A. C. African populations and the evolution of human mitochondrial DNA. Science. 1991 Sep 27;253(5027):1503–1507. doi: 10.1126/science.1840702. [DOI] [PubMed] [Google Scholar]
  56. Wakeley J., Aliacar N. Gene genealogies in a metapopulation. Genetics. 2001 Oct;159(2):893–905. doi: 10.1093/genetics/159.2.893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Wall J. D., Przeworski M. When did the human population size start increasing? Genetics. 2000 Aug;155(4):1865–1874. doi: 10.1093/genetics/155.4.1865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. 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]
  59. Whitfield L. S., Sulston J. E., Goodfellow P. N. Sequence variation of the human Y chromosome. Nature. 1995 Nov 23;378(6555):379–380. doi: 10.1038/378379a0. [DOI] [PubMed] [Google Scholar]
  60. Wiehe T. The effect of selective sweeps on the variance of the allele distribution of a linked multiallele locus: hitchhiking of microsatellites. Theor Popul Biol. 1998 Jun;53(3):272–283. doi: 10.1006/tpbi.1997.1346. [DOI] [PubMed] [Google Scholar]
  61. Wooding S. P., Watkins W. S., Bamshad M. J., Dunn D. M., Weiss R. B., Jorde L. B. DNA sequence variation in a 3.7-kb noncoding sequence 5' of the CYP1A2 gene: implications for human population history and natural selection. Am J Hum Genet. 2002 Aug 9;71(3):528–542. doi: 10.1086/342260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Y Chromosome Consortium A nomenclature system for the tree of human Y-chromosomal binary haplogroups. Genome Res. 2002 Feb;12(2):339–348. doi: 10.1101/gr.217602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Yu A., Zhao C., Fan Y., Jang W., Mungall A. J., Deloukas P., Olsen A., Doggett N. A., Ghebranious N., Broman K. W. Comparison of human genetic and sequence-based physical maps. Nature. 2001 Feb 15;409(6822):951–953. doi: 10.1038/35057185. [DOI] [PubMed] [Google Scholar]
  64. Yu Ning, Chen Feng-Chi, Ota Satoshi, Jorde Lynn B., Pamilo Pekka, Patthy Laszlo, Ramsay Michele, Jenkins Trefor, Shyue Song-Kun, Li Wen-Hsiung. Larger genetic differences within africans than between Africans and Eurasians. Genetics. 2002 May;161(1):269–274. doi: 10.1093/genetics/161.1.269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Zhao Z., Jin L., Fu Y. X., Ramsay M., Jenkins T., Leskinen E., Pamilo P., Trexler M., Patthy L., Jorde L. B. Worldwide DNA sequence variation in a 10-kilobase noncoding region on human chromosome 22. Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11354–11358. doi: 10.1073/pnas.200348197. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Genetics are provided here courtesy of Oxford University Press

RESOURCES