Global patterns of linkage disequilibrium at the CD4 locus and modern human origins

Science

Volumn 271, Issue 5254, 1996, Pages 1380-1387

  Tishkoff, S A ^a,b   Dietzsch, E ^a,b   Speed, W ^a,b   Pakstis, A J ^a,b   Kidd, J R ^a,b   Cheung, K ^a,b   Bonne Tamir B ^b   Santachiara Benerecetti, A S ^a,b   Moral, P ^a,b   Krings, M ^a,b   Paabo S ^b   Watson, E ^a,b   Risch, N ^a,b   Jenkins, T ^a,b   Kidd, K K ^a,b  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b NONE

Author keywords

[No Author keywords available]

Indexed keywords

CD4 ANTIGEN;

AFRICA; ALLELE; AMERICAN INDIAN; ARTICLE; ASIA; CHROMOSOME 12; DNA POLYMORPHISM; EUROPE; GENE DELETION; GENE LINKAGE DISEQUILIBRIUM; GENE LOCUS; HAPLOTYPE; HUMAN; MIDDLE EAST; NONHUMAN; POPULATION; PRIORITY JOURNAL; TANDEM REPEAT;

EVOLUTION; HAPLOTYPE VARIATION; HOMINID; HOMO SAPIENS; LINKAGE DISEQUILIBRIUM;

EID: 0029667388     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.271.5254.1380     Document Type: Article

References (87)

1. M H. Wolpoff, in The Human Revolution Behavioral and Biological Perspectives on the Origins of Modern Humans, P. Mellers and C B. Stringer, Eds (Edinburgh Univ Press, Edinburgh, 1989), vol 1, pp. 62-108
2. M. H. Wolpoff, in Continuity or Replacement: Controversies in Homo sapiens Evolution, G. Bräuer and F. H. Smith, Eds. (Balkema, Rotterdam, 1992), pp. 25-63.
3. C. B Stringer, in (2), pp. 9-23.
4. C. C. Swisher III et al., Science 263, 1118 (1994); C. B. Stringer and P. Andrews, ibid 239, 1263 (1988).
5. C. C. Swisher III et al., Science 263, 1118 (1994); C. B. Stringer and P. Andrews, ibid 239, 1263 (1988).
6. M. M. Lahr and R. Foley, Evol. Anthropol. 3, 48 (1995)
7. R. L. Cann, M. Stoneking, A. C. Wilson, Nature 325, 31 (1987); L. Vigilant, M. Stoneking, H Harpending, K. Hawkes, A C. Wilson, Science 253, 1503 (1991).
8. R. L. Cann, M. Stoneking, A. C. Wilson, Nature 325, 31 (1987); L. Vigilant, M. Stoneking, H Harpending, K. Hawkes, A C. Wilson, Science 253, 1503 (1991).
9. Classical analyses of blood group and protein polymorphisms also support the out of Africa hypothesis. See, for example, M. Nei and G Livshits, Hum Hered. 39, 276 (1989).
10. S. B. Hedges, S. Kumar, K. Tamura, M. Stoneking, Science 255, 737 (1992); D R Maddison, M. Ruvolo, D. L. Swofford, Syst. Biol. 41, 111 (1992), A. Templeton, Science 255, 737 (1992); Am. Anthropol. 95, 51 (1993).
11. S. B. Hedges, S. Kumar, K. Tamura, M. Stoneking, Science 255, 737 (1992); D R Maddison, M. Ruvolo, D. L. Swofford, Syst. Biol. 41, 111 (1992), A. Templeton, Science 255, 737 (1992); Am. Anthropol. 95, 51 (1993).
12. S. B. Hedges, S. Kumar, K. Tamura, M. Stoneking, Science 255, 737 (1992); D R Maddison, M. Ruvolo, D. L. Swofford, Syst. Biol. 41, 111 (1992), A. Templeton, Science 255, 737 (1992); Am. Anthropol. 95, 51 (1993).
13. S. B. Hedges, S. Kumar, K. Tamura, M. Stoneking, Science 255, 737 (1992); D R Maddison, M. Ruvolo, D. L. Swofford, Syst. Biol. 41, 111 (1992), A. Templeton, Science 255, 737 (1992); Am. Anthropol. 95, 51 (1993).
14. M. Ruvolo, T R. Disotell, M. W. Allard, W. M. Brown, R. L Honeycutt, Proc. Natl. Acad Sci. U.S.A. 88, 1570 (1991); M. Hasegawa, A Di Rienzo, T. D. Kocher, A C. Wilson, J. Mol. Evol. 37, 347 (1993); K Tamura and M. Net, Mol. Biol. Evol. 10, 512 (1993); S. Horai, K. Hayasaka, R. Kondo, K. Tsugane, N. Takahata, Proc Natl. Acad Sci. U.S.A. 92, 532 (1995); D Penny, M. Steel, P. J. Waddell, M. D. Hendy, Mol. Biol. Evol 12, 863 (1995).
15. M. Ruvolo, T R. Disotell, M. W. Allard, W. M. Brown, R. L Honeycutt, Proc. Natl. Acad Sci. U.S.A. 88, 1570 (1991); M. Hasegawa, A Di Rienzo, T. D. Kocher, A C. Wilson, J. Mol. Evol. 37, 347 (1993); K Tamura and M. Net, Mol. Biol. Evol. 10, 512 (1993); S. Horai, K. Hayasaka, R. Kondo, K. Tsugane, N. Takahata, Proc Natl. Acad Sci. U.S.A. 92, 532 (1995); D Penny, M. Steel, P. J. Waddell, M. D. Hendy, Mol. Biol. Evol 12, 863 (1995).
16. M. Ruvolo, T R. Disotell, M. W. Allard, W. M. Brown, R. L Honeycutt, Proc. Natl. Acad Sci. U.S.A. 88, 1570 (1991); M. Hasegawa, A Di Rienzo, T. D. Kocher, A C. Wilson, J. Mol. Evol. 37, 347 (1993); K Tamura and M. Net, Mol. Biol. Evol. 10, 512 (1993); S. Horai, K. Hayasaka, R. Kondo, K. Tsugane, N. Takahata, Proc Natl. Acad Sci. U.S.A. 92, 532 (1995); D Penny, M. Steel, P. J. Waddell, M. D. Hendy, Mol. Biol. Evol 12, 863 (1995).
17. M. Ruvolo, T R. Disotell, M. W. Allard, W. M. Brown, R. L Honeycutt, Proc. Natl. Acad Sci. U.S.A. 88, 1570 (1991); M. Hasegawa, A Di Rienzo, T. D. Kocher, A C. Wilson, J. Mol. Evol. 37, 347 (1993); K Tamura and M. Net, Mol. Biol. Evol. 10, 512 (1993); S. Horai, K. Hayasaka, R. Kondo, K. Tsugane, N. Takahata, Proc Natl. Acad Sci. U.S.A. 92, 532 (1995); D Penny, M. Steel, P. J. Waddell, M. D. Hendy, Mol. Biol. Evol 12, 863 (1995).
18. M. Ruvolo, T R. Disotell, M. W. Allard, W. M. Brown, R. L Honeycutt, Proc. Natl. Acad Sci. U.S.A. 88, 1570 (1991); M. Hasegawa, A Di Rienzo, T. D. Kocher, A C. Wilson, J. Mol. Evol. 37, 347 (1993); K Tamura and M. Net, Mol. Biol. Evol. 10, 512 (1993); S. Horai, K. Hayasaka, R. Kondo, K. Tsugane, N. Takahata, Proc Natl. Acad Sci. U.S.A. 92, 532 (1995); D Penny, M. Steel, P. J. Waddell, M. D. Hendy, Mol. Biol. Evol 12, 863 (1995).
19. R. L. Dont, H. Akashi, W. Gilbert, Science 268, 1183 (1995); M. F. Hammer, Nature 378, 376 (1995); P. N. Goodfellow, ibid., p.379.
20. R. L. Dont, H. Akashi, W. Gilbert, Science 268, 1183 (1995); M. F. Hammer, Nature 378, 376 (1995); P. N. Goodfellow, ibid., p.379.
21. R. L. Dont, H. Akashi, W. Gilbert, Science 268, 1183 (1995); M. F. Hammer, Nature 378, 376 (1995); P. N. Goodfellow, ibid., p.379.
22. The CD4 gene, which encodes the T4 glycoprotein expressed on the surface of T lymphocytes, is important for proper immune function and has been the site of active investigation; neither of the markers lies within coding or known regulatory elements [M. D Blum, G. T. Wong, K. M Higgins, M J Sunshine, E Lacy, J. Exp Med. 177, 1343 (1993); F. P. Gillespie et al., Mol. Cell. Biol. 13, 2952 (1993); D. D. Duncan, A. Stupakoff, S. M. Hedrick, K. B Marcu, G Siu, ibid 15, 3179 (1995)].
23. The CD4 gene, which encodes the T4 glycoprotein expressed on the surface of T lymphocytes, is important for proper immune function and has been the site of active investigation; neither of the markers lies within coding or known regulatory elements [M. D Blum, G. T. Wong, K. M Higgins, M J Sunshine, E Lacy, J. Exp Med. 177, 1343 (1993); F. P. Gillespie et al., Mol. Cell. Biol. 13, 2952 (1993); D. D. Duncan, A. Stupakoff, S. M. Hedrick, K. B Marcu, G Siu, ibid 15, 3179 (1995)].
24. The CD4 gene, which encodes the T4 glycoprotein expressed on the surface of T lymphocytes, is important for proper immune function and has been the site of active investigation; neither of the markers lies within coding or known regulatory elements [M. D Blum, G. T. Wong, K. M Higgins, M J Sunshine, E Lacy, J. Exp Med. 177, 1343 (1993); F. P. Gillespie et al., Mol. Cell. Biol. 13, 2952 (1993); D. D. Duncan, A. Stupakoff, S. M. Hedrick, K. B Marcu, G Siu, ibid 15, 3179 (1995)].
25. M. C. Edwards, P. R. Clemens, M Tristan, A. Pizzulti, R. A. Gibbs, Nucleic Acids Res. 19, 4791 (1991)
26. M C. Edwards and R. A. Gibbs, Genomics 14, 590 (1992)
27. -2 per generation [J. L Weber and C. Wong, Hum Mol. Genet. 2, 1123 (1993); M. M. Mahtani and H. F. Willard, ibid., p. 431; D. Tautz and C Schlötterer, Curr Opin. Genet Dev. 4, 832 (1994)].
28. -2 per generation [J. L Weber and C. Wong, Hum Mol. Genet. 2, 1123 (1993); M. M. Mahtani and H. F. Willard, ibid., p. 431; D. Tautz and C Schlötterer, Curr Opin. Genet Dev. 4, 832 (1994)].
29. -2 per generation [J. L Weber and C. Wong, Hum Mol. Genet. 2, 1123 (1993); M. M. Mahtani and H. F. Willard, ibid., p. 431; D. Tautz and C Schlötterer, Curr Opin. Genet Dev. 4, 832 (1994)].
30. A. Bowcock et al., Nature 368, 455 (1994); R. Deka et al , Am. J. Hum. Genet. 56, 461 (1995); L B Jorde et al., ibid 57, 523 (1995); D. B. Goldstein et al., Proc. Natl. Acad Sci. U.S.A 92, 6723 (1995); N. Risch et al., Nat. Genet. 9, 152 (1995).
31. A. Bowcock et al., Nature 368, 455 (1994); R. Deka et al , Am. J. Hum. Genet. 56, 461 (1995); L B Jorde et al., ibid 57, 523 (1995); D. B. Goldstein et al., Proc. Natl. Acad Sci. U.S.A 92, 6723 (1995); N. Risch et al., Nat. Genet. 9, 152 (1995).
32. A. Bowcock et al., Nature 368, 455 (1994); R. Deka et al , Am. J. Hum. Genet. 56, 461 (1995); L B Jorde et al., ibid 57, 523 (1995); D. B. Goldstein et al., Proc. Natl. Acad Sci. U.S.A 92, 6723 (1995); N. Risch et al., Nat. Genet. 9, 152 (1995).
33. A. Bowcock et al., Nature 368, 455 (1994); R. Deka et al , Am. J. Hum. Genet. 56, 461 (1995); L B Jorde et al., ibid 57, 523 (1995); D. B. Goldstein et al., Proc. Natl. Acad Sci. U.S.A 92, 6723 (1995); N. Risch et al., Nat. Genet. 9, 152 (1995).
34. A. Bowcock et al., Nature 368, 455 (1994); R. Deka et al , Am. J. Hum. Genet. 56, 461 (1995); L B Jorde et al., ibid 57, 523 (1995); D. B. Goldstein et al., Proc. Natl. Acad Sci. U.S.A 92, 6723 (1995); N. Risch et al., Nat. Genet. 9, 152 (1995).
35. Others (12, 13) count the 3′ flanking sequence CTTCTTTT as two repeats Sequencing shows that all humans and nonhuman primates sampled share this same flanking sequence, therefore, we have not considered them part of the STRP. STRP alleles were amplified with the primers and protocol described in (12). Our 85-bp allele contains five perfect repeats and corresponds to the 88-bp allele listed in (12).
36. Sequencing analysis shows that chimpanzee and gorilla alleles contain only perfect repeats, whereas some alleles in orangutan and gibbon contain small insertions or deletions within one or two of the repeat units (data not shown).
37. PCR products from nine individuals homozygous for the Alu(-) allele were sequenced with primer R106 (13) and a newly designed primer R107 (5′-TATCT-CAGGCTGTCTCAGTG-3′).
38. A C Wilson and V M. Sarich, Proc Natl Acad. Sci. U.S.A. 63, 1088 (1969); A. Hill, in Integrative Paths to the Past: Paleoanthropological Advances in Honor of F Clark Howell, R S. Corruccine and R L Ciochon, Eds. (Prentice-Hall, Englewood Cliffs, NJ, 1994), pp 123-145.
39. A C Wilson and V M. Sarich, Proc Natl Acad. Sci. U.S.A. 63, 1088 (1969); A. Hill, in Integrative Paths to the Past: Paleoanthropological Advances in Honor of F Clark Howell, R S. Corruccine and R L Ciochon, Eds. (Prentice-Hall, Englewood Cliffs, NJ, 1994), pp 123-145.
40. Information on origins of population samples, sampling procedures, and preparation of DNA samples can be found by checking from the Kidd Lab Home Page on the World Wide Web at
41. M. E. Hawley and K. K. Kidd, J. Hered. 86, 409 (1995). Program and documentation are available via anonymous FTP from paella.med.yale edu, in the directory pub/haplo.
42. S. Michalatos-Beloin, S. A. Tishkoff, K. K. Kidd, G Ruano, in preparation Among the sub-Saharan African Alu(-) haplotypes, 115 of 132 were unambiguously resolved by allele-specific long-range PCR or homozygosity. The remainder were inferred by HAPLO (21). Haplotypes in all sub-Saharan African populations were >90% resolved except in the Herero (50% resolved), Bantu speakers (79%), and Woloff (88%) Outside of Africa, all six non- 90-bp Alu(-) haplotypes were unambiguously resolved. The genotypes of an additional 30 doubly heterozygous individuals (Alu +/-, 90 bp/non-90 bp) from assorted non-African populations were unambiguously resolved; the 90-bp allele was associated with the Alu(-) allele in all cases.
43. 2 = 7.12, df = 10, P > 0.05.
44. 2 = 38.70, df = 10, P < 0.001 with methods described in (23).
45. B. O Bengtsson and G Thomson, Tissue Antigens 18, 356 (1981).
46. A. Rogers and L. Jorde, Hum. Biol. 67, 1 (1995).
47. J. S. Wainscoat et al., Nature 319, 491 (1986), J S. Jones and S. Rouhani, ibid., p. 449.
48. J. S. Wainscoat et al., Nature 319, 491 (1986), J S. Jones and S. Rouhani, ibid., p. 449.
49. F. J. Ayala, A. Escalante, C. O'hUigin, J. Klein, Proc. Natl Acad. Sci. U.S.A 91, 6787 (1994).
50. Y. Satta, C. O'hUigin, N. Takahata, J. Klein, ibid., p. 7184
51. C. Sheba et al., Am J Phys. Anthropol. 20, 167 (1962); I Hakim, M. Gross, B. Bonné-Tamir, in Plundisciplinary Approach of Human Isolates, A. Chaventre and D F. Roberts, Eds (Institut National Etudes Demographiques, Paris, 1990), pp. 43-57; U Ritte et al., Hum. Biol. 65, 359 (1993); Z. Zoossmann-Diskin et al., Isr. J. Med. Sci. 27, 245 (1991).
52. C. Sheba et al., Am J Phys. Anthropol. 20, 167 (1962); I Hakim, M. Gross, B. Bonné-Tamir, in Plundisciplinary Approach of Human Isolates, A. Chaventre and D F. Roberts, Eds (Institut National Etudes Demographiques, Paris, 1990), pp. 43-57; U Ritte et al., Hum. Biol. 65, 359 (1993); Z. Zoossmann-Diskin et al., Isr. J. Med. Sci. 27, 245 (1991).
53. C. Sheba et al., Am J Phys. Anthropol. 20, 167 (1962); I Hakim, M. Gross, B. Bonné-Tamir, in Plundisciplinary Approach of Human Isolates, A. Chaventre and D F. Roberts, Eds (Institut National Etudes Demographiques, Paris, 1990), pp. 43-57; U Ritte et al., Hum. Biol. 65, 359 (1993); Z. Zoossmann-Diskin et al., Isr. J. Med. Sci. 27, 245 (1991).
54. C. Sheba et al., Am J Phys. Anthropol. 20, 167 (1962); I Hakim, M. Gross, B. Bonné-Tamir, in Plundisciplinary Approach of Human Isolates, A. Chaventre and D F. Roberts, Eds (Institut National Etudes Demographiques, Paris, 1990), pp. 43-57; U Ritte et al., Hum. Biol. 65, 359 (1993); Z. Zoossmann-Diskin et al., Isr. J. Med. Sci. 27, 245 (1991).
55. D. A Mernwether et al., J Mol Evol. 33, 543 (1991); A. Di Rienzo and A C. Wilson, Proc. Natl Acad Sci. U.S.A 88, 1597 (1991)
56. D. A Mernwether et al., J Mol Evol. 33, 543 (1991); A. Di Rienzo and A C. Wilson, Proc. Natl Acad Sci. U.S.A 88, 1597 (1991)
57. L L. Cavalli-Sforza, A. Piazza, P Menozzi, J. C. Mountain, Proc. Natl Acad Sci. U.S.A. 85, 6002 (1988); A. M. Bowcock et al., ibid. 88, 839 (1991); A. M. Bowcock et al., Gene Geogny 5, 151 (1991); M. Nei and A. K. Roychoudhury, Mol. Biol. Evol 10, 927 (1993), M. A. Batzer et al , Proc Natl Acad. Sci. U.S A. 91, 12288 (1994); J J. Martinson et al., Am. J. Hum. Genet 57,1186 (1995); H.Zischler, H Geisert, A. von Haeseler, S. Paabo, Nature 378, 489 (1995)
58. L L. Cavalli-Sforza, A. Piazza, P Menozzi, J. C. Mountain, Proc. Natl Acad Sci. U.S.A. 85, 6002 (1988); A. M. Bowcock et al., ibid. 88, 839 (1991); A. M. Bowcock et al., Gene Geogny 5, 151 (1991); M. Nei and A. K. Roychoudhury, Mol. Biol. Evol 10, 927 (1993), M. A. Batzer et al , Proc Natl Acad. Sci. U.S A. 91, 12288 (1994); J J. Martinson et al., Am. J. Hum. Genet 57,1186 (1995); H.Zischler, H Geisert, A. von Haeseler, S. Paabo, Nature 378, 489 (1995)
59. L L. Cavalli-Sforza, A. Piazza, P Menozzi, J. C. Mountain, Proc. Natl Acad Sci. U.S.A. 85, 6002 (1988); A. M. Bowcock et al., ibid. 88, 839 (1991); A. M. Bowcock et al., Gene Geogny 5, 151 (1991); M. Nei and A. K. Roychoudhury, Mol. Biol. Evol 10, 927 (1993), M. A. Batzer et al , Proc Natl Acad. Sci. U.S A. 91, 12288 (1994); J J. Martinson et al., Am. J. Hum. Genet 57,1186 (1995); H.Zischler, H Geisert, A. von Haeseler, S. Paabo, Nature 378, 489 (1995)
60. L L. Cavalli-Sforza, A. Piazza, P Menozzi, J. C. Mountain, Proc. Natl Acad Sci. U.S.A. 85, 6002 (1988); A. M. Bowcock et al., ibid. 88, 839 (1991); A. M. Bowcock et al., Gene Geogny 5, 151 (1991); M. Nei and A. K. Roychoudhury, Mol. Biol. Evol 10, 927 (1993), M. A. Batzer et al , Proc Natl Acad. Sci. U.S A. 91, 12288 (1994); J J. Martinson et al., Am. J. Hum. Genet 57,1186 (1995); H.Zischler, H Geisert, A. von Haeseler, S. Paabo, Nature 378, 489 (1995)
61. L L. Cavalli-Sforza, A. Piazza, P Menozzi, J. C. Mountain, Proc. Natl Acad Sci. U.S.A. 85, 6002 (1988); A. M. Bowcock et al., ibid. 88, 839 (1991); A. M. Bowcock et al., Gene Geogny 5, 151 (1991); M. Nei and A. K. Roychoudhury, Mol. Biol. Evol 10, 927 (1993), M. A. Batzer et al , Proc Natl Acad. Sci. U.S A. 91, 12288 (1994); J J. Martinson et al., Am. J. Hum. Genet 57,1186 (1995); H.Zischler, H Geisert, A. von Haeseler, S. Paabo, Nature 378, 489 (1995)
62. L L. Cavalli-Sforza, A. Piazza, P Menozzi, J. C. Mountain, Proc. Natl Acad Sci. U.S.A. 85, 6002 (1988); A. M. Bowcock et al., ibid. 88, 839 (1991); A. M. Bowcock et al., Gene Geogny 5, 151 (1991); M. Nei and A. K. Roychoudhury, Mol. Biol. Evol 10, 927 (1993), M. A. Batzer et al , Proc Natl Acad. Sci. U.S A. 91, 12288 (1994); J J. Martinson et al., Am. J. Hum. Genet 57,1186 (1995); H.Zischler, H Geisert, A. von Haeseler, S. Paabo, Nature 378, 489 (1995)
63. L L. Cavalli-Sforza, A. Piazza, P Menozzi, J. C. Mountain, Proc. Natl Acad Sci. U.S.A. 85, 6002 (1988); A. M. Bowcock et al., ibid. 88, 839 (1991); A. M. Bowcock et al., Gene Geogny 5, 151 (1991); M. Nei and A. K. Roychoudhury, Mol. Biol. Evol 10, 927 (1993), M. A. Batzer et al , Proc Natl Acad. Sci. U.S A. 91, 12288 (1994); J J. Martinson et al., Am. J. Hum. Genet 57,1186 (1995); H.Zischler, H Geisert, A. von Haeseler, S. Paabo, Nature 378, 489 (1995)
64. C. M. Castiglione et al , Am J. Hum. Genet. 57, 1445 (1995).
65. Analyses with the η coefficient [Q. McNemar, Psychological Statistics (Wiley, New York, 1969)] and several genetic distance measures on STRP frequencies normalized on Alu(+) and Alu(-) chromosomes - Fst [J Reynolds, B. S Weir, C C Cockerham, Genetics 105, 767 (1983)], Rst (48), Nei's index of similarity (l) [M. Nei, Molecular Evolutionary Genetics (Columbia Univ. Press, New York, 1987] - all show high levels of similarity in the distributions of STRP alleles on Alu(+) chromosomes in all sub-Saharan populations, an equivalent level of similarity on Alu(-) chromosomes, but much less similarity between Alu(+) and Alu(-) chromosomes whether from the same or different populations For example, with the ηcoefficient as a measure of similarity, the means of the pairwise values among the 10 sub-Saharan populations is 0.90 for Alu(+) chromosomes and O 84 for Alu(-) chromosomes. The lower similarity for Alu(-) chromosomes reflects the smaller number of Alu(-) chromosomes (and hence high variance) in several populations. If we consider only those five populations with more than 10 Alu(-) chromosomes, the mean similarity values are 0.89 for Alu(+) and 0 88 for Alu(-) chromosomes. We contrast these with the means of comparisons of Alu(+) with Alu(-) chromosomes within a population (0.63) and between populations (0.70). Limiting the comparisons to the five populations with more than 10 Alu(-) chromosomes changes these mean values minimally to 0.68 (within populations) and 0.69 (between populations).
66. Analyses with the η coefficient [Q. McNemar, Psychological Statistics (Wiley, New York, 1969)] and several genetic distance measures on STRP frequencies normalized on Alu(+) and Alu(-) chromosomes - Fst [J Reynolds, B. S Weir, C C Cockerham, Genetics 105, 767 (1983)], Rst (48), Nei's index of similarity (l) [M. Nei, Molecular Evolutionary Genetics (Columbia Univ. Press, New York, 1987] - all show high levels of similarity in the distributions of STRP alleles on Alu(+) chromosomes in all sub-Saharan populations, an equivalent level of similarity on Alu(-) chromosomes, but much less similarity between Alu(+) and Alu(-) chromosomes whether from the same or different populations For example, with the ηcoefficient as a measure of similarity, the means of the pairwise values among the 10 sub-Saharan populations is 0.90 for Alu(+) chromosomes and O 84 for Alu(-) chromosomes. The lower similarity for Alu(-) chromosomes reflects the smaller number of Alu(-) chromosomes (and hence high variance) in several populations. If we consider only those five populations with more than 10 Alu(-) chromosomes, the mean similarity values are 0.89 for Alu(+) and 0 88 for Alu(-) chromosomes. We contrast these with the means of comparisons of Alu(+) with Alu(-) chromosomes within a population (0.63) and between populations (0.70). Limiting the comparisons to the five populations with more than 10 Alu(-) chromosomes changes these mean values minimally to 0.68 (within populations) and 0.69 (between populations).
67. Analyses with the η coefficient [Q. McNemar, Psychological Statistics (Wiley, New York, 1969)] and several genetic distance measures on STRP frequencies normalized on Alu(+) and Alu(-) chromosomes - Fst [J Reynolds, B. S Weir, C C Cockerham, Genetics 105, 767 (1983)], Rst (48), Nei's index of similarity (l) [M. Nei, Molecular Evolutionary Genetics (Columbia Univ. Press, New York, 1987] - all show high levels of similarity in the distributions of STRP alleles on Alu(+) chromosomes in all sub-Saharan populations, an equivalent level of similarity on Alu(-) chromosomes, but much less similarity between Alu(+) and Alu(-) chromosomes whether from the same or different populations For example, with the ηcoefficient as a measure of similarity, the means of the pairwise values among the 10 sub-Saharan populations is 0.90 for Alu(+) chromosomes and O 84 for Alu(-) chromosomes. The lower similarity for Alu(-) chromosomes reflects the smaller number of Alu(-) chromosomes (and hence high variance) in several populations. If we consider only those five populations with more than 10 Alu(-) chromosomes, the mean similarity values are 0.89 for Alu(+) and 0 88 for Alu(-) chromosomes. We contrast these with the means of comparisons of Alu(+) with Alu(-) chromosomes within a population (0.63) and between populations (0.70). Limiting the comparisons to the five populations with more than 10 Alu(-) chromosomes changes these mean values minimally to 0.68 (within populations) and 0.69 (between populations).
68. A. M. Valdes, M. Slatkin. N B Freimer, Genetics 133, 737 (1993), M. D Shriver, L Jin, R Chakraborty, E Boerwinkle, ibid 134, 983 (1993); A. Di Rienzo et al., Proc. Natl. Acad. Sci. U.S.A. 91, 3166 (1994).
69. A. M. Valdes, M. Slatkin. N B Freimer, Genetics 133, 737 (1993), M. D Shriver, L Jin, R Chakraborty, E Boerwinkle, ibid 134, 983 (1993); A. Di Rienzo et al., Proc. Natl. Acad. Sci. U.S.A. 91, 3166 (1994).
70. A. M. Valdes, M. Slatkin. N B Freimer, Genetics 133, 737 (1993), M. D Shriver, L Jin, R Chakraborty, E Boerwinkle, ibid 134, 983 (1993); A. Di Rienzo et al., Proc. Natl. Acad. Sci. U.S.A. 91, 3166 (1994).
71. Variation at the STRP and linkage disequilibrium between the markers will be affected by the demographic history of the populations [H C Harpending, S. T Sherry, A. R. Rogers, M. Stoneking, Curr. Anthropol 34, 483 (1993); M. Slatkin, Genetics 137, 331 (1994)]. Because allelic variation may have been lost in a small ancestral population some time after leaving Africa but before rapid population expansion, we could be estimating the time since divergence and expansion of the ancestral non-African population, which may have occurred subsequent to migration out of Africa
72. Variation at the STRP and linkage disequilibrium between the markers will be affected by the demographic history of the populations [H C Harpending, S. T Sherry, A. R. Rogers, M. Stoneking, Curr. Anthropol 34, 483 (1993); M. Slatkin, Genetics 137, 331 (1994)]. Because allelic variation may have been lost in a small ancestral population some time after leaving Africa but before rapid population expansion, we could be estimating the time since divergence and expansion of the ancestral non-African population, which may have occurred subsequent to migration out of Africa
73. Other assumptions may be warranted for other haplotype loci. Specifically, for markers with low mutation rate but proportionately higher recombination rates than evident at CD4, models and analyses based primarily on recombination would be most appropriate.
74. Ethiopian Jews, Somalis, and Egyptians have been excluded from the analysis because of the possibility of admixture with sub-Saharan Africans and non-Africans.
75. Sequencing analysis of more than 100 alleles from chromosomes of humans of diverse geographical origin shows that alleles of 110 bp or larger on Alu(+) chromosomes have an imperfect CTTTC as the fourth repeat from the 5′ end Thus, the ancestral STRP allele was most likely a small-sized perfect repeat of TTTTC (17), and alleles 110 bp or larger are derived from a single mutation that generated a higher repeat-number allele with the imperfect CTTTC. Sequencing analysis of several large-sized alleles from Alu(-) chromosomes demonstrates that they share the point mutation present on Alu(+) chromosomes; thus, these alleles most likely derive from an ancient recombination event transferring a large-sized allele from an Alu(+) chromosome to an Alu(-) chromosome with subsequent mutation by one or few repeats to other large-sized alleles.
76. B, we obtain a value for R of In(0 53)/ In(0.961) = 16.0 (or maximum age of 5 million/16.0 = 313,000 Y.B P )
77. B = 264/270, R = 28.2, for a maximal age of 177,000 years Various models that assume stepwise mutation of the STRP imply that the variation of allele sizes increases linearly with time (48) [D. B. Goldstein, A. Ruiz Linares, L L. Cavalli-Sforza, M. W Feldman. Genetics 139, 463 (1995)]. Thus, we can estimate R as the ratio of variances of allele sizes (in base pairs) for alleles less than 110 bp (22 5/0 75 = 30.0), giving a maximum age of 167,000 Y.B.P Because we have considered only a single locus, the standard error on this vanance-ratio estimate is high. However, the apparent lower boundary of 85 bp to the STRP allele size results in an underestimate of the time of origin of the Alu(-) chromosome in Africa, so again this estimate of R is conservative.
78. Despite a smaller effective population size of Alu(-) chromosomes (because of a lower frequency), the mean variance of STRP alleles on Alu(-) chromsomes among the 10 sub-Saharan African populations is still substantial [64% of the mean variance of STRP alleles on Alu(+) chromosomes], suggesting that while the origin of the Alu(-) chromosome is more recent than the origin of the Alu(+) chromosome, it is still quite ancient
79. C. B Stringer, in The Origin and Evolution of Humans and Humanness, D T. Rasmussen Ed. (Jones and Bartlett, Boston, 1993), pp. 75-94
80. M. Slatkin, Mol. Biol. Evol 12, 473 (1995).
81. Both the STRP and the Alu deletion polymorphism are located in noncoding regions of the CD4 gene and are unlikely to have any functional significance. Except in the unlikely case of strong positive cisacting epistasis of functional variants flanking exons 1 and 2 of the 90-bp Alu(-) chromosomes, selection cannot explain the maintenance of the linkage disequilibrium seen in non-African populations because there would be nothing to prevent formation of "non- 90 bp" Alu(-) chromosomes by recombination between the markers or mutation at the STRP. In addition, the very low frequency of the Alu(-) chromosomes in Asia, the Pacific islands, and the New World, as well as the very high frequency of 85-bp Alu(+) and 110bp Alu(+) chromosomes in all non-African populations, argues against strong positive selection for the Alu(-) chromosome
82. S A. Tishkoff, W C Speed, J R Kidd, K K. Kidd, Am J Phys. Anthropol Suppl. 20, 211 (1995); S. A Tishkoff et al., Am. J Hum Genet 57S, A42 (1995); K. K. Kidd et al., Alcoholism. Clinical and Experimental Research, in press.
83. S A. Tishkoff, W C Speed, J R Kidd, K K. Kidd, Am J Phys. Anthropol Suppl. 20, 211 (1995); S. A Tishkoff et al., Am. J Hum Genet 57S, A42 (1995); K. K. Kidd et al., Alcoholism. Clinical and Experimental Research, in press.
84. S A. Tishkoff, W C Speed, J R Kidd, K K. Kidd, Am J Phys. Anthropol Suppl. 20, 211 (1995); S. A Tishkoff et al., Am. J Hum Genet 57S, A42 (1995); K. K. Kidd et al., Alcoholism. Clinical and Experimental Research, in press.
85. Very large and unlikely amounts of gene flow and drift acting in a similar manner in many geographically dispersed populations would be required for the 90 bp Alu(-) haplotype to have been recently introduced into preexisting H. erectus populations and achieve the frequencies seen today. The low frequency of the 90-bp Alu(-) chromosome in all Asian, Pacific island, and New World populations argues against high levels of gene flow from European or Middle Eastern populations into these regions before historical times
86. M. Slatkin, Genetics 139, 457 (1995).
87. We thank A Deinard for providing nonhuman primate samples. For assistance with collecting African DNA samples, we thank H. Soodyall and G. Sirugo as well as R Aman from the National Museums of Kenya. We thank M. Hawley for assistance with the HAPLO program. We also thank our many colleagues for helpful comments and criticisms in the course of this study, including J. Cheng, A. G. Clark, A. Di Rienzo, R. Dont, R. Harding, L. B. Jorde, M. Slatkin, and an anonymous reviewer Supported in part by the Medical Research Council of South Africa and by a grant to M.K. from Boehringer Ingelheirn Fonds, NiH grant HG00348 to N.R., USPHS grants AA09379 and MH39239 to K.K K., USNSF grant DBS9208917 to K.K.K. and SBR-9408934 to J.R.K., and a grant from the Alfred P. Sloan Foundation to K K K