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Genetic variability in a genomic region with long-range linkage disequilibrium reveals traces of a bottleneck in the history of the European population

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The inference of the demographic history of populations from genetic variability data is not only of academic interest. It also provides background information for the identification of genes which may have played a role in human evolution or in the aetiology of human disease. To obtain a clear picture of this background, it is necessary to compare data obtained from a number of genomic loci. Due to its very low recombination rate, the NF1 gene region can be regarded as a further suitable locus. A combined resequencing and SNP typing project in a European population disclosed the presence of only two well separated subgroups of NF1 sequences. Statistical analysis revealed a bimodal distribution of the pairwise differences, a positive value of Tajima’s D and a TMRCA of 700,000 years for the whole sample, and pairwise differences indicative for a growing population and TMRCAs of 130,000 to 150,000 years for the subgroups. Together, the data lead to a model that the recent European population went through a bottleneck during the last 150,000 years of its history. Regarding the given timeframe, this bottleneck could either reflect a speciation event which led to the anatomically modern human (AMH), or a severe reduction of the population size during the emigration of AMHs out of Africa or the immigration into Europe.

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Anatomically modern human


Fu and Li’s D


Fu and Li’s F


Linkage disequilibrium


Most recent common ancestor


Tajima’s D


Time to most recent common ancestor


  1. Akey JM, Eberle MA, Rieder MJ, Carlson CS, Shriver MD, Nickerson DA, Kruglyak L (2004) Population history and natural selection shape patterns of genetic variation in 132 genes. PLoS Biol 2:e286

  2. Bamshad M, Wooding SP (2003) Signatures of natural selection in the human genome. Nat Rev Genet 4:99–111

  3. Bamshad MJ, Mummidi S, Gonzalez E, Ahuja SS, Dunn DM, Watkins WS, Wooding S, Stone AC, Jorde LB, Weiss RB, Ahuja SK (2002) A strong signature of balancing selection in the 5′ cis-regulatory region of CCR5. Proc Natl Acad Sci USA 99:10539–10544

  4. Barbujani G, Bertorelle G (2001) Genetics and the population history of Europe. Proc Natl Acad Sci USA 98:22–25

  5. Black FL, Hedrick PW (1997) Strong balancing selection at HLA loci: evidence from segregation in South Amerindian families. Proc Natl Acad Sci USA 94:12452–12456

  6. Cavalli-Sforza LL, Feldman MW (2003) The application of molecular genetic approaches to the study of human evolution. Nat Genet 33(Suppl):266–275

  7. Chikhi L, Nichols RA, Barbujani G, Beaumont MA (2002) Y genetic data support the Neolithic demic diffusion model. Proc Natl Acad Sci USA 99:11008–11013

  8. Daly MJ, Rioux JD, Schaffner SF, Hudson TJ, Lander ES (2001) High-resolution haplotype structure in the human genome. Nat Genet 29:229–232

  9. Devlin B, Risch N (1995) A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics 29:311–322

  10. Eisenbarth I, Vogel G, Krone W, Vogel W, Assum G (2000) An isochore transition in the NF1 gene region coincides with a switch in the extent of linkage disequilibrium. Am J Hum Genet 67:873–880

  11. Enard W, Przeworski M, Fisher SE, Lai CS, Wiebe V, Kitano T, Monaco AP, Paabo S (2002) Molecular evolution of FOXP2, a gene involved in speech and language. Nature 418:869–872

  12. Evans PD, Anderson JR, Vallender EJ, Gilbert SL, Malcom CM, Dorus S, Lahn BT (2004) Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans. Hum Mol Genet 13:489–494

  13. Ewens WJ (2004) Mathematical population genetics, 2nd edn. Springer, New York

  14. Excoffier L (2002) Human demographic history: refining the recent African origin model. Curr Opin Genet Dev 12:675–682

  15. Fahsold R, Hoffmeyer S, Mischung C, Gille C, Ehlers C, Kucukceylan N, Abdel-Nour M, Gewies A, Peters H, Kaufmann D, Buske A, Tinschert S, Nurnberg P (2000) Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet 66:790–818

  16. Frisse L, Hudson RR, Bartoszewicz A, Wall JD, Donfack J, Di Rienzo A (2001) Gene conversion and different population histories may explain the contrast between polymorphism and linkage disequilibrium levels. Am J Hum Genet 69:831–843

  17. Fu YX, Li WH (1993) Statistical tests of neutrality of mutations. Genetics 133:693–709

  18. Gilad Y, Rosenberg S, Przeworski M, Lancet D, Skorecki K (2002) Evidence for positive selection and population structure at the human MAO-A gene. Proc Natl Acad Sci USA 99:862–867

  19. Griffiths RC, Tavare S (1994) Simulating Probability Distributions in the Coalescent. Theor Popul Biol 46:131–159

  20. Harding RM, Healy E, Ray AJ, Ellis NS, Flanagan N, Todd C, Dixon C, Sajantila A, Jackson IJ, Birch-Machin MA, Rees JL (2000) Evidence for variable selective pressures at MC1R. Am J Hum Genet 66:1351–1361

  21. Harpending H, Rogers A (2000) Genetic perspectives on human origins and differentiation. Annu Rev Genomics Hum Genet 1:361–385

  22. Hinds DA, Stuve LL, Nilsen GB, Halperin E, Eskin E, Ballinger DG, Frazer KA, Cox DR (2005) Whole-genome patterns of common DNA variation in three human populations. Science 307:1072–1079

  23. Hinks LJ, Price SE, Mason CR, Thompson RJ (1995) Single strand conformation analysis of two genes contained within the first intron of the neurofibromatosis type I gene in patients with multiple sclerosis. Neuropathol Appl Neurobiol 21:201–207

  24. Hoffmeyer S, Assum G, Griesser J, Kaufmann D, Nurnberg P, Krone W (1995) On unequal allelic expression of the neurofibromin gene in neurofibromatosis type 1. Hum Mol Genet 4:1267–1272

  25. Jenne DE, Tinschert S, Dorschner MO, Hameister H, Stephens K, Kehrer-Sawatzki H (2003) Complete physical map and gene content of the human NF1 tumor suppressor region in human and mouse. Genes Chromosomes Cancer 37:111–120

  26. Jobling MA, Tyler-Smith C (2003) The human Y chromosome: an evolutionary marker comes of age. Nat Rev Genet 4:598–612

  27. Jorde LB, Watkins WS, Viskochil D, O’Connell P, Ward K (1993) Linkage disequilibrium in the neurofibromatosis 1 (NF1) region: implications for gene mapping. Am J Hum Genet 53:1038–1050

  28. Kaessmann H, Heissig F, von Haeseler A, Paabo S (1999) DNA sequence variation in a non-coding region of low recombination on the human X chromosome. Nat Genet 22:78–81

  29. Kong A, Gudbjartsson DF, Sainz J, Jonsdottir GM, Gudjonsson SA, Richardsson B, Sigurdardottir S, Barnard J, Hallbeck B, Masson G, Shlien A, Palsson ST, Frigge ML, Thorgeirsson TE, Gulcher JR, Stefansson K (2002) A high-resolution recombination map of the human genome. Nat Genet 31:225–226

  30. Kreitman M, Di Rienzo A (2004) Balancing claims for balancing selection. Trends Genet 20:300–304

  31. Labuda D, Zietkiewicz E, Yotova V (2000) Archaic lineages in the history of modern humans. Genetics 156:799–808

  32. Marjoram P, Donnelly P (1994) Pairwise comparisons of mitochondrial DNA sequences in subdivided populations and implications for early human evolution. Genetics 136:673–683

  33. Marth G, Schuler G, Yeh R, Davenport R, Agarwala R, Church D, Wheelan S, Baker J, Ward M, Kholodov M, Phan L, Czabarka E, Murvai J, Cutler D, Wooding S, Rogers A, Chakravarti A, Harpending HC, Kwok PY, Sherry ST (2003) Sequence variations in the public human genome data reflect a bottlenecked population history. Proc Natl Acad Sci USA 100:376–381

  34. Mead S, Stumpf MP, Whitfield J, Beck JA, Poulter M, Campbell T, Uphill JB, Goldstein D, Alpers M, Fisher EM, Collinge J (2003) Balancing selection at the prion protein gene consistent with prehistoric kurulike epidemics. Science 300:640–643

  35. Messiaen L, De Bie S, Moens T, Van den Enden A, Leroy J (1993) Lack of independence between five DNA polymorphisms in the NF1 gene. Hum Mol Genet 2:485

  36. Purandare SM, Cawthon R, Nelson LM, Sawada S, Watkins WS, Ward K, Jorde LB, Viskochil DH (1996) Genotyping of PCR-based polymorphisms and linkage-disequilibrium analysis at the NF1 locus. Am J Hum Genet 59:159–166

  37. Rana BK, Hewett-Emmett D, Jin L, Chang BH, Sambuughin N, Lin M, Watkins S, Bamshad M, Jorde LB, Ramsay M, Jenkins T, Li WH (1999) High polymorphism at the human melanocortin 1 receptor locus. Genetics 151:1547–1557

  38. Richards M, Macaulay V, Hickey E, Vega E, Sykes B, Guida V, Rengo C, Sellitto D, Cruciani F, Kivisild T, Villems R, Thomas M, Rychkov S, Rychkov O, Rychkov Y, Golge M, Dimitrov D, Hill E, Bradley D, Romano V, Cali F, Vona G, Demaine A, Papiha S, Triantaphyllidis C, Stefanescu G, Hatina J, Belledi M, Di Rienzo A, Novelletto A, Oppenheim A, Norby S, Al Zaheri N, Santachiara-Benerecetti S, Scozari R, Torroni A, Bandelt HJ (2000) Tracing European founder lineages in the Near Eastern mtDNA pool. Am J Hum Genet 67:1251–1276

  39. Rogers AR (1995) Genetic evidence for a Pleistocene population explosion. Evolution 49:608–615

  40. Rozas J, Sanchez-DelBarrio JC, Messeguer X, Rozas R (2003) DnaSP, DNA polymorphism analyses by the coalescent and other methods. Bioinformatics 19:2496–2497

  41. Semino O, Passarino G, Oefner PJ, Lin AA, Arbuzova S, Beckman LE, De Benedictis G, Francalacci P, Kouvatsi A, Limborska S, Marcikiae M, Mika A, Mika B, Primorac D, Santachiara-Benerecetti AS, Cavalli-Sforza LL, Underhill PA (2000) The genetic legacy of Paleolithic Homo sapiens sapiens in extant Europeans: a Y chromosome perspective. Science 290:1155–1159

  42. Semino O, Magri C, Benuzzi G, Lin AA, Al Zahery N, Battaglia V, Maccioni L, Triantaphyllidis C, Shen P, Oefner PJ, Zhivotovsky LA, King R, Torroni A, Cavalli-Sforza LL, Underhill PA, Santachiara-Benerecetti AS (2004) Origin, diffusion, and differentiation of Y-chromosome haplogroups E and J: inferences on the neolithization of Europe and later migratory events in the Mediterranean area. Am J Hum Genet 74:1023–1034

  43. Slatkin M, Hudson RR (1991) Pairwise comparisons of mitochondrial DNA sequences in stable and exponentially growing populations. Genetics 129:555–562

  44. Stajich JE, Hahn MW (2005) Disentangling the effects of demography and selection in human history. Mol Biol Evol 22:63–73

  45. Stephens M, Donnelly P (2003) A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73:1162–1169

  46. Stephens JC, Schneider JA, Tanguay DA, Choi J, Acharya T, Stanley SE, Jiang R, Messer CJ, Chew A, Han JH, Duan J, Carr JL, Lee MS, Koshy B, Kumar AM, Zhang G, Newell WR, Windemuth A, Xu C, Kalbfleisch TS, Shaner SL, Arnold K, Schulz V, Drysdale CM, Nandabalan K, Judson RS, Ruano G, Vovis GF (2001) Haplotype variation and linkage disequilibrium in 313 human genes. Science 293:489–493

  47. Stumpf MP, Goldstein DB (2001) Genealogical and evolutionary inference with the human Y chromosome. Science 291:1738–1742

  48. Tajima F (1989) Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123:585–595

  49. Wang YQ, Su B (2004) Molecular evolution of microcephalin, a gene determining human brain size. Hum Mol Genet 13:1131–1137

  50. Wang E, Ding YC, Flodman P, Kidd JR, Kidd KK, Grady DL, Ryder OA, Spence MA, Swanson JM, Moyzis RK (2004) The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus. Am J Hum Genet 74:931–944

  51. Wells RS, Yuldasheva N, Ruzibakiev R, Underhill PA, Evseeva I, Blue-Smith J, Jin L, Su B, Pitchappan R, Shanmugalakshmi S, Balakrishnan K, Read M, Pearson NM, Zerjal T, Webster MT, Zholoshvili I, Jamarjashvili E, Gambarov S, Nikbin B, Dostiev A, Aknazarov O, Zalloua P, Tsoy I, Kitaev M, Mirrakhimov M, Chariev A, Bodmer WF (2001) The Eurasian heartland: a continental perspective on Y-chromosome diversity. Proc Natl Acad Sci USA 98:10244–10249

  52. Wooding S, Kim UK, Bamshad MJ, Larsen J, Jorde LB, Drayna D (2004) Natural selection and molecular evolution in PTC, a bitter-taste receptor gene. Am J Hum Genet 74:637–646

  53. Xiao FX, Yotova V, Zietkiewicz E, Lovell A, Gehl D, Bourgeois S, Moreau C, Spanaki C, Plaitakis A, Moisan JP, Labuda D (2004) Human X-chromosomal lineages in Europe reveal Middle Eastern and Asiatic contacts. Eur J Hum Genet 12:301–311

  54. Xie X, Ott J (1993) Testing linkage disequilibrium between a disease gene and marker loci. Am J Hum Genet 53(Suppl):1107

  55. Yu N, Zhao Z, Fu YX, Sambuughin N, Ramsay M, Jenkins T, Leskinen E, Patthy L, Jorde LB, Kuromori T, Li WH (2001) Global patterns of human DNA sequence variation in a 10-kb region on chromosome 1. Mol Biol Evol 18:214–222

  56. Zhang J, Rowe WL, Clark AG, Buetow KH (2003) Genomewide distribution of high-frequency, completely mismatching SNP haplotype pairs observed to be common across human populations. Am J Hum Genet 73:1073–1081

  57. Zhao Z, Jin L, Fu YX, Ramsay M, Jenkins T, Leskinen E, Pamilo P, Trexler M, Patthy L, Jorde LB, Ramos-Onsins S, Yu N, Li WH (2000) Worldwide DNA sequence variation in a 10-kilobase noncoding region on human chromosome 22. Proc Natl Acad Sci USA 97:11354–11358

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We thank Britta Pietsch, Birgit Schmoll and Sigrid Wieland-Lange for excellent technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft.

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Correspondence to Günter Assum.

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Schmegner, C., Hoegel, J., Vogel, W. et al. Genetic variability in a genomic region with long-range linkage disequilibrium reveals traces of a bottleneck in the history of the European population. Hum Genet 118, 276–286 (2005).

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  • Population genetics
  • Genetic variability
  • Long-range LD
  • Ancient European subpopulations