Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A common inversion under selection in Europeans


A refined physical map of chromosome 17q21.31 uncovered a 900-kb inversion polymorphism. Chromosomes with the inverted segment in different orientations represent two distinct lineages, H1 and H2, that have diverged for as much as 3 million years and show no evidence of having recombined. The H2 lineage is rare in Africans, almost absent in East Asians but found at a frequency of 20% in Europeans, in whom the haplotype structure is indicative of a history of positive selection. Here we show that the H2 lineage is undergoing positive selection in the Icelandic population, such that carrier females have more children and have higher recombination rates than noncarriers.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: A 900-kb inversion polymorphism was detected on one of the RP11 chromosomes at the 17q21.31 locus.
Figure 2: The sequence divergence of the H1 and H2 lineages.
Figure 3: Networks depicting the haplotype structure of the inversion.
Figure 4: The impact of the inversion on LD patterns.
Figure 5: Worldwide distribution of the H2 lineage based on allele frequencies of two diagnostic SNPs obtained from the ALFRED database19.
Figure 6: The genome-wide impact of the number of H2 copies on the rate of recombination in mothers.

Accession codes




  1. Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).

    CAS  Article  Google Scholar 

  2. Iafrate, A.J. et al. Detection of large-scale variation in the human genome. Nat. Genet. 36, 949–951 (2004).

    CAS  Article  Google Scholar 

  3. Jin, H. et al. Structural evolution of the BRCA1 genomic region in primates. Genomics 84, 1071–1082 (2004).

    CAS  Article  Google Scholar 

  4. Shaw, C.J. & Lupski, J.R. Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Hum. Mol. Genet. 13 Spec No 1 R57–R64 (2004).

    CAS  Article  Google Scholar 

  5. Giglio, S. et al. Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements. Am. J. Hum. Genet. 68, 874–883 (2001).

    CAS  Article  Google Scholar 

  6. Baker, M. et al. Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum. Mol. Genet. 8, 711–715 (1999).

    CAS  Article  Google Scholar 

  7. Pittman, A.M. et al. The structure of the tau haplotype in controls and in progressive supranuclear palsy. Hum. Mol. Genet. 13, 1267–1274 (2004).

    CAS  Article  Google Scholar 

  8. Skipper, L. et al. Linkage Disequilibrium and Association of MAPT H1 in Parkinson Disease. Am. J. Hum. Genet. 75, 669–677 (2004).

    CAS  Article  Google Scholar 

  9. Oliveira, S.A. et al. Linkage disequilibrium and haplotype tagging polymorphisms in the Tau H1 haplotype. Neurogenetics 5, 147–155 (2004).

    CAS  Article  Google Scholar 

  10. Farrer, M. et al. The tau H1 haplotype is associated with Parkinson's disease in the Norwegian population. Neurosci. Lett. 322, 83–86 (2002).

    CAS  Article  Google Scholar 

  11. Conrad, C. et al. Molecular evolution and genetics of the Saitohin gene and tau haplotype in Alzheimer's disease and argyrophilic grain disease. J. Neurochem. 89, 179–188 (2004).

    CAS  Article  Google Scholar 

  12. Kwok, J.B. et al. Tau haplotypes regulate transcription and are associated with Parkinson's disease. Ann. Neurol. 55, 329–334 (2004).

    CAS  Article  Google Scholar 

  13. Chen, F.C. & Li, W.H. Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. Am. J. Hum. Genet. 68, 444–456 (2001).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  15. The International HapMap Consortium. The International HapMap Project. Nature 426, 789–796 (2003).

  16. The International HapMap Consortium. Integrating ethics and science in the International HapMap Project. Nat. Rev. Genet. 5, 467–475 (2004).

  17. Bamshad, M. & Wooding, S.P. Signatures of natural selection in the human genome. Nat. Rev. Genet. 4, 99–111 (2003).

    CAS  Article  Google Scholar 

  18. Toomajian, C., Ajioka, R.S., Jorde, L.B., Kushner, J.P. & Kreitman, M. A method for detecting recent selection in the human genome from allele age estimates. Genetics 165, 287–297 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Osier, M.V. et al. ALFRED: An allele frequency database for anthropology. Am. J. Phys. Anthropol. 119, 77–83 (2002).

    Article  Google Scholar 

  20. Evans, W. et al. The tau H2 haplotype is almost exclusively Caucasian in origin. Neurosci. Lett. 369, 183–185 (2004).

    CAS  Article  Google Scholar 

  21. Kong, A. et al. Recombination rate and reproductive success in humans. Nat. Genet. 36, 1203–1206 (2004).

    CAS  Article  Google Scholar 

  22. Kong, A. et al. A high-resolution recombination map of the human genome. Nat. Genet. 31, 241–247 (2002).

    CAS  Article  Google Scholar 

  23. Broman, K.W., Murray, J.C., Sheffield, V.C., White, R.L. & Weber, J.L. Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am. J. Hum. Genet. 63, 861–869 (1998).

    CAS  Article  Google Scholar 

  24. Schaeffer, S.W. et al. Evolutionary genomics of inversions in Drosophila pseudoobscura: evidence for epistasis. Proc. Natl. Acad. Sci. USA 100, 8319–8324 (2003).

    CAS  Article  Google Scholar 

  25. Carroll, S.B. Genetics and the making of Homo sapiens. Nature 422, 849–857 (2003).

    CAS  Article  Google Scholar 

  26. Andolfatto, P., Depaulis, F. & Navarro, A. Inversion polymorphisms and nucleotide variability in Drosophila. Genet. Res. 77, 1–8 (2001).

    CAS  Article  Google Scholar 

  27. Brown, P. et al. A new small-bodied hominin from the Late Pleistocene of Flores, Indonesia. Nature 431, 1055–1061 (2004).

    CAS  Article  Google Scholar 

  28. Reed, D.L., Smith, V.S., Hammond, S.L., Rogers, A.R. & Clayton, D.H. Genetic analysis of lice supports direct contact between modern and archaic humans. PLoS Biol. 2, 340 (2004).

    Article  Google Scholar 

  29. Lewin, R. & Foley, R.A. Principles of Human Evolution (Blackwell, Oxford, 2004).

    Google Scholar 

  30. Sabeti, P.C. et al. Detecting recent positive selection in the human genome from haplotype structure. Nature 419, 832–837 (2002).

    CAS  Article  Google Scholar 

  31. Nachman, M.W. & Crowell, S.L. Contrasting evolutionary histories of two introns of the duchenne muscular dystrophy gene, Dmd, in humans. Genetics 155, 1855–1864 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  Google Scholar 

  33. Thompson, E.E. et al. CYP3A variation and the evolution of salt-sensitivity variants. Am. J. Hum. Genet. 75, 1059–1069 (2004).

    CAS  Article  Google Scholar 

  34. Akey, J.M. et al. Population history and natural selection shape patterns of genetic variation in 132 genes. PLoS Biol. 2, e286 (2004).

    Article  Google Scholar 

  35. Gulcher, J.R., Kristjansson, K., Gudbjartsson, H. & Stefansson, K. Protection of privacy by third-party encryption in genetic research in Iceland. Eur. J. Hum. Genet. 8, 739–742 (2000).

    CAS  Article  Google Scholar 

  36. Kumar, S., Tamura, K. & Nei, M. MEGA3: Integrated software for Molecular Evolutionary Genetics Analysis and sequence alignment. Brief Bioinform. 5, 150–163 (2004).

    CAS  Article  Google Scholar 

  37. Schwartz, S. et al. Human-mouse alignments with BLASTZ. Genome Res. 13, 103–107 (2003).

    CAS  Article  Google Scholar 

  38. Gretarsdottir, S. et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat. Genet. 35, 131–138 (2003).

    CAS  Article  Google Scholar 

  39. Bandelt, H.J., Forster, P. & Rohl, A. Median-joining networks for inferring intraspecific phylogenies. Mol. Biol. Evol. 16, 37–48 (1999).

    CAS  Article  Google Scholar 

  40. Slatkin, M. & Bertorelle, G. The use of intraallelic variability for testing neutrality and estimating population growth rate. Genetics 158, 865–874 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Laval, G. & Excoffier, L. SIMCOAL 2.0: a program to simulate genomic diversity over large recombining regions in a subdivided population with a complex history. Bioinformatics 20, 2485–2487 (2004).

    CAS  Article  Google Scholar 

  42. Navarro, A., Barbadilla, A. & Ruiz, A. Effect of inversion polymorphism on the neutral nucleotide variability of linked chromosomal regions in Drosophila. Genetics 155, 685–698 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Dempster, A., Laird, N. & Rubin, D. Maximum likelihood from incomplete data via the EM algorithm. J. R. Stat. Soc. B 39, 1–38 (1977).

    Google Scholar 

  44. Spielman, R.S., McGinnis, R.E. & Ewens, W.J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J. Hum. Genet. 52, 506–516 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Conrad, C. et al. Genetic evidence for the involvement of tau in progressive supranuclear palsy. Ann. Neurol. 41, 277–281 (1997).

    CAS  Article  Google Scholar 

Download references


We thank D. Reich, N. Patterson and D. Donnelly for constructive comments regarding this work.

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Augustine Kong or Kari Stefansson.

Ethics declarations

Competing interests

H. Stefansson, A. Helgason, G. Thorleifsson, V. Steinthorsdottir, G. Masson, A. Baker, A. Jonasdottir, A. Ingason, V. G. Gudnadottir, N. Desnica, A. Hicks, A. Gylfason, D. F. Gudbjartsson, G. M. Jonsdottir, J. Sainz, K. Agnarsson, B. Birgisdottir, S. Ghosh, A. Olafsdottir, J.-B. Cazier, K. Kristjansson, M. L. Frigge, T. E. Thorgeirsson, J. R. Gulcher, A. Kong & K. Stefansson own stock or stock options in deCODE Genetics.

Supplementary information

Supplementary Fig. 1

Genotype analysis on homozygous samples sharing (identical-by-descent) over the 17q21.31 locus. (PDF 597 kb)

Supplementary Fig. 2

The relative copy number for H1D1 and H1D3 variants compared to H2 variants estimated by gene dose analysis at three loci. (PDF 97 kb)

Supplementary Fig. 3

Five chromosomal variants with considerable variation in size at the inverted locus on 17q21.31. (PDF 87 kb)

Supplementary Fig. 4

Positive correlation is found between copy numbers of the 5′ end of the NSF gene per sample. (PDF 62 kb)

Supplementary Fig. 5

A sliding window analysis of sequence divergence in 5 kb sequence segments inside the inverted region of a 77 kb fragment that spans much of intron 1 and 2 from the MAPT gene from 44.444005-44.520949 Mb in the H1 orientation in Build 34. (PDF 203 kb)

Supplementary Fig. 6

LD between SNP markers spanning the inversion at 17q21.31. (PDF 241 kb)

Supplementary Fig. 7

The estimate frequency of H2 for females and males who have 0, 1, 2, 3, 4 and 5 or more children. (PDF 261 kb)

Supplementary Table 1

Available sequences and contigs from the RP11 library mapping to 17q21.31. (PDF 160 kb)

Supplementary Table 2

Test for the impact of selection of H2 chromosomes in the Utah sample using the mutational diversity of five microsatellites. (PDF 319 kb)

Supplementary Table 3

The distribution of the number of children for 82,992 Icelandic males and for 79,811 Icelandic females born between 1925 and 1965. (PDF 251 kb)

Supplementary Table 4

Results from multiple regression analyses for a cohort of 16959 females and 12178 males born between 1925 and 1965. (PDF 230 kb)

Supplementary Table 5

Primer sequences for markers shown in Figures 1 and 3. (PDF 305 kb)

Supplementary Table 6

Difference in mutation rate for microsatellites on H1 and H2 backgrounds. (PDF 189 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Stefansson, H., Helgason, A., Thorleifsson, G. et al. A common inversion under selection in Europeans. Nat Genet 37, 129–137 (2005).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing