Skip to main content

Thank you for visiting nature.com. 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.

  • Article
  • Published:

Structural diversity and African origin of the 17q21.31 inversion polymorphism

Nature Genetics volume 44, pages 872–880 (2012)Cite this article

Subjects

This article has been updated

Abstract

The 17q21.31 inversion polymorphism exists either as direct (H1) or inverted (H2) haplotypes with differential predispositions to disease and selection. We investigated its genetic diversity in 2,700 individuals, with an emphasis on African populations. We characterize eight structural haplotypes due to complex rearrangements that vary in size from 1.08–1.49 Mb and provide evidence for a 30-kb H1-H2 double recombination event. We show that recurrent partial duplications of the KANSL1 gene have occurred on both the H1 and H2 haplotypes and have risen to high frequency in European populations. We identify a likely ancestral H2 haplotype (H2′) lacking these duplications that is enriched among African hunter-gatherer groups yet essentially absent from West African populations. Whereas H1 and H2 segmental duplications arose independently and before human migration out of Africa, they have reached high frequencies recently among Europeans, either because of extraordinary genetic drift or selective sweeps.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Duplication architecture of 17q21.31.
Figure 2: Alternative structural haplotypes of 17q21.31.
Figure 3: Haplotype frequency of 17q21.31 inversion in Africa.
Figure 4: Phylogenetic relationship between H1 and H2 haplotypes.
Figure 5: Historical exchange between H1 and H2 haplotypes.
Figure 6: Evolutionary history of 17q21.31 haplotypes.

Similar content being viewed by others

Accession codes

Primary accessions

Sequence Read Archive

Change history

  • 11 July 2012

    In the version of this article initially published online, the final sentence in the second paragraph of the Results section incorrectly referred to the H2-specific duplication as CNP205. The correct designation for the H2-specific duplication is CNP155. Also, in the legend to Figure 5, the phrases describing panels c and d were inadvertently switched. These errors have been corrected for the print, PDF and HTML versions of this article.

References

  1. Dobzhansky, T. The genetics of natural populations. Genetics 35, 288–302 (1950).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Dobzhansky, T. & Sturtevant, A.H. Inversions in the chromosomes of Drosophila pseudoobscura. Genetics 23, 28–64 (1938).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Lowry, D.B. & Willis, J.H. A widespread chromosomal inversion polymorphism contributes to a major life-history transition, local adaptation, and reproductive isolation. PLoS Biol. 8, e1000500 (2010).

    Article  Google Scholar 

  4. Tuzun, E. et al. Fine-scale structural variation of the human genome. Nat. Genet. 37, 727–732 (2005).

    Article  CAS  Google Scholar 

  5. Kidd, J.M. et al. Mapping and sequencing of structural variation from eight human genomes. Nature 453, 56–64 (2008).

    Article  CAS  Google Scholar 

  6. Bailey, J.A. et al. Recent segmental duplications in the human genome. Science 297, 1003–1007 (2002).

    Article  CAS  Google Scholar 

  7. Sharp, A.J. Emerging themes and new challenges in defining the role of structural variation in human disease. Hum. Mutat. 30, 135–144 (2009).

    Article  CAS  Google Scholar 

  8. Lupski, J.R. Genome structural variation and sporadic disease traits. Nat. Genet. 38, 974–976 (2006).

    Article  CAS  Google Scholar 

  9. Antonacci, F. et al. Characterization of six human disease-associated inversion polymorphisms. Hum. Mol. Genet. 18, 2555–2566 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. Sharp, A.J. et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat. Genet. 38, 1038–1042 (2006).

    Article  CAS  Google Scholar 

  12. Koolen, D.A. et al. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat. Genet. 38, 999–1001 (2006).

    Article  CAS  Google Scholar 

  13. Zody, M.C. et al. Evolutionary toggling of the MAPT 17q21.31 inversion region. Nat. Genet. 40, 1076–1083 (2008).

    Article  CAS  Google Scholar 

  14. Koolen, D.A. et al. Clinical and molecular delineation of the 17q21.31 microdeletion syndrome. J. Med. Genet. 45, 710–720 (2008).

    Article  CAS  Google Scholar 

  15. Sudmant, P.H. et al. Diversity of human copy number variation and multicopy genes. Science 330, 641–646 (2010).

    Article  CAS  Google Scholar 

  16. Donnelly, M.P. et al. The distribution and most recent common ancestor of the 17q21 inversion in humans. Am. J. Hum. Genet. 86, 161–171 (2010).

    Article  CAS  Google Scholar 

  17. Schuster, S.C. et al. Complete Khoisan and Bantu genomes from southern Africa. Nature 463, 943–947 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Rao, P.N., Li, W., Vissers, L.E., Veltman, J.A. & Ophoff, R.A. Recurrent inversion events at 17q21.31 microdeletion locus are linked to the MAPT H2 haplotype. Cytogenet. Genome Res. 129, 275–279 (2010).

    Article  CAS  Google Scholar 

  20. Boettger, L.M., Handsaker, R.E., Zody, M.C. & McCarroll, S.A. Structural haplotypes and recent evolution of the human 17q21.31 region. Nat. Genet. published online, doi:10.1038/ng.2334 (1 July 2012).

    Article  CAS  Google Scholar 

  21. Henn, B.M. et al. Hunter-gatherer genomic diversity suggests a southern African origin for modern humans. Proc. Natl. Acad. Sci. USA 108, 5154–5162 (2011).

    Article  CAS  Google Scholar 

  22. Kidd, J.M. et al. Haplotype sorting using human fosmid clone end-sequence pairs. Genome Res. 18, 2016–2023 (2008).

    Article  CAS  Google Scholar 

  23. Cargill, M. et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat. Genet. 22, 231–238 (1999).

    Article  CAS  Google Scholar 

  24. Heim, C. et al. Effect of childhood trauma on adult depression and neuroendocrine function: sex-specific moderation by CRH receptor 1 gene. Front. Behav. Neurosci. 3, 41 (2009).

    Article  Google Scholar 

  25. Liu, Z. et al. Association of corticotropin-releasing hormone receptor 1 gene SNP and haplotype with major depression. Neurosci. Lett. 404, 358–362 (2006).

    Article  CAS  Google Scholar 

  26. Liu, Z. et al. Association study of corticotropin-releasing hormone receptor 1 gene polymorphisms and antidepressant response in major depressive disorders. Neurosci. Lett. 414, 155–158 (2007).

    Article  CAS  Google Scholar 

  27. Bradley, R.G. et al. Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene. Arch. Gen. Psychiatry 65, 190–200 (2008).

    Article  CAS  Google Scholar 

  28. Polanczyk, G. et al. Protective effect of CRHR1 gene variants on the development of adult depression following childhood maltreatment: replication and extension. Arch. Gen. Psychiatry 66, 978–985 (2009).

    Article  CAS  Google Scholar 

  29. Shaw-Smith, C. et al. Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat. Genet. 38, 1032–1037 (2006).

    Article  CAS  Google Scholar 

  30. Cooper, G.M. et al. A copy number variation morbidity map of developmental delay. Nat. Genet. 43, 838–846 (2011).

    Article  CAS  Google Scholar 

  31. Mefford, H.C. et al. A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease. Genome Res. 19, 1579–1585 (2009).

    Article  CAS  Google Scholar 

  32. Tishkoff, S.A. et al. The genetic structure and history of Africans and African Americans. Science 324, 1035–1044 (2009).

    Article  CAS  Google Scholar 

  33. Fledel-Alon, A. et al. Variation in human recombination rates and its genetic determinants. PLoS ONE 6, e20321 (2011).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  35. Coop, G., Wen, X., Ober, C., Pritchard, J.K. & Przeworski, M. High-resolution mapping of crossovers reveals extensive variation in fine-scale recombination patterns among humans. Science 319, 1395–1398 (2008).

    Article  CAS  Google Scholar 

  36. Ramensky, V., Bork, P. & Sunyaev, S. Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 30, 3894–3900 (2002).

    Article  CAS  Google Scholar 

  37. Simón-Sánchez, J. et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat. Genet. 41, 1308–1312 (2009).

    Article  Google Scholar 

  38. Koolen, D.A. et al. Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nat. Genet. 44, 639–641 (2012).

    Article  CAS  Google Scholar 

  39. Zollino, M. et al. Mutations in KANSL1 cause the 17q21.31 microdeletion syndrome phenotype. Nat. Genet. 44, 636–638 (2012).

    Article  CAS  Google Scholar 

  40. Tobin, J.E. et al. Haplotypes and gene expression implicate the MAPT region for Parkinson disease: the GenePD Study. Neurology 71, 28–34 (2008).

    Article  CAS  Google Scholar 

  41. Skipper, L. et al. Linkage disequilibrium and association of MAPT H1 in Parkinson disease. Am. J. Hum. Genet. 75, 669–677 (2004).

    Article  CAS  Google Scholar 

  42. Myers, A.J. et al. The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts. Neurobiol. Dis. 25, 561–570 (2007).

    Article  CAS  Google Scholar 

  43. 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).

    Article  CAS  Google Scholar 

  44. Höglinger, G.U. et al. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat. Genet. 43, 699–705 (2011).

    Article  Google Scholar 

  45. Setó-Salvia, N. et al. Dementia risk in Parkinson disease: disentangling the role of MAPT haplotypes. Arch. Neurol. 68, 359–364 (2011).

    Article  Google Scholar 

  46. Dubourg, C. et al. Clinical and molecular characterization of 17q21.31 microdeletion syndrome in 14 French patients with mental retardation. Eur. J. Med. Genet. 54, 144–151 (2011).

    Article  Google Scholar 

  47. Dawkins, R. et al. Genomics of the major histocompatibility complex: haplotypes, duplication, retroviruses and disease. Immunol. Rev. 167, 275–304 (1999).

    Article  CAS  Google Scholar 

  48. Reich, D. et al. Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature 468, 1053–1060 (2010).

    Article  CAS  Google Scholar 

  49. Green, R.E. et al. A draft sequence of the Neandertal genome. Science 328, 710–722 (2010).

    Article  CAS  Google Scholar 

  50. Jiang, Z. et al. Ancestral reconstruction of segmental duplications reveals punctuated cores of human genome evolution. Nat. Genet. 39, 1361–1368 (2007).

    Article  CAS  Google Scholar 

  51. Tamura, K., Dudley, J., Nei, M. & Kumar, S. MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol. Biol. Evol. 24, 1596–1599 (2007).

    Article  CAS  Google Scholar 

  52. Antonacci, F. et al. A large and complex structural polymorphism at 16p12.1 underlies microdeletion disease risk. Nat. Genet. 42, 745–750 (2010).

    Article  CAS  Google Scholar 

  53. Adey, A. et al. Rapid, low-input, low-bias construction of shotgun fragment libraries by high-density in vitro transposition. Genome Biol. 11, R119 (2010).

    Article  CAS  Google Scholar 

  54. Igartua, C. et al. Targeted enrichment of specific regions in the human genome by array hybridization. Curr. Protoc. Hum. Genet. Chapter 18, Unit 18 3 (2010).

    PubMed  Google Scholar 

  55. Campbell, C.D. et al. Population-genetic properties of differentiated human copy-number polymorphisms. Am. J. Hum. Genet. 88, 317–332 (2011).

    Article  CAS  Google Scholar 

  56. Browning, B.L. & Browning, S.R. A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am. J. Hum. Genet. 84, 210–223 (2009).

    Article  CAS  Google Scholar 

  57. Browning, S.R. & Browning, B.L. Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am. J. Hum. Genet. 81, 1084–1097 (2007).

    Article  CAS  Google Scholar 

  58. Felsenstein, J. PHYLIP—Phylogeny Inference Package (Version 3.2). Cladistics 5, 164–166 (1989).

    Google Scholar 

  59. Larkin, M.A. et al. Clustal W and Clustal X version 2.0. Bioinformatics 23, 2947–2948 (2007).

    Article  CAS  Google Scholar 

  60. Librado, P. & Rozas, J. DnaSP v5: a software for comprehensive analysis of DNA polymorphism data. Bioinformatics 25, 1451–1452 (2009).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Akey, M. Dennis and B. Dumont for helpful discussions and C. Alkan for computational assistance. We thank Z. Jiang for his initial work on the H1-H2 alignments. We are grateful to T. Brown for assistance with manuscript preparation, to C. Lee for technical assistance and to the anonymous reviewers of this paper who provided insightful comments. We thank the 1000 Genomes Project Consortium for access to unpublished sequence data for the 17q21.31 locus. K.M.S. was supported by a Ruth L. Kirschstein National Research Service Award (NRSA) training grant to the University of Washington (T32HG00035) and an individual NRSA Fellowship (F32GM097807). C.D.C. was supported by an individual NRSA Fellowship (F32HG006070). P.H.S. was supported by a Natural Sciences and Engineering Research Council of Canada Fellowship. J.M.K. was supported by a Ruth L. Kirschstein NRSA training grant to Stanford University (T32HG000044). This work was supported by the US National Institutes of Health (grants HG002385 and HG004120 to E.E.E.). E.E.E. is an Investigator of the Howard Hughes Medical Institute.

Author information

Author notes

  1. Jeffrey M Kidd & Michael P Donnelly

    Present address: Present addresses: Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA (J.M.K.), Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA (J.M.K.) and Department of Human Genetics, University of Chicago, Chicago, Illionois, USA (M.P.D.).,

  2. Karyn Meltz Steinberg and Francesca Antonacci: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genome Sciences, University of Washington, Seattle, Washington, USA

    Karyn Meltz Steinberg, Francesca Antonacci, Peter H Sudmant, Jeffrey M Kidd, Catarina D Campbell, Laura Vives, Maika Malig & Evan E Eichler

  2. Department of Genetics and Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Laura Scheinfeldt, William Beggs & Sarah A Tishkoff

  3. Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan

    Muntaser Ibrahim

  4. Department of Biochemistry, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania

    Godfrey Lema & Thomas B Nyambo

  5. Kenya Medical Research Institute, Center for Biotechnology Research and Development, Nairobi, Kenya

    Sabah A Omar

  6. Unité Mixte de Recherche (UMR) 208, Institut de Recherche pour le Dévelopment (IRD)–Muséum National d'Histoire Naturelle (MNHN), Musée de l'Homme, Paris, France

    Jean-Marie Bodo

  7. Ministère de la Recherche Scientifique et de l'Innovation, Yaoundé, Cameroon

    Alain Froment

  8. Department of Genetics, Yale University, New Haven, Connecticut, USA

    Michael P Donnelly & Kenneth K Kidd

  9. Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA

    Evan E Eichler

Authors
  1. Karyn Meltz Steinberg
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Francesca Antonacci
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Peter H Sudmant
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Jeffrey M Kidd
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Catarina D Campbell
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Laura Vives
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Maika Malig
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Laura Scheinfeldt
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. William Beggs
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Muntaser Ibrahim
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Godfrey Lema
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Thomas B Nyambo
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Sabah A Omar
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Jean-Marie Bodo
    View author publications

    You can also search for this author inPubMed Google Scholar

  15. Alain Froment
    View author publications

    You can also search for this author inPubMed Google Scholar

  16. Michael P Donnelly
    View author publications

    You can also search for this author inPubMed Google Scholar

  17. Kenneth K Kidd
    View author publications

    You can also search for this author inPubMed Google Scholar

  18. Sarah A Tishkoff
    View author publications

    You can also search for this author inPubMed Google Scholar

  19. Evan E Eichler
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

K.M.S., F.A. and E.E.E. designed the study. K.M.S. performed aCGH, genotyping and sequence analysis. F.A. performed FISH experiments and fosmid shotgun sequencing library construction. P.H.S. performed read depth–based copy-number analysis. J.M.K. performed sequence analysis on the double recombination region. C.D.C. performed aCGH analysis. L.V. and M.M. performed whole-genome shotgun sequencing library construction and PCR genotyping. L.S. and W.B. performed PCR genotyping and SNP array genotyping. M.I., G.L., T.B.N., S.A.O., J.-M.B. and A.F. contributed to African sample collection. M.P.D. and K.K.K. contributed to H2 Diversity Panel sample collection and genotyping. S.A.T. contributed to African sample collection and SNP array data. K.M.S., F.A., J.M.K., S.A.T. and E.E.E. contributed to data interpretation. K.M.S., F.A. and E.E.E. wrote the manuscript.

Corresponding author

Correspondence to Evan E Eichler.

Ethics declarations

Competing interests

E.E.E. is on the scientific advisory boards for Pacific Biosciences, Inc., SynapDx Corp and DNAnexus, Inc.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–4 and Supplementary Tables 1 and 3–11 (PDF 1517 kb)

Supplementary Table 2

Individual-level 17q21.31 haplotype results (XLS 627 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Steinberg, K., Antonacci, F., Sudmant, P. et al. Structural diversity and African origin of the 17q21.31 inversion polymorphism. Nat Genet 44, 872–880 (2012). https://doi.org/10.1038/ng.2335

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2335

This article is cited by

Search

Advanced search

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