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Evolutionary toggling of the MAPT 17q21.31 inversion region

Nature Genetics volume 40, pages 1076–1083 (2008)Cite this article

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Abstract

Using comparative sequencing approaches, we investigated the evolutionary history of the European-enriched 17q21.31 MAPT inversion polymorphism. We present a detailed, BAC-based sequence assembly of the inverted human H2 haplotype and compare it to the sequence structure and genetic variation of the corresponding 1.5-Mb region for the noninverted H1 human haplotype and that of chimpanzee and orangutan. We found that inversion of the MAPT region is similarly polymorphic in other great ape species, and we present evidence that the inversions occurred independently in chimpanzees and humans. In humans, the inversion breakpoints correspond to core duplications with the LRRC37 gene family. Our analysis favors the H2 configuration and sequence haplotype as the likely great ape and human ancestral state, with inversion recurrences during primate evolution. We show that the H2 architecture has evolved more extensive sequence homology, perhaps explaining its tendency to undergo microdeletion associated with mental retardation in European populations.

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Figure 1: Comparative segmental duplication analysis of the 17q21.31 region.
Figure 2: Inversion polymorphism among primates.
Figure 3: Sequence comparison of the human H1, H2, chimpanzee and orangutan 17q21.31 region.
Figure 4: Phylogenetic and SNP haplotype analysis.
Figure 5: Evolutionary model of inversion toggling, segmental duplication formation and relationship with disease susceptibility.

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NCBI Reference Sequence

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  • 17 August 2008

    NOTE: In the version of this article initially published online, the left side of Figure 4c was mislabeled. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank T. Marques, D. Reich, A. Navarro, N. Patterson, S. McCarroll, T. Brown and K. Augustyn for critical comments and valuable discussions in the preparation of this manuscript; C. Alkan for providing computational assistance; and members of the Broad Institute Sequence Platform (BISP) and Washington University Genome Sequencing Center (WUGSC) for generating clone-based sequencing data for this project. M.C.Z., A.A., W.C.W., L.W.H., T.A.G., R.K.W., A.D.R., J.W., J.G. and the BISP and WUGSC were supported by grants from the National Human Genome Research Institute. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services, project number Z01 AG000957-05. This work was supported by NIH grants GM058815 and HG002385 to E.E.E. and a Rosetta Inpharmatics Fellowship (Merck Laboratories) to Z.J. E.E.E. is an investigator of the Howard Hughes Medical Institute.

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Author notes

  1. Michael C Zody and Zhaoshi Jiang: These authors contributed equally to this work.

Authors and Affiliations

  1. Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Michael C Zody & Amr Abouelleil

  2. Department of Medical Biochemistry and Microbiology, Uppsala University, Box 597, Uppsala, SE-751 24, Sweden

    Michael C Zody

  3. Department of Genome Sciences, Howard Hughes Medical Institute, University of Washington, Seattle, 98195, Washington, USA

    Zhaoshi Jiang, Francesca Antonacci, Jeffrey M Kidd, Ze Cheng, Lin Chen & Evan E Eichler

  4. Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, London, WC1N 3BG, UK

    Hon-Chung Fung & John Hardy

  5. Department of Neurology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, 199 Tung Hwa North Road, Taipei, 10591, Taiwan

    Hon-Chung Fung

  6. Genome Sequencing Center, Washington University School of Medicine, Campus Box 8501, 4444 Forest Park Avenue, St. Louis, 63108, Missouri, USA

    LaDeana W Hillier, Tina A Graves, John Wallis, Jarret Glasscock, Richard K Wilson, Amy Denise Reily & Wesley C Warren

  7. Department of Genetics and Microbiology, University of Bari, Via Amendola 165/A, Bari, 70126, Italy

    Maria Francesca Cardone & Mario Ventura

  8. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Jaime Duckworth

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Contributions

Z.J., M.C.Z. and E.E.E. analyzed and annotated sequence organization; J.M.K. did the haplotype analyses; F.A., M.F.C. and M.V. developed the FISH inversion assay and typed all primate metaphase chromosomes; L.C. and Z.C. did the segmental duplication analyses; M.C.Z., W.C.W., A.A., T.A.G., L.W.H., A.D.R., H.C.F., J.W., J.G. and J.D. generated, sequenced and analyzed the BAC clone assembly; R.K.W. oversaw sequence production; E.E.E., M.C.Z., Z.J., W.C.W., J.H. and J.M.K. drafted the manuscript; W.C.W., J.H. and E.E.E. designed the study; and E.E.E. finalized the manuscript.

Corresponding authors

Correspondence to Wesley C Warren or Evan E Eichler.

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Zody, M., Jiang, Z., Fung, HC. et al. Evolutionary toggling of the MAPT 17q21.31 inversion region. Nat Genet 40, 1076–1083 (2008). https://doi.org/10.1038/ng.193

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