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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NCBI Reference Sequence
Change history
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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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.
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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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DOI: https://doi.org/10.1038/ng.193
