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Structural haplotypes and recent evolution of the human 17q21.31 region

Abstract

Structurally complex genomic regions are not yet well understood. One such locus, human chromosome 17q21.31, contains a megabase-long inversion polymorphism1, many uncharacterized copy-number variations (CNVs) and markers that associate with female fertility1, female meiotic recombination1,2,3 and neurological disease4,5. Additionally, the inverted H2 form of 17q21.31 seems to be positively selected in Europeans1. We developed a population genetics approach to analyze complex genome structures and identified nine segregating structural forms of 17q21.31. Both the H1 and H2 forms of the 17q21.31 inversion polymorphism contain independently derived, partial duplications of the KANSL1 gene; these duplications, which produce novel KANSL1 transcripts, have both recently risen to high allele frequencies (26% and 19%) in Europeans. An older H2 form lacking such a duplication is present at low frequency in European and central African hunter-gatherer populations. We further show that complex genome structures can be analyzed by imputation from SNPs.

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Figure 1: Inference of complex CNV and SNP haplotypes at the 17q21.31 locus.
Figure 2: Structural forms of the human 17q21.31 locus and their population frequencies.
Figure 3: Structural forms of 17q21.31 segregate on specific SNP haplotype backgrounds.

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Primary accessions

Sequence Read Archive

Referenced accessions

NCBI Reference Sequence

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Acknowledgements

J. Korn provided an early version of software for visualizing haplotype diversity. N. Rohland and T. Mullen contributed expertise on laboratory experiments. We thank N. Patterson, D. Reich, D. Altshuler, E. Lander, B. Browning, J. Korn, J. Gray, C. Patil, G. Genovese, A. Sekar and S. Grossman for helpful conversations and/or comments on the manuscript. This work was supported by a Smith Family Award for Excellence in Biomedical Research to S.A.M., by the National Human Genome Research Institute (U01HG005208) and by startup resources from the Harvard Medical School Department of Genetics.

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Authors

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S.A.M., L.M.B. and R.E.H. conceived the strategy for population genetics dissection of structurally complex loci. L.M.B. performed all laboratory experiments and multiple computational analyses, including the estimation of haplotype frequencies, delineation of CNV regions and alignment of next-generation sequence data. R.E.H. performed computational analyses of the 1000 Genomes Project data, including finding breakpoint-spanning reads for CNVs and integrated analyses of SNP-CNV haplotypes. M.C.Z. performed analyses of sequence data to determine large-scale structures, estimate coalescence and mutation dates and reconstruct the evolutionary history of the locus. R.E.H. and L.M.B. developed the imputation strategy. S.A.M., L.M.B., R.E.H. and M.C.Z. wrote the manuscript.

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Correspondence to Steven A McCarroll.

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The authors declare no competing financial interests.

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Supplementary Note, Supplementary Tables 1–17 and Supplementary Figures 1–8 (PDF 3406 kb)

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Boettger, L., Handsaker, R., Zody, M. et al. Structural haplotypes and recent evolution of the human 17q21.31 region. Nat Genet 44, 881–885 (2012). https://doi.org/10.1038/ng.2334

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