There is a complex relationship between the evolution of segmental duplications and rearrangements associated with human disease. We performed a detailed analysis of one region on chromosome 16p12.1 associated with neurocognitive disease and identified one of the largest structural inconsistencies in the human reference assembly. Various genomic analyses show that all examined humans are homozygously inverted relative to the reference genome for a 1.1-Mb region on 16p12.1. We determined that this assembly discrepancy stems from two common structural configurations with worldwide frequencies of 17.6% (S1) and 82.4% (S2). This polymorphism arose from the rapid integration of segmental duplications, precipitating two local inversions within the human lineage over the last 10 million years. The two human haplotypes differ by 333 kb of additional duplicated sequence present in S2 but not in S1. Notably, we show that the S2 configuration harbors directly oriented duplications, specifically predisposing this chromosome to disease-associated rearrangement.
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We thank P. Sudmant for useful discussions, G.M. Cooper and T. Brown for critical review of the manuscript and L. Zhou, Y. Fu, R. Shi, J. Wu, S. Shaull and B.A. Roe for sequencing of clone AC120780. This work was supported by a US National Science Foundation Graduate Research Fellowship (to J.M.K.) and a Marie Curie fellowship (FP7 to T.M.-B.), and by the US National Institutes of Health (grants T32 GM07215 and 5T15 LM007359 to B.T., HG000225 to D.C.S. and HG002385 to E.E.E.). E.E.E. is an investigator of the Howard Hughes Medical Institute.
E.E.E. is a member of the Scientific Advisory Board of Pacific Biosciences. J.A.R. and B.C.B. are employees of PerkinElmer (previously Signature Genomic Laboratories). L.G.S. is an employee of PerkinElmer, sits on the Board of the Washington Biotechnology & Biomedical Association and sits on the Board of the American College of Medical Genetics Foundation.
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Antonacci, F., Kidd, J., Marques-Bonet, T. et al. A large and complex structural polymorphism at 16p12.1 underlies microdeletion disease risk. Nat Genet 42, 745–750 (2010). https://doi.org/10.1038/ng.643
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