Abstract
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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References
Itsara, A. et al. Population analysis of large copy number variants and hotspots of human genetic disease. Am. J. Hum. Genet. 84, 148–161 (2009).
McCarroll, S.A. et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat. Genet. 40, 1166–1174 (2008).
Conrad, D.F. et al. Origins and functional impact of copy number variation in the human genome. Nature 464, 704–712 (2010).
Cheung, V.G. et al. Integration of cytogenetic landmarks into the draft sequence of the human genome. Nature 409, 953–958 (2001).
Bailey, J.A. et al. Recent segmental duplications in the human genome. Science 297, 1003–1007 (2002).
Cheung, J. et al. Genome-wide detection of segmental duplications and potential assembly errors in the human genome sequence. Genome Biol. 4, R25 (2003).
Ji, Y., Eichler, E.E., Schwartz, S. & Nicholls, R.D. Structure of chromosomal duplicons and their role in mediating human genomic disorders. Genome Res. 10, 597–610 (2000).
Inoue, K. & Lupski, J.R. Molecular mechanisms for genomic disorders. Annu. Rev. Genomics Hum. Genet. 3, 199–242 (2002).
Stankiewicz, P. & Lupski, J.R. Genome architecture, rearrangements and genomic disorders. Trends Genet. 18, 74–82 (2002).
Scherer, S.W. et al. Human chromosome 7: DNA sequence and biology. Science 300, 767–772 (2003).
Eichler, E.E., Clark, R.A. & She, X. An assessment of the sequence gaps: unfinished business in a finished human genome. Nat. Rev. Genet. 5, 345–354 (2004).
Shaw, C.J. & Lupski, J.R. Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Hum. Mol. Genet. 13 Spec No 1, R57–R64 (2004).
Lupski, J.R. & Stankiewicz, P. Genomic disorders: molecular mechanisms for rearrangements and conveyed phenotypes. PLoS Genet. 1, e49 (2005).
Girirajan, S. et al. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat. Genet. 42, 203–209 (2010).
Lupski, J.R. Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet. 14, 417–422 (1998).
Kidd, J.M. et al. Mapping and sequencing of structural variation from eight human genomes. Nature 453, 56–64 (2008).
Tuzun, E. et al. Fine-scale structural variation of the human genome. Nat. Genet. 37, 727–732 (2005).
Zhou, S. et al. A single molecule scaffold for the maize genome. PLoS Genet. 5, e1000711 (2009).
Teague, B. et al. High-resolution human genome structure by single-molecule analysis. Proc. Natl. Acad. Sci. USA 107, 10848–10853 (2010).
Fan, J.B. et al. Paternal origins of complete hydatidiform moles proven by whole genome single-nucleotide polymorphism haplotyping. Genomics 79, 58–62 (2002).
Marques-Bonet, T. et al. A burst of segmental duplications in the genome of the African great ape ancestor. Nature 457, 877–881 (2009).
Lander, E.S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).
Martin, J. et al. The sequence and analysis of duplication-rich human chromosome 16. Nature 432, 988–994 (2004).
Cáceres, M., Sullivan, R.T. & Thomas, J.W. A recurrent inversion on the eutherian X chromosome. Proc. Natl. Acad. Sci. USA 104, 18571–18576 (2007).
Zody, M.C. et al. Evolutionary toggling of the MAPT 17q21.31 inversion region. Nat. Genet. 40, 1076–1083 (2008).
Kehrer-Sawatzki, H. & Cooper, D.N. Molecular mechanisms of chromosomal rearrangement during primate evolution. Chromosome Res. 16, 41–56 (2008).
Murphy, W.J. et al. A rhesus macaque radiation hybrid map and comparative analysis with the human genome. Genomics 86, 383–395 (2005).
Johnson, M.E. et al. Positive selection of a gene family during the emergence of humans and African apes. Nature 413, 514–519 (2001).
Jiang, Z. et al. Ancestral reconstruction of segmental duplications reveals punctuated cores of human genome evolution. Nat. Genet. 39, 1361–1368 (2007).
Weiss, L.A. et al. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358, 667–675 (2008).
Kumar, R.A. et al. Recurrent 16p11.2 microdeletions in autism. Hum. Mol. Genet. 17, 628–638 (2008).
Ullmann, R. et al. Array CGH identifies reciprocal 16p13.1 duplications and deletions that predispose to autism and/or mental retardation. Hum. Mutat. 28, 674–682 (2007).
Hannes, F.D. et al. Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. J. Med. Genet. 46, 223–232 (2009).
Ballif, B.C. et al. Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2. Nat. Genet. 39, 1071–1073 (2007).
Bochukova, E.G. et al. Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 463, 666–670 (2010).
Koolen, D.A. et al. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat. Genet. 38, 999–1001 (2006).
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).
Stefansson, H. et al. A common inversion under selection in Europeans. Nat. Genet. 37, 129–137 (2005).
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).
Osborne, L.R. et al. A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome. Nat. Genet. 29, 321–325 (2001).
Giglio, S. et al. Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements. Am. J. Hum. Genet. 68, 874–883 (2001).
Antonacci, F. et al. Characterization of six human disease-associated inversion polymorphisms. Hum. Mol. Genet. 18, 2555–2566 (2009).
Jiang, Z., Hubley, R., Smit, A. & Eichler, E.E. DupMasker: a tool for annotating primate segmental duplications. Genome Res. 18, 1362–1368 (2008).
Laan, M. et al. Mechanically stretched chromosomes as targets for high-resolution FISH mapping. Genome Res. 5, 13–20 (1995).
Lichter, P. et al. High-resolution mapping of human chromosome 11 by in situ hybridization with cosmid clones. Science 247, 64–69 (1990).
Bailey, J.A., Yavor, A.M., Massa, H.F., Trask, B.J. & Eichler, E.E. Segmental duplications: organization and impact within the current human genome project assembly. Genome Res. 11, 1005–1017 (2001).
Church, D.M. et al. Lineage-specific biology revealed by a finished genome assembly of the mouse. PLoS Biol. 7, e1000112 (2009).
Zhou, S. et al. Validation of rice genome sequence by optical mapping. BMC Genomics 8, 278 (2007).
Ng, S.B. et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461, 272–276 (2009).
Quail, M.A. et al. A large genome center's improvements to the Illumina sequencing system. Nat. Methods 5, 1005–1010 (2008).
Craig, D.W. et al. Identification of genetic variants using bar-coded multiplexed sequencing. Nat. Methods 5, 887–893 (2008).
Parsons, J.D. Miropeats: graphical DNA sequence comparisons. Comput. Appl. Biosci. 11, 615–619 (1995).
Acknowledgements
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.
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F.A. and E.E.E. designed the study. F.A. performed FISH experiments and constructed shotgun sequencing libraries. J.M.K. performed sequence analysis and haplotype reconstructions. B.T. and D.C.S. performed optical mapping analysis. T.M.-B., T.A.G. and R.K.W. performed nonhuman primate BAC clone sequencing and analysis. M.V. performed FISH experiments on stretched chromosomes. C.A. performed Illumina sequencing data analysis. S.G., C.D.C. and L.V. performed high-density array CGH experiments. M.M. performed PCR experiments. J.A.R., B.C.B. and L.G.S. contributed to 16p12.1 microdeletion data collection. F.A., J.M.K. and E.E.E. contributed to data interpretation. F.A. and E.E.E. wrote the manuscript.
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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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DOI: https://doi.org/10.1038/ng.643
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