Abstract
Genomic disorders are characterized by the presence of flanking segmental duplications that predispose these regions to recurrent rearrangement. Based on the duplication architecture of the genome, we investigated 130 regions that we hypothesized as candidates for previously undescribed genomic disorders1. We tested 290 individuals with mental retardation by BAC array comparative genomic hybridization and identified 16 pathogenic rearrangements, including de novo microdeletions of 17q21.31 found in four individuals. Using oligonucleotide arrays, we refined the breakpoints of this microdeletion, defining a 478-kb critical region containing six genes that were deleted in all four individuals. We mapped the breakpoints of this deletion and of four other pathogenic rearrangements in 1q21.1, 15q13, 15q24 and 17q12 to flanking segmental duplications, suggesting that these are also sites of recurrent rearrangement. In common with the 17q21.31 deletion, these breakpoint regions are sites of copy number polymorphism in controls, indicating that these may be inherently unstable genomic regions.
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References
Bailey, J.A. et al. Recent segmental duplications in the human genome. Science 297, 1003–1007 (2002).
Cheung, V.G. et al. Integration of cytogenetic landmarks into the draft sequence of the human genome. Nature 409, 953–958 (2001).
Stankiewicz, P. & Lupski, J.R. Genome architecture, rearrangements and genomic disorders. Trends Genet. 18, 74–82 (2002).
Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).
Iafrate, J.A. et al. Detection of large-scale variation in the human genome. Nat. Genet. 36, 949–951 (2004).
Fredman, D. et al. Complex SNP-related sequence variation in segmental genome duplications. Nat. Genet. 36, 861–866 (2004).
Sharp, A.J. et al. Segmental duplications and copy-number variation in the human genome. Am. J. Hum. Genet. 77, 78–88 (2005).
Tuzun, E. et al. Fine-scale structural variation of the human genome. Nat. Genet. 37, 727–732 (2005).
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).
Locke, D.P. et al. Linkage disequilibrium and heritability of CNPs within duplicated regions of the human genome. Am. J. Hum. Genet. 79, 275–290 (2006).
Knight, S.J. et al. Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet 354, 1676–1681 (1999).
Edelmann, L. et al. A common molecular basis for rearrangement disorders on chromosome 22q11. Hum. Mol. Genet. 8, 1157–1167 (1999).
Potocki, L. et al. Molecular mechanism for duplication 17p11.2 – the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat. Genet. 24, 84–87 (2000).
Heilstedt, H.A. et al. Physical map of 1p36, placement of breakpoints in monosomy 1p36, and clinical characterization of the syndrome. Am. J. Hum. Genet. 72, 1200–1212 (2003).
Stefansson, H. et al. A common inversion under selection in Europeans. Nat. Genet. 37, 129–137 (2005).
de Vries, B.B. et al. Diagnostic genome profiling in mental retardation. Am. J. Hum. Genet. 77, 606–616 (2005).
Amos-Landgraf, J.M. et al. Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints. Am. J. Hum. Genet. 65, 370–386 (1999).
Gimelli, G. et al. Genomic inversions of human chromosome 15q11-q13 in mothers of Angelman syndrome patients with class II (BP2/3) deletions. Hum. Mol. Genet. 12, 849–858 (2003).
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).
Visser, R. et al. Identification of a 3.0-kb major recombination hotspot in patients with Sotos syndrome who carry a common 1.9-Mb microdeletion. Am. J. Hum. Genet. 76, 52–67 (2005).
Kurotaki, N., Stankiewicz, P., Wakui, K., Niikawa, N. & Lupski, J.R. Sotos syndrome common deletion is mediated by directly oriented subunits within inverted Sos-REP low-copy repeats. Hum. Mol. Genet. 14, 535–542 (2005).
Zhou, Y. & Mishra, B. Quantifying the mechanisms for segmental duplications in mammalian genomes by statistical analysis and modeling. Proc. Natl. Acad. Sci. USA 102, 4051–4056 (2005).
Kato, T. et al. Genetic variation affects de novo translocation frequency. Science 311, 971 (2006).
Evans, W. et al. The tau H2 haplotype is almost exclusively Caucasian in origin. Neurosci. Lett. 369, 183–185 (2004).
International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).
Selzer, R.R. et al. Analysis of chromosome breakpoints in neuroblastoma at sub-kilobase resolution using fine-tiling oligonucleotide array CGH. Genes Chromosom. Cancer 44, 305–319 (2005).
Liehr, T. et al. Mosaicism for the Charcot-Marie-Tooth disease type 1A duplication suggests somatic reversion. Hum. Genet. 98, 22–28 (1996).
Juyal, R.C. et al. Mosaicism for del(17)(p11.2p11.2) underlying the Smith-Magenis syndrome. Am. J. Med. Genet. 66, 193–196 (1996).
Acknowledgements
The authors would like to thank all participating families and clinicians, particularly J. Flint, P. Bolton, A. Clarke, C. Fairhurst, T. Wolff, S. Mansour, S. Holder, R. Gibbons, L. Brueton, P. Day, F. Stewart, S. Keane, N. Meston, A. Seller, P. Clouston and K. Smith. This work was supported by grants from the US National Institutes of Health (NIH) (HD043569; E.E.E.), Merck Research Laboratories (A.J.S.), The Health Foundation (S.J.L.K.) and the Oxford Genetics Knowledge Park (S.J.L.K., R.R., C.G.). E.E.E. is an Investigator of the Howard Hughes Medical Institute.
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This study was coordinated by A.J.S., P.S.E., S.S., S.J.L. and E.E.E.; the manuscript was written by A.J.S. and E.E.E.; experimental work was performed by A.J.S., S.H., R.R.S., R.R., C.A.F., R.S. and C.G.; clinical work was performed by J.A.H., H.S., S.M.P., E.B. and R.C.H.; computational analysis was performed by Z.C.; and array production was performed by T.A.R., D.G.A. and D.P.
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P.S.E., R.R.S. and T.A.R. are employees of NimbleGen Systems, Inc. and have stock options in the company.
Supplementary information
Supplementary Fig. 1
FISH validation of 13 rearrangements detected using the SD BAC array. (PDF 1361 kb)
Supplementary Fig. 2
Parental origin and inversion analysis of the 17q21.31 deletion in the family of IMR103. (PDF 1588 kb)
Supplementary Table 1
A non-redundant set of 130 potential rearrangement hotspots in the human genome. (PDF 46 kb)
Supplementary Table 2
Copy number variations detected in 269 HapMap samples and in 290 patients with mental retardation using the SD BAC array. (PDF 3016 kb)
Supplementary Table 3
Nine additional rearrangements, including seven of uncertain significance, detected using the SD BAC array in 290 patients with mental retardation. (PDF 16 kb)
Supplementary Table 4
Comparison of phenotypes between four of the five cases of del 17q21.31 ascertained using the SD BAC array and three previously reported overlapping deletions, plus phenotype details of six further pathogenic rearrangements ascertained using the SD BAC array. (PDF 16 kb)
Supplementary Table 5
Segmental duplication clusters at five rearragement breakpoints as defined by high-density oligonucleotide array analysis. (PDF 21 kb)
Supplementary Table 6
PCR primers used in this study. (PDF 8 kb)
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Sharp, A., Hansen, S., Selzer, R. et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet 38, 1038–1042 (2006). https://doi.org/10.1038/ng1862
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DOI: https://doi.org/10.1038/ng1862
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