Segmental duplications and copy-number variation in the human genome

Andrew J. Sharp, Devin P. Locke, Sean D. McGrath, Ze Cheng, Jeffrey A. Bailey, Rhea U. Vallente, Lisa M. Pertz, Royden A. Clark, Stuart Schwartz, Rick Segraves, Vanessa V. Oseroff, Donna Albertson, Daniel Pinkel, Evan E. Eichler

Research output: Contribution to journalArticle

Abstract

The human genome contains numerous blocks of highly homologous duplicated sequence. This higher-order architecture provides a substrate for recombination and recurrent chromosomal rearrangement associated with genomic disease. However, an assessment of the role of segmental duplications in normal variation has not yet been made. On the basis of the duplication architecture of the human genome, we defined a set of 130 potential rearrangement hotspots and constructed a targeted bacterial artificial chromosome (BAC) microarray (with 2,194 BACs) to assess copy-number variation in these regions by array comparative genomic hybridization. Using our segmental duplication BAC microarray, we screened a panel of 47 normal individuals, who represented populations from four continents, and we identified 119 regions of copy-number polymorphism (CNP), 73 of which were previously unreported. We observed an equal frequency of duplications and deletions, as well as a 4-fold enrichment of CNPs within hotspot regions, compared with control BACs (P < .000001), which suggests that segmental duplications are a major catalyst of large-scale variation in the human genome. Importantly, segmental duplications themselves were also significantly enriched >4-fold within regions of CNP. Almost without exception, CNPs were not confined to a single population, suggesting that these either are recurrent events, having occurred independently in multiple founders, or were present in early human populations. Our study demonstrates that segmental duplications define hotspots of chromosomal rearrangement, likely acting as mediators of normal variation as well as genomic disease, and it suggests that the consideration of genomic architecture can significantly improve the ascertainment of large-scale rearrangements. Our specialized segmental duplication BAC microarray and associated database of structural polymorphisms will provide an important resource for the future characterization of human genomic disorders.

Original languageEnglish (US)
Pages (from-to)78-88
Number of pages11
JournalAmerican Journal of Human Genetics
Volume77
Issue number1
DOIs
StatePublished - Jul 2005

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Genomic Segmental Duplications
Human Genome
Bacterial Artificial Chromosomes
DNA Copy Number Variations
Population
Comparative Genomic Hybridization
Sequence Homology
Genetic Recombination
Databases

ASJC Scopus subject areas

  • Genetics

Cite this

Sharp, A. J., Locke, D. P., McGrath, S. D., Cheng, Z., Bailey, J. A., Vallente, R. U., ... Eichler, E. E. (2005). Segmental duplications and copy-number variation in the human genome. American Journal of Human Genetics, 77(1), 78-88. https://doi.org/10.1086/431652

Segmental duplications and copy-number variation in the human genome. / Sharp, Andrew J.; Locke, Devin P.; McGrath, Sean D.; Cheng, Ze; Bailey, Jeffrey A.; Vallente, Rhea U.; Pertz, Lisa M.; Clark, Royden A.; Schwartz, Stuart; Segraves, Rick; Oseroff, Vanessa V.; Albertson, Donna; Pinkel, Daniel; Eichler, Evan E.

In: American Journal of Human Genetics, Vol. 77, No. 1, 07.2005, p. 78-88.

Research output: Contribution to journalArticle

Sharp, AJ, Locke, DP, McGrath, SD, Cheng, Z, Bailey, JA, Vallente, RU, Pertz, LM, Clark, RA, Schwartz, S, Segraves, R, Oseroff, VV, Albertson, D, Pinkel, D & Eichler, EE 2005, 'Segmental duplications and copy-number variation in the human genome', American Journal of Human Genetics, vol. 77, no. 1, pp. 78-88. https://doi.org/10.1086/431652
Sharp AJ, Locke DP, McGrath SD, Cheng Z, Bailey JA, Vallente RU et al. Segmental duplications and copy-number variation in the human genome. American Journal of Human Genetics. 2005 Jul;77(1):78-88. https://doi.org/10.1086/431652
Sharp, Andrew J. ; Locke, Devin P. ; McGrath, Sean D. ; Cheng, Ze ; Bailey, Jeffrey A. ; Vallente, Rhea U. ; Pertz, Lisa M. ; Clark, Royden A. ; Schwartz, Stuart ; Segraves, Rick ; Oseroff, Vanessa V. ; Albertson, Donna ; Pinkel, Daniel ; Eichler, Evan E. / Segmental duplications and copy-number variation in the human genome. In: American Journal of Human Genetics. 2005 ; Vol. 77, No. 1. pp. 78-88.
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