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Complex patterns of copy number variation at sites of segmental duplications: an important category of structural variation in the human genome

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Abstract

The structural diversity of the human genome is much higher than previously assumed although its full extent remains unknown. To investigate the association between segmental duplications that display constitutive copy number differences (CNDs) between humans and the great apes and those which exhibit polymorphic copy number variations (CNVs) between humans, we analysed a BAC array enriched with segmental duplications displaying such CNDs. This study documents for the first time that in addition to human-specific gains common to all humans, these duplication clusters (DCs) also exhibit polymorphic CNVs > 40 kb. Segmental duplication is known to have been a frequent event during human genome evolution. Importantly, among the CNV-associated genes identified here, those involved in transcriptional regulation were found to be significantly overrepresented. Complex patterns of variation were evident at sites of DCs, manifesting as inter-individual differentially sized copy number alterations at the same genomic loci. Thus, CNVs associated with segmental duplications do not simply represent insertion/deletion polymorphisms, but rather constitute a wide variety of rearrangements involving differential amplification and partial gains and losses with high inter-individual variability. Although the number of CNVs was not found to differ between Africans and Caucasians/Asians, the average number of variant patterns per locus was significantly lower in Africans. Thus, complex variation patterns characterizing segmental duplications result from relatively recent genomic rearrangements. The high number of these rearrangements, some of which are potentially recurrent, together with differences in population size and expansion dynamics, may account for the greater diversity of CNV in Caucasians/Asians as compared with Africans.

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Acknowledgements

We thank Antje Kollak, Helene Spöri and Stefanie Raith for technical assistance. This research was funded by the Deutsche Forschungsgemeinschaft (DFG KE 724/2-1). L.A. is supported by Genome Spain and the „Generaliyay de Catalunya”.

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Authors and Affiliations

  1. Department of Human Genetics, University of Ulm, Albert Einstein Allee 11, 89081 , Ulm, Germany

    Violaine Goidts, Horst Hameister & Hildegard Kehrer-Sawatzki

  2. Institute of Medical Genetics, Cardiff University, Heath Part, Cardiff, UK

    David N. Cooper

  3. Program in Genes and Disease, Center for Genomic Regulation, Barcelona Biomedical Research Park, Barcelona, Spain

    Lluis Armengol & Xavier Estivill

  4. Institute of Human Genetics and Anthropology, University of Freiburg, Freiburg, Germany

    Werner Schempp

  5. Department of Cancer Genetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, USA

    Jeffrey Conroy & Norma Nowak

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  1. Violaine Goidts
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Correspondence to Hildegard Kehrer-Sawatzki.

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Goidts, V., Cooper, D.N., Armengol, L. et al. Complex patterns of copy number variation at sites of segmental duplications: an important category of structural variation in the human genome. Hum Genet 120, 270–284 (2006). https://doi.org/10.1007/s00439-006-0217-y

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