Mosaic Uniparental Disomies and Aneuploidies as Large Structural Variants of the Human Genome |
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Authors: | Benjamín Rodríguez-Santiago Núria Malats Nathaniel Rothman Lluís Armengol Manolis Kogevinas Olaya Villa Amy Hutchinson Gaëlle Marenne Daniel Rico Alfredo Carrato Alfonso Valencia Francisco X Real Stephen J Chanock Luis A Pérez-Jurado |
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Institution: | 1 Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, E-08003 Barcelona, Spain 2 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), E-08003 Barcelona, Spain 3 Centro Nacional de Investigaciones Oncológicas, E-28029 Madrid, Spain 4 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20852-4907, USA 5 Quantitative Genomic Medicine Laboratory, qGenomics, E-08003 Barcelona, Spain 6 Municipal Institute of Medical Research (IMIM-Hospital del Mar), E-08003 Barcelona, Spain 7 Centre for Research in Environmental Epidemiology (CREAL), E-08003 Barcelona, Spain 8 Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), E-08003 Barcelona, Spain 9 National School of Public Health, G-11521 Athens, Greece 10 Core Genotyping Facility, SAIC-Frederick, Frederick, MD 21702, USA 11 Departamento de Epidemiología y Medicina Preventiva, Universidad de Oviedo, E-33003 Oviedo, Spain 12 Grupo de Oncología Molecular, Hospital General Universitario de Elche, E-03203 Elche, Spain 13 Programa de Medicina Molecular i Genètica, Hospital Universitari Vall d'Hebron, E-08035 Barcelona, Spain 14 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA |
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Abstract: | Mosaicism is defined as the coexistence of cells with different genetic composition within an individual, caused by postzygotic somatic mutation. Although somatic mosaicism for chromosomal abnormalities is a well-established cause of developmental and somatic disorders and has also been detected in different tissues, its frequency and extent in the adult normal population are still unknown. We provide here a genome-wide survey of mosaic genomic variation obtained by analyzing Illumina 1M SNP array data from blood or buccal DNA samples of 1991 adult individuals from the Spanish Bladder Cancer/EPICURO genome-wide association study. We found mosaic abnormalities in autosomes in 1.7% of samples, including 23 segmental uniparental disomies, 8 complete trisomies, and 11 large (1.5–37 Mb) copy-number variants. Alterations were observed across the different autosomes with recurrent events in chromosomes 9 and 20. No case-control differences were found in the frequency of events or the percentage of cells affected, thus indicating that most rearrangements found are not central to the development of bladder cancer. However, five out of six events tested were detected in both blood and bladder tissue from the same individual, indicating an early developmental origin. The high cellular frequency of the anomalies detected and their presence in normal adult individuals suggest that this type of mosaicism is a widespread phenomenon in the human genome. Somatic mosaicism should be considered in the expanding repertoire of inter- and intraindividual genetic variation, some of which may cause somatic human diseases but also contribute to modifying inherited disorders and/or late-onset multifactorial traits. |
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