Human Molecular Genetics Advance Access published online on November 20, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl436
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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Genome-wide SNP assay reveals structural genomic variation, extended homozygosity and cell-line induced alterations in normal individuals
1 Molecular Genetics Unit 2 Unidad de Genética Molecular, Departamento de Genómica y Proteómica, Instituto de Biomedicina de Valencia-CSIC, 46010, Valencia, Spain 3 Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA 4 Computational Biology Core 5 Human Motor Control Section, National Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA 6 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA 7 Coriell Institute for Medical Research, Camden, NJ 08103, USA
* singleta{at}mail.nih.gov t 301 451 6079; f 301 451 5466;
Received July 31, 2006; Revised November 11, 2006; Accepted November 11, 2006
The recent hapmap effort has placed focus on the application of genome-wide SNP analysis to assess the contribution of genetic variability, particularly SNPs, to traits such as disease. Here we describe the utility of genome wide SNP analysis in the direct detection of extended homozygosity and structural genomic variation. We use this approach to assess the frequency of genomic alterations resulting from the lymphoblast immortalization and culture processes commonly used in cell repositories. We have assayed 408,804 SNPs in 276 DNA samples extracted from Epstein-Barr virus immortalized cell lines, which were derived from lymphocytes of elderly neurologically normal subjects. These data reveal extended homozygosity (contiguous tracts>5Mb) in 9.5% (26/272) and 340 structural genomic alterations in 182 (66.9%) of DNA samples assessed, 66% of which did not overlap with previously described structural variations. Examination of DNA extracted directly from the blood of 30 of these subjects confirmed all examined instances of extended homozygosity (6 of 6), 75% of structural genomic alteration <5Mb in size (12 of 16), and 13% (1 of 8) of structural genomic alteration>5Mb in size. These data suggest that structural genomic variation is a common phenomenon in the general population. While a proportion of this variability may be caused or its relative abundance altered by the immortalization and clonal process this will have only a minor effect on genotype and allele frequencies in a large cohort. It is likely that this powerful methodology will augment existing techniques in the identification of chromosomal abnormalities.
These authors contribute equally to the work
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