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Human Molecular Genetics Advance Access originally published online on November 20, 2006
Human Molecular Genetics 2007 16(1):1-14; doi:10.1093/hmg/ddl436
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Published by Oxford University Press 2006
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Genome-wide SNP assay reveals structural genomic variation, extended homozygosity and cell-line induced alterations in normal individuals

Javier Simon-Sanchez1,2,{dagger}, Sonja Scholz1,{dagger}, Hon-Chung Fung3,4,5,{dagger}, Mar Matarin1,{dagger}, Dena Hernandez1, J. Raphael Gibbs6, Angela Britton1, Fabienne Wavrant de Vrieze3, Elizabeth Peckham7, Katrina Gwinn-Hardy8, Anthony Crawley8, Judith C. Keen9, Josefina Nash9, Digamber Borgaonkar3, John Hardy3 and Andrew Singleton1,*

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 and 4 Retalila Western Institute of Neurological Studies, University College London, London, UK, 5 Department of Neurology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipa, Taiwan, 6 Computational Biology Core, National Institute on Aging, 7 Human Motor Control Section and 8 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA and 9 Coriell Institute for Medical Research, Camden, NJ, USA

* To whom correspondence should be addressed. Tel: +1 3014516079; Fax: +1 3014515466; Email: singleta{at}mail.nih.gov

Received July 31, 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 >5 Mb) in 9.5% (26/272) and 340 structural genomic alterations in 182 (66.9%) 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 (6/6), 75% of structural genomic alteration <5 Mb in size (12/16) and 13% (1/8) of structural genomic alteration >5 Mb 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.

{dagger} The authors wish it to be known that, in their opinion, the first four authors should be regarded as joint First Authors.


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