title: Genome-wide SNP assay reveals structural genomic variation, extended homozygosity and cell-line induced alterations in normal individuals.
abstract: 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.
authors.affiliation: Molecular Genetics Unit, Departamento de Genómica y Proteómica, Instituto de Biomedicina de Valencia-CSIC, 46010, Valencia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Simon-Sanchez
authors.forename: Sonja
authors.initials: S
authors.lastname: Scholz
authors.forename: Hon-Chung
authors.initials: HC
authors.lastname: Fung
authors.forename: Mar
authors.initials: M
authors.lastname: Matarin
authors.forename: Dena
authors.initials: D
authors.lastname: Hernandez
authors.forename: J Raphael
authors.initials: JR
authors.lastname: Gibbs
authors.forename: Angela
authors.initials: A
authors.lastname: Britton
authors.forename: Fabienne Wavrant
authors.initials: FW
authors.lastname: de Vrieze
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Peckham
authors.forename: Katrina
authors.initials: K
authors.lastname: Gwinn-Hardy
authors.forename: Anthony
authors.initials: A
authors.lastname: Crawley
authors.forename: Judith C
authors.initials: JC
authors.lastname: Keen
authors.forename: Josefina
authors.initials: J
authors.lastname: Nash
authors.forename: Digamber
authors.initials: D
authors.lastname: Borgaonkar
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002461:Cell Line, Transformed; D002869:Chromosome Aberrations; D015331:Cohort Studies; D003199:Computer Systems; D004247:DNA / Q000235:genetics; D005787:Gene Frequency; D014644:Genetic Variation; D015894:Genome, Human; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
chemical_list: D004247:DNA