Journal Article

Identification of single nucleotide polymorphisms in human DNA repair genes

Barry N. Ford, Cindy C. Ruttan, Victoria L. Kyle, Moyra E. Brackley and Barry W. Glickman

in Carcinogenesis

Volume 21, issue 11, pages 1977-1981
Published in print November 2000 | ISSN: 0143-3334
Published online November 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.11.1977
Identification of single nucleotide polymorphisms in human DNA repair genes

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Variation in gene coding sequence represents a significant factor in predisposition to disease, including cancer. Variants of some DNA repair genes (e.g. MLH1, MSH2 and MSH6) are known to predispose to cancer. We identified single nucleotide polymorphisms (SNPs) in five DNA repair genes in 142 healthy individuals using a DNA sequencing protocol optimized for the direct detection of single nucleotide polymorphisms. This approach, called the heterozygote sequencing protocol (HSP), enables moderate-scale population surveys of SNPs. HSP uses fluorescently tagged primers and exploits the large dynamic range and low background of automated fluorescent sequencing. HSP may be used for any sequence that can be amplified by PCR. A total of 12 SNP variants in MGMT, ERCC1, CDK7, CCNH and XRCC4 were identified, 11 at polymorphic frequencies, with an average frequency of 0.22 (95% confidence interval 0.20–0.24). Among the 82 individuals for whom complete SNP profiles were available, no one person carried the GenBank reference sequence for all five genes. The extensive heterogeneity observed in these five genes is intriguing. All variants are in Hardy–Weinberg equilibrium, although the meaning of this equilibrium is unclear. Using this approach, possible associations of sequence variation, and hence of variation in DNA repair, with disease risk can be assessed.

Keywords: CCNH, cyclin H; CDK7, cyclin-dependent kinase 7; ERCC1, excision-repair, complementing defective, in Chinese hamster, 1; HSP, heterozygote sequencing protocol; MGMT, methylguanine-DNA methyltransferase; SNP, single nucleotide polymorphism; XRCC4, X-ray repair, complementing defective, in Chinese hamster, 4.

Journal Article.  4046 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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