Elsevier

Genomics

Volume 83, Issue 6, June 2004, Pages 970-979
Genomics

Many amino acid substitution variants identified in DNA repair genes during human population screenings are predicted to impact protein function

https://doi.org/10.1016/j.ygeno.2003.12.016Get rights and content

Abstract

Over 520 different amino acid substitution variants have been previously identified in the systematic screening of 91 human DNA repair genes for sequence variation. Two algorithms were employed to predict the impact of these amino acid substitutions on protein activity. Sorting Intolerant from Tolerant (SIFT) classified 226 of 508 variants (44%) as “Intolerant.” Polymorphism Phenotyping (PolyPhen) classed 165 of 489 amino acid substitutions (34%) as “Probably or possibly damaging.” Another 9–15% of the variants were classed as “Potentially intolerant or damaging.” The results from the two algorithms are highly associated, with concordance in predicted impact observed for ∼62% of the variants. Twenty-one to thirty-one percent of the variant proteins are predicted to exhibit reduced activity by both algorithms. These variants occur at slightly lower individual allele frequency than do the variants classified as “Tolerant” or “Benign.” Both algorithms correctly predicted the impact of 26 functionally characterized amino acid substitutions in the APE1 protein on biochemical activity, with one exception. It is concluded that a substantial fraction of the missense variants observed in the general human population are functionally relevant. These variants are expected to be the molecular genetic and biochemical basis for the associations of reduced DNA repair capacity phenotypes with elevated cancer risk.

Section snippets

Prediction of impact of substitutions on function and association with allele frequency

The dataset for analysis of the potential impact of common polymorphisms in DNA repair genes was 523 amino acid substitution variants identified in systematic sequencing of 91 human DNA repair and repair-related genes (summarized under Methods, Table 5). No missense variants were identified in the screening of 9 genes.

PolyPhen scores were obtained for 489 missense variants in 81 genes. Table 1 presents the distribution of the variants by PolyPhen score. To provide an overview of the

Discussion

It is generally acknowledged that most of the burden of common disease in the population exists as sporadic or noninherited cases and results from modest exposures in individuals with elevated susceptibility. This is expected to be especially important in diseases with late age of onset [42], [43], [44]. The hypothesis that elevated susceptibility is associated with polymorphic variants in disease-related genes, the “common variant–common disease” hypothesis has been extensively discussed [43],

The dataset

The majority of the variants included in this analysis were identified during the screening of 88–90 samples from the DNA Polymorphism Discovery Resource available at the Coriell Institute for Medical Research (Camden, NJ, USA). This resource was established by the NIH as a set of samples available to investigators screening for common genetic variants existing in the general population of the United States [76]. The samples are from U.S. residents and the major ethnic groupings of the

Acknowledgements

This work was performed under the auspices of the U.S. Department of Energy by the University of California, Lawrence Livermore National Laboratory, Contract W-7405-ENG-48, and supported by Interagency Agreement Y1-ES-8054-05 from NIEHS and NCI Grant 1 U-1 CA 83180-03. We thank David Wilson 3rd (National Institute of Aging) for many discussions, especially related to the APE1 variants, and Chad Garner (University of California at Irvine) for assistance with statistical analyses. We also

References (78)

  • A. Wright et al.

    A polygenic basis for late-onset disease

    Trends Genet

    (2003)
  • D.E. Reich et al.

    On the allelic spectrum of human disease

    Trends Genet

    (2001)
  • C.T. Saunders et al.

    Evaluation of structural and evolutionary contributions to deleterious mutation prediction

    J. Mol. Biol

    (2002)
  • J. Majewski et al.

    Amino acid substitutions in the human genome: evolutionary implications of single nucleotide polymorphisms

    Gene

    (2003)
  • C. Ferrer-Costa et al.

    Characterization of disease-associated single amino acid polymorphisms in terms of sequence and structure properties

    J. Mol. Biol

    (2002)
  • N.O. Stitziel

    Structural location of disease-associated single-nucleotide polymorphisms

    J. Mol. Biol

    (2003)
  • R.G. Tirona et al.

    Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans

    J. Biol. Chem

    (2001)
  • C. Bernstein et al.

    DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis

    Mutat. Res

    (2002)
  • R. Sachidanandam

    A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms

    Nature

    (2001)
  • M. Halushka

    Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis

    Nat. Genet

    (1999)
  • Y. Ohnishi

    Identification of 187 single nucleotide polymorphisms (SNPs) among 41 candidate genes for ischemic heart disease in the Japanese population

    Hum. Genet

    (2000)
  • R. Yamada

    Identification of 142 single nucleotide polymorphisms in 41 candidate genes for rheumatoid arthritis in the Japanese population

    Hum. Genet

    (2000)
  • M. Cargill

    Characterization of single-nucleotide polymorphisms in coding regions of human genes

    Nat. Genet

    (1999)
  • A. Iida

    Catalog of 434 single-nucleotide polymorphisms (SNPs) in genes of the alcohol dehydrogenase, glutathione S-transferase, and nicotinamide adenine dinucleotide, reduced (NADH) ubiquinone oxidoreductase families

    J. Hum. Genet

    (2001)
  • K.M. Small

    Gene and protein domain-specific patterns of genetic variability within the G-protein coupled receptor superfamily

    Am. J. Pharmacogenom

    (2003)
  • M.K. Leabman

    Natural variation in human membrane transporter genes reveals evolutionary and functional constraints

    Proc. Natl. Acad. Sci. USA

    (2003)
  • A. Iida

    Catalog of 605 single-nucleotide polymorphisms (SNPs) among 13 genes encoding human ATP-binding cassette transporters: ABCA4, ABCA7, ABCA8, ABCD1, ABCD3, ABCD4, ABCE1, ABCF1, ABCG1, ABCG2, ABCG4, ABCG5, and ABCG8

    J. Hum. Genet

    (2002)
  • H.W. Mohrenweiser et al.

    Identification of 127 amino acid substitution variants in screening 37 DNA repair genes in humans

    Cancer Epidemiol. Biomarkers Prev

    (2002)
  • P.L. Welcsh et al.

    BRCA1 and BRCA2 and the genetics of breast and ovarian cancer

    Hum. Mol. Genet

    (2001)
  • A. Muller et al.

    Mismatch repair and the hereditary non-polyposis colorectal cancer syndrome (HNPCC)

    Cancer Invest

    (2002)
  • L. Grossman

    DNA repair as a susceptibility factor in chronic diseases in human populations

  • M.R. Spitz et al.

    Genetic susceptibility to lung cancer: the role of DNA damage and repair

    Cancer Epidemiol. Biomarkers Prev

    (2003)
  • X. Wu

    A parallel study of in vitro sensitivity to benzo[a]pyrene diol epoxide and bleomycin in lung cancer cases and controls

    Cancer

    (1998)
  • M. Berwick et al.

    Markers of DNA repair and susceptibility to cancer in humans: an epidemiologic review

    J. Natl. Cancer Inst

    (2000)
  • M. Berwick et al.

    Studies of DNA repair and human cancer: an update

  • J. Cloos

    Inherited susceptibility to bleomycin-induced chromatid breaks in cultured peripheral blood lymphocytes

    J. Natl. Cancer Inst

    (1999)
  • M.Z. Hadi et al.

    Functional characterization of Ape1 variants identified in the human population

    Nucleic Acids Res

    (2000)
  • Y. Qiao

    Modulation of repair of ultraviolet damage in the host-cell reactivation assay by polymorphic XPC and XPD/ERCC2 genotypes

    Carcinogenesis

    (2002)
  • E.L. Goode et al.

    Polymorphisms in DNA repair genes and associations with cancer risk

    Cancer Epidemiol. Biomarkers Prev

    (2002)
  • Cited by (0)

    View full text