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PMID: 15364900 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Pattern of sequence variation across 213 environmental response genes.

Genome research ·Vol. 14 ·No. 10A ·2004-10-00 ·Pages 1821-31

Livingston RJ, von Niederhausern A, Jegga AG, Crawford DC, Carlson CS, Rieder MJ, Gowrisankar S, Aronow BJ, Weiss RB, Nickerson DA

Abstract

To promote the clinical and epidemiological studies that improve our understanding of human genetic susceptibility to environmental exposure, the Environmental Genome Project (EGP) has scanned 213 environmental response genes involved in DNA repair, cell cycle regulation, apoptosis, and metabolism for single nucleotide polymorphisms (SNPs). Many of these genes have been implicated by loss-of-function mutations associated with severe diseases attributable to decreased protection of genomic integrity. Therefore, the hypothesis for these studies is that individuals with functionally significant polymorphisms within these genes may be particularly susceptible to genotoxic environmental agents. On average, 20.4 kb of baseline genomic sequence or 86% of each gene, including a substantial amount of introns, all exons, and 1.3 kb upstream and downstream, were scanned for variations in the 90 samples of the Polymorphism Discovery Resource panel. The average nucleotide diversity across the 4.2 MB of these 213 genes is 6.7 x 10(-4), or one SNP every 1500 bp, when two random chromosomes are compared. The average candidate environmental response gene contains 26 PHASE inferred haplotypes, 34 common SNPs, 6.2 coding SNPs (cSNPs), and 2.5 nonsynonymous cSNPs. SIFT and Polyphen analysis of 541 nonsynonymous cSNPs identified 57 potentially deleterious SNPs. An additional eight polymorphisms predict altered protein translation. Because these genes represent 1% of all known human genes, extrapolation from these data predicts the total genomic set of cSNPs, nonsynonymous cSNPs, and potentially deleterious nonsynonymous cSNPs. The implications for the use of these data in direct and indirect association studies of environmentally induced diseases are discussed.

MeSH Terms
Apoptosis/genetics Cell Cycle/genetics DNA Repair/genetics Environmental Exposure Exons Genetic Variation Humans Regulatory Sequences, Nucleic Acid
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Livingston Robert J
Department of Genome Sciences, University of Washington, Seattle, Washington 98195-7730, USA.
von Niederhausern Andrew
Jegga Anil G
Crawford Dana C
Carlson Christopher S
Rieder Mark J
Gowrisankar Sivakumar
Aronow Bruce J
Weiss Robert B
Nickerson Deborah A
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Article Info
Journal
Genome research
Abbr.
Genome Res
ISSN
1088-9051
DOI
10.1101/gr.2730004
Published
2004-10-00
Epub
2004-00-13
Pages
1821-31
Language
English
Region
United States
NLM ID
9518021
PMCID
PMC524406
Subset
IM
Grants
NIEHS NIH HHS · U01 ES011038 · United States
NIEHS NIH HHS · N01ES15478 · United States
NIEHS NIH HHS · N01ES35501 · United States
NIEHS NIH HHS · U01-ES-11038 · United States
NIEHS NIH HHS · N01-ES-15478 · United States
External Links
PubMed source DOI: 10.1101/gr.2730004 PMC Full Text View journal details
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