Pattern of Sequence Variation Across 213 Environmental Response Genes

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 × 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

Inferring causality and functional significance of human coding DNA variants

“…Log-log scale plot is shown for theoretical model assuming constant population and no natural selection (27) (green line); population genetic model assuming recent population growth and no natural selection (40) (blue line); population genetic model that incorporates both population growth and natural selection (40) (red line). Results of theoretical models are shown together with estimates based on real data obtained by re-sampling from three available systematic re-sequencing data sets [Environmental Genome Project data set (78), Seattle SNP data set (78) and Obesity Sequencing Study data set (27)…”

Analysis and implications of mutational variation

“…Third, a substantial fraction of the mutational variance for fitness detected in Drosophila MA experiments may be generated by transposable element insertions, whose average effects seem to be quite high (Lyman et al 1996;Houle and Nuzhdin 2004). Consistent with this, transposable elements Loewe et al (2006) (a) PGA data set (b) EGP data set (Livingston et al 2004) segregate at very low frequencies within populations (Charlesworth and Langley 1989). The final explanation is that the DEM is inadequately described by a gamma distribution, and may be multimodal: a few large-effect mutations effectively do not contribute to DNA polymorphisms in natural populations, but are the major contributors to V M in MA experiments.…”

“…The first approach that fully utilises the SFS was developed by Eyre-Walker et al (2006), and applied to a large human polymorphism data set obtained by resequencing candidate loci in samples of individuals from the American population as part of the ''Environmental Genome Project'' (EGP; Livingston et al 2004). Under the assumption that f(s) is a gamma distribution, Eyre-Walker et al (2006) used ML to estimate the distribution parameters that best explain the SFS for nonsynonymous sites (assumed to be under purifying selection), using intronic sites as a neutrally evolving standard.…”

Variants in DNA double‐strand break repair and DNA damage‐response genes and susceptibility to lung and head and neck cancers

“…In addition, for several polymorphisms in DNA repair genes the variant allele frequencies observed in our hospital control population was within the range of previously published frequencies in European populations. For example, we found variant allele frequencies for XRCC3 T241M (rs861539), MDM2 E354E (rs769412) and p53 R72P (rs1042522) polymorphisms of 0.44, 0.06, Table S3 for information on SNPs retained in haplotype analysis.-2 The estimated haplotype frequencies for cases or controls do not always sum up to 1 because they were recalculated from the parameter estimates in the adjusted unconditional logistic regression model.-3 Adjusted for age, pack-years of smoking, and daily consumption of alcohol where relevant.- 4 Reference category determined by the haplotype with the highest frequency (total of cases and controls). and 0.25, respectively.…”

“…Hundreds of single nucleotide polymorphisms (SNPs) in genes involved in the maintenance of genome integrity have been identified from several large sequencing efforts [3][4][5][6] and reported in public databases. For many of these polymorphisms, however, the impact on repair phenotype and cancer susceptibility remains unknown.…”