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Pattern of Sequence Variation Across 213 Environmental Response Genes

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.

Comparative analysis of 1196 orthologous mouse and human full-length mRNA and protein sequences.

A large set of mRNA and encoded protein sequences, from orthologous murine and human genes, was compiled to analyze statistical, biological, and evolutionary properties of coding and noncoding transcribed sequences. Protein sequence conservation varied between 36% and 100% identity, with an average value of 85%. The average degree of nucleotide sequence identity for the corresponding coding sequences was also approximately 85%, whereas 5' and 3' untranslated regions (UTRs) were less conserved, with aligned identities of 67% and 69%, respectively. For some mouse and human genes, nucleotide sequences are more highly conserved than the encoded protein sequences. A subset of 32 sequences, consisting of only mouse/human protein pairs for which the human sequence represents a positionally cloned disease gene, had properties very similar to the larger data set, suggesting that our data are representative of the genome as a whole. With respect to sequence conservation, two interesting outliers are the breast cancer (BRCAI) gene product and the testis-determining factor (SRY), both of which display among the lowest degrees of sequence identity. The occurrence of both introns and repetitive elements (e.g., Alu, Bl) in 5' and 3' UTRs was also studied. These results provide one benchmark for the "comparative genomics" of mice and humans, with practical implications for the cross-referencing of transcript maps. Also, they should prove useful in estimating the additional sampling diversity provided by mouse EST sequencing projects designed to complement the existing human cDNA collection.