According to James Selkirk, a chemist at NIEHS and the Deputy Director of the NCT, the research is currently progressing in a two-phase manner.
The first phase involves resequencing genes associated with cell cycle regulation and DNA repair.The genes studied at the EGP have already been sequenced elsewhere and are all fairly well known."We're not in the business of gene discovery," Selkirk
emphasizes.The goal is a definitive catalogue of all the variations in these genes, which Selkirk
says will "allow us to have closure on a given cellular pathway."The initial plan called for assessing 200 genes in a population of 500 anonymous individuals at an estimated cost of $200 million.But Selkirk
says economies of scale resulting from high-throughput technologies using Applied Biosystems
3700 sequencers and improved computation have sharply reduced costs.So far, nearly 100 genes from 90 people have been resequenced at a cost of only about $10 million.In the second phase, EGP researchers will assess the major SNPs for their frequency in populations of people with environmentally-suspect diseases.Further down the line, links between SNP frequency, disease, and environmental exposures will be elucidated in multi-disciplinary toxicology and epidemiology studies.In a related effort, the EGP is also investigating the ethical, social, and legal issues raised by its findings.
Click here to see full chartCourtesy of NIEHS
says the agenda at the newly formed National Center for Toxicogenomics
revolves around a number of key goals.These include enhanced methods for assessing gene expression, developing an additional database relating microarrays and proteomics to environmental exposures, and improving mathematical paradigms to study protein function.Referring to chemical effects on gene expression, Selkirk
says, "There's this huge kinetic process happening, a multitude of factors such as post-translational modification that guide the functionality of the protein.We don't think the available mathematical and computational tools can handle this amount of data."An additional challenge, he
adds, is that environmentally induced biochemical cascades in the cell can be highly sensitive to temporal factors and dose.Changes in either of these parameters can exert a major influence on gene expression."We're talking about a monumental kinetic problem in biochemistry," Selkirk
The EGP's activities are centered in three locations.So-called 'intramural activities' are based at the NIEHS' facilities at Research Triangle Park, NC, and involve collaboration with the Lawrence Livermore National Laboratories, CA.A major agenda item for the intramural staff has been to confer with NIEHS
and outside researchers to identify candidate genes for resequencing.