|Populations and Polymorphisms|
|Building the new science of environmental genomics|
Charles W. Schmidt
November 3, 2000
Genetic milestones of the past decade have brought us to a greater understanding of disease. Now, modern biomedical science views illness as the outcome of three interdependent factors: genetic susceptibility, environmental exposures, and aging. Like death and taxes, aging is largely beyond our control. But within the complex interplay of genes and the environment are many potential targets for disease prevention and treatmentparticularly for cancer, pulmonary disease, neuro-degenerative disorders, developmental disorders, birth defects, reproductive function, and auto-immune disease. Introducing genomics into the study of environmental health fills a long-standing gap in the science.
One of the leading research groups on gene/environment interactions is the Environmental Genome Project, headquartered at the National Institutes of Environmental Health Sciences (NIEHS) in North Carolina. The EGP, founded in the spring of 1997, is a long-term effort to characterize both the common and rare genetic variations (primarily single nucleotide polymorphisms or SNPs) that contribute to resistance or susceptibility to environmentally induced illnesses. Once identified, the SNPs will be published on a website called 'egSNPs,' which is expected to be launched by the end of 2000. The most recent addition to environmental genomics activities at NIEHS and the EGP is the newly formed National Center for Toxicogenomics (NCT), to be announced in December 2000, which will investigate patterns of gene expression and protein function in response to environmental exposures.
Researchers have known for a long time that genetic susceptibility mediates environmental illnesses. However, until recently the tools available to study the influence of genetics on environmental exposures have been limited at best. For example, researchers have compared incidence rates among different ethnic groups, or cohorts comprised of pairs of fraternal and identical twins. (Unlike fraternal twins, identical twins share the same DNA and therefore the same genetic predisposition for inherited illness.) But with the availability of a public SNPs database, scientists will be able to control for the role of specific polymorphisms with much greater resolution.
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.
Selkirk 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 concedes.
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. Extramural research is ongoing at genome centers based at the University of Utah, under Robert Weiss, and the University of Washington, under Maynard Olson. Weiss' group has developed its own website, called GeneSNPs, which is geared towards the non-expert. Describing the site, Weiss says, "It contains pre-computed information about gene structure, the location of variations, and their functional implications."
As the variants are identified, EGP researchers will begin moving deeper into the dynamics of gene expression and biochemical activity in response to chemicals. Weiss describes this as a long-term goal, saying the objective will be to "look into the signaling pathways that feed into cell cycle regulation and xenobiotic metabolism." But in the meantime, he stresses that the EGP is trying to maintain a tight focus on resequencing the genes in the relevant categories, and enabling researchers to develop assays for use in assessing how the variations affect protein expression.
The EGP's ultimate goal is to sponsor and support epidemiological studies of gene/environment interactions, both at the NIEHS and among outside researchers funded through the extramural grant program. Empowered by databases with useful information about genes and gene functions, researchers in the genomic era will be able to more clearly determine how defined populations respond to their environment. The activities now underway at the Environmental Genome Project constitute a critical step in that direction.
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