Environmental Genome Project: A Positive Sequence of Events.

Why does one person develop disease following exposure to a certain environmental agent but another person doesn't? That question lies at the heart of the NIEHS's Environmental Genome Project (EGP), begun in late 1997. To find an answer, the EGP is studying variations of certain genes and their interactions with the environment. Scientists believe that if they can understand what comprises genetic susceptibility to environmental agents, they will be able to determine or predict what the true risks of exposures are, and susceptible individuals can be better protected.

The scientific community has identified some 500 genes as being responsive to environmental factors such as diet and exposure to particular exogenous agents. The EGP is especially interested in the genes in two specific categories, DNA repair and cell cycle control, although these are not the only types of genes being studied. Currently, the EGP sponsors genome centers at the University of Washington and the University of Utah where much of the resequencing research is being conducted.

The first step in understanding the provenance of what have been called "environmentally related diseases" is to resequence environmentally responsive genes to determine their possible allelic variations (single nucleotide polymorphisms, or SNPs). SNP variations play a key role in explaining why people react in different ways to different exposures.

Perhaps the most exciting product of the EGP to date is a central database of gene SNPs--the only one of its kind--which presents the information gathered through the EGP on an easy-to-use Web site. Housed at the Utah Genome Center, the database is accessible through the GeneSNPs link on the EGP home page at http://www.niehs.nih.gov/envgenom/. The database is constantly being updated and currently contains information on 485 different genes. Entries for each SNP include its length, genomic position, and frequency, as well as a model of the gene.

The next step in understanding the relationship between genes, environment, and disease is functional analysis--understanding the biologic significance of gene variations, and how variations cause their respective effects. Under the auspices of the EGP, grants for up to five Comparative Mouse Genomics Centers across the United States and Europe will be made by April 2001. The centers will develop mouse models that mimic human gene variations in order to examine the functional implications of these variations.

In addition to resequencing and functional analysis studies, the EGP funds population-based studies, which examine how different SNPs are distributed through various U.S. subpopulations and how they affect their carriers in terms of increased disease susceptibility or resistance. The NIEHS Division of Extramural Research and Training is in the process of developing programs to distribute planning grants for molecular epidemiologists. Once SNPs are determined, the EGP will need people who call assess the frequency of SNP expression in the population. Molecular epidemiologists will be trained to effectively translate the data currently being generated by the EGP into population-based research.

Other components of the EGP include biostatistics/bioinformatics projects to develop statistical and computer models for analyzing gene-environment interactions, and to develop means for analyzing data on macromolecular cellular components such as DNA and proteins. In addition, technology development projects will create better, faster ways to conduct EGP studies. Finally, ethical, legal, and social implications projects look at developing policies to address the complex issues raised by the ability to delve deeply into an individual's DNA.

The NIEHS is also involved in an interagency agreement with Lawrence Livermore National Laboratory to resequence a subset of 40-50 genes to determine the major background SNPs in the U.S. population. To date, resequencing has been completed for 15 genes among 90 disease-free people representing the racial distribution of the United States, with 18 more in progress. The project will next search the DNA of people with particular disease for SNPs that may be implicated in disease causation.