Although all people are equipped with the same basic set of genes and DNA regulatory regions, close comparisons among individuals reveal their true diversity, with a variation occurring about once every 500 to 1000 bp along the 3-billion-bp human genome. Some of these changes account for such obvious traits as the shape of the nose, height, and hair color, but some gene variations produce no apparent phenotypic differences. Other DNA variations affecting fundamental biological processes and gene-to-gene and environmental interactions can result in a wide range of susceptibility to diseases.

In a new program initiated by the NIH National Institute of Environmental Health Sciences (NIEHS), researchers in the Environmental Genome Project (EGP) will investigate how some genetic differences, called polymorphisms (for "many forms"), influence susceptibility to environmental exposure. Identifying and studying genes and other genetic regions that affect individual responses to environmental toxins can help scientists better predict health risks and develop environmental policies to protect the most vulnerable population groups.

EGP plans to systematically identify sequence variations in about 200 genes associated with environmental disease susceptibility in the U.S. population, develop a central database of polymorphisms for these genes, and foster studies of gene-environment interaction in disease susceptibility. NIEHS expects the multiyear effort to cost at least $60 million.

EGP's objective will be to sequence coding and regulatory regions of each of 200 genes in 1000 individuals. Susceptibility genes, to be chosen through a peer-reviewed process, are expected to include five broad classes: genes controlling toxicant distribution and metabolism, genes for nucleic acid?Crepair pathways, genes for the cell cycle control system, cell death and differentiation genes, and genes for signal transduction systems controlling gene expression in the other classes. A central database of polymorphisms found in these genes will be developed to support both functional studies of variants and population-based studies of disease risk. The latter studies are central to identifying specific alleles as well as the environmental exposures that cause disease.

Working with genetically susceptible subgroups will enable researchers to identify more precisely the environmental agents with roles in disease causation as well as the true risks of exposure. These results could lead to public health programs for protecting susceptible populations and for targeting screening to groups at greater risk of disease. The project, which will use technology produced in part through the Human Genome Project, will also foster development of new high-throughput technology for a broader application of molecular genetics in epidemiology and environmental exposure.

In a presentation to the House Appropriations Committee in July 1997, NIEHS Director Kenneth Olden stated that it is time to take advantage of the tools developed and skills learned in 30 years of environmental research-- to break with the past and lead in bold, new initiatives. In presenting EGP as part of a new 'vision' for environmental health research, Olden also suggested a survey of chemicals taken up by humans, using blood and urine tests to determine American population exposure to specific agents; further development and approval of customized mice and other quick-throughput methods to screen chemicals and drugs; and a study of chemical mixtures to explore their effects on people. Olden hopes to launch EGP in 1998 with $10 million.