Normal biological activities also contribute to the risk of genetic damage. A body's own 

 cells produce some potentially damaging molecules in the course of normal metabolic 

 processes; some of these molecules are produced in considerable abundance during 

 defensive actions against microbes and during detoxification of harmful environmental 

 substances. The genome replication system itself sometimes errs during cell prolifer- 

 ation. Even DNA is not completely stable chemically: its nomial methyl-cytosine 

 constituent has a low but measurable rate of spontaneous mutagenic change. 



Life has thus evolved under a continuous low-level infliction of genomic damage and 

 mutation. Under this pressure, systems that reverse or ameliorate many types of DNA 

 damage have evolved, so that a wide range of repair mechanisms exists within cells of 

 all species. Several of the human genes contributing to DNA repair processes are being 

 characterized now, and others await detection and molecular cloning. Repair gene 

 deficiencies are manifested as cellular sensitivity to low-level DNA damage and in 

 diseases such as cancer. Humans exhibit genetic diversity in capacity for DNA repair in 

 response to ubiquitous DNA-damaging agents. 



In recognition of this diversity, a major goal of the current OHER health effects and 

 general life sciences program areas has been formulated: the development of capacities 

 to diagnose individual susceptibility to genome damage imposed by energy-related 

 factors. Some major components of this OHER research are: 



• molecular cloning and characterization of DNA repair genes; 



• improvement of methodologies and development of new resources for use in 

 quantitating and characterizing mutations (molecular epidemiology); and. most 

 recently, 



• focused resource and technology development needed to map and sequence the 

 human aenome — the Human Genome Program. 



