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Enhancing Mutation Research by Application of Genomic Technologies and Resources
The field of "Mutation Research" encompasses a broad area of scientific inquiry, including the study of molecular mechanisms of mutagenesis, the biochemical and molecular aspects of DNA damage and repair, the development and use of genotoxicity testing methods (for DNA damage and related effects), human population monitoring and surveillance for genotoxic effects, and genetic and health risk assessment of chemical and radiation exposure. Genetic damage at the somatic and germ-cell level have both been of concern, the former associated frequently with cancer, and the latter, heritable genetic diseases.
While environmental agents have been shown to induce DNA mutations and other genotoxic events in non-human organisms (in vitro and in vivo), this has yet to be unequivocally demonstrated in humans. It was the need to develop methodologies capable of detecting induced mutations in humans (esp. in Hiroshima atomic bomb survivors and their children) that provided the impetus for initiation of the Human Genome Project (HGP) by the U.S. Department of Energy (DOE) in the late 1980s. The U.S. National Institutes of Health and the worldwide scientific community have since become involved in the HGP. Two sets of 5-year research goals have been developed jointly by DOE and NIH thus far to guide the U.S.: the initial goals for FY 1991-1995, and the revised goals for FY 1994-1998. Goals include the cloning, mapping, sequencing, and total gene identification of all the chromosomes of a reference human genome, as well as of several other organisms. There has been tremendous progress in meeting the goals of the HGP, both by the U.S. and internationally, and many resources have been developed including innovative instrumentation, recombinant DNA and cDNA clones, genetic and physical maps, and computerized information management systems (informatics).
As many exciting discoveries and innovations were made in the course of the HGP, however, its link and origin in the field of Mutation Research was largely forgotten (Wassom, 1996). Thus far, the mutation research community has been slow to capitalize on the infrastructure and technical resources that have been created by the HGP (Carrano, 1994). The Human Genome and Toxicology Group (HG&T) at the Life Sciences Division of the Oak Ridge National Laboratory (ORNL), has drafted a plan to catalyze the mutation research area to take greater advantage of technologies and resources developed by the HGP investigators as well as others working in related areas such as medical genetics, etc. All genome-related areas are referred to together as "genomics." A term proposed by J. J. Mulvihill (Univ. of Pittsburgh, USA) for a hybrid of Genomics and Mutation Research is "Mutation Research Genomics" or "Mutation Genomics", thus the origin our moniker, "Mutation Research Genomics Initiative."
To carry out the objectives of the Mutation Research Genomics Initiative a series of workshops and discussions have been initiated for 1997-98. Genomics and genetic toxicology researchers will be brought together to determine which new technologies and resources of the HGP and related areas are important to the field of Mutation Research. These meetings will identify potential collaborations between scientists in the two areas, and review technologies currently being used in the field of Mutation Research. The findings and recommendations from these workshops will be presented to the genome and mutation research communities as a series of published reports and will lay the foundation for an international meeting in 1997 or 1998 geared for 150-250 participants. Additionally, more informal "brainstorming sessions" and personal interviews of outstanding scientists in the two fields will be conducted to garner ideas for consideration in the effort to blend the two disciplines.
Individuals invited to participate in the workshops and informal discussions will be initially identified through the Human Genome Management Information System (HGMIS) and the Environmental Mutagen Information Center (EMIC). Both of these two important national resources are part of the HG&T group at ORNL, putting it in a unique position to coordinate/spearhead the Mutation Research Genomics Initiative. Other interested individuals are invited to participate in the initiative, and a communication forum has been initiated to facilitate these interactions. The HG&T group will coordinate the ORNL initiative, maintaining continuity in the integration of ideas from experts in the various areas, and providing an up-to-date information source of the initiative's progress for all interested individuals.
In addition to the ORNL involvement in the Mutation Research Genomics Initiative, several other groups have become involved in complementary efforts. To help ensure international coverage and participation, the International Commission for the Protection Against Environmental Mutagens and Carcinogens (ICPEMC) was approached, and agreed to assist with the overall project. ICPEMC has an historic interest in the initiation of the HGP and in its integration with the field of mutation research (Lohman, 1995), as ICPEMC members were involved in at the Alta I and II meetings in Utah, USA (1984 and 1992, respectively), where methodologies used to find somatic and germline mutations were discussed.
The U.S. Environmental Mutagen Society (EMS) has recently become involved in a related effort (Tennant, 1996). Society members are formulating a strategy for the interfacing of experts in molecular, clinical, and epidemiological fields for the purpose of developing molecular-based methods to detect induced heritable mutations in humans. The EMS will sponsor several small meetings to garner ideas from its members to devise a strategic plan for this initiative.
We believe that the collaborations resulting from the Mutation Research Genomics Initiative will foster development of innovative, well-designed project proposals better able to compete for research money in the ever-increasingly competitive funding situation (Wassom, 1996). The application of genomics technologies to the field of Mutation Research has the potential to dramatically impact areas such as molecular analysis of mutations, mechanisms of DNA repair and cell cycle control, transgenic animal development, analysis of the consequences of premutational lesions, human population biomonitoring, and genetic risk assessment. The infusion of new ideas will undoubtedly result in new approaches to solve previously intractable problems, stimulating both genomic and Mutation Research into the 21st century.
Like a mutation, an idea may be recorded in
the wrong time, to lie latent
like a recessive gene and spring to life in a more auspicious
era!
Loren Eiseley
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Monday, November 17, 2003