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Mutation Genomics Report of Meeting Held September 24-28, 1995, Etang-Sur-Arroux, France. Summarized by John Wassom and Sylvia Milanez from a draft ICPEMC report, meeting notes, and tape recordings of committee discussions.
The International Commission for the Protection Against Environmental Mutagens and Carcinogens (ICPEMC), upon the initiative of John S. Wassom, proposes a series of meetings to examine the feasibility of using the new technologies and information emerging from the international Human Genome Project (HGP) to gain better estimates of spontaneous and induced mutation frequencies in human germ and somatic cells.
A recognized association exists between exposure to mutagens, somatic cell mutation, and the occurrence of human cancers of many different organ systems. Somatic cell mutations may also play a significant role in the expression of noncancerous disorders which affect the quality of life. In contrast, there has been no convincing demonstration of a human germ cell mutagen, either as a result of natural or experimental exposure to ionizing radiation or other mutagenic agents. The possible role of somatic cell mutations in noncarcinogenic phenomena, such as general aging, cell death, and autoimmunity, have largely not been considered in past studies.
During the last five years, the HGP and other genomics-related research have developed new technologies for rapidly determining DNA sequence, DNA mapping, and detecting mutations. In addition, there is an improved understanding of the range, frequency, and types of mutations involved in genetically determined human disease. ICPEMC considers this time to be an appropriate juncture to debate whether the techniques for genome research are now sufficiently mature to detect the presumed low mutation levels present in germ and somatic cells and to assess their correlation with a disease state.
ICPEMC proposes convening scientists to consider and define the issues necessary to measure mutation at low levels using genomic techniques. This effort will be a multidisciplinary approach and will involve representatives from the fields of mutation research, genomics, medical genetics, and epidemiology, among others. It is intended that the first meeting will be attended by some 40-60 scientists in the fall of 1996 to frame the initial recommendations and guidelines, followed by a larger international meeting attended by some 250 scientists sometime in 1997.
One of the closest areas of interface between genomics and mutation research is the finding of specific mutations in human cancer associated with specific environmental agents, such as aflatoxin B1, ultraviolet radiation, and polycyclic aromatic hydrocarbons, in, for example, the p53 gene. Another vital area of interest to both disciplines is determining the causes of human heritable mutations and whether or not an environmental agent can be definitively implicated. In attempting to address these and other issues of mutual concern, the possible contribution of each discipline to a joint effort can be anticipated based on the strengths of each discipline.
Genomics, for example, (1) offers sophisticated instrumentation, often using automation and robotics in applications such as PCR and DNA sequencing techniques; (2) has developed highly advanced computerized information management capabilities, known as informatics; (3) often has direct or foreseeable applications to clinical medicine and is familiar to many physicians; and (4) has raised public policy concerns regarding the inappropriate use of derived information [i.e., ethical, legal, and social issues (ELSI)], that are being studied with funding from NIH and DOE. These and other areas of genomics research, also known as human molecular genetics, have much to offer the field of mutation research.
In other areas, however, mutation researchers have addressed topics not covered to date by genome researchers. For example, (1) mutation research has an environmental perspective or orientation lacking in genomics; (2) in studies involving both germ and somatic cell mutation, mutation researchers take a mechanistic approach asking When? Which agent? and How?; (3) mutation researchers screen possible footprints or sets of genetic lesions that would suggest induction by a specific environmental agent; and (4) mutation dosimetry is a vital part of the field of mutation research.
The blending of these two disciplines, with their unique yet complementary perspectives, provides a powerful approach for developing methods to better detect spontaneous and induced mutations in somatic and germ cells. The proposed format for addressing these questions is a series of 2 1/2 day workshops, attended by 20 to 30 participants from each field. Categories of participants that will need to be involved in this endeavor include: genomics center directors, government scientists in positions of leadership, selected individuals fluent in both disciplines, genomics instrumentation experts involved in DNA chip design, rapid sequencing, robotics, informatics, sperm biologists, reproductive biologists, medical geneticists, computer and informatics scientists, epidemiologists, and mouse geneticists. Below is a listing of possible participants, picked to ensure international representation, a broad range of expertise, and a willingness to debate the issues and to contribute to drafting conclusions.
The questions that need to be addressed by these participants to focus their efforts on devising new methods of measuring low levels of DNA mutations in somatic and germ cells using genomic techniques are as follows: (Note: the term "mutation" includes spontaneous and induced mutations; "germ cell" refers to both sperm and oocytes.)
The following is an outline of the format proposed for the ICPEMC-sponsored 2 1/2 day workshop(s) at which these questions will be addressed by genomics and mutation researchers.
Day One
Day Two
Day Three
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Monday, November 17, 2003