This article is a US Government work and, as such, is in the public domain in the United States of America.
Assessing human germ-cell mutagenesis in the Postgenome Era: A celebration of the legacy of William Lawson (Bill) Russell†
Version of Record online: 12 FEB 2007
Published 2007 Wiley-Liss, Inc.
Environmental and Molecular Mutagenesis
Volume 48, Issue 2, pages 71–95, March 2007
How to Cite
Wyrobek, A. J., Mulvihill, J. J., Wassom, J. S., Malling, H. V., Shelby, M. D., Lewis, S. E., Witt, K. L., Preston, R. J., Perreault, S. D., Allen, J. W., DeMarini, D. M., Woychik, R. P. and Bishop, J. B. (2007), Assessing human germ-cell mutagenesis in the Postgenome Era: A celebration of the legacy of William Lawson (Bill) Russell. Environ. Mol. Mutagen., 48: 71–95. doi: 10.1002/em.20284
Workshop Presenters: Diana Anderson (U. Bradford, UK), Norman Arnheim (U. Southern California, LA), John D. Boice (Vanderbilt U., Nashville, TN), Bryn A. Bridges (U. Sussex, UK), James F. Crow (U. Wisconsin, Madison), Yuri E. Dubrova (U. Leicester, UK), Ursula Eichenlaub-Ritter (U. Bielefeld, Germany), Robert P. Erickson (U. Arizona, Tucson), Jane Fridlyand (U. California, San Francisco), Joe Gray (Lawrence Berkeley Laboratory, CA), Philip C. Hanawalt (Stanford U., CA), Mary Ann Handel (The Jackson Laboratory, Bar Harbor, ME), Francesco Marchetti (Lawrence Berkeley Laboratory, CA), Harvey W. Mohrenweiser (Oregon Health Sciences U., Portland), Robert K. Moyzis (U. California, Irvine), Michael Primig (Biozentrum and Swiss Institute Bioinformatics, Basel), Liane B. Russell (Oak Ridge National Laboratory, TN), K. Sankaranarayanan (Leiden U., The Netherlands), Michael K. Skinner (Washington State U., Pullman), Eric A. Shoubridge (McGill U., Montreal, Canada), Jack A. Taylor (NIEHS, RTP, NC), Jaquetta M. Trasler (Montreal Children's Hospital Research Institute, Canada), and Thomas J. Vasicek (Medtronic, Minneapolis, MN).
- Issue online: 15 FEB 2007
- Version of Record online: 12 FEB 2007
- Manuscript Accepted: 26 DEC 2006
- Manuscript Revised: 12 MAY 2006
- Manuscript Received: 14 APR 2006
- National Institute of Child Health and Human Development, National Institutes of Health. Grant Number: R13 HD040151
- Environmental Mutagen Society
- The Jackson Laboratory
- US Environmental Protection Agency
- US Department of Energy
- Lawrence Livermore National Laboratory
- Oak Ridge National Laboratory
- National Institute of Environmental Health Sciences
- Office of Rare Diseases, National Institutes of Health
- inherited disease;
- mutation detection;
- molecular genetic analysis;
- human genetic risk
Birth defects, de novo genetic diseases, and chromosomal abnormality syndromes occur in ∼5% of all live births, and affected children suffer from a broad range of lifelong health consequences. Despite the social and medical impact of these defects, and the 8 decades of research in animal systems that have identified numerous germ-cell mutagens, no human germ-cell mutagen has been confirmed to date. There is now a growing consensus that the inability to detect human germ-cell mutagens is due to technological limitations in the detection of random mutations rather than biological differences between animal and human susceptibility. A multidisciplinary workshop responding to this challenge convened at The Jackson Laboratory in Bar Harbor, Maine. The purpose of the workshop was to assess the applicability of an emerging repertoire of genomic technologies to studies of human germ-cell mutagenesis. Workshop participants recommended large-scale human germ-cell mutation studies be conducted using samples from donors with high-dose exposures, such as cancer survivors. Within this high-risk cohort, parents and children could be evaluated for heritable changes in (a) DNA sequence and chromosomal structure, (b) repeat sequences and minisatellites, and (c) global gene expression profiles and pathways. Participants also advocated the establishment of a bio-bank of human tissue samples from donors with well-characterized exposure, including medical and reproductive histories. This mutational resource could support large-scale, multiple-endpoint studies. Additional studies could involve the examination of transgenerational effects associated with changes in imprinting and methylation patterns, nucleotide repeats, and mitochondrial DNA mutations. The further development of animal models and the integration of these with human studies are necessary to provide molecular insights into the mechanisms of germ-cell mutations and to identify prevention strategies. Furthermore, scientific specialty groups should be convened to review and prioritize the evidence for germ-cell mutagenicity from common environmental, occupational, medical, and lifestyle exposures. Workshop attendees agreed on the need for a full-scale assault to address key fundamental questions in human germ-cell environmental mutagenesis. These include, but are not limited to, the following: Do human germ-cell mutagens exist? What are the risks to future generations? Are some parents at higher risk than others for acquiring and transmitting germ-cell mutations? Obtaining answers to these, and other critical questions, will require strong support from relevant funding agencies, in addition to the engagement of scientists outside the fields of genomics and germ-cell mutagenesis. Environ. Mol. Mutagen., 2007. Published 2007 Wiley-Liss, Inc.