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Harnessing genomics to identify environmental determinants of heritable disease
Yauk, C. L., L. Argueso, S. S. Auerbach, S. R. David, D. M. DEMARINI, G. R. Douglas, Y. E. Dubrova, R. K. Elespuru, T. W. Glover, B. F. Hales, M. E. Hurles, C. B. Klein, J. R. Lupski, D. K. Manchester, F. Marchetti, A. Montpetit, J. J. Mulvhill, B. Robaire, W. A. Robbins, G. Rouleau, D. T. Shaughnessy, C. M. Somers, J. Taylor, J. Trasler, M. D. Waters, T. E. Wilson, K. L. Witt, AND J. B. Bishop. Harnessing genomics to identify environmental determinants of heritable disease. MUTATION RESEARCH. Elsevier Science Ltd, New York, NY, 752(1):6-9, (2013).
De novo mutation is increasingly being recognized as the cause for a range of human genetic diseases and disorders. Important examples of this include inherited genetic disorders such as autism, schizophrenia, mental retardation, epilepsy, and a broad range of adverse reproductive outcomes, all now linked to specific copy number variants 1-3. There are currently published studies on the ability of 39 chemicals and 3 complex mixtures (urban air and main-and side-stream cigarette smoke) to cause rodent germ cell mutation 4-6; 33 of these 42 agents are germ-cell mutagens in rodents. However, no compound has been definitively demonstrated to produce heritable mutations in humans despite the high degree of conservation between human and rodent germline mutation processes. The primary reason for the contradiction between rodent and human germline mutation data has been a lack of sensitive molecular tools to adequately 1 • • decipher the complex types of genomic changes that underlie much of human inherited disease 7,8. Recent work has demonstrated the promise of new technologies to transform our knowledge of the rates and spectra of inherited genomic alterations, and has confirmed a wide range of germline mutation rates across individuals, yet we have little understanding ofthe causes of these differences and the factors that influence these processes. In addition, the recent determination by the International Agency for Research on Cancer (IARC) that paternal exposure to tobacco smoke is associated with childhood cancer strongly implicates effects on germ cells 9 and has refocused attention on the role of environmental factors on de novo inherited mutations. An international working group comprised of experts in this field met recently to assess the current state of knowledge and address ways the powerful new technologies can be brought to bear on genetic and epigenetic studies of germ cell biology and trans-generational effects", Our current knowledge of the key variables that influence germline genomic stability is limited, and focused studies in this area are required to allow us to begin exploring variables and processes that influence individuals and populations. Given the current state of the science, the group developed a clear vision of how research in this area should proceed. We agreed that large-scale harmonized efforts are needed to quantify and characterize the levels of both single nucleotide and structural genetic variation that arise across generations and the factors that influence this variation.
Enclosed is the clearance package for a manuscript that summarizes a l-day workshop on germcell mutations that was held at the EMS meeting in Montreal 2 weeks ago. I was a co-organizer ofthis workshop. Our plan is to submit this as an Opinion piece to Nature Medicine because there will be a special issue ofthat journal that will be covering related issues that emerged from the International Congress of Human Genetics (ICHG), which met prior to the EMS meeting in Montreal. We arranged for nearly half ofthe workshop attendees to be from the ICHG, who graciously agreed to stay in Montreal for an extra day to participate in our workshop. All 30 workshop participants are listed as authors.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
INTEGRATED SYSTEMS TOXICOLOGY DIVISION
GENETIC AND CELLULAR TOXICOLOGY BRANCH