Ionizing radiation and genetic risksXIV. Potential research directions in the post-genome era based on knowledge of repair of radiation-induced DNA double-strand breaks in mammalian somatic cells and the origin of deletions associated with human genomic disorders

Sankaranarayanan, K.; Wassom, John S.

doi:10.1016/j.mrfmmm.2005.06.020

Cited by 44 publications

(57 citation statements)

References 244 publications

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“…Further, large DNA deletions that are viable are likely to cause developmental abnormalities in multiple organs/systems. Sankaranarayanan described a recent approach for predicting the rate at which nonlethal radiation-induced multi-gene deletions should occur in the mouse or human genome [Sanakaranarayanan and Wassom, 2005]. This analysis is based on a molecular understanding of the mechanisms by which such deletions occur and the distribution of DNA repetitive sequences, e.g., segmental duplications or low-copy repeats (LCRs) in the mouse and human genomes.…”

Section: Risk Assessmentmentioning

confidence: 99%

Assessing human germ‐cell mutagenesis in the Postgenome Era: A celebration of the legacy of William Lawson (Bill) Russell

Wyrobek

Mulvihill

Wassom

et al. 2007

Environ and Mol Mutagen

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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, multipleendpoint studies. Additional studies could involve the examination of transgenerational effects NIH Public AccessAuthor Manuscript Environ Mol Mutagen. Author manuscript; available in PMC 2007 November 8. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 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 germcell 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.

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Section: Risk Assessmentmentioning

confidence: 99%

Assessing human germ‐cell mutagenesis in the Postgenome Era: A celebration of the legacy of William Lawson (Bill) Russell

Wyrobek

Mulvihill

Wassom

et al. 2007

Environ and Mol Mutagen

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“…Base modifications can cause base substitutions (Shibutani et al, 1991;Tajiri et al, 1995). Double strand breaks (DSBs) are repaired by two major pathways, namely homologous recombination (HR) and non-homologous end-joining (NHEJ) (Britt, 1999;Sankaranarayanan and Wassom, 2005;Kimura and Sakaguchi, 2006). HR is an error-free repair pathway, whereas…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of mutations induced by gamma irradiation in rice

et al. 2009

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In order to analyze mutations induced by gamma irradiation in higher plants, we irradiated rice with gamma rays and screened for mutations expressing phenotypes of glutinous endosperm (wx), chlorophyll b deficiency, endosperm protein deficiency, gibberellin-related dwarfism, and shortened plastochron-in order to clarify types of mutations. Nucleotide sequence analysis showed that the most frequent mutation induced by gamma rays was deletion, particularly small deletion. Of the 24 mutations, 15 were small deletions (1-16 bp), four were large deletions (9.4 -129.7 kbp), three were single-base substitutions, and two were inversions. Deletions 100 bp-8 kbp in length were not found, suggesting that gamma irradiation is unlikely to induce deletions of 100 bp to 8 kbp but is more likely to induce deletions between 1 and several ten bp or those of around 10 kbp or more. Based on the results, reverse genetics applications may be possible for gamma irradiation-induced deletions in rice by mismatch cleavage analysis used in Targeting Induced Local Lesions IN Genomes (TILLING) to detect small deletions and base substitutions or by using array comparative genomic hybridization (aCGH) to detect large deletions.

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“…The latter concept challenges the basic assumption that has dominated the field thus far that radiation-induced mutations will cause genetic diseases similar to those occurring naturally as a result of mutations in single genes. Sankaranarayanan and Wassom [2005] believe that the two concepts mentioned above provide a convenient framework for computational modeling to determine genetic risk estimation in the 21st Century using the human genome as a starting point. They have used knowledge from two contemporary fields of research, namely, repair of DNA double-strand breaks (DSBs) in mammalian somatic cells and human genomic disorders to construct the framework for modeling.…”

Section: The Way Forward In Estimating the Genetic Risks Of Radiationmentioning

confidence: 99%

“…We hope EMS will ponder these questions. In the case of ionizing radiation, induced adverse effects seem more likely to manifest themselves as multisystem developmental abnormalities in the progeny rather than as genetic diseases similar to those occurring naturally as a result of spontaneous mutations in single genes [Sankaranarayanan and Wassom, 2005].…”

Section: Future History Considerations As Ems Enters Its 41st Yearmentioning

confidence: 99%

Reflections on the origins and evolution of genetic toxicology and the environmental mutagen society

Wassom

Malling

Sankaranarayanan

et al. 2010

Environ and Mol Mutagen

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This article traces the development of the field of mutagenesis and its metamorphosis into the research area we now call genetic toxicology. In 1969, this transitional event led to the founding of the Environmental Mutagen Society (EMS). The charter of this new Society was to "encourage interest in and study of mutagens in the human environment, particularly as these may be of concern to public health." As the mutagenesis field unfolded and expanded, new wording appeared to better describe this evolving area of research. The term "genetic toxicology" was coined and became an important subspecialty of the broad area of toxicology. Genetic toxicology is now set for a thorough reappraisal of its methods, goals, and priorities to meet the challenges of the 21st Century. To better understand these challenges, we have revisited the primary goal that the EMS founders had in mind for the Society's main mission and objective, namely, the quantitative assessment of genetic (hereditary) risks to human populations exposed to environmental agents. We also have reflected upon some of the seminal events over the last 40 years that have influenced the advancement of the genetic toxicology discipline and the extent to which the Society's major goal and allied objectives have been achieved. Additionally, we have provided suggestions on how EMS can further advance the science of genetic toxicology in the postgenome era. Any oversight or failure to make proper acknowledgment of individuals, events, or the citation of relevant references in this article is unintentional.

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Ionizing radiation and genetic risksXIV. Potential research directions in the post-genome era based on knowledge of repair of radiation-induced DNA double-strand breaks in mammalian somatic cells and the origin of deletions associated with human genomic disorders

Cited by 44 publications

References 244 publications

Assessing human germ‐cell mutagenesis in the Postgenome Era: A celebration of the legacy of William Lawson (Bill) Russell

Assessing human germ‐cell mutagenesis in the Postgenome Era: A celebration of the legacy of William Lawson (Bill) Russell

Molecular characterization of mutations induced by gamma irradiation in rice

Reflections on the origins and evolution of genetic toxicology and the environmental mutagen society

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