Induction of genetic recombination: Consequences and model systems

Hoffmann, George

doi:10.1002/em.2850230614

Cited by 29 publications

(7 citation statements)

References 53 publications

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“…A variety of assays have been developed to identify mitotic CN mutagens in different model systems. These include selection‐based assays that can identify CNVs at targeted genomic regions [Petes and Hill ; Schiestl ; Zimmermann ; Hoffmann ; Myung and Kolodner ; Reliene and Schiestl ; Payen et al, ; Lynch et al, ; Zhang et al, ] and selection‐free genome‐wide assays in yeast and mammalian cell culture [Argueso et al, ; Arlt et al, ; Arlt et al, ; Arlt et al, ; Arlt et al, ]. To the best of our knowledge, there are currently no validated assays available to specifically detect meiotic recurrent CNVs, although at least one promising prototype is under development [Argueso et al, ].…”

Section: Conclusion: New and Diverse Copy Number Mutagenesis Assays Amentioning

confidence: 99%

Contrasting mechanisms of de novo copy number mutagenesis suggest the existence of different classes of environmental copy number mutagens

Conover

Argueso

2015

Environ and Mol Mutagen

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While gene copy number variations (CNVs) are abundant in the human genome, and often are associated with disease consequences, the mutagenic pathways and environmental exposures that cause these large structural mutations are understudied relative to conventional nucleotide substitutions in DNA. The members of the environmental mutagenesis community are currently seeking to remedy this deficiency, and there is a renewed interest in the development of mutagenicity assays to identify and characterize compounds that may induce de novo CNVs in humans. To achieve this goal, it is critically important to acknowledge that CNVs exist in two very distinct classes: nonrecurrent and recurrent CNVs. The goal of this commentary is to emphasize the deep contrasts that exist between the proposed pathways that lead to these two mutation classes. Nonrecurrent de novo CNVs originate primarily in mitotic cells through replication-dependent DNA repair pathways that involve microhomologies (<10 bp), and are detected at higher frequency in children of older fathers. In contrast, recurrent de novo CNVs are most often formed in meiotic cells through homologous recombination between nonallelic large low-copy repeats (>10,000 bp), without an associated paternal age effect. Given the biological differences between the two CNV classes, it is our belief that nonrecurrent and recurrent CN mutagens will probably differ substantially in their modes of action. Therefore, each CNV class may require their own uniquely designed assays, so that we as a field may succeed in uncovering the broadest possible spectrum of environmental CN mutagens.

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Section: Conclusion: New and Diverse Copy Number Mutagenesis Assays Amentioning

confidence: 99%

Contrasting mechanisms of de novo copy number mutagenesis suggest the existence of different classes of environmental copy number mutagens

Conover

Argueso

2015

Environ and Mol Mutagen

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“…It provides an evaluation of mutational events, as well as recombinogenic events, as shown in the present study. It is known that substances that cause DNA damage also induce recombination, which generates more DNA damage ( Hoffman, 1994 ). Recombination can promote loss of heterozygosity in somatic cells and germ cells which, in turn, may influence cancer progression ( Happle, 1999 ).…”

Section: Resultsmentioning

confidence: 99%

Recombinogenic activity of Pantoprazole® in somatic cells of Drosophila melanogaster

et al. 2015

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Pantoprazole® is one of the leading proton pump inhibitors (PPIs) used in the treatment of a variety of diseases related to the upper gastrointestinal tract. However, studies have shown an increased risk of developing gastric cancer, intestinal metaplasia and hyperplasia of endocrine cells with prolonged use. In the present study, the somatic mutation and recombination test (SMART) was employed to determine the mutagenic effects of Pantoprazole on Drosophila melanogaster. Repeated treatments with Pantoprazole were performed on 72-hour larvae of the standard (ST) and high bioactivation (HB) crosses at concentrations of 2.5, 5.0, and 10.0 μM. In addition, doxorubicin (DXR) was administered at 0.4 mM, as a positive control. When administered to ST descendants, total number of spots were statistically significant at 2.5 and 5.0 μM concentrations. For HB descendants, a significant increase in the total number of spots was observed among the marked transheterozygous (MH) flies. Through analysis of balancer heterozygous (BH) descendants, recombinogenic effects were observed at all concentrations in descendants of the HB cross. In view of these experimental conditions and results, it was concluded that Pantoprazole is associated with recombinogenic effects in Drosophila melanogaster.

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“…Although there is a large number of short-term in vitro assays for screening of possible inducers of mitotic recombination [Hoffman, 1994], fewer assays are available for monitoring germline mutations, that is, heritable changes that could be established in future gene pools and contribute to human disease. The screening for induction of germline mutations has been based on in vivo assays, and the classical endpoints have required large data samples due to low spontaneous mutation frequencies.…”

Section: Introductionmentioning

confidence: 99%

Polychlorinated biphenyls induce meiotic length mutations at the human minisatellite MS32 in yeast

Appelgren

Hedenskog

Sandström

et al. 1999

Environ. Mol. Mutagen.

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Polychlorinated biphenyls (PCBs) are lipophilic compounds, several of which are toxic and carcinogenic. Complex mixtures of PCBs (e.g., Aroclor) have been widely used in the industry. The persistence of PCBs, in combination with poor waste management, has led to a large‐scale distribution of PCBs in the biosphere. The toxic and carcinogenic effects of PCBs are poorly understood, but are suggested to be associated with Ah receptor binding and induction of the Ah‐gene battery. We have previously shown that a higher‐chlorinated PCB mixture, Aroclor 1254, significantly increased the germline mutation rate at the mouse minisatellite PC‐1. We have recently developed an in vitro model system to study and characterize spontaneous and induced meiotic mutations in human minisatellites integrated in yeast. Here, for the first time, we have used this model system to show that chemicals, in this case Aroclor 1254, can induce meiotic length mutations at the human minisatellite MS32 in a yeast strain harboring 38‐ and 42‐repeat‐unit alleles. The results also show that the size distribution of mutant MS32 alleles differs between PCB and the control, with a larger proportion of mutant allele sizes below 29 repeat units in the PCB series. These alleles were not structurally different from the alleles of the same size in the control. We conclude that PCBs induce minisatellite mutations in meiosis and have recombinogenic properties, and that the mutations are induced in an Ah receptor‐independent manner. The induction of minisatellite mutations in meiosis as an indication of genomic damage must be taken into account in the risk assessment of PCBs and other environmental contaminants. Environ. Mol. Mutagen. 34:285–290, 1999. © 1999 Wiley‐Liss, Inc.

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Induction of genetic recombination: Consequences and model systems

Cited by 29 publications

References 53 publications

Contrasting mechanisms of de novo copy number mutagenesis suggest the existence of different classes of environmental copy number mutagens

Contrasting mechanisms of de novo copy number mutagenesis suggest the existence of different classes of environmental copy number mutagens

Recombinogenic activity of Pantoprazole® in somatic cells of Drosophila melanogaster

Polychlorinated biphenyls induce meiotic length mutations at the human minisatellite MS32 in yeast

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