The effects of MSH2 deficiency on spontaneous and radiation-induced mutation rates in the mouse germline

Burr, Karen; Duyn-Goedhart, A. Van; Hickenbotham, Peter; Monger, Karen; Buul, Paul P.W. van; Dubrova, Yuri E.

doi:10.1016/j.mrfmmm.2007.01.010

Cited by 19 publications

(22 citation statements)

References 23 publications

(49 reference statements)

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“…Our study involved chronic exposure and did not estimate the frequency of DNA strand breaks, so a similar conclusion cannot be made from our data. However, several experiments have demonstrated that mutation spectra (i.e., patterns of gains and losses in repeat units) are identical in exposed and control mice, confirming the hypothesis that the same mechanism may operate in induced and spontaneous ESTR mutation (6,47,48). In our study, the ESTR mutation spectra of HEPA and whole air sperm samples were also identical (data not shown), suggesting that the same nontargeted mechanism may operate for chronic exposure to airborne particulates.…”

Section: Discussionsupporting

confidence: 85%

Germ-line mutations, DNA damage, and global hypermethylation in mice exposed to particulate air pollution in an urban/industrial location

Yauk¹,

Polyzos²,

Rowan-Carroll³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

274

202

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Particulate air pollution is widespread, yet we have little understanding of the long-term health implications associated with exposure. We investigated DNA damage, mutation, and methylation in gametes of male mice exposed to particulate air pollution in an industrial/ urban environment. C57BL/CBA mice were exposed in situ to ambient air near two integrated steel mills and a major highway, alongside control mice breathing high-efficiency air particulate (HEPA) filtered ambient air. PCR analysis of an expanded simple tandem repeat (ESTR) locus revealed a 1.6-fold increase in sperm mutation frequency in mice exposed to ambient air for 10 wks, followed by a 6-wk break, compared with HEPA-filtered air, indicating that mutations were induced in spermatogonial stem cells. DNA collected after 3 or 10 wks of exposure did not exhibit increased mutation frequency. Bulky DNA adducts were below the detection threshold in testes samples, suggesting that DNA reactive chemicals do not reach the germ line and cause ESTR mutation. In contrast, DNA strand breaks were elevated at 3 and 10 wks, possibly resulting from oxidative stress arising from exposure to particles and associated airborne pollutants. Sperm DNA was hypermethylated in mice breathing ambient relative to HEPAfiltered air and this change persisted following removal from the environmental exposure. Increased germ-line DNA mutation frequencies may cause population-level changes in genetic composition and disease. Changes in methylation can have widespread repercussions for chromatin structure, gene expression and genome stability. Potential health effects warrant extensive further investigation.DNA adducts ͉ DNA strand breaks ͉ tandem repeat mutation C ombustion of fossil fuels results in the production of complex mixtures of chemicals that are released into the environment and potentially affect millions of people globally. Previous work demonstrated that the offspring of wild birds breeding near integrated steel mills on the North American Great Lakes inherited increased numbers of tandem repeat DNA sequence mutations compared with those from areas without steel mills (1, 2). Subsequent studies investigated expanded simple tandem repeat (ESTR) mutation in outbred laboratory mice caged near two integrated steel mills and a major highway in Hamilton, Ontario, Canada, and at a rural reference site (3, 4). Using a pedigree approach (5), a significant increase in germ-line mutation rate was found in mice housed in the industrial environment compared with the reference site. The majority of mutations were transmitted through the paternal germ line. High-efficiency particulate-air (HEPA) filtration of the ambient air resulted in a significant reduction in mutation frequency, down to levels measured at the reference location (4). Therefore, the particulate fraction of air in this industrial location was largely responsible for the mutagenic hazard.These findings show that chemical pollutants may cause heritable mutation. Further research is required to confirm these results...

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Section: Discussionsupporting

confidence: 85%

Germ-line mutations, DNA damage, and global hypermethylation in mice exposed to particulate air pollution in an urban/industrial location

Yauk¹,

Polyzos²,

Rowan-Carroll³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

274

202

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“…Given that spontaneous ESTR mutation is most probably attributed to replication slippage (5,38,39), replication pausing caused by the delayed recognition/ repair of endogenous DNA damage by GGR may enhance this process, thus affecting the stability of ESTR loci. The current and previous data (5)(6)(7)(8) showing the very similar spectra of germline mutations in the deficient and isogenic wild-type strains further support this hypothesis, as they suggest that spontaneous ESTR instability across all genotypes may be attributed to the same mutation mechanism. The pattern of ESTR mutation induction in the germ line of irradiated DNA repair-deficient mice clearly differs (Fig.…”

Section: Discussionsupporting

confidence: 79%

“…Our recent data showing elevated ESTR mutation rate in the germ line of Polj knockout mice with compromised translesion synthesis (7) further support this hypothesis. The same is true for Msh2 knockout mice (8), which are deficient in the removal a variety of mismatched DNA pairs arising during replication and recombination (1). The delay in recognition and repair of bulky lesions and some other type of DNA damage may also affect DNA replication in Xpc À/À mice, resulting in replication fork pausing.…”

Section: Discussionmentioning

confidence: 99%

“…However, to date, little is known about the effects of NER deficiency on mutation rate in the germ line. In our previous studies, we have analyzed the germline effects of several DNA repair deficiencies on spontaneous and radiation-induced mutation rates at the mouse expanded simple tandem repeat (ESTR) DNA loci (5)(6)(7)(8). Using the same experimental approach, we report here that defective NER in Xpc knockout mice affects spontaneous and radiation-induced mutation rates in the mouse germ line.…”

Section: Introductionmentioning

confidence: 99%

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The Combined Effects of Xeroderma Pigmentosum C Deficiency and Mutagens on Mutation Rates in the Mouse Germ Line

Miccoli¹,

Burr

Hickenbotham

et al. 2007

Cancer Research

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Spontaneous and induced mutation rates at two expanded simple tandem repeat (ESTR) loci were studied in the germ line of xeroderma pigmentosum group C (Xpc) knockout mice defective in global genome nucleotide excision repair. Spontaneous and radiation-induced mutation rates in homozygous Xpc À/À males were significantly higher than those in isogenic wild-type (Xpc +/+ ) and heterozygous (Xpc +/À

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“…Because tumor development generally occurs late in life, the effects on reproductive fitness are small to moderate. Homozygous knockouts of MMR genes can elevate mutation rates by as much as 100-fold, whereas the effects in heterozygotes are much more modest, again implying partial dominance (' 10% penetrance) (Borgdorff et al 2005;Hegan et al 2006;Burr et al 2007). On the other hand, consistent with the observations on heterologous systems noted above, the degree of dominance for missense mutations with moderate effects on repair efficiency can be much more pronounced (Parsons et al 1995;Drotschmann et al 1999), with some data suggesting that heterozygous mammalian carriers of missense mutations at MMR loci have mutation rates elevated by factors of 5-10 (Coolbaugh- Murphy et al 2004;Alazzouzi et al 2005).…”

Section: Expected Frequency Of Detrimental Alleles For Replication/rementioning

confidence: 99%

The Cellular, Developmental and Population-Genetic Determinants of Mutation-Rate Evolution

2008

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Although the matter has been subject to considerable theoretical study, there are numerous open questions regarding the mechanisms driving the mutation rate in various phylogenetic lineages. Most notably, empirical evidence indicates that mutation rates are elevated in multicellular species relative to unicellular eukaryotes and prokaryotes, even on a per-cell division basis, despite the need for the avoidance of somatic damage and the accumulation of germline mutations. Here it is suggested that multicellularity discourages selection against weak mutator alleles for reasons associated with both the cellular and the population-genetic environments, thereby magnifying the vulnerability to somatic mutations (cancer) and increasing the risk of extinction from the accumulation of germline mutations. Moreover, contrary to common belief, a cost of fidelity need not be invoked to explain the lower bound to observed mutation rates, which instead may simply be set by the inability of selection to advance very weakly advantageous antimutator alleles in finite populations.

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The effects of MSH2 deficiency on spontaneous and radiation-induced mutation rates in the mouse germline

Cited by 19 publications

References 23 publications

Germ-line mutations, DNA damage, and global hypermethylation in mice exposed to particulate air pollution in an urban/industrial location

Germ-line mutations, DNA damage, and global hypermethylation in mice exposed to particulate air pollution in an urban/industrial location

The Combined Effects of Xeroderma Pigmentosum C Deficiency and Mutagens on Mutation Rates in the Mouse Germ Line

The Cellular, Developmental and Population-Genetic Determinants of Mutation-Rate Evolution

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