Germline minisatellite mutations in survivors of childhood and young adult cancer treated with radiation

Tawn, E. Janet; Rees, Gwen S.; Leith, Cheryl; Winther, Jeanette Falck; Curwen, Gillian B.; Stovall, Marilyn; Olsen, Jørgen H.; Rechnitzer, Catherine; Schrøeder, Henrik; Guldberg, Per; Boice, John D.

doi:10.3109/09553002.2011.530338

Cited by 31 publications

(27 citation statements)

References 25 publications

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“…We also recommend that additional dose-response studies and analysis of other mutagens be conducted to establish fully the sensitivity of the assay for germ-cell mutation analysis. This method can be applied potentially to environmental biomonitoring using sentinel species and to human populations to assess the effects of variables that influence heritable mutagenesis [1,4,33,[60][61][62][63][64][65][66]. Our new method expands our ability to detect mutations in germ cells, but we must consider the diverse types of mutation mechanisms and continue to expand the mutational landscape that we can capture in toxicological screening [67].…”

Section: Discussionmentioning

confidence: 99%

Single-molecule PCR analysis of an unstable microsatellite for detecting mutations in sperm of mice exposed to chemical mutagens

Beal

Rowan-Carroll

Campbell

et al. 2015

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Single-molecule PCR (SM-PCR) analysis of long and repetitive DNA sequences, known as expanded simple tandem repeats (ESTRs), has been the most efficient method for studying germline mutation induction in endogenous sequences to date. However, the long length of these sequences makes mutation detection imprecise and laborious, and they have been characterized only in mice. Here, we explore the use of unstable microsatellite sequences that can be typed with high precision by capillary electrophoresis as alternative loci for detecting germline mutations. We screened 24 microsatellite loci across inbred mouse strains and identified Mm2.2.1 as the most polymorphic microsatellite locus. We then optimized SM-PCR of Mm2.2.1 to detect mutations in sperm. SM-PCR analysis of sperm from untreated B6C3F1 and Muta(™)Mouse samples revealed mutation frequencies that are consistent with rates derived from family pedigree analysis (∼ 5 × 10(-3)). To determine whether this locus can be used to detect chemically induced germline mutations, Muta(™)Mouse males were exposed by oral gavage to a single dose of 100mg/kg of N-ethyl-N-nitrosourea (ENU) or to 100mg/kg of benzo(a)pyrene (BaP) for 28 days alongside vehicle treated controls. Sperm were collected 10 weeks post-ENU exposure to sample sperm exposed as spermatogonial stem cells and 6 weeks post-BaP exposure to sample sperm that were dividing spermatogonia when the exposure was terminated. Both treatments resulted in a significant (approximately 2-fold) increase in mutation frequency in sperm compared to the control animals. The work establishes the utility of this microsatellite for studying mutation induction in the germ cells of mice. Because microsatellites are found in virtually every species, this approach holds promise for other organisms, including humans.

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Section: Discussionmentioning

confidence: 99%

Single-molecule PCR analysis of an unstable microsatellite for detecting mutations in sperm of mice exposed to chemical mutagens

Beal

Rowan-Carroll

Campbell

et al. 2015

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…Blood samples were taken from 44 subjects from 17 Danish families and one Finnish family. The same samples have been used in a variety of previous studies (Curwen et al, 2010; Curwen et al, 2005; Tawn et al, 2011; Tawn et al, 2005) that describe in detail the sample collection and DNA extraction protocols. Because mitochondria are solely maternally inherited, and paternal samples were not available, only mothers and their offspring were included in this study.…”

Section: Methodsmentioning

confidence: 99%

Very Low-Level Heteroplasmy mtDNA Variations Are Inherited in Humans

Guo¹,

Sheng³

et al. 2013

Journal of Genetics and Genomics

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Little is known about the inheritance of very low heteroplasmy mitochondria DNA variations. Even with the development of new next-generation sequencing methods, the practical lower limit of measured heteroplasmy is still about 1% due to the inherent noise level of the sequencing. In this study, we sequenced the mitochondrial genome of 44 individuals using Illumina high-throughput sequencing technology and obtained high-coverage mitochondria sequencing data. Our study population contains many mother-offspring pairs. This unique study design allows us to bypass the usual heteroplasmy limitation by analyzing the correlation of mutation levels at each position in the mtDNA sequence between maternally related pairs and non-related pairs. The study showed that very low heteroplasmy variants, down to almost 0.1%, are inherited maternally and that this inheritance begins to decrease at about 0.5%, corresponding to a bottleneck of about 200 mtDNA.

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“…The children of cancer survivors who received radiotherapy constitute another population which has recently received attention [56]. DNA samples from 100 families, where one parent was a cancer survivor, were analysed for mutations at 8 hypervariable minisatellite loci by Southern hybridisation.…”

Section: Evidence Indicative Of Transgenerational Effects In Expermentioning

confidence: 99%

Evidence relevant to untargeted and transgenerational effects in the offspring of irradiated parents

Little

Goodhead

Bridges

et al. 2013

Mutation Research/Reviews in Mutation Research

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In this article we review health effects in offspring of human populations exposed as a result of radiotherapy and some groups exposed to chemotherapy. We also assess risks in offspring of other radiation-exposed groups, in particular those of the Japanese atomic bomb survivors and occupationally and environmentally exposed groups. Experimental findings are also briefly surveyed. Animal and cellular studies tend to suggest that the irradiation of males, at least at high doses (mostly 1 Gy and above), can lead to observable effects (including both genetic and epigenetic) in the somatic cells of their offspring over several generations that are not attributable to the inheritance of a simple mutation through the parental germ line. However, studies of disease in the offspring of irradiated humans have not identified any effects on health. The available evidence therefore suggests that human health has not been significantly affected by transgenerational effects of radiation. It is possible that transgenerational effects are restricted to relatively short times post-exposure and in humans conception at short times after exposure is likely to be rare. Further research that may help resolve the apparent discrepancies between cellular/animal studies and studies of human health are outlined.

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Germline minisatellite mutations in survivors of childhood and young adult cancer treated with radiation

Cited by 31 publications

References 25 publications

Single-molecule PCR analysis of an unstable microsatellite for detecting mutations in sperm of mice exposed to chemical mutagens

Single-molecule PCR analysis of an unstable microsatellite for detecting mutations in sperm of mice exposed to chemical mutagens

Very Low-Level Heteroplasmy mtDNA Variations Are Inherited in Humans

Evidence relevant to untargeted and transgenerational effects in the offspring of irradiated parents

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