Deviation from Mendelian transmission of autosomal SNPs can be used to estimate germline mutations in humans exposed to ionizing radiation (original) (raw)
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Monitoring of radiation-induced germline mutation in humans
Swiss medical weekly, 2003
Estimating the genetic hazards of radiation and other mutagens in humans depends on extrapolation from experimental systems. Recent data have shown that minisatellite loci provide a useful and sensitive experimental approach for monitoring radiation-induced mutation in humans. This review describes the progress made in validating this approach and presents the results of recent publications on the analysis of minisatellite mutation rates in the irradiated families.
Multisite de novo mutations in human offspring after paternal exposure to ionizing radiation
Scientific reports, 2018
A genome-wide evaluation of the effects of ionizing radiation on mutation induction in the mouse germline has identified multisite de novo mutations (MSDNs) as marker for previous exposure. Here we present the results of a small pilot study of whole genome sequencing in offspring of soldiers who served in radar units on weapon systems that were emitting high-frequency radiation. We found cases of exceptionally high MSDN rates as well as an increased mean in our cohort: While a MSDN mutation is detected in average in 1 out of 5 offspring of unexposed controls, we observed 12 MSDNs in altogether 18 offspring, including a family with 6 MSDNs in 3 offspring. Moreover, we found two translocations, also resulting from neighboring mutations. Our findings indicate that MSDNs might be suited in principle for the assessment of DNA damage from ionizing radiation also in humans. However, as exact person-related dose values in risk groups are usually not available, the interpretation of MSDNs in...
Mutagenesis, 2011
A serious radiological accident occurred in 1987 in Goiânia, Brazil, which lead to extensive human and environmental contamination as a result of ionising radiation (IR) from caesium-137. Among the exposed were those in direct contact with caesium-137, their relatives, neighbours, liquidators and health personnel involved in the handling of the radioactive material and the clean-up of the radioactive sites. The exposed group consisted of 10 two-generation families, totalling 34 people. For each exposed family, at least one of the progenitors was directly exposed to very low doses of g-IR. The control group consisted of 215 non-irradiated families, composed of a father, mother and child, all of them from Goiânia, Brazil. Genomic DNA was purified using 100 ml of whole blood. The amplification reactions were prepared according to PowerPlexÒ 16, following the manufacturer's instructions. Genetic profiles were obtained from a single polymerase chain reaction amplification. The exposed group had only one germline mutation of a paternal origin in the 'locus' D8S1179 and the observed mutation presented a gain of only one repeat unit. In the control group, 11 mutations were observed and the mutational events were distributed in five loci D16S539, D3S1358, FGA, Penta E and D21S11. The mutation rates for the exposed and control groups were 0.006 and 0.002, respectively. There was no statistically significant difference (P 5 0.09) between the mutation rate of the exposed and control groups. In conclusion, the quantification of mutational events in short tandem repeats can provide a useful system for detecting induced mutations in a relatively small population.
The genome-wide effects of ionizing radiation on mutation induction in the mammalian germline
The ability to predict the genetic consequences of human exposure to ionizing radiation has been a long-standing goal of human genetics in the past 50 years. Here we present the results of an unbiased, comprehensive genome-wide survey of the range of germline mutations induced in laboratory mice after parental exposure to ionizing radiation and show irradiation markedly alters the frequency and spectrum of de novo mutations. Here we show that the frequency of de novo copy number variants (CNVs) and insertion/deletion events (indels) is significantly elevated in offspring of exposed fathers. We also show that the spectrum of induced de novo single-nucleotide variants (SNVs) is strikingly different; with clustered mutations being significantly over-represented in the offspring of irradiated males. Our study highlights the specific classes of radiation-induced DNA lesions that evade repair and result in germline mutation and paves the way for similarly comprehensive characterizations of other germline mutagens.
Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident
Science, 2021
Effects of radiation exposure from the Chernobyl nuclear accident remain a topic of interest. We investigated germline de novo mutations (DNMs) in children born to parents employed as cleanup workers or exposed to occupational and environmental ionizing radiation after the accident. Whole-genome sequencing of 130 children (born 1987–2002) and their parents did not reveal an increase in the rates, distributions, or types of DNMs relative to the results of previous studies. We find no elevation in total DNMs, regardless of cumulative preconception gonadal paternal [mean = 365 milligrays (mGy), range = 0 to 4080 mGy] or maternal (mean = 19 mGy, range = 0 to 550 mGy) exposure to ionizing radiation. Thus, we conclude that, over this exposure range, evidence is lacking for a substantial effect on germline DNMs in humans, suggesting minimal impact from transgenerational genetic effects.
Genetic Radiation Risks-A Neglected Topic in the Low Dose Dabate
Environmental Health and Toxicology, 2016
The United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) as well as the International Commission on Radiological Protection (ICRP) present very low risk factor for hereditary diseases in humans based on experiments in mice. The claim is based on reportedly absent genetic effects in the acute exposed Japanese A-bomb survivors. We question the safety of these assumptions and have made a compilation of findings about early deaths, congenital malformations, Down´s syndrome, cancer and other genetic effects observed in humans after the exposure of parents. We review evidence from occupationally exposed groups, from studies in populations exposed to Chernobyl fallout and from the descendants of liquidators and nuclear test veterans. Nearly all types of hereditary defects were found at very low doses. We discuss this clash between risk models and observation on the basis of knowledge of biological mechanisms and the effect of assumptions about linear relations between dose and end point in neonatal epidemiology. Using data from Chernobyl effects we derive an Excess Relative Risk for all Malformations of 1.0 per 10mSv cumulative exposure to fission product contamination. The dose response is non-linear "hogs-back" or biphasic and saturates at doses above 10mSv
American Journal of Epidemiology, 2020
Although transgenerational effects of exposure to ionizing radiation have long been a concern, human research to date has been confined to studies of disease phenotypes in groups exposed to high doses and high dose rates, such as the Japanese atomic bomb survivors. Transgenerational effects of parental irradiation can be addressed using powerful new genomic technologies. In collaboration with the Ukrainian National Research Center for Radiation Medicine, the US National Cancer Institute, in 2014–2018, initiated a genomic alterations study among children born in selected regions of Ukraine to cleanup workers and/or evacuees exposed to low–dose-rate radiation after the 1986 Chornobyl (Chernobyl) nuclear accident. To investigate whether parental radiation exposure is associated with germline mutations and genomic alterations in the offspring, we are collecting biospecimens from father-mother-offspring constellations to study de novo mutations, minisatellite mutations, copy-number chang...
Hereditary Minisatellite Mutations among the Offspring of Estonian Chernobyl Cleanup Workers
Radiation Research, 2003
Kiuru, A., Auvinen, A., Luokkamäki, M., Makkonen, K., Veidebaum, T., Tekkel, M., Rahu, M., Hakulinen, T., Servomaa, K., Rytömaa, T. and Mustonen, R. Hereditary Minisatellite Mutations among the Offspring of Estonian Chernobyl Cleanup Workers. Radiat. Res. 159, 651-655 (2003).
Evaluation of radiation risk: cytogenetic and molecular markers of low-dose radiation effects
For last 15 years, we have investigated low-dose radiation genetic effects on human populations affected by the Chernobyl accident. Cytogenetic longitudinal investigations showed that radiation markers for cleanup workers remained at an elevated level and had a trend to grow up with time. A dynamic profile of the amount of aberrations confirms that this group has symptoms of the genomic instability state formation. This situation correlated with the incidence of morbidity. The state of genomic instability correlates with accumulation in cleanup workers blood clastogenic factors, which are responsible for increased genomic instability. As a model, we used keratinocyte human line with blocked first check point of cell cycle. The same situation took place for gene mutations (investigated by T-cell receptor [TCR] test) and mitochondrial "common deletion" frequencies (in situ polymerase chain reaction [PCR]) in cleanup workers as for other groups in the affected population (for children, especially). The outcomes of biology dose reconstruction will be presented. Results of longitudinal investigations confirm that cytogenetic and molecular effects of irradiation can be fixed even 20 years after the Chernobyl accident.