Role of mouse germ-cell mutagenesis in understanding genetic risk and in generating mutations that are prime tools for studies in modern biology

Abstract

Highlights are presented on (1) the role mouse germ-cell mutagenesis has played in assessing the genetic harm from radiations and chemicals, and (2) the contributions to the field of modern biology that are being made by the products of this research--the propagated mutations. Among the numerous findings in radiation mutagenesis were the humped dose-effect curve for spermatogonial stem cells, the major differences between the sexes and between germ-cell stages of each sex in both yield and nature of mutations, the dose-rate effect, which provided the first evidence for repair of mutational (or premutational) damage, the augmenting effect of certain regimes of dose fractionation, and many others. Chemical mutagenesis studies that followed revealed at least three patterns of mutation yield and demonstrated that germ-cell stage--much more than the nature of the chemical--governs the nature of the DNA lesions induced. Two "supermutagens," one for intragenic mutations and one for deletions and other rearrangements, have become very useful in the manufacture of mutations for specific purposes. The mutations propagated from radiation- and chemical-mutagenesis experiments are providing prime resources for basic studies in genome organization, gene structure, and function. DNA lesions that involve specific loci have made possible increasingly detailed characterization of extensive deletion complexes that facilitate high-intensity physical and functional mapping within them. Numerous loci associated with interesting developmental anomalies have been identified and have become accessible to positional cloning. Several of the genes accessed with the aid of induced mutations (deletions, other rearrangements, and point mutations) are furnishing prime reagents for elucidating human disease conditions.

Medical radiation exposure and risk of retinoblastoma resulting from new germline RB1 mutation

“…Therefore, the exposure must have occurred to stem cell spermatogonia, cells that persist throughout reproductive life. Radiation to stem cell spermatogonia in animals is well known to induce new heritable mutations 1 . It would seem that an effect on a stem cell might result in multiple affected children within a single family.…”

“…For all time intervals before the child's conception, more case mothers had a lower GI series compared with the control mothers, but the difference was smaller beyond 10 years. 1 Differences between fathers of all cases and fathers of controls were statistically significant for race or ethnicity (p < 0.001), educational level (p < 0.001), marital status (p ¼ 0.02) and smoking (p ¼ 0.006). The difference between fathers of cases in case-control sets and fathers of controls was statistically significant for educational level (p ¼ 0.02).…”

“…ORs of at least 2.0 and/or ORs significantly >1.0 were observed for mother's injury to the upper leg, hips, back, pelvis or internal organs; back problem other than scoliosis, slipped disc, arthritis, pain or surgery; arthritis of knees or hips; hip pain; constipation; blood in urine; bladder or kidney problem other than infection or blood in urine; sur-gery of the digestive system or internal organs; and injury to the head, neck or face (Supporting Information Table 2). Another indication for lower GI series, irritable bowel Interval before conception Radiation treatment for breast cancer, 95 mGy 0 (0) 0 (0) 2 (0.8) 1 No mothers reported a PET scan or MUGA scan. 2 Results from logistic regression model with race (non-Hispanic white and other), educational level (less than college degree, college degree or greater) and child's birth year; odds ratios not calculated for procedures with <10 exposed participants.…”

Heavy‐ion‐induced mutations in the gpt delta transgenic mouse: Comparison of mutation spectra induced by heavy‐ion, X‐ray, and γ‐ray radiation

“…One possible explanation is that apoptosis might occur more efficiently in germ cells than in somatic cells to exclude the damaged cells with double-strand DNA breaks [Beumer et al, 2000;Burger et al, 1998;Gartner et al, 2000]. Other possibilities-for example, more efficient and faithful rejoining of double-strand breaks in germ cells or different chromatin structures between germ cells and somatic cells-may explain the better preservation in germ cells [Choi et al, 1997;Russell, 1994]. Obviously, further research is needed to identify the exact mechanism(s).…”

Parental diet and risk of retinoblastoma resulting from new germline RB1 mutation

“…We studied diet in the year before the child's conception, a time period that encompasses the complete process of spermatogenesis, which is about 3 months long [Clermont, 1972]. In animals, radiation and chemicals induce germline mutations at all stages of spermatogenesis, including stem cell spermatogonia, which persist throughout reproductive life [Russell, 1994]. As adult diet is fairly stable, our findings do not rule out an effect beyond the 1 year interval that we studied.…”