Germinal Mutations

M8. Marafioti, T., Hummel, M., Anagnostopoulos, I., Foss, H. D., Falini, B., Delsol, G., Isaacson, P. G., Pileri, S., and Stein, H., Origin of nodular lymphocyte-predominant Hodgkin s disease from a clonal expansion of highly mutated germinal-center B cells. N. Engl. J. Med. 337, 453— 458 (1997). 

Marafioti T, Hummel M, Anagnostopoulos I, et al. Origin of nodular lymphocyte-predominant Hodgkin s disease from a clonal expansion of highly mutated germinal-center B cells. NEngl JMed. 1997 337 453-458. 

Sierra, L.M., A.R. Barros, M. Garcia, J.A. Ferreiro, and M.A. Comendador. 1991. Acrolein genotoxicity in Drosophila melanogaster. I. Somatic and germinal mutagenesis under proficient repair conditions. Mutat. Res. 260 247-256. 

The ACE gene encodes two isozymes (somatic ACE isozyme and germinal ACE isozyme). ACE is a membrane-bound enzyme on the surface of vascular endothelial cells that also circulates in plasma and shows great individual variability determined by an I/D polymorphism in intron 16 of the ACE gene (ACE-I/D polymorphism). More than 160 ACE polymorphisms have been reported, 34 of which are located in coding regions, and 18 are missense mutations (606). ACE-related polymorphic variants have been associated with hypertension, atherosclerosis, stroke, left ventricular hypertrophy, chronic renal failure in IgA nephropathy, Henoch-Schonlein purpura nephritis, mechanical efficiency of skeletal muscle, intracranial aneurysms, susceptibility to myocardial infarction, diabetic nephropathy, AD, and longevity (12,606,607). 

Leopardi, P, Zijno, A.. Bassani. B. Pacchierotti, F. (1993) In vivo studies on chemically induced aneuploidy in mouse somatic and germinal cells. Mutat. Res., 287, 119-130... 

Liu, Y.J., Malisan, F., de Bouteiller, O., Guret, C., Lebecque, S., Banchereau, J., Mills, F.C., Max, E.E., Martinez-Valdez, H. (1996). Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation. Immunity 4,241-250. 

The ALS inhibitors are at the highest risk for the selection of resistance in weeds because they have a single target site, are effective against a wide spectrum of weeds, are now used extensively on many crops, and are relatively persistent - often providing season-long control of germinating weed seeds (Brown et al., 1995). Also, the various sites of mutations for resistance are not near the active site of the enzyme. As a result, there is no fitness loss due to a lower affinity for the normal substrates (Christoffoleti et al., 1997). 

The final stage of B cell differentiation where the BCR repertoire is shaped is the germinal centre (GC) reaction. In the T cell dependent GC reaction, the BCR is adapted for its cognate antigen by somatic hypermutation (SMH) and class switch recombination (CSR), both of which are driven by activation induced cytidine deaminase (AID). Since AID induces targeted point mutations in the CDRs of the Ig HCs and Ig LCs, this can dramatically alter the BCR affinity or even its specificity. As AID activity may also result in the formation of an autoreactive BCR, a stringent counterselection of such self-reactive B cells is required. By analysis in human of the BCR repertoire of post-GC IgG+ memory B cells, it was demonstrated that indeed new auto-reactive B cells develop by SHM whereas 20% of naive B cells is self-reactive, up to 40% of the IgG+ memory B cells expressed a true de novo created self-reactive BCR. Apparently, lack of T cell help prevents activation of these self-... 

Mutation breeding Seeds are put in a highly carcinogenic solution or treated with radiation to induce random changes in the DNA. After germination, surviving seedlings that have new and useful traits are then used by breeders. 

The organism most closely related to man for which any germinal-mutation rates have been measured is the mouse. 

STRATEGIES FOR RISK ASSESSMENT THE CHOICE AND USE OF TEST SYSTEMS TO ESTIMATE HUMAN GERMINAL MUTATION... 

The transmission of the mutation. Tests on germinal tissue are preferable to those on somatic cells. 

It would be valuable for making estimates of human germinal risk to know the strength of a correlation between Drosophila data and those on the mouse. It is instructive to compare the results of tests of the same chemical in the two organisms. For the present discussion, we use qualitative comparisons only a chemical either produced or did not produce a significant increase in the mutation rate. 

Until direct human dosimetry and germinal mutation-rate measurement are possible, we have to develop and study such testing bridges. It is not expected that a single... 

Chapter 6 considered the estimation of the human germinal mutation rate. Because of the paucity of information from direct human observation, it is necessary to extrapolate from studies of experimental organisms, cell cultures, and the like. The results of extrapolation are uncertain. 

For example, female first-degree relatives of women who have had breast cancer have a risk of breast cancer 2-3 times as great as normal, but the data do not fit any simple hypothesis. For most cancers, heritability is rather low. Therefore, the mutation component is likely to be low. There may be a mutation component acting through both germinal and somatic effects. If the two-mutation hypothesis for childhood tumors is correct, an environmental chemical could increase not only the frequency with which the first mutation would be inherited but also the frequency with which the second, somatic mutation would occur. Most calculations concerning retinoblastoma assume that the second mutation is almost certain to happen somewhere in the retina, provided that the first, inherited mutant gene is present. 

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