Wednesday, May 23, 2012

Mutations: Germ Line Mosaicism

Majia here: This post is a follow up from yesterday's post on genetic mutations and ionizing radiation

Today I examined some UN reports. It is worth noting that the World Health Organization (and probably all health related UN organizations) is subordinate in authority to the IAEA and is barred from conducting their own independent research on the effects of ionizing radiation.

Enenews had a report on this subordination

It is clear from the research I'm doing that the effects of ionizing radiation have been extraordinarily politicized in order to legitimize the insanity of nuclear bombs and nuclear "energy."

However, I will make that particular argument later.

Right now I'm focusing on current research summaries of the effects of ionizing radiations on mutations.

The following report offers a discussion of germ line mosaicism that accords with the 1956 report I looked at yesterday: Genetics Committee Report Concerning Effects of Radioactivity on Heredity

ANNEX UNSCAR REPORT: Hereditary effects of radiation 2001

page 62

[excerpted] "Germ-line mosaicism (the occurrence of a de novo mutation in a germ-line cell or one of its precursors during early embryonic development), however, will result in a “mutant sector” in the gonad of an otherwise phenotypically normal individual, and such an individual will generate gametes carrying the mutation, which in turn may result in individuals carrying the same mutation in the following generation (“mutant clusters”).

The occurrence of germ-line mosaicism provides an explanation for the inheritance patterns in cases where multiple affected children are born to clinically normal parents. For instance, some diseases that satisfy two of the requirements for autosomal recessive inheritance, namely, expression in the offspring of unaffected parents and recurrence within sibs, may actually be due to a dominant mutation that was present as a mosaic in the parental germ line.

In organisms such as the Drosophila and the mouse, a sizeable proportion of spontaneous mutations is known to arise as mosaics in the germ line and can be readily inferred from the occurrence of clusters of identical mutations in the progeny of singlepair matings [F27, R40, S99, S100, S101, S102, W28]." [end excerpt from page 62]

MAJIA HERE: NOTE the report argues that the calculations of risk for mice mutations should not be directly generalized (in a formula) to calculate human mutation rates:

[excerpted] (a) the use of entirely mouse-data based doubling doses to estimate human genetic risks is conceptually incorrect; (b) it is not possible to extrapolate from mouse data on mosaics and clusters to human spontaneous rates at present; and (c) the prudent way forward is to use spontaneous mutation rates of human genes and rates of induced mutations in mouse genes to estimate doubling doses, as was first done in the 1972 BEIR Report." (page 64)

MAJIA HERE: Limits of mice studies for calculating specific risk factors duly noted.


This point was noted and emphasized in the 1956 Genetics Committee Report Concerning Effects of Radioactivity on Heredity I discussed yesterday.

It is an important point because it implies that many of the genetic mutations caused by radiation (and chemicals) may not be visible until they accumulate to such an extent that they cause gross mutations. The mutations can effectively "sneak" up on a population across generations:

[excerpted] "It can be argued, however, that a significant proportion of mutations or deletions in developmental genes is recessive, i.e. heterozygotes do not manifest the abnormal developmental phenotype. Some support for this line argument comes from homozygosity tests of radiation-induced specific locus mutations in mice which uncovered the existence of this class of mutations that were not detected by phenotypic analysis (e.g. [R12]).

Majia here: The report yesterday noted that although the mutations may be latent, they can still affect the health of the affected individual and may be carried down generations whereupon the accumulation of errors produces greater magnitude problems, since each generation inherits all genetic damage to germ line cells acquired by his/her family line.

On Friday or later this weekend I plan on examining ANNEX C: Non-Targeted and Delayed Effects of Exposure to Ionizing Radiation 2006

Before concluding this post, I would like to point to a research study on mice that found that older male mice exposed to ionizing radiation had more permanent germ-line damage.

I found this study interesting because a correlation has been observed between advanced paternal age and autism.

The study still has bearing on this problem I think, while I acknowledge the error of extrapolating  actual quantitative risk figures for humans from mice:

Ionizing radiation-induced mutant frequencies increase transiently in male germ cells of older mice  Guogang Xua, C. Alex McMahanb, Kim Hildretha, Rebecca A. Garciaa, Damon C. Herberta, Christi A. Walter Mutation Research/Genetic Toxicology and Environmental Mutagenesis Available online 31 January 2012


[excerpt] Spontaneous mutant frequency in the male germline increases with age, thereby increasing the risk of siring offspring with genetic disorders. In the present study we investigated the effect of age on ionizing radiation-induced male germline mutagenesis. lacI transgenic mice were treated with ionizing radiation at 4-, 15- and 26-month-old, and mutant frequencies were determined for pachytene spermatocytes and round spermatids at 15 days or 49 days after ionizing radiation treatment.

Cells collected 15 days after treatment were derivatives of irradiated differentiating spermatogenic cells while cells collected 49 days later were derivatives of spermatogonial stem cells. The results showed that (1) spontaneous mutant frequency increased in spermatogenic cells recovered from nonirradiated old mice (26-months-old), particularly in the round spermatids; (2) mutant frequencies were significantly increased in round spermatids obtained from middle-aged mice (15-months-old) and old age mice (26-months-old) at 15 and 49 days after irradiation compared to the sham-treated old mice; and (3) pachytene spermatocytes obtained from 15- or 26-month-old mice displayed a significantly increased mutant frequency at 15 days post irradiation.

This study indicates that age modulates the mutagenic response to ionizing radiation in the male germline.

[excerpt from article] "Advanced paternal age (about 40 years or older at the time of conception) is associated with an increased incidence of a wide range of genetic and epigenetic diseases in offspring [2]. For example de novo mutations (C to G in fibroblast growth factor receptor 2 (FGFR2) gene) in 57 Apert cases were all of paternal origin…In addition to several diseases with clear Mendelian inheritance, advanced paternal age is also linked to an increased risk for diabetes with a genetic component such as childhood cancers [5-7], diabetes mellitus type [8], multiple sclerosis [9], autism [10] and congenital malformations [11], and others. The association between paternal age and increased risk for diseases in offspring may be at least partially ascribed to mutagenesis in male gametes [12-16]."

Majia here: My previous post on this study and its potential implications for autism

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