Mutational load

Error-prone PCR alteration of PCR amplification protocol introduces errors low yield of product and some amino acid substitutions are inaccessible libraries contain increasing fraction of inactive clones with higher mutational loads You, 1996... 

C6. Chinnery, R F., Howell, N., Lightowlers, R. N., and Turnbull, D. M., Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes. Brain 120, 1713-1721 (1997). 

Another problem is the impact of "mild" mutations— those which produce only small effects, which arise at relatively high rates, and which are inefficiently selected out of populations. Although it is currently virtually impossible to detect such effects clinically in humans, it is clear that they contribute markedly to the total mutational load in Drosophila, where they outnumber "severe" (recessive lethal and semilethal) mutations by a factor of at least 10 and significantly reduce the health of the typical wild fly. The same is true for mutations induced by ethyl methanesulfonate, but other chemicals have not been tested. 

Klekowski, E.J., Jr. Mutational load in a fern population growing in a polluted environment. Amer. 

A detailed analysis of the effect of the mutational load on the distribution of protein activity within a mutant population has been carried out... 

Miller Ify is principally a reflection of mutation load, and it s not a component of fitness but rather it is a subfactor of fitness, this might explain its heritability, the... 

Miller If g is basically an index of fitness and if it is indeed the case that fitness is determined by the deleterious mutation load, there is not going to be sexual dimorphism in mutation load. After all, the two sexes basically share the same genes except those on the Y chromosome. 

Many heritable mutations are correlated with a reduced fitness, i.e. a reduced survival probability of the offspring of the mutant. The reduction in average fitness with the arrival of new mutations is called mutation load (Crow and Kimura, 1970). However, the more deleterious a mutation is, the sooner it will... 

The mutation and malfunction of key components of DNA repair and DNA damage checkpoints will lead to an increased mutational load on the cell and will favor the accumulation of further genetic changes. One hypothesis is that tumor cells acquire - at some state of the tumor development - a mutator phenotype, which is characterized by an increased mutation rate due to a malfunction of gene products responsible for the maintenance of genetic stability (see Section 14.1.5). 

Knowing which pathways of PAH activation prevail provides a rationale for the detection and quantitation of PAH-derived DNA adducts in population-based studies. Measurement of these adducts provides a method for biomonitoring PAH exposure and provides a risk assessment for susceptibility to diseases such as lung cancer. This could be particularly useful if it is assumed that there is a correlation between DNA adducts, mutational load, and, ultimately, tumor formation. 

Iivneh, Z. (2006) Keeping mammalian mutation load in check. Regulation of the activity of error-prone DNA polymerases by p53 andp21. Cell Cycle, 5,1918-1922. 

Fig. 3 The two phases of variant colorectal carcinogenesis. The dots symbolize the numerous mutations accumulated because of the RER mutator phenotype. The arrows symbolize the three assumptions of the model (1) The first step is acquisition of the RER mutator phenotype. Cells with MMR deficiency have no growth advantage. (2) Cells with an RER mutator phenotype may undergo malignant transformation through a several-step process that is purely mutation driven initially. (3) The mutation load rapidly causes the elimination of nontransformed cells with an RER mutator phenotype. Apoptosis or senescence restrict their life span to a limited number of replications.

The probability p2 and p3 is proportional to the number of viable progeny of a RER+ stem cell, which depends on two parameters the number X of viable self-maintenance divisions of the stem cell (which in turn essentially depends on the threshold of mutations induced apoptosis), and the number N of mitoses that ephemeral colonocytes undergo in the crypt on their way to maturation (Fig. 4B). Since neither X (defined by the tolerable mutation load) nor N should vary at a given point in the colon, p2 and p3 should also remain constant throughout life, and likewise the product pt (p2 and p3). The accumulation of these rate-limiting steps of RER+ carcinogenesis can thus be assimilated to an accident that can happen any time with a constant risk. 

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