Mutator mutations

Fig. 2.9. The thermodynamic cycle used for the determination of protein-ligand relative binding free energies. Instead of carrying the horizontal transformations one can mutate the ligand in the free state - i.e., the left, vertical alchemical transformation , and in the bound state -i.e., the right, vertical alchemical transformation. This yields the difference in the binding free energies. AA I, jI,I j T. binding A mutation mutation...

Sankaranarayanan, K. 1991c. Ionizing radiation and genetic risks IV. Current methods, estimates of risk of Mendelian disease, human data and lessons from biochemical and molecular studies of mutations. Mutat. Res. 258 99-122. 

Zimmermann, F.K., Kern, R. and Rasenberger, H.A. (1975) Yeast strain for simultaneous detection of induced mitotic crossing over, mitotic gene conversion and reverse mutation. Mutation Research, 28, 381-388. 

The best way to illustrate the importance of DNA repair is to consider the effects of unrepaired DNA damage (a lesion). The most serious outcome is a change in the base sequence of the DNA, which, if replicated and transmitted to future cell generations, becomes permanent. A permanent change in the nucleotide sequence of DNA is called a mutation. Mutations can involve the replacement of one base pair with another (substitution mutation) or the addition or deletion of one or more base pairs (insertion or deletion mutations). If the mutation affects nonessential DNA or if it has a negligible... 

Schneikert, J., and Herscovics, A. (1995). Two naturally occurring mouse a-mannosidase IB cDNA clones differ in three point mutations. Mutation of Phe592 to Ser592 is sufficient to abolish enzyme activity. J. Biol. Chem., 270, 17736-17740. 

BACK MUTATION Mutation of a mutated gene to its former condition. (See also REVERSION and SUPPRESSION)... 

FORWARD MUTATION Mutation at any site in a nonmutant gene giving rise to a mutant allele of that gene. 

GENE MUTATION Mutation due to a molecular change in a gene, as opposed to a large chromosomal mutation includes point mutations and intragenic deletions. 

REVERSE MUTATION Mutation that restores the wild-type phenotype or gene function in a mutant may occur either by restoration of the original DNA sequence (back mutation) or by indirect compensation for the original mutation (suppression). 

Russell, L.B. Definition of functional units in a small chromosomal segment of the mouse and its use in interpreting the nature of radiation-induced mutations. Mutat. Res. 11 107-123, 1971. 

Selby, P.B., and P.R. Selby. Gamma-ray-induced dominant mutations that cause skeletal abnormalities in mice. II. Description of proved mutations. Mutat. 

Base-pair substitution Frameshift mutations mutations... 

Non-additivity arises from the simultaneous disruption of coupled residues by multiple mutations. Mutations affecting some functions, such as protein-protein and DNA-protein interactions, tend to be remarkably additive, while others, such as mutations in the catalytic site, tend to be non-additive (Jencks, 1981 Wells, 1990). Mutational studies on T4 lysozyme (Zhang et al., 1995) and catalase I (Trakulnaleamsai et al., 1995) indicate that thermostability is largely additive, and therefore relatively uncoupled. Non-additivity is most commonly observed when the mutated residues are close in space and large, or when chemically disparate side chains are introduced. 

The overmodification of collagen from patients 1 and 2 is weak because it occurs only on the N-terminal side of the mutation. Mutations located closer to the C-terminal end lead to substantially larger overhydroxylation and overgly-cosylation. In principle, this overmodification gradient could explain milder OI symptoms observed for N-terminal glycine substitutions (e.g., almost no lethal substitutions in the N-ter-minal quarter of collagen were reported, and many of these cases were classified as type I OI). However, no consistent severity gradient and no correlations of symptoms with over-modification were found for mutations located further toward the C-terminal end. Thus, the role of overmodification in OI phenotype still remains unclear. 

The main source of information about the sequence requirements of promoters is provided by mutations. Mutations in promoters affect the level of expression of the gene they control without altering the gene product. 

Tannoka H. 1977. Development and application of Bacillus subtilis test systems for mutagens, involving DNA-repair deficiency and suppressible auxotrophic mutations. Mutat Res 42 19-32. 

Fig. 13 PARK9 ATP13A2 structure and mutations. Mutations found in young-onset PD (T12M, G504R, and G533R Di Fonzo et al., 2007) and Kufor-Rakeb syndrome PD (1306+5G/A, 1632 1653dup22, 3057delC Ramirez et al., 2006) are shown. TM, transmembrane domain. Scale is approximate...

Patient Genotype Exon Mutation Mutation Phenotype RNA Splicing Aminoacid Substitution Ref... 

Frame shift mutation—Mutation caused by the deletion or insertion one or more bases into the DNA molecule, shifting the frame of the triplet code for an amino acid. Such mutations can change a long string of amino acids, thereby severely altering the structure and function of a protein product. 

Germinal mutation—mutation in the germ cells (sperm or egg cells). This mutation can be passed on to succeeding generations. 

Essential for assessment of the impact of pollutants at population level is the distinction that is made between somatic and germ-line mutations. Mutations in somatic cells may (among other effects) induce neoplasia, but because they do not occur in cells that give rise to gametes the mutation will not be passed on to the next generations. 

Ross, J. A., and Nesnow, S. (1999). Polycyclic aromatic hydrocarbons Correlations between DNA adducts and ras oncogene mutations. Mutat Res 424, 155-166. 

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