Molecular mechanism of mutation

Molecular Basis of Gene Mutation Mutations are changes in the DNA sequence of genes. Point mutations typically refer to alterations of single base pairs of DNA or of a small number of adjacent base pairs.           Mutations in DNA cause substitutions in protein  

New mutations are categorized as induced or spontaneous. Induced mutations are defined as those that arise after purposeful treatment with mutagens, environmental agents that are known to increase the rate of mutations Spontaneous mutations are those that arise in the absence of known mutagen treatment. They account for the "background rate" of mutation and are presumably the ultimate source of natural genetic variation that is seen in populations. The frequency at which spontaneous mutations occur is low, generally in the range of one cell in 105 to 108

Mutation can be classified as: germline - affecting tissues that produces eggs & sperm ( heritable meiotically between generations) somatic  - affecting other body tissues (heritable mitotically, e.g. cancer)

Most mutations are transitions: interchanges of bases of same shape Molecular mechanisms of DNA mutagenesis: Nucleotide interchanges are of two types: transition  is the replacement of a base by the other base of the same chemical category (purine replaced by purine: either A to G or G to A; pyrimidine replaced by pyrimidine: either C to T or T to C). transversion is the replacement of a base of one chemical category by a base of the other (pyrimidine replaced by purine: C to A, C to G, T to A, T to G; purine replaced by pyrimidine: A to C, A to T, G to C, G to T).           Most mutations are transitions: interchanges of bases of same shape

At the DNA level, there are two main types of point mutational changes base substitutions base additions or deletions.

Single-base mutations - interchanges of one DNA base type for another Genetic Consequences of Mutation : Single-base mutations - interchanges of one DNA base type for another recognized as SNPs (single nucleotide polymorphisms) Consequences of exon mutations depend on position in triplet (examples)             3rd position                  typically a silent mutation - if position "wobbles", no change to amino acid sometimes a missense mutation - results in different amino acid 2nd position - always a missense mutation    1st position - almost always a missense replacement [Leu codons are major exception]             Stop codon mutations may occur at any position: nonsense (termination) mutation terminates polypeptide prematurely                    

Missense mutations in DNA cause replacement substitutions in protein          Consequences depend on position of substitution in polypeptide     none:  substitution not in active site or binding site     minor: substitution of same type (synonymous substitution) allozymes are proteins with minor changes in electric charge     major: substitution affects 20, 30, or 40 structure (nonsynonymous substitution)              Ex.: Sickle-cell hemoglobin (HbS)                        glu - val  in sixth residue of beta chain                         because GAG  GUG in sixth codon of beta-chain mRNA                             

1- Silent substitutions: the mutation changes one codon for an amino acid into another codon for that same amino acid. 2- Missense mutations: the codon for one amino acid is replaced by a codon for another amino acid. 3- Nonsense mutations: the codon for one amino acid is replaced by a translation termination (stop) codon.

Insertion / Deletion (indel) mutations Gain or loss of one or more nucleotides produces: Frameshift mutations ( triplet reading frame change) Single & double nucleotide indel = all downstream amino acids change (e.g.)nonsense mutation eventually (quickly) produced Triplet indel - insertion / deletion of single amino acid produce milder consequences Multiple triplets may produce major effects (e.g.) length mutations - larger indels may affect cytology of chromosomes ("Fragile X", )