Download DNA repair mechanism File

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)
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.
•
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", )