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Genetic variations
and Gene
Rearrangements
Mutation
Def.: It is a physical change of one or more
nucleotide pairs in the DNA of a cell. The change
is inherited by every descendant of the mutant
cell.
Classification:•Genotypic classification.
•Phenotypic classification (functional).
•Classification according to the inducibility.
A. Genotypic CLASSIFICATIONPoint mutation (micro lesion):
•Changes in a single nucleotide
base pair by substitution,
addition or deletion
(frame shift )
•Substitution of purine
by purine or pyrimidine
by pyrimidine is called
Transition.
•Substitution of purine
by pyrimidines is called
transversion.
Multisite Mutation ( macro lesion ):
Change of multiple nucleotides :-
•Deletion: Missing of nucleotides
•Duplication: a number of nucleotides are
repeated.
•Insertion: addition of novel base pairs.
•Rearrangements: all the base pairs are present
but the order changes.
•Frame shift: may be point (addition or deletion
of one bp) also multisite (addition or deletion of
more than one base pairs).
Original:
The fat cat ate the wee rat.
Frame Shift (“a” added):
The fat caa tet hew eer at
B. Phenotypic mutation
Because not all mutations are harmful and many point mutations are silent this classification is done on the basis of the effect of mutation ( phenotypic changes )
Same sense
Missense
Non-sense
Same sense mutation: Means mutation in one base in a codon
that results in another codon for the same
amino acid for example leucine.
UUA UUG
Leucine Mutation Leucine
Missense mutationMeans mutation in an amino acid codon
that results in a codon of another amino
acid.
TTG GTG
Tryptophan Glycine
The effect of missense depends on the
location of the changed amino acid in the
polypeptide chain.
Nonsense mutation:• Means mutation that changes a codon into
one of the 3 chain termination codons
( UAG , UAA, UGA)
•The effect of nonsense mutation depends
on where the chain is terminated i.e. the
truncated protein may have no activity,
some activity or full activity.
C. Classification according to inducibilityMutation can occur spontaneously with no external
applied agent, also can be induced by the application of
physical or chemical agents (mutagens).
Spontaneous mutation
Induced mutation
•Physical (UV- ionizing irradiation)
•Chemical
-Base analogs
-Base modifiers
-Intercalators
Spontaneous mutationIt can arise as a result of:
DNA polymerase incorporation errors during
replication or repair by mispairing and
misrepairing. (errors of DNA polymerase 10-4 base
pair/cell/generation.
After editing dropped to 10-6 to 10-7; after
repairing dropped to 10-9 to 10-10.
•Tautomeric shift in the bases (structure isomer).
involves the movement of hydrogen and
shifting of bonding
Induced mutation Mutation rates can be increased by chemical or physical
mutagens
Physical agents 1. Ultra violet light (UV):
Cause pyrimidine dimers (covalent linking of two
adjacent pyrimidine on the same strand) like T-T (68%)
C-T (13%), T-C (19%) and C-C (3%)..
2. Ionizing radiation
Causes DNA strand break either single or double strands
and inter stand covalent cross linking (hydrogen bonds
changes to covalent bonds).
Chemical mutagens Chemicals that make mutation in DNA can
be categorized in 3 groups
1. Chemicals that mimic normal DNA
bases (Base analogs ).
2. Chemical that react with DNA bases
(Base modifiers )
3. Chemicals that bind DNA bases
(Intercalators) .
1. Chemicals that mimic normal DNA
bases ( Base analogs ):
5- Bromouracil mimics Thymine.
2- Aminopurine mimics Adenine
•These analogs are structurally related to
bases but differ in pairing manner.
2. Chemical that react with DNA bases
( base modifiers ) These chemical react directly with the nucleotide bases ,
altering the chemical structure as examples:-
•Nitrous oxide and Hydroxyl amine.
•Alkylating agents: These are the most commonly
mutagenic agents adding methyl or ethyl group to the
oxygen of bases.
Examples : Nitrosoguanidine (NTG) nitrogen mustard
gas, methyl-methane sulfonate (MMS) and ethyl methane
sulfonate (EMS).
3. Chemicals that bind DNA bases
(Intercalators) .Some molecules
such as Acridine dyes
and Acridine–like
derivatives (proflavin,
ethidium bromide) have
the same dimensions as
the normal bases so can
slide between two
adjacent base pairs
( intercalating ) causing
frame shift.
Effects of Mutation 1- Have no effect on the expression of a gene means
silent mutation.
2- Changes the level of gene expression (increase or
decrease).
3- Produce a related but structurally different protein.
4- Mutation may proceed to carcinogenesis.
5- Deletion mutation of the virulence gene in bacteria
can be used as a reference strain for vaccine (low
virulent or avirulent strain).