Mutations

YASMIN ABDO
Mutations are alterations in the base
sequence of genes

Such alterations can occur due to:

Accidental errors during replication

Exposure to ultra-violet light,

ionizing radiation and mutagens
Generally, repair mechanisms correct
most of these errors and defects

Rarely, some errors escape detection

and/or correction

The altered base sequence becomes

stably incorporated in the genome
 These stable alterations in base
sequence are known as mutations

Mutations can affect the proteins

encoded by the affected genes
Mutations can be of two types:

Point Frameshift
mutations mutations
 Point mutations
Substitution of a single base by
another is known as a point mutation

A point mutation affects only one codon

Substitution can be:

• Transition
• Transversion
 Transition Transversion

Substitution of a Substitution of a
purine by a purine purine by a pyrimidine

Substitution of a Substitution of a
pyrimidine by a pyrimidine by a
pyrimidine purine
Point mutations can be:

Silent mutations

Mis-sense mutations

Nonsense mutations
 3rd base
replaced by G ---UCG---
Ser
(Silent)

---UCA--- 2nd base

replaced by U ---UUA---
Ser
Leu
(Normal)
(Mis-sense)

2nd base ------UAA------

replaced by A
Stop
(Nonsense)
 Silent mutations

Substitution of 3rd base may not change

the meaning of codon due to degeneracy

For example, GGC → GGG will not change

the meaning (both are codons for glycine)

Mutations which do not change the code

words are known as silent mutations
 Mis-sense mutations

The base substitution changes the

code word

The amino acid sequence of the

encoded protein is changed

The effect of amino acid

substitution is variable
 Effect depends upon structures of the
substituted and the original amino acids

If structures of new and original amino

acids are similar, effect may be minimal
The effect also depends upon the site
where the substitution has occurred

Some areas of a protein molecule are

critical to its function

If substitution occurs in a critical area,

the effect will be severe
The mis-sense mutations
may be:

Acceptable

Partially acceptable

Unacceptable
 Acceptable mis-sense mutations

Haemoglobin Hikari is an example of

acceptable mis-sense mutation

Lysine at position 61 in the β-chain is

substituted by asparagine

This mutant haemoglobin is capable of

normal functioning
Partially acceptable mis-sense mutations

Haemoglobin S (HbS) is an example of

partially acceptable mis-sense mutation

Substitution of Glu by Val at position six

of b-chain partially impairs the functioning

HbS functions normally at high oxygen tension

but gets precipitated at low oxygen tension
 Effect of haemoglobin S

RBC at normal RBC at low

oxygen tension oxygen tension
Unacceptable mis-sense mutations

Haemoglobin MBoston is an example

of unacceptable mis-sense mutation

Histidine at position 58 of a chain

is replaced by tyrosine

This makes Hb MBoston incapable of

combining with oxygen
 Nonsense mutations

The base substitution changes a

sense codon into a nonsense codon

Protein synthesis is terminated

prematurely

The resulting protein is usually

non-functional
 Nonsense mutations are
responsible for some cases of:

Cystic fibrosis

Hurler syndrome

Duchenne muscular dystrophy

 Frameshift mutations

Frameshift mutations occur due to

insertion or deletion of bases

Insertion or deletion of one or two

bases changes the reading frame

The resulting protein has a garbled

amino acid sequence distal to mutation

Such proteins are generally non-

functional
 Deletion or addition

TH E CAT SAW THE DOG THE CAT RAN

Deletion of H after
the first letter
TEC ATS AWT HED OGT HEC ATR AN
Insertion of H after
the first letter
THH ECA TSA WTH EDO GTH ECA TRA
 Frameshift can convert a sense
codon into a nonsense codon

This can cause premature termination

of translation

Conversely, a stop codon may be

changed into a sense codon

An abnormally large protein may be

formed as a result
 Frameshift mutations are
responsible for some cases of:

Cystic fibrosis

Crohn's disease

Tay–Sachs disease
 Suppressor mutations

In prokaryotes and lower eukaryotes,

mutations are seen in anticodons of tRNAs

These can sometimes neutralize the

effect of mutations in structural genes

This type of mutations are known as

suppressor mutations
 For example, the codon UAC (tyrosine)
in a gene changes to UAG (nonsense)

Nonsense codons do not have

complementary anticodons

Translation will be prematurely

terminated
 But at the same time, the anticodon of
tRNATYR may change from GUA to CUA

CUA is complementary to the nonsense

codon, UAG

The mutant tRNA will add tyrosine

Such mutant tRNAs are known as

suppressor tRNAs
 Suppressor mutation
UAC UAC
5’ | || | || 3’ Normal mRNA having two
codons for tyrosine

UAG UAC
5’ || | | || 3’ mRNA having one mutant (UAG)
and one normal (UAC) codon for
tyrosine
UAG UAC
5’ || | | || 3’ A mutant tRNATYR having the
||| ||| anticodon CUA recognises the
AUC AUG mutant (UAG) codon and another
normal tRNATYR having the
anticodon GUA recognises the
normal (UAC) codon for tyrosine;
the mutant tRNA TYR acts as a
Tyr Tyr suppressor tRNA
Suppressor Normal
tRNA tRNA