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Types
of
Mutations
Lecture 13
27/08/1438
Dr. Faisal Al-Allaf, [email protected]
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Mutations

Types of mutations
 Base substitutions
 Synonymous
 Nonsense
 Missense
 Conservative
 Non conservative
 Readthrough
 Insertions
 Duplication
 Deletions
 Splicing
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Mutations

Mutation is a permanent change in nucleotide
sequence. It can be at chromosomal or DNA
levels.
 Gross lesions (chromosomal accounts for
less than 8%)
 Micro-lesions (molecular accounts for more
than 92%)

At the chromosomal level:
 Numerical abnormalities include
Aneuploidy (Monosomy, Trisomy and
Tetrasomy) and Polyploidy (Triploidy and
Tetraploidy)

Structural abnormalities includes
translocations, deletions, insertions,
inversions and rings formation
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Types of mutations

Base substitutions
 Synonymous or Silent mutations
 Nonsense mutation
 Missense mutation
 Conservative
 Non conservative
 Readthrough

Insertions may cause frameshift

Duplication duplications of part of a
gene or DNA sequence

Deletions may cause frameshift
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Base substitutions

Substitution is the replacement of a
single nucleotide by another with no net
gain or loss of chromosomal material.

Base substitutions are most prevalent
and missense mutations accounts for
nearly half of all mutations.

If the substitution involves replacement
by the same type of nucleotide, i.e. a
pyrimidine for a pyrimidine (C for T or
vice versa) or a purine for a purine (A
for G or vice versa), this is termed a
transition.

Substitution of a pyrimidine by a purine
or vice versa is termed a transversion.
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Synonymous or silent mutations

Based on the structural effects of the
mutations on the polypeptide sequence
of the encoded protein, mutations can
also be subdivided into two main groups,
being either synonymous or nonsynonymous mutations.

Synonymous or Silent mutations: when a
mutation does not alter the polypeptide
product of the gene

Because of the degeneracy of the
genetic code, a single base pair
substitution, particularly if it occurs in the
third position of a codon, will often result
in another triplet which codes for the
same amino acid with no alteration in the
properties of the resulting protein.
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Non synonymous mutation

Non synonymous mutation occurs when the
mutation leads to an alteration in the
encoded polypeptide.

Alteration of the amino acid sequence of
the protein product of a gene is likely to
result in abnormal function.
 Occur less frequent than synonymous
mutation

Non-synonymous mutations can occur in
one of two main ways.
 Nonsense mutation
 Missense mutation
 Conservative
 Non conservative
 Readthrough
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Missense mutations

A single bp substitution can
result in coding for a different
amino acid and the synthesis
of an altered protein, a socalled missense mutation.

The wrong sense (but it still
makes a kind of sense)

Examples:
Cystic fibrosis: CFTR G551D
Sickle cell anaemia: defective
haemoglobin due to mutation
in β-globin gene


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Nonsense mutations




A substitution which leads to the
generation of one of the stop codons
will result in premature termination
of translation of a peptide chain or
what is termed a nonsense mutation.
Makes no sense
Change of a codon for an AA to a
STOP codon
Eg: Cystic fibrosis: CFTR G542X

Premature termination of translation
produces truncated (shortened)
protein

Almost always pathogenic due to
loss of large amount of the normal
protein
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Deletions and insertions

Deletions and insertions/duplications
involves the loss or gain of one or more
nucleotides.

The addition or deletion of a single
nucleotide will cause the amino acids to
be grouped incorrectly.

The effects of deletion and insertion on
protein depend on:
 The amount of material lost
 Whether the reading frame is
affected
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Mutations in non-coding DNA

Mutations in non-coding DNA are less likely to have a phenotypic effect.
Exceptions include mutations in promoter sequences, or other regulatory regions.

Mutations in regulatory elements can affect the level of gene expression.

Recently, it has become apparent that mutations in UTRs are also likely to result in
disease.
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Stable and unstable mutations

Mutations which transmitted unaltered are termed fixed or stable
mutations and mutations which undergo further alteration as they
are transmitted in families are termed dynamic or unstable
mutations.

Fixed/stable mutations are point mutation (single base pair
substitutions, insertions, deletions or duplications of part of a
gene or DNA sequence).

Unstable or dynamic mutations consist of triplet repeat expansion
which, in affected persons, occur in increased copy number when
compared to the general population.
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Examples of unstable trinucleotide repeat expansions
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Functional effects of mutations on the protein




The mutations effect can
appear either through
 Loss-of-function or
 Gain-of-function
Loss-of-function mutations can result in either reduced activity or
complete loss of the gene product. In the heterozygous state would
be associated with half normal levels of the protein product. They
may be dominantly or recessively inherited.
Gain-of-function mutations, are inherited dominantly and result in
either increased levels of gene expression (simple gain of function)
or the development of new protein function (dominant negative
mutations).
Rarely, a mutation may be advantageous and favored by natural
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selection.
Summary of DNA mutation types
Mutations and their effects on protein products
Class
Group
Type
Effect on protein product
Stable/
fixed
Synonymous
Substitution
Silent – same amino acid
Non-synonymous
Substitution
1.Missense
 Non-conservative
 Conservative
Altered amino acid
Altered activity, function or stability
No effect
2. Nonsense
Deletions/insertion
1.Multiple of 3 (codon)
Dynamic/u
nstable
Triplet repeat
Stop codon – premature termination with loss
of function/activity/stability
In frame deletion/insertion of one or more
amino acid(s) in protein – may altered
activity/ function/stability
2.Not multiple of 3
Altered reading frame (frameshift),
premature termination of protein – altered
amino acid sequence, loss of
function/activity/stability
Expansion
Altered gene expression, reduced
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transcription or translation, altered transcript
– altered activity/ function/stability
Types of
Chromosomes
Mutations
Lecture 14
16
Chromosome Mutations

May Involve:
 Changing the structure
of a chromosome
 The loss or gain of part of
a chromosome

Five types exist:
 Deletion : Loss of DNA
 Inversion : Order of DNA switched
 Translocation : DNA segment joins a non-homologous
chromosomes
 Duplication: Additional DNA on homologue
 Non disjunction
Deletion
Due to breakage
 A piece of a chromosome is lost

Inversion
Chromosome segment breaks off
 Segment flips around backwards
 Segment reattaches

Duplication

Occurs when a gene sequence is repeated
Translocation
Involves two chromosomes
that aren’t homologous
 Part of one chromosome is
transferred to another
chromosomes

Translocation
Reciprocal translocation: DNA segments are exchanged
between non-homologous chromosomes
 Nonreciprocal translocation: a chromosome transfers a
DNA segment to a non-homologous chromosome without
receiving one in return

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Non disjunction



Failure of chromosomes to separate during meiosis
Causes gamete to have too many or too few chromosomes
Disorders:
 Down Syndrome – three 21st chromosomes
 Turner Syndrome – single X chromosome
 Klinefelter’s Syndrome – XXY chromosomes
Chromosome Mutation Animation
Summary of chromosome mutation types