Download MUTATIONS

Dr. Fadwah Al-Ghalib
Mutations
Molecular Biology
2nd year
MUTATIONS
Mutations are defines as heritable alteration or change in the genetic material. Or are
changes in the nucleotide sequence of the DNA.
They are usually harmful, occur either in non-coding or coding sequences.
In coding sequences causes inherited disorder or disease. If occurred in somatic cell
no transmission to offspring
If occurred in gonadal tissue or a gamete transmission to future generation.
Causes of Mutations
Arise due to :
1.
exposure to mutagenic agents such as:
a. Ionizing radiation (X-Rays- gamma rays,) Atomic Radiation
b.Chemical mutagens (mustard gas, formaldehyde)
c. Physical mutagens ( heat in animals)
2. errors in DNA replication and repair
[ includes chromosomal breakage syndromes]
Types of Mutations :
1- Fixed Mutations or ( Stable):
A. Single base substitution
B. Insertion
C. Deletion
D. Dublication :
I.
part of a gene
II. DNA sequence
2- Dynamic or unstable mutations:
Triplet repeat sequence [ triplet amplification or triplet expansion]
The simplest type of mutation called a base substitution mutation, involves a
change in only one pair of nucleotides. Often these mutations result from errors in
base pairing that occurred during replication process.
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Dr. Fadwah Al-Ghalib
2nd year
Mutations
Molecular Biology
Wild Type: is the genotype that is characteristic of the majority of individuals of a
species, also called the normal, standard or reference genotype. It refers to the
unmutated sequence.
Example:
 ATG CCG TGT CAG ATG TTC
---------------- DNA
 AUG CCG UGU CAG AUG UUC
------------ mRNA
Met
Pro Cys Gln
met
phe ------ Amino acid sequence
For Example: an AT base pair might be replaced by a GC,CC, or TA pair. Such
mutation may cause the altered DNA to be transcribed as an altered mRNA. The
altered mRNA may then be translated into a peptide chain with only one amino acid
different from the normal sequence.
Dynamic/Unstable Mutations
Consists of triplet repeat sequences  occur in increased copy number
e.g. [Huntington’s disease, fragile X mental retardation]
Triplet repeat sequences appear to be neurological disorders have serious central
nervous system involvement
Disease
Repeat
Repeat number Mutation
Sequence
Huntington’s
Repeat
number
location
CAG
9-35
37-100
coding
CTG
5-35
50-4000
3’ UTR
disease
Myotonic
dystrophy
Structural Effects of Mutations on Protein
1-Synonymous / Silent Mutations
1. No alteration in polypeptide product of the gene
2. Single base pair substitution
3. Occur in the third position of a codon
4. Codes for the same amino acid
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Dr. Fadwah Al-Ghalib
Mutations
Molecular Biology
2nd year
5. No alteration of the protein
Example: Samesense Mutation:
a codon is changed to a different codon that specifies the same amino acid.
Samesense mutation: a codon is changed to a different codon that specifies the
same amino acid.
ATG CCG TGC CAG ATG TTC
----- DNA
AUG CCG UGC CAG AUG UUC ----- mRNA
Met
Pro Cys
Gln
Met Phe -------- amino acid sequence
2-Non-Synonymous Mutations
1. Occur less frequently than synonymous mutations
2. Leads to alteration in the encoded polypeptide
3. Result in abnormal function disease
Occur in one of three main ways:
1. Missense
2. Nonsense
3. Frameshift
The different Types of Mutations:
Base substitutions that result in the replacement of one amino acid by another are
sometimes referred to as missense mutations.
1- Missence mutation: a codon is changed to a different codon that specifies a
different amino acid. It may occur at the active site of an enzyme, or may involve a
change in an amino acid that is not part of the active site.
ATG CCG TGG CAG ATG TTC
----- DNA
AUG CCG UGG CAG AUG UUC ----- mRNA
Met
Pro Trp
Gln
Met Phe -------- amino acid sequence
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Dr. Fadwah Al-Ghalib
Mutations
Molecular Biology
2nd year
2- Nonsense Mutation: A codon that specifies an amino acid is changed to a stop
codon. (termination codon), this mutation usually destroys the function of the gene
product.
ATG CCG TGA CAG ATG TTC
----- DNA
AUG CCG UGA CAG AUG UUC
-----
Met Pro STOP
mRNA
-------- amino acid sequence
3- Frameshift Mutations: One or 2 nucleotide pairs are inserted into or deleted
from the molecule, causing an alteration of the reading frame
As the result of this shift, codons downstream of the insertion or deletion site specify
an entirely new sequence of amino acids. Depending on where the insertion or
deletion occurs in the gene, different effects can be generated.
In addition to producing an entirely new polypeptide sequence immediately after the
change, frameshift mutations usually produce a stop or termination codon within a
short distance of the mutation. This codon terminates the already altered polypepetide
chain. A frame shift in a gene specifying an enzyme usually result in a loss of
enzyme activity. If the enzyme is an essential one, the effect on the organism can be
disastrous.
Mutation in non-coding DNA
They will have a phenotyping effect if it occurs in
1. Regulatory elements (e.g. TATA box)  affect level of gene expression
2. Splicing of introns: highly conserved GT & AG at the end of introns
Either:
a.
coding sequences being lost
b. intronic sequences being added to the mRNA
Functional effects of Mutation on the Protein
1. Loss of function
2. Gain of Function
Loss of Function
 Reduce in activity (hypomorph)
In heterzygous state half normal levels of the protein product
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Dr. Fadwah Al-Ghalib
Mutations
Molecular Biology
2nd year
 Or complete loss of the gene product (amorph)
Gain of Function:
1. Increased levels of gene expression
2. Development of a new function(s) of the gene product
3. Mutations alter timing or tissue specificity of expression (chromosomal
rearrangement)
4. Gain of function mutations are dominantly inherited
5. In homozygous state causes prenatally lethal disorder
Chromosomal Mutations:
Chromosomal mutations are grouped into four broad types:
1)
Deletion: are chromosomal changes in which one or more genes or segments
of chromosomal DNA are lost.
2)
Duplication: are chromosomal changes in which one copy or more copies of
a gene are present on the same chromosome
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Dr. Fadwah Al-Ghalib
Mutations
Molecular Biology
2nd year
3) Inversion: in which a segment of DNA is released and rotated 180 degrees
before being reinserted into the DNA. If the inverted DNA segment carries part of
the protein-coding sequence, the resulting protein would be drastically altered and
most likely nonfunctional.
4) Translocation: occur when a segment of DNA moves from one chromosome and
inserted into a different nonhomologous chromosome. Translocation can also be
reciprocal, that is two nonhomologous chromosome may break and trade pieces of
DNA. Translocation mutations frequently cause problems in meiosis and sometimes
lead to aneuploidy ( the gain or loss of chromosome)
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