Dr. Fadwah Al-Ghalib Mutations 2 nd
year
Molecular Biology
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 :
1Fixed Mutations or ( Stable):
A.
Single base substitution
B.
Insertion
C.
Deletion
D.
Dublication :
I.
part of a gene
II.
DNA sequence
2Dynamic 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 Mutations 2 nd
year
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
Sequence
Repeat number Mutation number
Repeat location
Huntington’s disease
Myotonic dystrophy
CAG
CTG
9-35
5-35
37-100
50-4000
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 coding
3’ UTR
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Dr. Fadwah Al-Ghalib Mutations 2 nd
year
Molecular Biology
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 TG C CAG ATG TTC ----- DNA
AUG CCG UG C 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 TG G CAG ATG TTC ----- DNA
AUG CCG UG G CAG AUG UUC ----- mRNA
Met Pro Trp Gln Met Phe -------- amino acid sequence
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Dr. Fadwah Al-Ghalib Mutations 2 nd
year
Molecular Biology
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 TG A CAG ATG TTC ----- DNA
AUG CCG UG A CAG AUG UUC ----- mRNA
Met Pro STOP -------- 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)
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Dr. Fadwah Al-Ghalib Mutations 2 nd
year
Molecular Biology
In heterzygous state
 half normal levels of the protein product

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 2 nd
year
Molecular Biology
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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