Overview of mutations in genes for biochemistry, medical and biology undergraduates; diseases caused by mutations

1. Mutations
R.C. Gupta
Professor and Head
Dept. of Biochemistry
National Institute of Medical Sciences
Jaipur, India

2. EMB-RCG
Mutations are alterations in the base
sequence of genes
Exposure to ultra-violet light,
ionizing radiation and mutagens
Accidental errors during replication
Such alterations can occur due to:

3. 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
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4. These stable alterations in base
sequence are known as mutations
Mutations can affect the proteins
encoded by the affected genes
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5. Mutations can be of two types:
Point
mutations
Frameshift
mutations
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6. Substitution of a single base by
another is known as a point mutation
Point mutations
Substitution can be:
• Transition
• Transversion
A point mutation affects only one codon

7. EMB-RCG
Transition Transversion
Substitution of a
purine by a purine
Substitution of a
pyrimidine by a
pyrimidine
Substitution of a
purine by a pyrimidine
Substitution of a
pyrimidine by a
purine

8. Point mutations can be:
Silent mutations
Mis-sense mutations
Nonsense mutations
EMB-RCG

9. ---UCG---
Ser
(Silent)
---UCA---
Ser
(Normal)
------UAA------
Stop
(Nonsense)
---UUA---
Leu
(Mis-sense)
3rd base
replaced by G
2nd base
replaced by U
2nd base
replaced by A

10. 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
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11. Mis-sense mutations
The base substitution changes the
code word
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The effect of amino acid
substitution is variable
The amino acid sequence of the
encoded protein is changed

12. If structures of new and original amino
acids are similar, effect may be minimal
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Effect depends upon structures of the
substituted and the original amino acids

13. Some areas of a protein molecule are
critical to its function
If substitution occurs in a critical area,
the effect will be severe
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The effect also depends upon the site
where the substitution has occurred

14. The mis-sense mutations
may be:
Acceptable
Partially acceptable
Unacceptable
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15. 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
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16. 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
EMB-RCG

17. Effect of haemoglobin S
RBC at normal
oxygen tension
RBC at low
oxygen tension

18. 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
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This makes Hb MBoston incapable of
combining with oxygen

19. 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
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20. EMB-RCG
Nonsense mutations are
responsible for some cases of:
Duchenne muscular dystrophy
Hurler syndrome
Cystic fibrosis

21. 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

22. Deletion or addition
THE CAT SAW THE DOG THE CAT RAN
Deletion of H after
the first letter
Insertion of H after
the first letter
TEC ATS AWT HED OGT HEC ATR AN
THH ECA TSA WTH EDO GTH ECA TRA

23. Conversely, a stop codon may be
changed into a sense codon
Frameshift can convert a sense
codon into a nonsense codon
This can cause premature termination
of translation
An abnormally large protein may be
formed as a result

24. EMB-RCG
Frameshift mutations are
responsible for some cases of:
Tay–Sachs disease
Crohn's disease
Cystic fibrosis

25. 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
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Suppressor mutations

26. 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
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27. 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
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28. Suppressor mutation
UAC
AUC
Tyr
Suppressor
tRNA
Normal
tRNA
5’ 3’| | |
UAC
| | |
UAG
5’ 3’| | |
UAC
| | |
UAG
5’ 3’| | |
UAC
| | |
| | | | | |
AUG
Tyr
A mutant tRNATYR having the
anticodon CUA recognises the
mutant (UAG) codon and another
normal tRNATYR having the
anticodon GUA recognises the
normal (UAC) codon for tyrosine;
the mutant tRNATYR acts as a
suppressor tRNA
mRNA having one mutant (UAG)
and one normal (UAC) codon for
tyrosine
Normal mRNA having two
codons for tyrosine