1. Mutation
Dr. Shumaila Asim Lecture # 4

2. Mutation Derived from “mutare (muta)” – to change
change in form, quality, or some other characteristic
A permanent change in DNA sequence is called mutation Or
It is a permanent transmissible change in the genetic material, usually in a single gene

3. Types Base substitution (Substitution mutation or Point Mutation)
Deletion of one or more bases
Insertion of one or more bases

4. Types 1. Base substitution (Substitution mutation or Point Mutation)
Most common type of mutation
One base is replaced
Two subtypes:
Transitions
One purine is replaced by another purine or one pyrimidine is replaced by another pyrimidine
Transversions
One purine is replaced by a pyrimidine or vice versa

5. Point Mutations

6. If base substitution is in the coding region of a gene, it results in a. Mis-sense b. Non-sense or c. Silent Mutation
a. Mis-sense mutation leads to a codon change resulting in amino acid change; may have no effect or a serious effect e.g.
Hemoglobin – lys( AAA or AAG) is replaced by Asn (AAU or AAC) at 61 of -chain; no effect on function of hemoglobin
Hemoglobin – Glu (GAA,GAG) is replaced by Val (GUA,GUG,GUU,GUC) at number Affects the function of hemoglobin & has serious health consequences i.e. Sickle cell anemia

8. Sickle Cell Anemia

9. Mis-sense, Non-sense or Silent Mutation
Non-sense mutation leads to the conversion of an amino acid codon to a stop codon resulting in premature termination of translation e.g.
One base substitution
UAU, UUA, UUG
(Tyr) (Leu) (Leu)
UAA, UAG
Stop codons
Incomplete proteins are produced which are mostly non-functional e.g. as in thalassemias
-thalassemia = insufficient production of -globin
-thalassemia = insufficient production of -globin

10. Mis-sense, Non-sense or Silent Mutation
Silent mutation leads to the formation of a codon synonym or affects the non-essential DNA
It has no or a negligible effect on protein formation
e.g. leucine is coded by CUU, CUC, CUA & CUG if mutation affects the third nucleotide it will have no effect on protein / polypeptide sequence.

11. Types 2. Deletion of one or more bases
Frame-shift mutation
Deletion of one base in a gene
Reading-frame of translation changes
Results in non-functional gene product
b. Deletion of three (or multiple of three) bases
Codon (or codons) deleted, leading to deletion of one or more amino acids
Less severe than frame-shift mutation

12. Types Deletion of one base
Normal mRNA
AUG – GCC – UCU – UGC – AAA – GGC – UAU – AGU – AGU – UAG
Met Ala Ser Cys Lys Gly Tyr Ser Ser Stop
mRNA after Deletion of one base
AUG – GCC – CUU – GCA – AAG – GCU – AUA – GUA – GUU – AG –
Met Ala Leu Ala Lys Ala Thr Val Val
U Deleted

13. Types Deletion of three bases
Normal mRNA
AUG – GCC – UCU – UGC – AAA – GGC – UAU – AGU – AGU – UAG
Met Ala Ser Cys Lys Gly Tyr Ser Ser Stop
Deletion of 3 bases mRNA
AUG – GCC – UGC – AAA – GGC – UAU – AGU – AGU – UAG
Met Ala Cys Lys Gly Tyr Ser Ser Stop
UCU deleted

14. Types 3. Insertion of one or more bases
Frame-shift mutation
Insertion of one base
Reading-frame of translation changes
Insertion of three (or multiple of three) bases
Condon (or codons) added leading to addition of one or more amino acids
Less severe than frame-shift mutation

15. Types Insertion of one base
Normal mRNA
AUG – GCC – UCU – UGC – AAA – GGC – UAU – AGU – AGU – UAG
Met Ala Ser Cys Lys Gly Tyr Ser Ser Stop
Insertion type mRNA
AUG – GCC – CUC – UUG – CAA – AGG – CUA – UAG
Met Ala Leu Leu Glu Arg Leu Stop
C Inserted

16. Types Insertion of three bases
Normal mRNA
AUG – GCC – UCU – UGC – AAA – GGC – UAU – AGU – AGU – UAG
Met Ala Ser Cys Lys Gly Tyr Ser Ser Stop
Deletion of 3 bases mRNA
AUG – GCC – UAU – UCU – UGC – AAA – GGC – UAU – AGU – AGU – UAG
Met Ala Tyr Ser Cys Lys Gly Tyr Ser Ser Stop
UAU inserted

17. Sickle-cell hemoglobin
Normal hemoglobin DNA
Mutant hemoglobin DNA
mRNA
mRNA
Normal hemoglobin
Sickle-cell hemoglobin
Glu
Val
Figure 10.16A

18. Types of mutations NORMAL GENE mRNA Protein Met Lys Phe Gly Ala
BASE SUBSTITUTION
Met
Lys
Phe
Ser
Ala
BASE DELETION
Missing
Met
Lys
Leu
Ala
His
Figure 10.16B

19. Chromosomal changes can be large or small
Deletion
Homologous chromosomes
Duplication
Inversion
Reciprocal translocation
Nonhomologous chromosomes
Figure 8.23A, B

20. Types Deletion / Insertion of one or more bases
Deletion / insertion of one base results in garbled (distorted) translation
Deletion / insertion of three bases results in deletion / insertion of one amino acid ,remaining sequence of amino acids does not change

21. Mutation & Cancer
Cancer can be caused by different agents which damage or alter DNA sequence (mutation)
Mutation in DNA sequence may alter the regulatory controls; if it occurs in somatic cells, it may result in uncontrolled cell divisions leading to excessive proliferation of cells – – cancer.
Therefore most mutagens can cause cancer and are said to be carcinogenic

22. Mutation & Cancer
Certain genes (which control growth & cell-to-cell interaction) are abnormal in cancer cells ; these genes being capable of causing cancer are known as oncogenes
Tumor suppressor genes –these genes play akey role in controlling cancer ; if there is mutation in these specific genes, it results in cancer
Incidence of many cancers increases with age because the frequency of mutations increases with age

23. Mutation & Cancer Mutagens, agents causing cancer fall in three groups
Physical agents e.g. Radiant energy (irradiation)
Chemical agents or compounds &
Biological agents i.e. Viruses

24. Mutation & Cancer 1. Radiant Energy
X-rays, -rays, UV rays are mutagenic & carcinogenic
These radiations damage DNA molecule through / by
Dimerization of pyrimidines
Opening of bases
Loss of bases
Breaking of diester bonds
Cross linking of strands
Free radicals are formed which interact with & damage DNA

25. Mutation & Cancer 2. Chemical Compounds Base analogs;
Bromo-uracil (a thymine analog) when incorporated in DNA strand, pairs with guanine (instead of adenine) (transition)
Similarly, Amino-purine (adenine analog) pairs with cytosine (instead of thymine) (transition)

26. Mutation & Cancer b. Chemicals i) Non-alkylating agents
Formaldehyde (reacts with amine groups & cross-links DNA, RNA etc)
Hydroxyl-amine (reacts with cytosine, which now pairs with adenine – transversion)
Nitrous oxide (de-aminates C, A & G to form U, HX & X leading to transition)

27. Mutation & Cancer ii) Alkylating agents iii) Inter-calating agents
Ethyl methane sulfonate (causes depurination)
N-methyl-N-nitroso-guanidine
Acts on replication fork & causes both transitions & transversions
iii) Inter-calating agents
e.g. acridines – cause frame shift mutation

28. Mutation & Cancer Viruses (Tumor viruses) DNA Viruses RNA Viruses
Papovavirus
Adenovirus
Herpesvirus
Hepadnavirus
RNA Viruses
Retrovirus Type C
Retrovirus Type B