SLSC0402

Mutations
DNA Repair Mechanisms
Syllabus for ESE – 31st March 2023

Dr Maya Murdeshwar
[email protected]
 Mutations: FINAL Syllabus for ESE (2022-23)

• What are mutations? Classification (flowchart with at least one example of each type)
• What are mutagens? Classification: Physical, Chemical and Biological
(flowchart with at least one example each type and sub-type)
• Point mutations: Base substitution (transition & transversion), Base addition/ deletion
Sense/ Missense (conserved and non-conserved)/ Nonsense/ Frameshift
• Chromosomal deletion/addition/translocation/ inversion mutations as diagrams
• Human genetic disorders (cause, symptoms, available diagnosis and treatment
strategies): Sickle cell anemia, Down’s syndrome,
• Light repair mechanism (Photoreactivation) - what type of damage is repaired,
mechanism, enzymes and proteins,
• Dark repair mechanisms - different types (names only)

Ref: - Genetics by Russell

- Any standard Genetics reference book
Mutations: Question pattern for ESE (2022-23)
1. Using a flowchart, depict the classification of mutations/ mutagens. Cite appropriate
examples of each type.

2. With suitable examples, define/explain the following terms.

3. Write a brief note on a human genetic disorder resulting from a missense mutation.
Enlist the cause, symptoms, and available diagnosis and treatment strategies.

4. Identify the type of mutation shown below. With an appropriate example, name and
describe the resulting genetic disorder (cause, symptoms, and available diagnosis
and treatment strategies). 22 22
eg:

9 9
Answer 4:
- Chromosomal mutation: Translocation (between Chromosome 9 and 22)
- Translocation between chromosomes 9 and 22 causes Chronic Myeloid Leukaemia
- Mention the symptoms, diagnosis and treatment for CML
Mutations: Question pattern for ESE (2022-23)
5. Identify the type of mutations shown below. Give reason for your answer.
Enlist all categories of mutations that the particular mutation falls under.
(eg, Point - Base substitution – transition/ transversion,
Point - Base addition/deletion – frameshift
Point - Reversion
Point - sense/ missense/ nonsense/ Suppressor mutation
Chromosomal - Inversion / Translocation/ Addition/ Deletion
Genomic - Aneuploidy/ Euploidy)

Answer 5:
Point mutation: Base substitution mutation –
Transition mutation Genomic mutation
Sense mutation Aneuploidy (Trisomy 21)
(state reasons for each type of mutation listed) Down’s syndrome
 Classification of Mutations
Mutation - Permanent, stable, heritable change in DNA structure
(nucleotide sequence/ number of nucleotides)
Somatic vs Germline mutations

Mutations in coding v/s non-coding regions of DNA

 Classification of Mutations

https://ib.bioninja.com.au/standard-level/topic-3-genetics/33-meiosis/somatic-vs-germline-mutatio.html#:~:text=Somatic%20mutations%20%E2%80%93%20occur%20in%20a,entire%20organism%20will%20be%20affected)
 Classification of Mutations

Point Gross/ Chromosomal Genomic

Base Substitution Inversion Aneuploidy

Transition
Pu Pu Translocation Polyploidy
Py Py

Transversion Insertion/ Deletion (affect the number of

Pu Py chromosomes)
(chromosomal abnormalities)

Base Addition/ Deletion

(change of reading frame)
 Classification of Mutations
• Spontaneous vs Induced mutations (based on cause)

• Gain-of-function mutations Beneficial /

• Loss-of-function mutations Deleterious /

Neutral

• Sense/ Silent mutation (codes for the same amino acid)

• Missense mutation (codes for a different amino acid)

• Nonsense mutation (introduces stop codon)

• Suppressor mutation (stop codon ‘read through’)

• Reverse mutation/ reversion (reverts back to original sequence)

• Frameshift mutation (changes the reading frame after it)

 POINT MUTATIONS

• Base Substitution • Sense

- Transition • Missense
- Transversion • Nonsense
• Reversion
• Base addition/ Deletion
- Frameshift • Nonsense suppression
 Classification the Mutations
Types of Mutations

Sense

Missense

Nonsense
 Classification of Mutations

Lys STOP Lys → Arg Lys → Thr

http://www.bio.miami.edu/dana/250/250S19_15.html
 Classification of Mutations
Reversion Mutations

alone

https://link.springer.com/article/10.1007/s00018-020-03519-6
 Reading Frames
6 Reading Frames!
(3 on each strand of DNA)

https://www.khanacademy.org/science/biology/gene-expression-central-dogma/central-dogma-transcription/a/the-genetic-code-discovery-and-properties

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Frameshift Mutations
 Frameshift Mutations

eg: +1 / +2 / +3 -1/ -2/ -3 +1, -2 / +2, -1 / +5, -10

→ Significance in Gene Cloning https://slideplayer.com/slide/8284821/

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 Types of Mutations
Classification of Mutations

Normal Nonsense Suppressor

 Reason for Nonsense Suppression
Mutation in 1 base of anticodon of tRNA

https://biocyclopedia.com/index/genetics/the_genetic_code/suppressor_mutations_base_substitutions_and_suppressor_trnas.php
 Reason for Nonsense Suppression
Mutant gene encoding mutant tRNA → mutated anticodon → Nonsense Suppressor’
Overcomes abnormal protein truncation

http://www.bio.miami.edu/dana/250/250S19_15.html
 Missense Mutation

DNA
HbB gene
mRNA
(Haemoglobi
n beta chain)
Protein

- Ashutosh Lambhade (117)

 Missense Mutation
Haemochromatosis
HFE gene mutations (HFE protein mutated)
C282Y Cys 282 Tyr (Cysteine at position 282 replaced with Tyrosine)
H63D His 63 Asp (Histidine at position 63 replaced with Aspartic acid)

Amyloidosis
TTR gene mutations (Transthyretin protein mutated)
V30M Val30Met (Valine at position 30 replaced with Methionine)
- Anika Shivhare (115)
Haemophilia B

- Racheal D’Costa (121)

CHROMOSOMAL MUTATIONS

Single chromosome Two chromosomes

• Deletion • Inversion

• Duplication • Translocation

• Insertion
 Single Chromosome Mutations

• Fragile X syndrome - Neil Chakraborty (114)

• Cri du chat (chr.5) - Naomi Thamarayoor (096)
• Cystic fibrosis (chr.7) - Fidah Thayeb (099)
• Thalassemia (chr.16 [HbA] and chr.11 [HbB]) - Riya Bahl (098)
• Angelman syndrome (chr. 15) - Neil Chakraborty (104)
• Charcot-Marie-Tooth disease - Naomi Thamarayoor (096)
• Duchenne Muscular Dystrophy - Ayesha Raj (142)
Inversion
Two Chromosome Mutations
Tay Sachs disease
Seventy-eight mutations in the
Hexaminidase A (hexA) gene have been
described and include 65 single base
substitutions, one large and 10 small
deletions, and two small insertions.
- Brianna Fernandes (122)
Duplication

- Racheal D’Costa (121)

 Deletion
Deletion in Chromosome 5

Cri-du-chat
A genetic disorder which results from a
deficiency in the short arm of chromosome 5
in human beings.

Chances of an infant being born with

cri-du-chat is around 1 in 50,000.

An infant born with cri-du-chat syndrome.

- Naomi Thamarayoor (096)

 Deletion
Deletion in CFTR gene present on Chromosome 7

- Fidah Thayeb (099)

 Deletion
Deletion in DMD gene present on X Chromosome

- Ayesha Raj
(142)
Inversion

- Racheal D’Costa (121)

 Translocation
Philadelphia Chromosome (Ph)

Chronic Myeloid Leukaemia (CML)

- Roshni David (119)
- Amaan Lopez (123)
GENOMIC MUTATIONS

Aneuploidy

• Monosomy

• Trisomy

Polyploidy
 Aneuploidy
Patau Syndrome (Trisomy 13)

- Fidha Thayeb (099)

 Aneuploidy
Edward’s Syndrome (Trisomy 18)

- Jerusha Varghese (126)

 Aneuploidy
Down’s Syndrome (Trisomy 21)

- Ashutosh Lambhade (117)

 Aneuploidy
Turner’s Syndrome (Monosomy X)

- Riya Bahl (098)

 Aneuploidy
Klinefelter Syndrome

- Brianna Fernandes (122)

 DNA Mutations: Causes

• Errors in DNA replication

- Error rates of various DNA polymerases

• Spontaneous mutations (naturally occuring)

- Tautomerism, Deamination, Depurination

• Induced mutations
- Environmental agents
- Physical/ Chemical/ Biological mutagens
 DNA Repair

DNA repair mechanisms are placed into different categories

on the basis of the way they operate

⚫ Direct correction or direct reversal

- reversing the damage

⚫ Excise the damaged areas and then repair the gap by

new DNA synthesis

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 DNA Repair Systems
Mechanisms of Prokaryotic and Eukaryotic DNA Repair
(a) Direct Repair/ Reversal – Photoreactivation (Light Repair)
(b) Excision of damaged DNA and gap filling synthesis of
new DNA
Mismatch Repair
Base Excision Repair (BER) Dark Repair
Nucleotide Excision Repair (NER)
Recombination lesion (Error-prone Translation)
SOS Repair

Defects in DNA repair systems → Diseases

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Direct Repair System: Photo-reactivation

• Pyrimidine dimer
• CPD Photolyase
(bacteria, fungi, plants, vertebrates; not in placental mammals))
• Primary chromophore: MTHF or 8-HDF (300 – 500 nm)
(Methenyl-tetrahydrofolate) (8-hydroxy-5-deazaflavin)
Primary light gatherers transfer energy to FADH-
• Secondary chromophore: FADH– Energy used to split the dimer
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Thymine Dimer Formation

5’--CCGAATTCAG--3’
3’--GGCTTAAGTC--5’

CPD – Cyclobutane Pyrimidine Dimer

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 Mutagens

Physical Chemical Biological

Ionizing Non-ionizing Hydroxylation Transposons

radiation radiation Deamination Viruses
Intercalation Mutator genes
X-rays UV-rays Alkylation
γ-rays Base analogs
α-particles
β-particles (State at least one
example of each)

Ref: Genetics by Russell

Smile Pill