Lecture 8

Introductory
Genetics
GEN201
Prof. Ranya Amer Dr. Zahra
Hussein
Mutations and Inherited
Diseases
Table of contents
Types of DNA Inherited

01 Mutations 03 diseases

02 DNA Repair
 What is meant by mutation?
Is it really bad?
• A mutation is a change in the
DNA sequence of an organism.
• Mutation are not always bad.
• They are reason for variation
and diversity.
• Genetic mutations result in
genetic variation among a
population which results in
evolution.
 Mutations
Somatic mutations
• Is a change in the DNA sequence of a somatic
cell.
• Cannot be inherited (only tissues derived from
mutated cell are affected).
Germ-cells
• Affected the individual during their lifetime.
mutations
• A change in the DNA sequence of
reproductive cell (gametes: egg or sperm).
• Can be passed onto offspring (every cell in
the entire organism will be affected).
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Types of DNA Mutations
 Types of Mutations
There are three types of DNA Mutations:

1. Point mutation (Base substitutions)

2. Frame-shift (Deletions & Insertions)

3. Non-frame shift
1. Substitutions of one base for another:
(point mutations)

• Transition mutation: interchanges of two-

ring purines (A/G), or of one-ring pyrimidines
(C/T): they therefore involve bases of similar
shape.

• Transversion mutation: interchanges of

purine for pyrimidine bases, which therefore
involve exchange of one-ring & two-ring
structures.
https://www.youtube.com/watch?v=GieZ3pk9YVo
❑ Silent mutation: mutated codon codes for the same amino acid. (i.e. occur
when the change of a single DNA nucleotide within a gene doesn’t affect the amino
acid).

Example: CAA (glutamine) → CAG (glutamine)……both of those codons translate to the same

amino acid
❑ Missense mutation: mutated codon codes for a different amino acid in the
resulting protein (One amino acid is changed).

Example: CAA (glutamine) → CCA (proline)….. both of those codons translate two different amino

acid
❑ Nonsense mutation: mutated codon is a premature stop codon (called
nonsense codons because they do not code for an amino acid and instead signal the

end of protein synthesis). It causes a protein to terminate or end its translation earlier
 2. Insertions and deletions of one or more bases

• Frameshift mutation: are insertions or deletions of nucleotides in DNA that

change the whole reading frame (the grouping of codons). It occurs if the

insertion or deletion of nucleotide bases in numbers that are not

multiples of three.

• Non-Frameshift mutation: It may result in a protein with sections missing or

substituted, but since the majority of the protein remains intact it may

still be partially functional. It occurs if Insertion or deletion of bases in

numbers that are multiples of three.

 Causes of mutation
A. Spontaneous mutations:
• They occur naturally in the genome in
the absence of mutagens.
• They generally arise from error during
replication.
1. Mismatches
2. Strand Slippage
3. Spontaneous chemical changes
(Depurination, Deamination)

B. Induced mutations:
• They occur purposefully by using
certain environmental agents called
mutagens (an agent, such as radiation
or a chemical substance, which causes
genetic mutation)
 A. Spontaneous mutation
1. Mismatches during replication (Tautomeric shifts)
DNA polymerase inserts the wrong nucleotide during replication, and if not corrected,
this results in spontaneous mutations. Most replication errors were caused by what is called
tautomeric shifts (The spontaneous intramolecular proton shift that changes a nitrogen base to an
alternative hydrogen-bonding form).

Thymine- Adenine
Thymine- Guanine wobble

Cytosine-Guanine
Cytosine -Adenine wobble
2. Slipped-strand mispairing (Strand Slippage)

It is a mutation process that occurs due to the mispairing of short repeat

sequences (tandem repeats) during DNA replication, which results in deleting
or adding a nucleotide in the new strand.
3. Spontaneous mutation due to chemical change
Depurination: Loss of a purine base (A or G) from DNA by hydrolysis and leaving a
depurinated sugar. Occurs when the bond connecting a purine to its deoxyribose sugar is
broken by a molecule of water, resulting in a purine-free nucleotide (apurinic site) that
can't act as a template during DNA replication
3. Spontaneous mutation due to chemical change
Deamination: or the removal of an amino group from a nucleotide base in DNA.
- Deamination of cytosine converts it to uracil, which will pair with adenine instead
of guanine at the next replication, resulting in a base substitution. Repair enzymes can
recognize uracil as not belonging to DNA, and they generally repair the
substitution.

C-G U-A C-G T-A

- However, if the cytosine residue is methylated (a common modification involved in

gene regulation), deamination will instead result in conversion to thymine. Because
 B. Induced mutation

• Induced mutation is caused by mutagens.

Types of Mutagens
⮚ Chemical
• Base analogs (5-bromouracil)
• Alkylating agents (Mustard gas)
• Reactive oxygen species (excessive alcohol intake and smoking
along with other environmental factors, such as toxins)
• Intercalating agents (ethidium bromide)
⮚ Radiation
• Ionizing radiation includes x, beta, and gamma radiation
• Non-ionizing radiation such as UV radiation
⮚ Chemical

⮚ Base analogue:
These are molecules that can substitute
the normal bases in nucleic acids.
They induce mutations because they often
have different base-pairing rules
than the bases they replace.
An example of base analogs is 5-
bromouracil (5BU) which is almost
identical to thymine.
However, can pair with guanine rather
than with adenine.
⮚ Chemical
⮚ Alkylating Agent:
It is the substance that replaces hydrogen atoms with alkyl groups (methyl or ethyl
groups) on DNA bases or the backbone phosphate group
For example, when guanine is alkylated it can be mispaired with thymine,
resulting in a mutation.
It causes the formation of cross-links within the DNA chain resulting in cytotoxic,
and carcinogenic effects. Mustard gas is one of the famous alkylating agents.

Alkylated Guanine -
Guanine-Cytosine Thymine
⮚ Chemical
⮚ Reactive Oxygen species (ROS)
▪ A type of unstable molecule that contains
oxygen and that easily reacts with other
molecules in a cell.
▪ ROS generated during mitochondrial
oxidative metabolism as well as in some
cellular processes.
▪ Excess of ROS can damage DNA by causing
strand breaks, removal of nucleotides,
and base mispairing, resulting in mutation
and carcinogenic effects.
▪ Excessive alcohol intake and smoking along
with other environmental factors, such as
toxins, can elevate ROS levels.
⮚ Chemical
⮚ Interacting Agent:
It is a substance that inserts itself into the DNA structure of a cell and binds to
the DNA such as ethidium bromide.
Insertion of these agents distorts the DNA double helix.
Replication of distorted regions of DNA results in insertions or deletions during
replication, which in turn cause frameshift mutations.
⮚ Radiation
Certain radiations (Ionizing radiation includes x, beta, and gamma
radiation; non-ionizing radiation such as UV) damages the genetic
material in reproductive cells and results in mutations that are transmitted
from generation to generation.
Radiation damage DNA by:
• single strand break
• double strand break
• chemical modification of bases
• loosing of base
• cross links within the DNA chain
• pyrimidine dimer (Thymine dimer)
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The DNA repair
mechanisms
 DNA repair mechanisms
A collection of processes by which a cell identifies and corrects damage
to the DNA molecules that encode its genome.

1. Mismatch Repair (Single-stranded Repair)

2. Base Excision Repair (Single-stranded Repair)

3. Nucleotide Excision Repair (Single-stranded Repair)

4. Homologous Recombination (Double-stranded Repair)

5. Non-Homologous End-Joining (Double-stranded Repair)

https://www.youtube.com/watch?v=ODsBTJ1KZY0
 1. Mismatch Repair (Single-
stranded Repair)
• Responsible for repairing mismatched
nucleotides after DNA replication.
• It corrects the errors that escaped
DNA Polymerase Proofreading.
• The misplaced nucleotides and
their neighbors are removed.
• Dysfunction mismatch repair is
the cause of Lynch Syndrome
(colorectal cancer)
 2. Base Excision Repair
(Single-Stranded Repair)
• A mechanism used to detect and
remove certain types of bases which
are susceptible to damage by
chemical reactions such as
deamination and alkylation.
• Responsible for repairing non-bulky
damaged bases (just the
damaged base is removed).
 3. Nucleotide Excision Repair
(Single-stranded Repair)
• Responsible for repairing bulky helix
DNA lesions such as Thymine
dimers produced via photochemical
irradiation
• In nucleotide excision repair, the
damaged nucleotide(s) are
removed along with a
surrounding patch of DNA
• Deficiency of Nucleotide Excision
repair associated with Xeroderma
4. Homologous Recombination (Double-stranded Repair)
A pathway that repairs double-strand breaks in DNA with the use of a
homologous template to guide repair.
In which, information from “homologous template” are used to repair a double-
strand break.
• Deficiency of Nucleotide Excision repair associated with Bloom Syndrome
5. Non-homologous end joining (Double-Stranded Repair)
A pathway that repairs double-strand breaks in DNA, in which, the breaking
ends are directly ligated without the need for a homologues
template.
• It leads to imperfect repair that will cause loss of nucleotides and mutation,
but it is better than leaving unrepaired.
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Inherited disorders
 Cystic Fibrosis (CF)
• It is an autosomal recessive disorder.
• The most common inherited disorder among Caucasians of northern European
descent.
• Causes: Among the known 1800 mutations that occur in the CFTR gene
located on chromosome 7, the most frequent one is termed CFTRdele2,3(21
kb), which deletes 21,080 bp spanning introns 1-3 of the CFTR gene.
• CFTR, the gene implicated in CF, called the Cystic Fibrosis Transmembrane
conductance Regulator gene, normally controls the passage of salt across
cell membranes.
• Symptoms: Persons affected with CF produce thick, sticky mucus in their
lungs, intestines, and pancreas. The buildup of thick mucus blocks breathing
passages and makes waste elimination difficult, causing severe
breathing and digestive difficulties and high susceptibility to respiratory
 Sickle Cell Anemia (SCA)
• Sickle cell anemia is the most common genetic disorder among those whose
ancestors came from sub-Saharan Africa.
• SCA is an autosomal recessive disease caused by a point mutation in the
hemoglobin beta gene (HBB) found on chromosome 11 which provides
instructions for making one part of hemoglobin.
• In the case of sickle cell, one base is mutated from adenine to thymine (a
transversion).
• The mistake changes one amino acid added during translation from glutamic acid
to valine, producing a protein that folds improperly and can’t carry oxygen
effectively.
• Symptoms: When red blood cells sickle, they break down prematurely, which
can lead to anemia. Anemia can cause shortness of breath, repeated
infections, fatigue, and delayed growth and development in children.
 Tay Sachs Disease

It is an autosomal recessive disorder that is caused by a mutation in the gene

Hexosaminidase A (HexA) located on the 15th chromosome.
The most common Tay Sach is due to a mutation caused by the addition of the four
base pairs TATC into the Hex A gene.
Symptoms: Tay-Sachs disease results in a deficiency of the enzyme beta-
hexosaminidase A. This enzyme is required to break down the fatty substance
GM2 ganglioside. The buildup of fatty substances damages nerve cells in the
brain and spinal cord.
Tay-Sachs disease is unusually common among Eastern and Central European Jewish
communities (Ashkenazi Jews).
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