MOLECULAR

GENETICS

Topic: Gene Mutation

Presenters: Ammara Rizvi
Irfan Ullah
Faiza Kuasar
M.Umar Muzaffar Khan
Maham Arshad
 Introduction of Gene Mutation
Gene
 From Greek word ‘Genos’ meaning ‘Generation or Birth’
 Basic unit of heredity and sequence of nucleotides in DNA
that encodes synthesis of gene product either RNA or Protein
 The number of genes in an organism’s genome (the entire set
of chromosomes) varies significantly between species
 For Example,
(a) Human genome contains an estimated 20,000 to 25,000
genes
(b) Arabidopsis thaliana—the first Plant for which a complete
genomic sequence was recovered—has roughly 25,500
genes
(c) The Bacterium Mycoplasma genitalium has the fewest
number of genes, just 517.
 Mutations
 Sudden heredity change in genetic material or character of an organism’s called mutation
 Occurs when a DNA gene is damaged or change

Gene Mutation
 Defined as an alteration in the sequence of nucleotides in
DNA
 Change in one or more gene
 This Change can affect a single nucleotide pair or larger gene
segment of a chromosome
 Some lead to genetic diseases or illness
 An individual showing an altered phenotype due to
mutations are known as variant
 Individuals showing these changes are known as mutants
 Factor or agents causing mutation are known as mutagens
 Direction of mutations

Forward mutation
When mutation occurs from the
normal/wild type allele to mutant
allele are known as forward mutation.

Reverse mutation

When mutation occurs in reverse

direction that is from mutant allele
to the normal/wild type allele are
known as reverse mutation.
 History
 The term mutation is coined by Hugo de Vries in 1900 by his observation in
Oenothera.
 English farmer Seth Wright
recorded case of mutation first
time in 1791 in male lamb with
unusual short legs.
 H.J.Muller induced mutation in drosophila by using X-rays in 1927; he
was awarded with Nobel prize in 1946.

 Systematic study of mutation was

started in 1910 when Morgan
genetically analyzed white eye
mutant of drosophila.
 Characteristics of Mutations

 Nature of change:
Mutations are more or less permanent and heritable changes in the
phenotype of an individual. Such changes occur due to alteration in
number, kind or sequence of nucleotides of genetic material, i.e.,
DNA in most of the cases.

 Site of Mutation

An average gene contains 500 to 1000 mutational sites.

 Frequency:
Spontaneous mutations occur at a very low frequency. However, the
mutation rate can be enhanced many fold by the use of physical and
chemical mutagens. The frequency of mutation for a gene is
calculated as follows:
 Frequency of mutation =

Where,
M= number of individuals expressing mutation for a gene
N= number of normal individuals in a population
 Mutation rate:

Mutation rate varies from gene to gene. Some genes exhibit high
mutation rate then other. Such genes are known as mutable genes. In
some genome, some genes enhance the natural mutation rate of other
genes. Such genes are termed as mutator genes. In some case, some
genes decrease the frequency of spontaneous mutations than other
genes in same genome, which are referred to as antimutator genes.

 Direction of changes:

Mutations usually occur from dominant to recessive allele or wild type

to mutant allele. However, reverse mutations are also known.
 Types of events:

Mutations are random events. They may occur in any gene (nuclear
or cytoplasmic), in any cell (somatic or reproductive) and at any stage
of development of an individual.
 Recurrence:

The same type of mutation may occur repeatedly

or again and again in different individual of the
same population. Thus mutations are recurrent
nature.
 Types Of Mutation
There are two main types of gene mutation, which further have sub
categories.
Point Mutation:
 Simplest type
 Also Known as base Substitution
 Only single nucleotide alternate or change

Base Substitution may be

 Transition: - Purine alternative with
 Transversion: - Purine is replaced by different pyrimidines.
 Point Mutation are further divided into

a. Silent Mutation b. Missense Mutation c. Nonsense Mutation

Silent Mutation:
 Alternate the codon
 But Codon still specifies for same amino acid
 No change occurs in amino acid sequence
 No phenotype change occurs
Missense Mutation:
 Base substitution
 Alternate the codon in mRNA
 Different amino acid sequence occurs
 Genotype as well as phenotype change
occur

Nonsense Mutation:

 Change sense codon into non-sense codon

 Sense codon (specifies an amino acid)
 Non-sense codon (Stop Codon)
 Stop codon terminates the amino acid
sequence.
 Frame Shift Mutation
 Mutation occurs when addition or loss of DNA bases changes a gene reading frame.
 A reading Frame consists of 3 bases, each code for amino acid.
 When changes occur in frame then resulting protein is usually nonfunctional.
 Types e.g, Insertion & Deletion.

Insertion:

 The addition of one or more nucleotides

 Changes the number of DNA bases in a gene
 As a result, the protein coded by gene may
not function properly
Deletion:

 The removal of one or more nucleotides

 Changes the number of DNA bases
 Small deletion may remove one or few bases
pairs within a gene
 Large deletion can remove one entire gene
 Causes of Gene Mutation
 A mutagen is a chemical or physical agent that has the ability to change our genetic code in a
harmful way.
 Mutagens may be of physical, chemical or biological origin. They may act directly on the DNA,
causing direct damage to the DNA and most often result in replication error.
 Powerful mutagens are called clastogens. (Chromosomal instability, causing translocation,
deletion and inversion).
Types of Mutagens
Biological Agents
Viruses:
 Insert their DNA into the genome of host organism
 Disrupts genetic function
 Causes cancer e.g, Rous sarcoma virus
Bacteria:
 Such as Helicobacter pylori cause inflammation during which oxidative species are produced
 Oxidative species causing DNA damage
 Reducing efficiency of DNA repair system & increasing mutation

Transposons:
 Known as jumping genes and causes DNA
fragments
 Its insertion into chromosomal DNA disrupts
functional elements of the gene
 Metals

 Many metals such as arsenic, cadmium,

chromium, nickel and their compounds are
mutagenic in action
 Arsenic, chromium, iron and nickel may be
associated with the production of ROS
 Cobalt, arsenic, nickel and cadmium may also
affect DNA repair processes such as DNA
mismatch repair, base and nucleotide repair
 Some metals alter the DNA replication
mechanism. Nickel involved in DNA
hypermethylation
 Physical Mutagens
 Ionizing radiations such as X-rays, gamma rays causes DNA breakage (breakage of covalent bonds) and
other damages.
 Ultraviolet radiations above 260nm wavelength causing a rearrangement of covalent bonds to give the
production of "pyrimidine dimers"

For example, exposure to UV light can result in

the formation of a covalent bond between two
adjacent thymines on a DNA strand, producing
a thymine dimer (this defect stops DNA
replication).

 Sources

Sunlight, Outer space & Powerplant

 Chemical Mutagen
Base analog
 Chemical that can substitute for a normal nucleobase in nucleic acid
 Categorized in two groups, (i) Purine analogues e.g. 2-aminopurine (ii) Pyrimidines analogues
e.g, 5-bromouracil
 5-Bromouracil (incorporated into DNA)
 It is most likely pair with A or either with G due to
tautomerization
 Lead to incorrect insertion of nucleotides opposite them
in replication
Intercalating agents
 Intercalating agents such as ethidium bromide
(EtBr) inserts between bases in DNA, causing
frameshift mutation during replication.
 They are flat, multiple ring molecules, that can
interact with and insert between DNA bases.
 Blocks transcription and replication.
 DNA reactive chemical
 Interact directly with DNA
 Reactive oxygen species (ROS) chemicals
like hydrogen peroxide, directly acts on
DNA strand & causes mutation
 Deaminating agents for example, nitrous
acid which can cause transition
mutations by converting Cytosine to
Uracil
 Alkylation agent such as ethyl
nitrosourea or ethyl methane
sulphonate transfer methyl or ethyl
group to bases e.g, Guanine when
alkylated may be mispaired with
thymine.
 Effects of Gene Mutation
Gene Mutation can be effect on three ways
 Beneficial
 Harmful
 Neutral
Depending on their context or location.

Beneficial effects
 They lead to new version of proteins that help organisms to adapt to change their w
environment
 Mutations are essential for evolution to occur
 They increase an organism’s chances of surviving or reproducing
 So, they are likely to become more common overtime
 Turn off harm full genes
 Harmful effect
 Harmful mutation may cause genetic disorder or cancer
 Genetic disorders is a disease caused by a mutation in one or more genes
 E.g, Cystic Fibrosis, Sickle Cell Anemia, Marfan Syndrome

Cystic Fibrosis

 These disorder are caused the mutation in a single gene

 It stops the development of fetus
 Genetic mutation is lethal to life
 Genetic mutation in a single gene causes and produce
thick sticky mucus
 That clog the lungs
 Sickle Cell Anemia

 The blood disease Sickle-cell anemia is caused by a simple

substitution mutation. In the mutation, a single nucleotide is
replaced in the portion of DNA which codes for a unit of
heamoglobin.
 In sickle cell anemia, the abnormal heamoglobin causes red
blood cells to become rigid, sticky and misshapen.
 Both mother and father must pass the defective form of the
gene for a child to be affected. If only one parent passes the
sickle cell gene to the child, that child will have the sickle cell
trait.
  Sickle cell disease is caused by mutations in the beta-globin
(HBB) gene that lead to the production of an abnormal version
of a subunit of heamoglobin.
 This mutated version of the protein is known as heamoglobin S.
 Marfan Syndrome

 Mutations in the FBN1 gene cause Marfan

syndrome.
 The FBN1 gene provides instructions for
making a protein called fibrillin-1.
 Fibrillin-1 attaches (binds) to other fibrillin-1
proteins and other molecules to form
threadlike filaments called microfibrils
 A disorder that affects the connective tissue
supporting the body's joints and organs.
 Abnormalities in the connective tissue lead to
heart and eye problems in people with this
disorder.
 Neutral effect

 In population genetic mutation in which natural selection

does not affect the spread of mutation in a species
 It not significant harm and beneficial for body
 Neutral mutation that are inheritable and are not linked
to any gene under selection will either be lost or will
replace all other alleles of the genes
The End