Transcript Genetic Mutations SDK Nov 2, 2012

Genetic Mutations
SDK
October 27, 2014
OBJECTIVES
By the end of this session the student should be able to:
 Define Mutation
 Frequency of mutations in normal individuals
 Classify different types of mutation
 Explain the mechanism of mutation
 Explain the role of mutation in biodiversity
 Explain how mutations can cause severe diseases
 Give examples of deletions, duplications, and insertions in genes
 Define trinucleotide repeat expansions and how they cause
neurological diseases
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What is a gene mutation?
Replacement or change of a nucleotide base with another,
in one or both strands, or addition or deletion of a base
pair in a DNA molecule .
Mutations are changes in genetic material(Nitrogenous
bases) – changes in DNA code – thus a change in a
gene(s)
In gene mutations, the DNA code will have a base
(or more) missing, added, or exchanged in a codon.
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Gene mutation out come
• Mutations can lead to missing or malformed
proteins, and that can lead to disease.
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Types of Mutations
 Germ-line mutations .Mutations that are inherited
from parents are called germ-line mutations.
 Acquired mutations. Mutations that are acquired
during your lifetime are called acquired mutations
 Some mutations happen during cell division, when
DNA gets duplicated.
 Still other mutations are caused when DNA gets
damaged by environmental factors, including UV
radiation, chemicals, and viruses.
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How common are mutations?
Mutations occurs at a frequency of about 1
in every 1 billion base pairs
Everybody has about 5-10 potentially
deadly mutations in our genes- in each cell
of our body!
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When everyone has mutations, Why
they are not always seen
Diseases
by because
just
one
of a
•They
Most
genetic
diseases
arecopy
recessive,
areinherited
notcaused
always
seen
the
mutation
which
means
that
ainperson
must
inherit
defective
gene
are not
manifested
with
the
may have
occurred
a section
of DNA
thattwo
copies of
the mutated
gene to inherit a
exception
ofdoesn’t
make a protein.
disorder.
Huntington's
disease, which is rare and
• This is one
reason are
that marriage
between
afflicted
carriers
more likely
toclose
die
relatives
is
discouraged;
two
genetically
before reproducing.
similar adults are more likely to give a child
two copies of a defective gene.
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Mutations Outcome
The affected gene may still function.
Mutations may be harmful.
Mutations may be beneficial.
Mutations may have no effect on the organism.
 Mutations are a major source of genetic variation in a
population increasing biodiversity.
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Beneficial Mutations
HIV - Virus, Genetics
1. Basic Structural Components
 The HIVirus is consists of two basic components:
 Envelop
 Genome
 Envelop
 The HIV envelope has projections known as spikes, which contain specific
chemical components (GP120 & GP 41) that may assist the virus when it
attaches to other cells.
 Genome,




Two SS RNA
P32 Integrase
P 10 Protease
P64 Reverse Transcriptase
 A bullet shape protein component that surrounds the genome called a
Capsid.
 capsid gives the virus its shape and protects the genome.
 The capsid is made up of subunits called capsomeres
HIV Binding to the Host Cell
 The HIV joins the host cell by spike on HIV
envelope and binding site on the host cells.
 On the host cell such as T-lymphocyte, macrophage,
or brain cell two binding sites are there
– A CD4 molecule ( a primary receptor)
– Co-receptors (CXCR4 & CCR5)
– CCR5 (Beta chemokine receptor)
– CXCR4 (alpha chemokine receptor)
– These second receptors loops through the cell membrane
7 times and is critical for infection to occur]
Beneficial Mutations
HIV - Virus, Genetics
• About 10% of Caucasians of Western European
descent have the mutation for chemokine receptorCCR5-▲32 making them resistant to HIV.
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Mutations a cause of Biodiversity
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Does all mutations passed on to next
generation?
NO
Only mutations in gametes (egg & sperm) are
passed onto offspring(Germline Mutation).
Mutations in somatic cells (body cells) only
affect the body in which they occur and are not
passed onto offspring.
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Brain Work 1
A mutation may happen in any gene.
TRUE OR FALSE?
TRUE
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Spontaneous and Induced Mutations
Spontaneous: Occur spontaneously without
obvious reason.
Induced mutations: caused by mutagens.
Mutagens are the agent that causes the DNA
code to change (mutate)
X-Ray,
Chemicals,
UV light,
Radiation, etc
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Brain Work 2
Which of the following may cause mutations?
A.
B.
C.
D.
Coffee
UV light (sun light)
Hair gel
Vaccines
UV Light (Sun Light)
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Types of Mutations
1. Point mutations. A point mutation is a simple change in
one base of the gene sequence.
• Original
• Point Mutation
The fat cat ate the wee rat.
The fat cat ate the wet rat.
2. Frame shift mutations. one or more bases are inserted
or deleted
Original.
Frame Shift
T h e f a t c a t a t e t h e we e r a t
The fat caa tet hew eer at
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Morphological Types of Point mutations
1. Transitions. Transitions occur when a
 Purine is converted to a purine
(A to G or G to A)
 Pyrimide is converted to a pyrimidine (T to C or C to T)
2. Transversion. A transversion results when
 Purine is converted to a pyrimidine (A to C or G to T)
 Pyrimidine is converted to a purine. (T to A or C to G)
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Types of Mutations according to their effects on
the protein (or mRNA).
Silent Mutations. Mutation in a codons that produce same amino
acid. These mutations affect the DNA but not the protein.
Therefore they have no effect on the organism’s phenotype.
CUU
CUC
Missense Mutations. Missense mutations substitute one amino
acid for another. Example. HbS, Sickle Cell Hemoglobin, is a
change in the beta-globin gene, where a GAG codon is converted to
GUG.
GAG
GUG
Nonsense mutations. convert an amino acid into a stop codon.
The effect is to shorten the resulting protein. Sometimes this has
only a little effect, however, often nonsense mutations result in
completely non-functional proteins.
UUU
UAA\ UGA
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Frame-shift
 In a frameshift mutation one or more bases are inserted, or
deleted.
 Because our cells read our DNA in three letter words,
adding or removing one letter changes each subsequent
word.
 This type of mutation can make the DNA sequence
meaningless .
 For example:
 Original=
T H E FAT C AT AT E T H E W E E R AT
 FRAMESHIFT= T H E FAT C A A T E T H E W E E R AT.
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Brain Work 3
Mutations are a natural part of the cellular
process reproduction. The cell has tools that
catch and repair 99.9% of mutations.
TRUE OR FALSE?
TRUE
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Brain Work 4
Most mutations are caught and repaired in the cell.
TRUE or FALSE?
TRUE
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Classical Types of Point mutation Mutations
Point mutation occurs when the base sequence of a
codon is changed. (ex. GCA is changed to GAA)
There are 3 types:
•Substitution
•Deletion
•Insertion
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Also called
frameshift
mutations
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Substitution
A substitution is a mutation that exchanges one
base for another (i.e. a change in a single
“chemical letter” such as switching an A to G.
For example:
CTGGAG
CTGGGG
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Substitution Mutations
Normal DNA: CGA – TGC – ATC
Alanine – Threonine - stop
Mutated DNA: CGA – TGC – TTC
Alanine – Threonine - Lysine
What
This
iswill
a substitution
happen
to the
the
mutation
amino
What
The
has
adenine
happened
was replaced
to
DNA?
with
acids?
thymine
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The cat ate the rat
The hat ate the rat
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Clinical Examples
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Sickle Cell Anemia
• Sickle cell anemia is the result of a (substitution) point
mutation in codon 6 of the -globin gene resulting in
the substitution of amino acid glutamic acid by valine
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Sickle Cell Anemia
Under conditions of low oxygen tension, such as
Following exercise or
In an atmosphere containing a low oxygen level,
The following changes occur:




The haemoglobin agglutinates to form insoluble rod-shaped polymers
Red blood cells become distorted and sickle-shaped
The sickle-shaped cells rupture easily causing haemolytic anaemia
The sickle shaped cells tend to block capillaries interfering with the blood flow
to various organs.
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 Thalassaemia
Substitution of C by U in mRNA that is coding  globin
chain of 146 amino acid.
Resulted in the formation of a stop signal UAG in place
CAG of glutamate in codon number 39.
 This result in a shortened globin chain containing only
39 instead of the normal 146 amino acids in the -globin
protein chain.
This protein is functionally useless and is equivalent to
absence of -globin gives clinical symptoms of 
thalassaemia,
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 Thalassaemia
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 Thalassemias
Beta thalassaemia is a genetic disorder in which there is
lack of beta globin.
It may be the result of:
 Deletion of the whole gene so that beta globin cannot not produced
(designated  o )
 Deletion of the promoter region so that transcription cannot occur
(designated  o )
 Deletion of a large part of the gene resulting in a grossly abnormal or
reduced synthesis functional protein (designated  + )
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Clinical Features of  -Thalassaemia
 Haemoglobin A (α2  2) cannot be produced
 Hb F (α2 g2) is produced even in adults
 Hb A2 (α 2 d2) formation is increased
 Eerythrocytes are microcytic (small) due to lack of normal
haemoglobin
 Erythrocytes rupture easily causing severe haemolytic anaemia,
requiring repeated blood transfusions
 The bone marrow expands trying to compensate by increasing
haemopoiesis.
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Clinical Features of  -Thalassaemia
 The bones of the face and skull are thickened causing a
characteristic facial appearance
 The spleen and liver enlarge because haemopoietic tissue forms in
them
 Excess iron accumulates in the blood and is deposited in the heart,
liver, pancreas and other organs (this is because of repeated
transfusions while no blood is actually lost from the body)
 Children have delayed growth and development and are prone to
repeated infections
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Point Mutation In alpha-Globin Gene
“Elongated α Globin Chain, Haemoglobin Constant spring \Wayne
Hb”
 Here the stop codon UAA at position 142 in the alpha (-)
globin gene was substituted by the codon for glutamine.
 Translation of the protein thus continued until a stop codon
was encountered at codon 173.
 The -globin was considerably elongated, resulting in a
variant of haemoglobin termed Haemoglobin Constant spring\
Wayne Hb.
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Elongated α Globin Chain Or Haemoglobin Wayne
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Insertion
Insertions are mutations in which extra base
pairs are inserted into a new place in the DNA.
CTGGAG
C T G G C C TA G
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Insertion Mutations
Normal DNA: CGA – TGC – ATC
Alanine – Threonine – stop
Mutated DNA: CGA – TAG – CAT – C
Alanine – Isoleucine – Valine
This
An
is adenine
an
insertion
was mutation,
inserted
thereby
also
a type
What
will
happen
to the
amino
What
has
happened
pushing all
the other bases
over.a frame.
of frameshift
mutation
acids?
to the
DNA?
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Insertion Mutations
The cat ate the rat
The cca tat eth era t
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