Genetic MutationsSDK

October 27, 2014

OBJECTIVES 

By the end of this session the student should be able to:Define MutationFrequency of mutations in normal individualsClassify different types of mutationExplain the mechanism of mutationExplain the role of mutation in biodiversityExplain how mutations can cause severe diseasesGive examples of deletions, duplications, and insertions in genesDefine 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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• Mutations can lead to missing or malformed proteins, and that can lead to disease.

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Gene mutation out come

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

They are not always seen because the mutation may have occurred in a section of DNA that

doesn’t make a protein.

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• Most inherited genetic diseases are recessive, which means that a person must inherit two copies of the mutated gene to inherit a disorder.

• This is one reason that marriage between close relatives is discouraged; two genetically similar adults are more likely to give a child two copies of a defective gene.

Diseases caused by just one copy of a defective gene are not manifested with the exception of Huntington's disease, which is rare and afflicted carriers are more likely to die before reproducing.

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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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

Beneficial Mutations HIV - Virus, Genetics

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]

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• About 10% of Caucasians of Western European descent have the mutation for chemokine receptor-CCR5-▲32 making them resistant to HIV.

• About 10% of Caucasians of Western European descent have the mutation for chemokine receptor-CCR5-▲32 making them resistant to HIV.

Beneficial Mutations HIV - Virus, Genetics

Mutations a cause of Biodiversity

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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.

Does all mutations passed on to next generation?

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NO

Brain Work 1 A mutation may happen in any gene.

TRUE OR FALSE?

TRUETRUE

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Spontaneous and Induced MutationsSpontaneous: 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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Which of the following may cause mutations?A. Coffee

B. UV light (sun light)

C. Hair gel

D. Vaccines

Brain Work 2

UV Light (Sun Light)

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Types of Mutations1. Point mutations. A point mutation is a simple change in

one base of the gene sequence.

2. Frame shift mutations. one or more bases are inserted or deleted

• Original The fat cat ate the wee rat.• Point Mutation The fat cat ate the wet rat.

• Original The fat cat ate the wee rat.• Point Mutation The fat cat ate the wet rat.

Original. The fat cat ate the wee rat

Frame Shift The fat caa tet hew eer at

Original. The fat cat ate the wee rat

Frame Shift 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 CUCMissense 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 GUGNonsense 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= THE FAT CAT ATE THE WEE RAT FRAMESHIFT= THE FAT CAA TET HEW EER AT.

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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?

TRUETRUE

Brain Work 3

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Most mutations are caught and repaired in the cell.

TRUE or FALSE?

Brain Work 4

TRUETRUE

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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:

Also called frameshift mutations

•Substitution

•Deletion•Insertion

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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:CTGGAGCTGGGG

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Normal DNA: CGA – TGC – ATC

Substitution Mutations

Mutated DNA: CGA – TGC – TTCAlanine – Threonine - stop

Alanine – Threonine - Lysine

What has happened to the DNA?The adenine was replaced with thymine

What will happen to the amino acids?

This is a substitution mutation

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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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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.

Sickle Cell Anemia

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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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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 + )

Thalassemias

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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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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

Clinical Features of -Thalassaemia

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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

CTGGCCTAG

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This is an insertion mutation, also a type

of frameshift mutation.

Normal DNA: CGA – TGC – ATC

Insertion Mutations

Mutated DNA: CGA – TAG – CAT – C

Alanine – Threonine – stop

Alanine – Isoleucine – Valine

What will happen to the amino acids?

An adenine was inserted thereby pushing all the other bases over a frame.

What has happenedto the DNA?

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The cca tat eth era t

The cat ate the rat

Insertion Mutations

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