S5 BIOLOGY 29/NOV/2021

GENE MUTATION.
Is the sudden change in the structure of DNA which occurs at a single locus on a chromosome.
It is also called point mutation. The change in the structure of the DNA involves change in the
nucleotide base sequence of the DNA, this can take place during DNA Replication.

The structure of a DNA molecule can change resulting into gene mutation in one or more of the
following ways,

♦ Duplication.
An extra portion of nucleotide base sequence may be added in the nucleotide chain of the DNA.
A portion of a nucleotide chain of a DNA may become repeated .

♦ Insertion (addition)
A portion of a nucleotide base sequence becomes inserted in the nucleotide chain of the DNA.

♦ Deletion
A portion of a nucleotide base sequence in the DNA nucleotide chain may be broken and lost.

♦ Inversion
A nucleotide base sequence in the DNA becomes separated from the chain. It rejoins in its original
position only inverted. The nucleotide sequence of this portion is then reversed.

♦ Substitution
One nucleotide base in the nucleotide chain of the DNA may be replaced (substituted) by another
nucleotide carrying a different nitrogenous base.

THE EFFECTS / CONSEQUENCES OF GENE MUTATIONS.

When these errors occur, the new DNA is not an exact copy of the original. Such changes in the
structure of the DNA is called gene mutation.

When a gene mutates, the changes in the sequence of the base in the DNA causes a
complementary changes in the sequence in codons of messenger RNA. The altered codon when
translated will cause the following errors,

▪ Synthesis of a polypeptide chain with one or more amino acids missing (Non-sense
translation).

▪ Synthesis of polypeptide chain where in the amino acid sequence, one aminoacid is substituted
or replaced with a nother different one or some amino acids simply added to the polypeptide chain
(Mis-sense Translation).

▪ The polypeptide chains formed with such errors are usually defective and can results into the
following,

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 - Formation of abnormal protein molecules which are defective and can not efficiently
perform their functions.

- Non-production of certain particular essential protein molecules required for normal

physiological functions.

- Production of certain protein molecules which may attain toxic properties.

- Inborn error of metabolism leading into in-ability to synthesise specific enzymes or

sythesise enzymes which can not catalyse certain essential metabolic reactions.

Non-production of certain proteins, or production of proteins which are non-functional or defective

or attain toxic properties and the inborn errors of metabolism leads to genetic diseases.

GENETIC DISEASES.
There are a number of genetic disorders arising from the consequences of gene mutations
causing production of abnormal proteins, non-production of certain important protein molecules,
or in-ability to synthesize specific enzymes or synthesis of enzymes that do not catalyse any
essential metabolic reactions and such genetic diseases include,

- Haemophilia.
- Red-green colour blindness.
- Duchene muscular dystrophy.
- Sickle cell anaemia.
- Cystic fibrosis.
- Huntington’s chorea.
- Phenylketonuria.
- Alkaptonuria.
- Galactosaemia.

HAEMOPHILIA.
Is caused by mutation of the genes in a DNA that provide intructions for production of clotting
factor VIII or IX proteins called antihaemophiliac globulin, this gene mutation leads to none
production of these clotting factor VIII or IX proteins or prevent them from working normally. This
causes a bleeding disorder that slows or prevents the process of blood clotting. It often results
into excessive bleeding both internally and externally in times of injuries which may cause death.

The gene for factor VIII is carried on the X chromosome. So, Haemophilia is a sex linked (X linked)
character caused by the mutatnt recessive allele, the normal allele is the dominant.

Haemophilia is more common among males than the females in a population.

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RED-GREEN COLOUR BLINDNESS.
Is caused by genetic mutation of genes responsible for production of proteins leading to Red
pigment , green pigment and blue pigment proteins in the retina of the eyes, leading to production
of defective red cones and green cones in the retina of the eye which can not properly work
causing red-green colour blindness.

Red-green colour blindness is controlled by sex linked mutant recessive alleles. The dominant
allele controls the normal condition. The person cannot distinguish between red and green shades
of colours. This condition is more common in males than females in a population.

DUCHENE MUSCULAR DYSTROPHY (DMD).

Is caused by mutation of Duchene muscular dystrophy gene that codes for production of the
proteins dystrophins which keep muscles intact and strong. This gene mutation prevents
production of the protein dystrophins in muscles. Muscles without the protein dystrophins are
more sensitive to damage, resulting in progressive loss of muscle tissues and function.

It is a severe progressive muscle wasting disease that leads to difficulty in movement and
eventually cardiac and respiratory failures occur resulting into death.

DMD is controlled by sex linked mutant recessive alleles, dominant alleles determine normal
condition involving production of protein dystrophin in muscles. It affects infant children mainly
boys. This disease can result into death of the sufferer at an early age (before the age of 20 years
is reached).

THE SICKLE CELL ANAEMIA.

Is caused by base substitution gene mutation of a gene that determines production of normal
haemoglobins in red blood cells. This gene mutation leads to production of abnormal
haemoglobins called haemoglobins S in red blood cells resulting into red blood cells attaining
sickle shaped structures causing conditions of sickle cell anaemia. Sickle cell anaemia is
associated with the following conditions, symptoms, consequences ,

- Anaemia, low Red blood cells count.

- Oxygen deficiency.
- Poor blood circulation.
- Enlargement of the spleen.

ANAEMIA AND OXYGEN DEFICIENCY.

Anaemia and tendency of the red blood cells to change shape from Biconcave to sickle shape.
Anaemia arises because the sickle shaped red blood cells are constantly destroyed in the spleen.
The efficiency of the red blood cells to transport oxygen is reduced, oxygen deficiency occurs in
the body. Deficiency of oxygen results into,
- Infections and frequent illness.
- Body weakness and fatique.
- Poor physical development.

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 - Dilation of the heart causing heart failure.

POOR BLOOD CIRCULATION.

Poor blood circulation. This is because the sickle shaped red blood cells get jammed in the blood
capillaries and small arteries. This will cause the following effects.
- Heart damage resulting into heart failures.
- Damage of the lungs causing pneumonia.
- Muscle and joint damage causing rheumatism and pain.
- Gut damage causing abdominal pain.
- Kidney damage causing kidney failure.
- Liver damage.

ENLARGEMENT OF THE SPLEEN.

Enlargement of the spleen. This is because sickle celled red blood cells collect in the spleen for
destruction so increase in the activities of the spleen leads to its enlargement.

NOTE :
Sickle cell anaemia affects mainly the African, Americans, the people of Mediterranean countries
and northern Africa.

CAUSES OF SICKLE CELL ANAEMIA (HOW SICKLE CELL ANAEMIA ARISE)

Sickle cell anaemia is caused by base substitution gene mutation. It occurs on one of the triplet
nucleotide bases i.e Cytocine, thymine, cytocine in a DNA located on the 11th pair of
chromosomes that carry genetic information for the production of beta polypeptide chain,
determining formation of haemoglobin molecule.

During this base substitution gene mutation, the nucleotide base, Adenine replaces thymine in
the DNA nucleotide triplet code i.e cytocine, thymine, cytocine (CTC), forming a wrong DNA triplet
nucleotide base sequence i.e Cytocine, Adenine, Cytocine (CAC).

During transcription, messenger RNA copies complementary DNA nucleotide base sequence
which will include the codon Guanine, Uracil, Guanine (GUG) as a result of the base substitution,
instead of the Guanine, Adenine, Guanine (GAG). This causes a mistake to occur on the 6 th
aminoacid in the beta polypeptide which is 146 amino acids long, where the amino acid valine
replaces the aminoacid glutamic acid.

The presence of valine instead of glutamic acid in the beta polypeptide leads to production of
abnormal haemoglobin called haemoglobin S. This is because the messenger RNA codon GAG
codes for aminoacid glutamic acid while GUG codes for amino acid valine.

Glutamic acid carries a negative charge and is polar where as valine is non-polar and
hydrophobic. So, abnormal haemoglobin S is much less soluble than normal haemoglobin and it
begins to crystallize when the oxygen concentration falls as it does in the capillaries of body
tissues, resulting into the red blood cells normally biconcave disc shaped to assume the shape of
a crescent or become sickle shaped, this reduces their surface area for absorption of oxygen and

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there fore, With their abnormal haemoglobins, the sickle shaped red blood cells are far less
efficient at carrying oxygen in blood.

INHERITANCE AND DISTRIBUTION OF THE SICKLE CELL ANAEMIA IN A POPULATION.

Is a genetic disorder or disease caused by the base substitution gene mutation occurring in DNA.

The genes controlling sickle cell anaemia show codominance in some cases but sometimes
described as recessive autosomal genes showing complete dominance. Homozygous recessive
individuals possess both recessive allele(HbsHbs) and suffer sickle cell anaemia and may die at
an early age.

It shows codominance because heterozygous individuals possess both the dominant allele (HbA)
and the recessive allele (Hbs) with a genotype (HbAHbs). The red blood cells of this individual
contain about half of normal haemoglobin and about half of the abnormal haemoglobin S. In this
case The Alleles HbA and Hbs are codominant but it shows complete dominance in some other
cases this is because the heterozygous individuals (HbAHbS) are described as showing sickle cell
traits and the individuals do not suffer from the conditions of the sickle cell anaemia.

Heterozygous individuals are only affected at unusually very low oxygen concentrations like
climbing at high altitudes. So some the haemoglobin can crystallize causing some few red blood
cells to attain sickle shapes.

The sickle cell condition shows some advantages. It is widely distributed in a population in and
remain persistent. The frequency of the recessive alleles for abnormal haemoglobin S is high in
malarial infected areas. This is because individuals carrying the recessive alleles do not suffer
from malaria (are less susceptible to malarial infections) since the plasmodium parasites do not
multiply in the red blood cells containing abnormal haemoglobins S, sickle celled red blood cells
have reduced surface area and cannot absorb sufficient oxygen. Lack of enough oxygen in the
red blood cells prevents adequate aerobic respirations to occur and many physiological processes
can not take place in the plasmodium and may be destroyed inside the sickle shaped red blood
cells, so its life cycle is not completed and many other red blood cells can not be infected. So,
heterozygous individuals have a selective advantage over non-carriers and are more likely to
survive and continue to pass the recessive alleles for abnormal haemoglobin in the next
generations. The final frequency of the genes in the population is determined by the levels of
malarial infections in the population. This is an example of balanced polymorphism.

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CYSTIC FIBROSIS.
Is caused by deletion of three nucleotide bases in a gene called cystic fibrosis transmembrane
conductance regulator (CFCR) gene. This mutation leads to production of defective proteins in
the plasma membranes called cystic fibrosis transmembrane regulators that work as chloride
channels in the cells that produce mucus, sweat and digestive enzymes.

In persons suffering from cystic fibrosis, the cystic fibrosis transmembrane regulators do not
function. Thus mucus lining the cell surfaces become thick and sticky. This affects mostly the
lungs, pancreas and the liver where unusually thick mucus clogs lungs, liver and pancreas.

In the pancreas fibrous patches called cysts develop and in the lungs, when the thick mucus dries
up, it causes blockage of air ways of the lungs, and branches of pancreatic ducts and the bile
duct from liver into the gut. This leads to repeated lung infections , difficulty in breathing and
digestive problems. Male and female infertility occurs, the individual may also show other
symptoms which include,
- Production of very salty sweat.
- Persistent coughing at times with phlegm.
- Frequent lung infections including pneumonia or bronchitis.
- Poor growth.
- Nasal polyps. These are soft, painless, non-cancerous growths on the lining of your nasal
passages or sinuses.

Note:
- Cyst is a growth or swellings containing liquids that form on the body of a person.
- Cystic fibrosis is a recessive gene mutation very common in Europe.

HUNTINGTON,S DISEASE (CHOREA).

Is a progressive brain disorder that causes uncontrolled movements, emotional problems and
loss of thinking ability(cognition).

Huntington,s chorea is caused by the mutation of the huntingtins gene located on chromosome 4
where nucleotide base sequence CAG on DNA is duplicated or repeated 40 to 60 times.
The mutant gene is an autosomal dominant allele, meaning that only one mutant gene of the two
copies of the gene in the cell is sufficient to cause the disease.

The normal Huntingtons gene provides instructions for making a protein called huntingtins.
Huntingtins is a soluble protein found in many of the body,s tissues with the highest levels in the
brain and the testes. Within cells the protein huntingtins seem to be involved in, chemical
signaling, transporting materials, binding to proteins and other structures and protecting the cells
from self destruction.

The mutation of the huntingtons gene by nucleotide base sequence CAG repeat, causes
alteration of the nature of the huntingtins protein which attain toxic properties (a toxic gain of
function phenotype). This results in neuro-degeneration and break down of the neurons in the

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part of the brain responsible for coordination of habit and emotional memories and voluntary
movements, resulting into,
- Deterioration of brain cells, resulting into loss of intellectual ability.
- Involuntary muscular movements or loss of control of voluntary muscles by motor
neurones. This results into uncontrollable shaking and dance (chorea) like movements.
- Hallucinations, mood and personality changes.

Genetic counseling and gene cloning techniques can be applied to diagnose the disease and
prevent frequency of its occurrences.

PHENYLKETONURIA.
Phenylketonuria (PKU) is caused by gene mutation of the gene for production of the enzyme
phenylalanine hydroxylase (PAH) found on chromosome 12. It is an autosomal recessive disorder
resulting from the essential amino acids phenylalanine accumulating the in the blood, causing
brain damage.

It Is a rare genetic disorder 0r disease where the individual can not synthesize the active form of
an enzyme phenylalanine hydroxylase which catalyze conversion of excess essential amino acid
phenylalanine to tyrosine in the liver or the enzyme produced is less efficient. Deficiency or
absence of the enzyme causes the amino acids phenylalanine to accumulate and become in
excess in the blood. The excess phenylalanine is converted to toxins. This will prevent the child.s
brain from absorbing sufficient amounts of other essential amino acids from the the blood, as a
result the brain, other organs and tissues such as muscles and cartilage fail to grow and develop
normally, leading into the,
- Mental retardation.
- Organ damage.
- Child can not walk properly and will have awkward posture during walking.
- Females with high concentration of phenylalanine in their blood, would have the risk of the
brain of their developing fotus getting damaged.
- Convulsions.

ALKAPTONURIA (THE BLACK URINE DISEASE).

Is a defect in the gene resulting into in-ability to synthesize certain enzymes needed for the proper
metaboilism of aminoacids tyrosine and phenylalanine. This leads into poor breakdown of the
amino acids tyrosine and phenylalanine in the body. The excess aminoacids tyrosine is converted
to acids called alkapton (homogentisic acids).
The alkapton(homogentisic acids) build up in the skin and other connective tissue like the
cartilage. The acids leave the body through the urine and if treatment delays, it will lead to severe
deformity of joints, spines and organ dysfunction.

The urine of people with alkaptonuria turns black when exposed to light due to high concentration
of the acids alkapton. When alkapton get deposited in the cartilage, it causes the tip of the nose
to turn black. It can also lead to severe joint pains.

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GALACTOSAEMIA.
Is caused by mutations of a gene that results into deficiency or in-ability to synthesize the enzyme
needed for conversion of the sugar galactose to glucose. Accumulation of the sugar galactose in
blood causes cataracts, damage of the liver or the kidney.

Children with galactosaemia are often normal when they are born but within weeks they begin to
vomit much of the milk they drink and fail to undergo normal processes of growth and
development. If the conditions are not dealt with quickly the child may become blind and mentally
retarded.