Classes Notes

Principles of Inheritance and Variation

Colour Blindness, Sickle Cell Anemia, Thalassemia
and Phenylketonuria

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 Key Takeaways

Mendelian disorders

Colour blindness

Sickle cell anemia

Thalassemia

Phenylketonuria

Summary
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 Recall! Human Karyotype

1 2 3 4 5 6 7 8

9 10 11 12 13 14 15 16
Sex
or
chromosomes
17 18 19 20 21 22 XX XY

● Out of the 23 pairs of chromosomes in humans, 22 are autosomal chromosomes, and X and
Y are sex chromosomes.
● Genes that are inherited via the sex chromosomes are called sex-linked, and the inheritance
is called sex-linked inheritance.
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 Recall! Pedigree Chart
A pedigree chart is a representation of a family chart showing
the transmission of a particular trait or disease.

II

III

IV
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 Recall! Genetic Disorders

Mendelian Chromosomal
disorders disorders

Sex-linked Autosomal

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 Recall! Mendelian Disorders

Sex-specific Sex-linked Autosomal Not sex-specific

Dominant Recessive Dominant Recessive

● Mendelian disorders are mainly determined by alteration or mutation in a single gene.

● The pattern of inheritance of such Mendelian disorders can be traced in a family by the
pedigree analysis.

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 Colour Blindness
● Sex-linked recessive disorder due to defect in either red or green cones
of eye resulting in failure to discriminate between red and green colour.
● Results from mutation in the X chromosome.
● Females are usually carriers, whereas males are more commonly affected
by the disorder.

1 2 3 4 5 6 7 8
Mutation in
X chromosome
9 10 11 12 13 14 15 16

or
17 18 19 20 21 22 XX XY
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 Colour Blindness

● Vision is, however, not affected and the colour blind person can
lead a normal life.

● The gene for the normal vision is dominant.

● The normal gene and its recessive allele are carried by

X-chromosomes.

● In females, colour blindness appears only when both the sex

chromosomes carry the recessive gene (Xc Xc).

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 Colour Blindness

0.4 %

8%

● Females are usually carriers.

● Males are at higher risk of getting colour blindness as they

have only 1 X-chromosome whereas females have 2.

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 Colour Blindness
Carrier mother x Unaffected father

Carrier mother with X Unaffected father without

colour blind gene XX XY colour blind gene

XX XY XX XY
Carrier daughter Affected son with Unaffected children
with colour blind colour blind gene without colour blind gene
gene

Pedigree chart

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 Colour Blindness
Carrier mother x Affected father

Carrier mother with x Affected father with

colour blind gene colour blind gene
XX XY

XX XY XX XY
Affected daughter Affected son Carrier daughter Unaffected son
with colour with colour with colour without colour
blind gene blind gene blind gene blind gene

Pedigree chart

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 Colour Blindness
Affected mother x Unaffected father

Affected mother with Unaffected father without

colour blind gene X colour blind gene
XX XY

XX XX XY XY

Carrier daughters with Affected sons With

colour blind gene colour blind gene
Pedigree chart

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2 2
 Which of the following figures represent parents
with a female child affected with a disease?

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 Which of the following figures represent parents
with a female child affected with a disease?

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 Sickle Cell Anemia (SCA)
Haemoglobin - The oxygen transporter
● Haemoglobin (Hb) present in the RBCs are important
for carrying O2 and CO2 across the body.
● Hb is a protein that has 2 alpha globin chains and 2
beta globin chains.

α α

β β

Haemoglobin

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Erythrocyte
 Sickle Cell Anemia (SCA)
● Sickle cell anemia is an inherited red blood cell disorder in which there
aren't enough healthy red blood cells to carry oxygen throughout the body.
● Affected person has abnormal haemoglobin.
● It is an autosomal recessive disorder.
● A mutation in the Hb gene causes abnormal Hb synthesis resulting in the
formation of sickle shaped cells.
● This change is caused by a single change of amino acid in the Hb protein.
● Glutamic acid in the 6th position of the beta globin chain is replaced by
Valine, which causes change in Hb and thereby in RBCs, from biconcave to
sickle shaped.
● This results in aggregation of RBCs in the blood capillaries leading to
blockage of arteries.
● Sickle shaped RBCs also get destroyed faster than normal RBCs, resulting in
severe anemia.
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 Sickle Cell Anemia (SCA)
Normal RBCs vs Sickled RBCs

Normal amino acid sequence Single change in amino acid sequence

Thr Pro Glu Glu Thr Pro Val Glu

4 5 6 7 4 5 6 7

Normal red blood cells Sickle shaped red

blood cells

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 Sickle Cell Anaemia (SCA)

Normal
hemoglobin
A gene (HbA)
Mutation Abnormal adult
Hemoglobin hemoglobin (HbS) Sickle trait (HbS)
gene

HbAHbA HbAHbS HbSHbS

Normal Carrier SCA
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 Sickle Cell Anemia (SCA)
Restricted and normal blood flow

Sickle red blood cells,

blocking the blood flow

Healthy red blood cell

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 Sickle Cell Anemia (SCA)
Inheritance (Carrier x Carrier)

HbAHbS HbAHbS HbA HbS

HbA HbS HbA HbS HbA HbAHbA HbAHbS

HbS HbAHbS HbSHbS

HbAHbA HbAHbS HbAHbS HbSHbS

Normal Carrier Carrier SCA

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 Sickle Cell Anemia (SCA)
Inheritance (Affected x Carrier)

HbSHbS HbAHbS HbA HbS

HbS HbAHbS HbSHbS

HbS HbS HbA HbS

HbS HbAHbS HbSHbS

HbAHbS HbAHbS HbSHbS HbSHbS

Carrier Carrier SCA SCA
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 Sickle Cell Anemia (SCA)
Inheritance (Unaffected x Carrier)

A A A S HbA HbS
Hb Hb Hb Hb

A A A S
HbA HbAHbA HbAHbS
Hb Hb Hb Hb

HbA HbAHbA HbAHbS

HbAHbS
HbAHbA HbAHbA HbAHbS
Normal Normal Carrier Carrier
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 Inheritance Pattern in Sickle Cell Anemia
If both the parents are carriers:

Gen I

Gen II

Gen III

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 Thalassemia
● It is a rare inherited autosomal blood disorder resulting from inadequate Hb
synthesis.
● It results in the extreme destruction of red blood cells that leads to anaemia.
● If any of the parents have thalassemia, the baby is likely to develop a
disease called “thalassemia minor”.
● If both the parents suffer from this disease, the child is more likely to get the
disease.
● It was discovered by Cooley but the term was given by Whipple and
Bradford after its prevalence in mediterranean region.
● Thalassemia is autosomal recessive blood disease which appears in children
of two unaffected carriers (heterozygous parents).
● The defect can occur due to mutation or deletion of the genes controlling
the formation of globin chains (commonly α and β) of haemoglobin.
● Imbalanced synthesis of globin chains of haemoglobin causes anaemia.

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 Thalassemia
Haemoglobin (Hb)
α globin chains (each
with 141 amino acids)

Heme group with Fe in the

centre around a porphyrin ring

β globin chains (each

with 146 amino acids)
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 Thalassemia

Mendelian
disorders Beta Alpha
thalassemia thalassemia

Autosomal

Thalassemia
Dominant Recessive

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 Thalassemia
Alpha thalassemia Beta thalassemia

Abnormal Hb Abnormal Hb
with affected with affected
α globin chains ß globin chains

HBB
Chromosome HBA 1 Chromosome 11 gene
HBA 2 16 alpha gene
gene beta globin
globin gene gene
● Alpha thalassemia is caused due to ● Beta thalassemia is controlled by a
defect in 2 closely linked genes single gene HBB on chromosome 11 of
HBA1 and HBA2 on chromosome each parent and occurs due to mutation
16 of each parent. of one or both the alleles of the gene.
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 Thalassemia
Alpha thalassemia
● It is caused by the defective formation of α-globin.
● It is controlled by two genes present on chromosome 16, HBA1 and
HBA2 with a total of four alleles.
● Persons with one defective allele are silent carriers while two defective
alleles produce α-thalassemia minor.

Beta thalassemia
● There is decreased synthesis of β-globin in this case.
● The defect is due to alleles of HBB gene present on chromosome 11.
● Persons with one defective allele suffer from thalassemia minor with
larger number of microcytic erythrocytes and lesser amount of
haemoglobin.
● Persons with both the defective alleles suffer from Cooley’s anaemia or
thalassemia major.

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 Thalassemia
Carrier x Carrier

T t T t T t

T TT Tt

t Tt tt
TT Tt Tt tt

Unaffected Carrier progeny Affected progeny

progeny TT (50%) Tt tt
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 Thalassemia
Carrier x Unaffected

T t T T T t

T TT Tt

TT Tt Tt TT T TT Tt

Unaffected Carrier progeny Unaffected

progeny TT (50%) Tt progeny TT
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 Thalassemia
Affected x Unaffected

t t T T t t

T Tt Tt

Tt Tt Tt Tt
T Tt Tt

Carrier progeny
Tt
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 Thalasemia
Affected x Carrier

t t T t t t

T Tt Tt

t tt tt
Tt Tt tt tt

Carrier progeny Affected progeny

Tt tt
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 Inheritance Pattern in Thalassemia
If both the parents are carriers:

Gen I

Gen II

Gen III

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 Abnormal forms of RBCs
● Thalassemia
○ A quantitative problem of synthesizing too few
globin molecules.
● Sickle cell anemia
○ A qualitative problem of synthesising an
incorrectly functioning globin.

Normal
red blood cell

Quantitative Thalassemia
problem red blood cell

Qualitative
Sickled
problem
red blood cell
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 Phenylketonuria(PKU)
● It is an autosomal recessive metabolic disorder resulting from lack
of an enzyme known as phenylalanine hydroxylase (PHL).
● PHL helps to convert phenylalanine into tyrosine.

PHL - Phenylalanine hydroxylase

PHL
Normal Phenylalanine Tyrosine

PHL
Diseased Phenylalanine Tyrosine

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 Phenylketonuria (PKU)
PHL
Phenylalanine Tyrosine

Accumulation of Phe Deficiency of Tyr

to toxic levels

● Phenylketonuria results in accumulation of phenylalanine to toxic levels

and deficiency of tyrosine.
● Tyrosine is required for synthesis of various neurotransmitters.
● Tyrosine deficiency results in reduced brain development and other
neurological conditions.
● Excess presence of Phe(Phenylalanine) in cerebrospinal fluid (CSF)
causes mental retardation, intellectual disability and mental disorders.

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 Phenylketonuria (PKU)
Symptoms
● Small sized head (microcephaly)

● Learning disability and delayed development

Microcephaly ● Neurological disorders

● Behavioural, emotional and social problems

● Fatigue

Normal sized head

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 Phenylketonuria(PKU)
Carrier x Carrier

Pp Pp

P p P p P p

P PP Pp

p Pp pp
PP Pp Pp pp

Unaffected Carrier Progeny Affected

progeny PP (50%) Pp progeny pp
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 Phenylketonuria (PKU)
Unaffected x Carrier

PP Pp
P P
P P P p
P PP PP

p Pp Pp
PP Pp PP Pp
Unaffected Carrier Unaffected Carrier
progeny progeny progeny progeny
PP Pp PP Pp
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 Phenylketonuria (PKU)
Unaffected x Affected

PP pp
p p
P P p p

P Pp Pp

P Pp Pp
Pp Pp Pp Pp

Carrier progeny
Pp
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 Inheritance Pattern in Phenylketonuria
If both the parents are carriers:

Gen I

Gen II

Gen III

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 Summary

● Pedigree analysis
○ It is the study of a particular trait that is inherited from one
generation to another.
○ It helps to understand the pattern of inheritance for a particular
trait, and also to know whether the trait is dominant or
recessive.

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 Summary
Understanding the symbols

Unaffected/Normal Unaffected/Normal Sex

male female unspecified Affected female Affected male Carrier female Carrier male

Carrier female Carrier male Deceased female and male Marriage

Consanguineous marriage Fraternal twins (non-identical) Identical twins

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 Summary
Haemophilia is an inherited genetic disorder that
Sex- linked Haemophilia impairs body’s ability to make clots.

Sex-linked recessive disorder due to defect in

Mendelian disorders

Colour blindness either red or green cone of eye resulting in failure

to discriminate between red and green colour.

Inherited red blood cell disorder in which there

Sickle cell anemia aren't enough healthy red blood cells to carry
oxygen throughout our body.
Autosomal

Thalassemia A rare inherited blood disorder resulting from

inadequate Hb synthesis.

Autosomal recessive metabolic disorder resulting

Phenylketonuria from lack of an enzyme phenylalanine hydroxylase
(PHL).
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