2.
The genes are linearly distributed on chromo-
Inheritance
and
Mutations
It is estimated that more than 6% of all infants born alive
suffer from genetic diseases and 1% from chromosomal
aberrations. The former conditions involve minor alterations in
DNA make up, e.g. phenylketonuria. The latter ones are due to
major changes in chromosomes; e.g. Down's syndrome,
Turner's syndrome. Gregor Johann Mendel (1822-84), who was
Abbot of Brun, described the principles of heredity in 1866. As
it was printed in an obscure journal, it remained unnoticed for
many years. In 1900, Hugo de Vries and C. Correns,
rediscovered and confirmed Mendel's theory. Walter Flemming
demonstrated chromosomes in 1882. In 1902, Walter Sutton
showed that chromosomes are in pairs and are the carriers of
Mendel's Unit of heredity. The word ‘Gene' was coined by
Wilhelm Johannsen in 1909. According to Mendel's law, if “A”
represents a dominant character and “b” recessive or latent
character in parents, then (A+b)2 = A2+2 Ab +b2, i.e. one-half
of progeny will have mixed parental characters (2Ab); one-fourth
will have dominant (A2) and one-fourth will have recessive (b2)
characters. All genes are not equal in the eyes of evolution.
Evolutionarily relevant mutations tend to accumulate in ‘hotspot
genes’ and at specific positions within genes. Genetic evolution
is constrained by gene function, the structure of genetic
networks, and population biology.
Basic Principles of Heredity
1. Heredity is transmitted from parent to offspring
as individual characters.
somes at fixed positions (loci).
3. Genes that may replace one another at the
same locus are called allelomorphic genes or
alleles. Alleles are genes responsible for
alternate or contrasting characters. Usually one
allele is inherited from father and the other from
mother.
4. When both alleles carry the same defect, it is
said to be homozygous.
5. When one allele is normal, and the counterpart
is defective; it is called heterozygous.
6. Genes on the same chromosome are linked; and
the linkages are more pronounced in the nearby
genes.
7. The observed character expressed by the gene
is called phenotype.
8. The genotype represents the set pattern of
genes present in the cell.
1. Dominant Inheritance
i. It is characterized by the phenotypic expression
of the disease, even if one allele is abnormal or
in heterozygous state. In the example shown in
Figure 42.1, the father has the defective gene,
marked as D. The possible permutations of
gametes are shown in the figure.
ii. Affected men and women transmit the abnormality
to their children. When an affected heterozygote
(Dd) marries a normal spouse (dd), half of the
progeny can have the disease.
iii. Examples of diseases with autosomal dominant
inheritance are chondrodystrophy (dwarfism)
and some types of porphyrias.

Fig. 42.1. Autosomal dominant inheritance
2. Autosomal Recessive Inheritance
i. Phenotype or a particular character is controlled
by a pair of alleles located on a specified area
on the chromosomes.
ii. If the disease is manifested only in homozygous
state (not expressed in heterozygous condition),
it is known as recessive transmission.
iii. For example, in a person suffering from sickle
cell anemia, both the alleles for beta globin gene
have mutated. Hence all beta globin chains will
be abnormal. He is homozygous for sickle cell
disease.
iv. In certain cases, the carrier state may be
identified biochemically, then it is referred to as
the trait of the disease. For example, in sickle
cell trait, one beta globin gene (allele) is normal;
while the other one is abnormal (carrier state).
Such individual is heterozygous to that character.
Therefore, normal gene produces normal Hb
and abnormal gene produces HbS. Thus inside
the RBC, 50% of hemoglobin molecules are
abnormal. This can be identified by electro-
phoresis.
v. When both father and mother are carriers, one-
quarter of siblings express the disease (both
alleles abnormal), another one-quarter of
siblings are normal, and half of the children are
carriers (Fig. 42.2). This chance factor is acting
on each progeny.
vi. If only one parent is carrier and the other is
normal; then there will be no affected child, but
50% children are carriers.
499
Fig. 42.2. Autosomal recessive inheritance
vii. Most of the inborn errors of metabolism are
recessively transmitted. A few examples are
phenylketonuria, albinism, galactosemia and
sickle cell anemia.
3. Sex-linked (X-linked) Recessive Inheritance
i. In the autosomal conditions, the disease occurs
in both sexes with equal frequency. But in sex-
linked conditions, X-chromosome carries the
abnormal gene. See Figure 42.3.
ii. In a wedding between a normal male and a
carrier female, the probabilities are that one-
quarter is male with disease; one-quarter is
female carrier; one-quarter normal male and
one-quarter normal female.
iii. If an affected male marries a normal female,
male children will be normal, but all female
children will be carriers, because they all inherit
the abnormal X from their father (Fig. 42.3).
iv. In X-linked recessive condition, normal X
dominates over abnormal X; but abnormal X is
expressed when present with Y.
v. Hemophilia, glucose-6-phosphate dehydro-
genase deficiency, pseudo-hypertrophic
muscular dystrophy (Duchenne type), and red
green color blindness are examples of sex-
linked recessive inheritance.
Population Genetics
A law stating the frequency of abnormal genes in population
was discovered in 1908 independently by Hardy (mathe-
matician) and Weinberg (physician). The Hardy-Weinberg law
states that, if there are "p" gametes of ‘A' type and "q" gametes
of ‘a' type and when p + q = 1 in one generation, the genotypes
and their frequency will be:
500
Fig. 42.3. Sex-linked recessive inheritance
Genotype AA Aa aa
relative frequency p2 2pq q2
The law states that (p2 + 2pq + q2) = 1 and the genotypes
in the population from one generation to another generation
will be in equilibrium. Or, p2 : 2pq : q2 ratio is maintained in all
generations (the ratio of normal and abnormal gene is
maintained in all generations).This law is useful to calculate
the frequency of a harmful gene in a population. It is known
that 1 in 20,000 live births is an albino, which is inherited
recessively. Let us say, they are ‘aa' genotypes. Thus the
remaining 19,999 are ‘AA' or ‘Aa' genotypes. The frequency of
q of the recessive albino gene can be calculated as follows: q2
= 1/20,000. Therefore q = 1/141. Since p + q = 1, in this
particular example, p = 140/141. Therefore the ‘Aa' genotype,
or 2pq = 1/70. Thus 1 out of 70 individuals, carries the abnormal
gene for albinism. In other words, 1.4% of all persons are
heterozygous for albino allele. So, there are 280 carriers for
each albino patient.
Spontaneous Mutations
The abnormal genes are produced by natural mutations and
deleted by Darwin's natural selection mechanism, e.g.
phenylketonuria patient is mentally retarded and therefore
lesser chances to procure a child. The law essentially states
that the rate of new mutation equals the elimination. That
means, spontaneous mutation is taking place on that gene in
successive generations.
Law of Selection Applied to Genes
However, an abnormal gene need not always be
eliminated from a population, if there is a selective
advantage for heterozygous state. The best
example is the sickle-cell anemia trait. The
geographical distribution of sickle-cell anemia fairly
well overlaps with malaria endemicity. Sickle-cell
anemia is a lethal disease; patient dies before the
reproductive age, and therefore the gene must have
been eliminated. But the heterozygous persons
carry RBCs having 50% normal Hb and 50%
abnormal hemoglobin. So, the oxygen pressure
inside the RBC is lesser than normal individuals.
Hence, malarial parasites do not multiply easily in
heterozygous individuals (Chapter 22). Therefore,
in the malarial endemic areas, the lethal nature of
the gene in the homozygous state is counter-
balanced by the advantage in heterozygous state.
This is called balanced polymorphism. Genes for
thalassemia, GPD deficiency, etc. are also
maintained in the population by such a mechanism.
Marriages with Close-cousins are Inadvisable
The probability of two carriers getting married is
increased in consanguinous marriages. (Latin, con
= with; sanguis = blood). So, there is increased
frequency of genetic diseases in their children. For
example, phenylketonuria has an incidence of 1 in
25,000 in general population; but it is 13 / 25,000 in
children of first cousin marriages.
Cytoplasmic Inheritance
This follows a maternal line of transmission, e.g. mitochondrial
inheritance. Transmission of mitochondrial genes ends with
each son, because son does not pass the mitochondrial genes
to his offspring. Mothers are heteroplasmic and are therefore
unaffected, e.g. Leber's optic neuropathy (Table 41.6),
myoclonic epilepsy, etc.
Chromosomal Recombination
During meiosis (reduction division), exchange of genetic
information between homologous chromosomes is taking
place. Homologous chromosomes are exactly aligned so that
respective genes oppose. Then a process of crossover
occurs, so that reciprocal exchange of genetic information is
obtained. Such a recombination can explain the fact that the

Table 42.1. Genes in human chromosomes
Chromo-
some No. Gene
1 : Alkaline phosphatase (liver, bone, kidney);
Salivary amylase; Apoprotein A-II
2 : Alkaline phosphatase (placental), Apolipoprotein-
B;Immunoglobulin Kappa chain
3 : Transferrin
4 : Alcohol dehydrogenase; Fibrinogen; Interleukin-
2; Huntington's chorea (disease)
5: HMG CoA reductase; Acute myelogenous
leukemia
6 : MHC (Major histocompatibility) locus
7 : Urea cycle enzymes; Cystic fibrosis (disease)
8 : Carbonic anhydrase
9 : Interferon
11: Hemoglobin β, γ and δ chains; Proinsulin;
Pepsinogen; Parathyroid hormone
12 : Alpha-2-macroglobulin; Glyceraldehyde-3-P-
dehydrogenase
13 : Adenosine deaminase
14 : Immunoglobulin heavy chains; α1-antitrypsin
15 : Cytochrome P-450
16 : Hemoglobin α-chain; polycystic kidney disease;
Breast cancer, Prostate cancer
17 : Growth hormone
18 : Prealbumin
19 : Carcinoembryonic antigen; β chain of hCG;
Creatine kinase M chain; LDL receptor
20 : Adenosine deaminase
21 : Superoxide dismutase
22 : Immunoglobulin, lambda chain
X : Glucose-6-P-dehydrogenase; Antihemophilic
globulin; HGPRTase; Duchenne type
muscular dystrophy
characteristics of offspring are not exactly like those of their
parents. Often a genius is born to ordinary parents. The pattern
of fingerprints will be different even in siblings.
Rarely, the alignment of chromosomes may not be exact;
then recombination results in unequal exchange of genes.
There may be deletion in one chromosome, while the other
one receives an insertion. A good example of unequal
recombination is the Lepore hemoglobin, where instead of
normal delta and beta hemoglobins a chimeric delta-beta
hemoglobin is produced (Chimera is a Greek demon, similar
to Narasimha, with lion's head and body of other animals).
Transposon
It is a DNA sequence able to insert itself at a new location in
the genome; these are jumping genes or movable genes.
Retroposon is a transposon that mobilizes via an RNA form;
the DNA element is transcribed into RNA, and then reverse-
transcribed into DNA, which is inserted at a new site in the
genome.
501
Genetic Disorders
The locations of many genes have been identified on
specific chromosomes. A small selected list is given
in Table 42.1. Genetic disorders are of different types:
A. Chromosomal disorders. These are identified by
karyotyping, e.g. 21 trisomy.
B. Single gene defect, sometimes identified by
biochemical methods, e.g. phenylketonuria.
C. Mitochondrial abnormalities.
D. Multifactorial disorders.
Treatment Policies of Genetic Diseases
1. Replace the end-product of the missing enzyme,
e.g. administer thyroxine in familial goitre.
2. Limit the substrate of the missing enzyme. In
phenylketonuria, reduce phenyl alanine in diet.
In galactosemia remove lactose from diet.
3. Replace missing protein, e.g. administer AHG
(anti-hemophilic globulin) in hemophilia.
4. Activity of abnormal enzyme is enhanced, e.g.
large quantities of vitamin B12 is useful in methyl
malonic aciduria.
5. Induction of enzyme; in Crigler-Najjar syndrome,
glucuronyl transferase enzyme can be induced
by phenobarbitone.
6. Gene therapy is still in experimental stages, but
may become common in the next generation.
MUTATIONS
i. A mutation is defined as a change in nucleotide
sequence of DNA. This may be either gross,
so that large areas of chromosome are
changed, or may be subtle with a change in
one or a few nucleotides.
ii. Mutation may be defined as an abrupt spon-
taneous origin of new character.
iii. Statistically, out of every 106 cell divisions, one
mutation takes place.
1. Classification of Mutations
A point mutation is defined as change in a single
nucleotide. This may be subclassified as (a) sub-
stitution, (b) deletion, and (c) insertion. All of them
may lead to mis-sense, nonsense or frameshift
effects.
1-A. Substitution
Replacement of a purine by another purine ( A to G
or G to A) or pyrimidine by pyrimidine (T to C or C to
T) is called Transition mutation. If a purine is
changed to a pyrimidine (e.g. A to C) or a pyrimidine
to a purine (e.g. T to G), it is called a transversion.
The point mutation present in DNA is transcribed
502
and translated, so that the defective gene produces
an abnormal protein.
1-B. Deletion
Deletions may be subclassified into–
i. Large gene deletions, e.g. alpha thalassemia
(entire gene) or hemophilia (partial)
ii. Deletion of a codon, e.g. cystic fibrosis (one
amino acid, 508th phenyl alanine is missing in
the CFTR protein.
iii. Deletion of a single base, which will give rise
to frameshift effect.
1-C. Insertion
Insertions or additions or expansions are sub-
classified into–
i. Single base additions, leading to frameshift
effect.
ii. Trinucleotide expansions. In Huntington's
chorea, CAG trinucleotides are repeated 30 to
300 times. This leads to a polyglutamine repeat
in the protein. The severity of the disease is
increased as the numbers of repeats are more.
iii. Duplications. In Duchenne Muscular Dys-
trophy (DMD) gene is duplicated in the disease.
2. Effects of Mutations
2-A. Silent Mutation
A point mutation may change the codon for one
amino acid to a synonym for the same amino acid.
Then the mutation is silent and has no effect on the
phenotype. For example, CUA is mutated to CUC;
both code for leucine, and so this mutation has no
effect.
2-B. Mis-sense but Acceptable Mutation
A change in amino acid may be produced in the
protein; but with no functional consequences. For
example, in the normal hemoglobin A molecule, the
67th amino acid in beta chain (HbA β-67) is valine.
The codon in mRNA is GUU. If a point mutation
changes it to GCU, the amino acid becomes alanine;
this is called Hb Sydney. This variant is functionally
normal. A conserved mutation occurs when the
altered amino acid has the same properties of the
original one; e.g. Glutamic acid to Aspartic acid.
2-C. Mis-sense; Partially Acceptable Mutation
In this type, the amino acid substitution affects the
functional properties of the protein. HbS or sickle-
cell hemoglobin is produced by a mutation of the
beta chain in which the 6th position is changed to
valine, instead of the normal glutamate. Here, the
normal codon GAG is changed to GUG (trans-
version). HbS has abnormal electrophoretic mobility
and subnormal function, leading to sickle-cell
anemia. Details are given in Chapter 22.
2-D. Mis-sense; Unacceptable Mutation
The single amino acid substitution alters the
properties of the protein to such an extent that it
becomes nonfunctional and the condition is
incompatible with normal life. For example, HbM
results from histidine to tyrosine substitution (CAU
to UAU) of the distal histidine residue of alpha chain.
There is met-hemoglobinemia.
2-E. Nonsense; Terminator Codon Mutation
A tyrosine (codon, UAC) may be mutated to a
termination codon (UAA or UAG). This leads to
premature termination of the protein, and so
functional activity may be destroyed, e.g. beta-
thalassemia. Or, a terminator codon is altered into
a coding codon (UAA to CAA). This results in
elongation of the protein to produce "run on
polypeptide" (Hb Constant spring) (Chapter 22).
2-F. Frameshift Mutation
This is due to addition or deletion of bases. From
that point onwards, the reading frame shifts. A
"garbled" (completely irrelevant) protein, with altered
amino acid sequence is produced. An example:
Normal mRNA AUG UCU UGC AAA......
Normal protein Met Ser Cys Lys.......
DeletedU mRNA AUG CUU GCA AA.........
Garbled protein Met Leu Ala .............
In this hypothetical example, deletion of one
uracil changes all the triplet codons thereafter.
Therefore, a useless protein or no protein is
produced. Frame shift mutation can lead to
thalassemia due to premature chain termination and
run-on-polypeptide that are non-functional.
2-G. Conditional Mutations
Most of the spontaneous mutations are conditional;
they are manifested only when circumstances are
appropriate. Bacteria acquire resistance, if treated
with antibiotics for a long time. This is explained by
spontaneous conditional mutations. In the normal
 503

circumstances, wild bacilli will grow. In the medium artificially selected in agriculture. Normal maize is
containing antibiotic, the resistant bacilli are deficient in tryptophan. Tryptophan-rich maize
selected. In a tuberculous patient, a lung cavity may varieties are now available for cultivation. Micro-
harbor about 1012 bacilli. This may contain about organisms often have antigenic mutation. These are
10 6 mutations, out of which a few could be beneficial to micro-organisms (but of course, bad
streptomycin resistant. Therefore if only one drug to human beings).
is given, there will be overgrowth of drug resistant
bacilli. To avoid this, a combination of two anti- 4-D. Carcinogenic Effect
tuberculous drugs is given. So, drug-1-resistant The mutation may not be lethal, but may alter the
mutants are killed by drug-2 and drug-2-resistant regulatory mechanisms. Such a mutation in a
mutants are removed by drug-1. The statistical somatic cell may result in uncontrolled cell division
probability of a single bacillus acquiring resistance leading to cancer. Any substance causing increased
against both drugs is negligible. rate of mutation can also increase the probability of
cancer. Thus all carcinogens are mutagens.
3. Mutagens and Mutagenesis
Any agent which will increase DNA damage or cell
proliferation can cause increased rate of mutations
also. Such substances are called mutagens. X-ray,
gamma-ray, UV ray, acridine orange, etc. are well
known mutagens. Muller (Nobel Prize, 1946)
showed that the rate of mutation was proportional
to the dose of irradiation. Beadle (Nobel Prize, 1958)
showed that the effect of X-irradiation on metabolism
was due to mutations of genes. Tatum (Nobel Prize,
1958) further showed that a mutation of a single
gene resulted only in a single chemical reaction,
which gave evidence to the concept of "one gene,
one enzyme".

4. Manifestations of Mutations
4-A. Lethal Mutations
The alteration is incompatible with life of the cell or
the organism. For example, mutation producing
alpha-4 Hb is lethal, and so the embryo dies.

4-B. Silent Mutations

Alteration at an insignificant region of a protein may
not have any functional effect.

4-C. Beneficial Mutations

Although rare, beneficial spontaneous mutations are
the basis of evolution. Such beneficial mutants are