Single Gene Inheritance

Dr. B. Shivaraj, Professor

Dr Cross, Assistant Professor
Dept. of Biochemistry & Genetics
American University of Antigua

FO1.29: Understand single gene inheritance and its significance in genetic disorders

Given a scenario on single gene inheritance, students should be able to:

FO1.29.1. Recognize the related nomenclatures, symbols, and pedigrees.

FO1.29.32. Differentiate autosomal dominant, autosomal recessive, X-linked
recessive, and X-linked dominant disorders based on the inheritance principle and a
pedigree.
FO1.29.3. Calculate the probability of inheriting a genotype and phenotype, using a
Punnett square.
FO1.29.4. Distinguish mitochondrial genetic disorders from other genetic disorders
with respect to pattern of inheritance and pedigree.
FO1.29.5. Explain the terms homoplasmy and heteroplasmy and their significance in
mitochondrial disorders.
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Learning Objectives:
FO1.29: Understand single gene inheritance and its significance in genetic
disorders

Given a scenario on single gene inheritance, students should be able to:

FO1.29.1. Recognize the related nomenclatures, symbols, and pedigrees.

FO1.29.2. Differentiate autosomal dominant, autosomal recessive, X-linked
recessive, and X-linked dominant disorders based on the inheritance
principle and a pedigree.
FO1.29.3. Calculate the probability of inheriting a genotype and phenotype,
using a Punnett square.
FO1.29.4. Distinguish mitochondrial genetic disorders from other genetic
disorders with respect to pattern of inheritance and pedigree.
FO1.29.5. Explain the terms homoplasmy and heteroplasmy and their
significance in mitochondrial disorders.

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During the reproduction, human genes are
inherited from parents to offspring, generally
by following the Mendelian pattern of single
gene inheritance
Incidentally this results in the inheritance of
specific characteritics from parents to offspring
• Familiar nomenclatures/symbols in single gene inheritance:
1. Gene: It is a sequence of DNA , that represents fundamental unit of
genetic expression for a gene product (usually protein). This gene
product is responsible for a Character (trait)
2. Locus (Loci): Specific location (site) of a gene in a chromosome
3. Alleles: Alternative forms of a gene for a specific protein
(character). Alleles occupy same (locus) in homologous chromosomes
4. Homozygous: If both the alleles, for a particular
character, are similar/identical Example – AA , aa
5. Heterozygous: If the alleles, for a particular
character, are different from each other, Ex. – Aa
6. Dominant allele: The allele/genewhich expresses its
character in both homozygous & heterozygous conditions
Denoted by Big (Uppercase) letter (AA Aa)

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7. Recessive allele: The allele which does express its character only
in homozygous condition. Denoted by small (Lowercase) letter (aa)
8. Autosomal Inheritance: Refers to the inheritance of characters
through the alleles/genes present in autosomes (Chrom 1-22)
9. X – Linked Inheritance: Refers to the inheritance of characters
through the alleles/genes present in X-chromosomes
10. Phenotype: Observable Features: such as Outward appearance,
Manifestations/Physical characteristics etc
Examples: Eye color, Curly/straight hair, Free/attached ear lobe,
Morphological abnormalities etc
11. Genotype: Genetic set up (pattern of alleles) in either autosomes
or sex chromosomes for a particular character.
Example : AA, Aa, aa, BB, Bb, bb etc

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• 12. Pedigree: Pedigree is the representation of family history using
standard symbols
• 13. Proband/Propositus/Index case: Refers to the affected
member (for a genetic disease) of a family, through whom the case
is brought first time to the attention of a Genetic consultant or a
Physician
• 14. Sibs: Brothers and sisters of the affected family
• 15. Kindred: The entire family
• 16. Consanguinity/Consanguineous: Couples having a common
ancestry with respect to the inheritance of genes
• 17. Unaffected: A person showing no phenotypic abnormalities
• 18. Affected: A person showing phenotypic abnormalities
• 19. Normal: A person having normal genotypes and phenotypes
• 20. Obligate carrier: An individual, who is a definite carrier
(heterozygous) for a mutant autosomal or X-linked recessive gene
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5
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 Display of Pedigree

In both the cases, all the members are “ Unaffected” with respect
to phenotypic abnormalities 8
• Basic aspects of Mendelian principle:

• Existence of two genes (Alleles) responsible for a character

• The two alleles may be similar (homozygous) or different
(heterozygous)
• If homozygous, both the alleles may be dominant (denoted by big
letters.. AA, BB etc) or recessive (denoted by small letters.. aa, bb
etc)
• If heterozygous, one allele is dominant (denoted by big letters.. A, B
etc), whereas another allele is recessive (denoted by small letters..
a, b etc). Example: Aa, Bb
• If homozygous, both the alleles are responsible for phenotypic
expression
• If heterozygous, the dominant allele is responsible for phenotypic
expression
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• During gamete formation, the two alleles meant for a character
undergo segregation and one gene passes into one gamete (Sperm
or Ovum) and another to other gamete
• The Mendelian pattern of Single gene inheritance is represented in
the following two examples
Example 1 Example 2

Please remember: In each example of single gene inheritance, only one pair of
alleles/genes and the corresponding phenotypic character are taken into account 10
• The probability of inheritance of single genes and the
corresponding phenotypes from parents to offspring can be
estimated by combination of genes between Gametes of the
parents, using Punnet square
Parent: Homozygous dominant (AA), Phenotype – Free ear lobe
Example 1
Gametes
All the offspring are
Heterozygous (Exhibit same
Parent: Homozygous genotypes) with phenotype
recessive (aa), Phenotype- Free ear lobe )
Attached ear lobe

Example 2 Parent: Heterozygous (Aa), Phenotype – Free ear lobe

Genotypes:
Gametes
25% AA (Homozygous dominant)
50% Aa (Heterozygous)
Parent: Heterozygous (Aa), 25% aa (Homozygous recessive)
Phenotype- Free ear lobe Genotype ratio of AA: Aa: aa = 1:2:1

Phenotypes:
Ratio of Free ear lobe to Attached ear
lobe is 3:1 (75%:25%)
ACTIVITY: Calculate the probability of inheritance of genotypes/phenotypes with the other
combination of parents’ genotypes/phenotypes 11
Learning Objectives:
FO1.29: Understand single gene inheritance and its significance in genetic
disorders

Given a scenario on single gene inheritance, students should be able to:

FO1.29.1. Recognize the related nomenclatures, symbols, and pedigrees.

FO1.29.2. Differentiate autosomal dominant, autosomal recessive, X-linked
recessive, and X-linked dominant disorders based on the inheritance principle and
a pedigree.
FO1.29.3. Calculate the probability of inheriting a genotype and phenotype, using
a Punnett square.
FO1.29.4. Distinguish mitochondrial genetic disorders from other genetic disorders
with respect to pattern of inheritance and pedigree.
FO1.29.5. Explain the terms homoplasmy and heteroplasmy and their significance
in mitochondrial disorders.
Occasionally, a gene may undergo mutation to form mutant gene.
These mutant genes when inherited are capable of causing
phenotypic abnormalities
• The abnormalities that appear because of the inheritance of
mutant single genes constitute single gene disorders
• Inheritance of both normal(Wild) and mutant(Defective) genes, in
general, follow Mendelian pattern of single gene inheritance
• Types of Single gene disorders:
• i) Autosomal Dominant, ii) Autosomal Recessive
• iii) X-Linked Dominant & iv) X-Linked Recessive
• v) Mitochondrial

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Inheritance of Autosomal Mutant Dominant Genes/Disorders
• In autosomal dominant disorders the mutant gene
(Defective gene) is dominant and normal (wild) gene is
recessive
• An autosomal dominant disease is expressed in both
homozygous and heterozygous conditions. However, in
homozygous individuals the phenotypic features are
severe due to double dose of the mutant gene.
• In general, an affected person has an affected parent
(Exceptions: New mutation and incomplete penetrance – to be discussed later)
• In general, both males and females are equally affected
• In general, the defect appears in every generation

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 Autosomal Dominant inheritance pedigree

Please note: In a given problem of autosomal dominant disease/pedigree, the

affected person is generally presumed to be heterozygous, unless mentioned
otherwise or given an evidence that the affected person is homozygous

Each affected individual has 50% chance of having an affected offspring

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 Incomplete penetrance

The term ‘penetrance’ is used to describe the probability with which a carrier of a
dominant mutation will actually show signs of the disorder
A typical dominant trait should have 100 % penetrance.
However, there is not always a direct connection between the genotype and the
phenotype
Incomplete penetrance: is when genotype of some persons completely fails to be
expressed
• No phenotype for the mutated genotype: presents with skipped
generations of the disorder
• Penetrance is an all-or-none measure. Non penetrant gene has no
phenotypic expression at all (distinguishes it from variable expression)
• Severity of the condition is not considered.
 Incomplete penetrance

Examples:
• Not all women who carry a BRCA 1 gene mutation will develop breast or
ovarian cancer
• Retinoblastoma
• Li fraumeni syndrome
Inheritance of Autosomal Mutant Recessive Genes/Disorders
• In Autosomal Recessive disorders the mutant gene (Defective gene)
is recessive and normal (wild) gene is dominant
• In Autosomal Recessive disorders the abnormal phenotypes are
seen only in homozygotes whereas heterozygotes act as Carriers
• In general, carriers are unaffected (phenotypically normal)
• Generally both males and females are equally affected
• Affected individual must get defective genes from both the parents
(one from each)
• Parents of the affected child may be affected or simply unaffected
carriers of the mutant gene (Affected person need not have an affected parent)
• Carriers (Heterozygous) of autosomal recessive genes are more
common than the affected (Homozygous) individuals
• Consanguinity of the parents ( both father & mother have common
ancestry) is one of the strong causes for the occurrence of
autosomal recessive disease 15
Autosomal Recessive inheritance pedigrees

Figure a) displays normal, carrier and affected individuals.

However, this type of pedigree is not expected to be
given in the examinations.
Hence, the students are expected to solve the problems
based on the examples of pedigrees represented in figures
b) and c)

In figure b) individuals II-1, II-2, II-3, III-1 and

III-2 are obligate heterozygous carriers
In figure c) individuals II-2, II-3, II-4, III-4 and
III-5 are obligate heterozygous carriers

Skipped generation effect with respect

to the affected individuals

Please note the consanguinity between

individual 4 and 5 of the generation III. They
share the common mutant gene inherited
from the common ancestry ie the individual
2 of generation I
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 Inheritance of Mutant X-linked Genes

• In general, inheritance pattern of genes present in X-chromosomes is

based on sex (Male or Female) of the parents and offspring
• All females have two sets of X- linked genes, one in each X
chromosome
• All males are mostly hemizygous (having only one copy of a gene for
a character) with respect to X-linked genes, since they have only one
set of X- linked genes present in a single X chromosome, (Exception:
Pseudoautosomal genes, where one copy is present in X-
chromosome and other copy in Y-chromosome)
• In a hemizygous condition, the gene present in X chromosome gives
its expression (Normal or Abnormal), no matter whether it is
dominant or recessive

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• A female transmits X chromosome (and thereby X-linked
genes/characters) to her both male & female offspring
• A male transmits his X chromosome (and thereby X-linked
genes/characters) to his daughters only but not to sons
• Hence, in general, the X-linked genes/characters are not transmitted
from father to son (No male to male transmission)
• That means, generally all X-linked genes/characters of son are
inherited from mother only
• Because of the presence 2 copies of X chromosomes, females can
exhibit 3 types of genotypes for X- Linked genes: (Homozygous
dominant- AA), (Heterozygous - Aa ) and (Homozygous recessive -
aa)
• On the other hand males can have only 2 genotypes (Due to the
presence of a single X -chromosome) A and a

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• Inheritance of X-linked Mutant Recessive Genes/Disorders
• Here the mutant allele is Recessive & normal allele is
Dominant
• An affected male (With a normal female partner)
transmits the mutant X-linked gene to all his daughters &
they become unaffected heterozygous carriers
• Each heterozygous carrier female (With a normal male
partner) has 50% chance of transmitting the mutant gene
to her children, irrespective of the sex. If transmitted, her
son becomes affected and daughter becomes
heterozygous carrier
• During the transmission of an X-linked recessive mutant
gene, females generally become carriers (unaffected),
whereas males generally become affected. Hence the
affected cases are noticed mainly among males 19
• Sons get the X- linked mutant genes from mothers only
• Whereas daughters may get the mutant gene either from father or
mother
• A daughter getting X-linked mutant genes from both the parents is
rare, but if it happens, she becomes affected
• An X - linked mutant recessive allele may be transmitted through a
series of unaffected heterozygote carriers (females)- thus causing
skipped affected generations
• Heterozygous females are usually unaffected, but occasionally may
express the symptoms (Manifesting heterozygotes ) with variable
severity. This happens if more proportion of normal X chromosomes
(compared to the mutant X chromosome) undergo X- inactivation
• Males are Hemizygous for X- chromosomal genes. Hence a single
mutant recessive gene inherited into a male is capable of abnormal
phenotypic expression

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 a) b)
Figure a) displays Normal, carrier and affected individuals. However, this type of pedigree is
unlikely to be given in the examinations.
Hence, the students are expected to solve the problems based on the example of pedigree
represented in figure b)

Note skipped generations II & IV with respect to the affected individuals

In figure b) individuals II-2 and II-5 are obligate heterozygous carriers for the mutant gene

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• Inheritance of X-linked Dominant Mutant Genes/Disorders
• Here the mutant allele is Dominant & Normal allele is Recessive
• Hence abnormal phenotypic expression is seen even in
heterozygous females
• An Affected son should have affected mother, but an affected
daughter should have either affected mother or affected father
• Generally the affected individuals are visible all the generations
(Similar to autosomal dominant)
• Affected males (with normal mates) have perfectly normal sons,
but have all affected daughters.
• In Males, generally the defect is severe and lethal, hence their
numbers are under-represented in a displayed pedigree
• An affected mother has a 50% chance of transmitting the disease
to both sons and daughters (same as autosomal dominant).
• Altogether there are less examples for X-linked dominant disorders
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 Pedigree for an X- Linked Dominant Disorder

Note more number of affected females than affected males

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Learning Objectives:
FO1.29: Understand single gene inheritance and its significance in genetic
disorders

Given a scenario on single gene inheritance, students should be able to:

FO1.29.1. Recognize the related nomenclatures, symbols, and pedigrees.

FO1.29.2. Differentiate autosomal dominant, autosomal recessive, X-linked
recessive, and X-linked dominant disorders based on the inheritance
principle and a pedigree.
FO1.29.3. Calculate the probability of inheriting a genotype and phenotype,
using a Punnett square.
FO1.29.4. Distinguish mitochondrial genetic disorders from other genetic
disorders with respect to pattern of inheritance and pedigree.
FO1.29.5. Explain the terms homoplasmy and heteroplasmy and their
significance in mitochondrial disorders.
Examples for Single Gene disorders

Autosomal Dominant X-Linked Recessive

1.Familial hypercholesterolemia 1.Duchenne muscular dystrophy
2.Neurofibromatosis type 1 2.Hemophilia A & B
3. Marfan syndrome 3.Glucose 6-phosphate dehydrogenase Deficiency
4. Achondroplasia 4.Ornithine transcarbamoylase deficiency
5. Osteogenesis Imperfecta 5.Hunter disease
6. Acute intermittent porphyria 6.Fabry disease
7. Porphyria cutanea tarda 7.Lesch Nyhan syndrome
8. Polycystic kidney disease 8. Sideroblastic anemia

Autosomal Recessive X-Linked Dominant

1.Cystic fibrosis 1.Ret syndrome
2.Phenylketonuria 2.Vitamin D resistant Rickets
3.Tay-Sach disease 3.Pyruvate dehydrogenase deficiency
4.Sickel cell anemia
5.Hemochromatosis
6. Von Gierke disease
7. Xeroderma pigmentosum
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Probability of Inheritance of Autosomal dominant Mutant Gene/Disorder

One parents is affected (heterozygous), another parent is normal

Normal parent (aa)

Gametes a a
Aa Aa Genotypes:

50% Heterozygotes(Aa)
A
50% Homozygous recessive (aa)
Affected parent (Aa) Genotype ratio:
Aa : aa = 1:1
a aa aa
Phenotypes:

Affected – 50%
Please note : Mutant gene is Unaffected (Normal) – 50%
Dominant & is represented by Big Phenotypes ratio:
(upper case) letter & normal gene is (Affected: Unaffected = 1:1)
recessive & denoted by small (lower
case) letter

ACTIVITY: Calculate the probability of inheritance of mutant autosomal dominant

gene/trait with the other combinations of Parents’ genotypes/phenotypes 25
 Probability of inheritance of Autosomal Recessive Mutant Gene/Disease

Affected parent (aa)

Gametes a a

Genotypes:
Heterozygous Aa Aa 50% Aa
/carrier A 50% aa
parent Ratio – 1:1
(Aa)
a aa aa Phenotypes:
50% unaffected (carriers)
50% affected
Ratio-1:1

Please note : Normal gene is

dominant & is represented by Big
letter & Mutant gene is recessive &
is denoted by small letter

ACTIVITY: Calculate the probability of inheritance of mutant autosomal recessive

gene/trait with the other combinations of Parents’ genotypes/phenotypes 26
 Probability of inheritance of X-Linked Recessive Mutant Gene/Disease

Normal Male (XAY)

Gametes XA Y

XAXA XAY Genotypes:

XA 25% daughters with XAXA
Heterozygous 25% daughters with XAXa
Female (XAXa) 25% of sons with XAY
25% of sons with XaY
Xa
XAXa XaY
Phenotypes:
All daughters are unaffected (50%
normal+ 50% unaffected carriers)
Among the sons, 50% are
Please note : X and Y indicate sex unaffected (normal) and 50% are
chromosomes. Normal gene affected
(Dominant) is represented by big
letter & Mutant gene (recessive) by
small letter

ACTIVITY: Calculate the probability of inheritance of mutant X-linked recessive

gene/trait with the other combinations of Parents’ genotypes/phenotypes 27
 Probability of inheritance of X-Linked Dominant Mutant Gene/Disorder

Normal Male (Xa Y)

Gametes Xa Y
Genotypes:
Affected X X
A a
X Y
A
25% daughters with XAX a
Female (XAXa) XA 25% daughters with X aXa
25% sons with XAY
25% sons with XaY
Xa
XaXa XaY
Phenotypes:
25% affected daughters
25% unaffected (normal) daughters
25% affected sons
Please note : X and Y indicate sex 25% unaffected (normal) sons
chromosomes. Mutant gene
(Dominant) is represented by big
letter & Normal gene (recessive)
by small letter

ACTIVITY: Calculate the probability of inheritance of mutant X-linked dominant gene/trait

with the other combinations of Parents’ genotypes/phenotypes 28
Learning Objectives:
FO1.29: Understand single gene inheritance and its significance in genetic
disorders

Given a scenario on single gene inheritance, students should be able to:

FO1.29.1. Recognize the related nomenclatures, symbols, and pedigrees.

FO1.29.2. Differentiate autosomal dominant, autosomal recessive, X-linked
recessive, and X-linked dominant disorders based on the inheritance
principle and a pedigree.
FO1.29.3. Calculate the probability of inheriting a genotype and phenotype,
using a Punnett square.
FO1.29.4. Distinguish mitochondrial genetic disorders from other genetic
disorders with respect to pattern of inheritance and pedigree.
FO1.29.5. Explain the terms homoplasmy and heteroplasmy and their
significance in mitochondrial disorders.
Inheritance of Mitochondrial Genes
Mitochondrion contains a few genes, capable of coding for a few
mitochondrial proteins
In general mit. Genes and mit. genetic disorders follow a typical
Maternal Inheritance pattern. (Hence its an example for non
Mendelian inheritance pattern)
This is because in fertilized zygote, mitochondria (with mit.genes) are
contributed almost entirely by female gamete, ovum
Thus the children inherit mit. genes (and also mitochondrial genetic
disorders) from mothers only
Mitochondrial DNA is circular in nature

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 Pedigree of the inheritance of a mitochondrial genetic disorder

• A Male does not contribute mit.DNA to his children. Hence a mit.

genetic disorder is not transmitted from father to his children
• Rarely, a maternal inheritance may not be seen in a mitochondrial
genetic disorder. Such a cases are mostly caused by a sporadic
somatic mutation. This mostly happens if the mutation of a
mitochondrial gene occurs due to a large deletion.
• Mit.DNA undergoes mutation at a rate of about 10 fold higher
compared to nuclear DNA.
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Learning Objectives:
FO1.29: Understand single gene inheritance and its significance in genetic
disorders

Given a scenario on single gene inheritance, students should be able to:

FO1.29.1. Recognize the related nomenclatures, symbols, and pedigrees.

FO1.29.2. Differentiate autosomal dominant, autosomal recessive, X-linked
recessive, and X-linked dominant disorders based on the inheritance
principle and a pedigree.
FO1.29.3. Calculate the probability of inheriting a genotype and phenotype,
using a Punnett square.
FO1.29.4. Distinguish mitochondrial genetic disorders from other genetic
disorders with respect to pattern of inheritance and pedigree.
FO1.29.5. Explain the terms homoplasmy and heteroplasmy and their
significance in mitochondrial disorders.
• Two patterns are known to exist in individuals with respect
to the presence of mitochondrial gene/DNA
• i) Homoplasmy: Presence of either only normal
mitochondria (with no mutant gene) or only abnormal
mitochondria (having mutant gene) in cells
• ii) Heteroplasmy: Presence of both normal mitochondria &
abnormal mitochondria (with mutant genes) in the cells
• A homoplasmic female having mutant mit. gene transmits
a mitochondrial disorder to all her offspring
• A heteroplasmic female also transmits mitochondrial
disorder to all of her offspring, but the severity of this
disease in her offspring depends on the proportion of
mutant and normal mitochondrial genes in her ovum –
This results in variable expression of abnormal phenotypes
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• Mitochondrial genes code for the proteins involved in
oxidative phosphorylation in mitochondria.
• Hence mutation of mitochondrial genes generally affects
oxidative phosphorylation – impairs ATP production
• Examples for mitochondrial genetic disorders:
• 1. Leber hereditary optic neuropathy (LHON) --- Homoplasmic
• 2. Mitochondrial encephalomyopathy lactic acidosis and stroke
(MELAS) ---Heteroplasmic
• 3. Deafness (certain cases) -- Homoplasmic
• 4. Leigh Syndrome (certain cases) -- Heteroplasmic
• 5. Myoclonic epilepsy with ragged red muscle fibers (MERRF) --
Heteroplasmic
• 6. Kearns Sayre syndrome –Sporadic somatic mutation (Caused by a
large deletion in a mito. gene) Mostly no maternal transmission --
Heteroplasmic
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