Mendelian Inheritance in human disease.pdf

Mendelian inheritance

1. Mendelian Inheritance

2. Learning objectives




Define some important terminologies.
Describe mendelian laws of inheritance
Define mendelian trait.
Describe the characteristic features of
autosomal and sex chromosomal diseases.

3. Some important terminologies





Gene: a functional part of the DNA molecule of a chromosome
which directs the synthesis of a specific polypeptide chain

Allele (allelomorph): alternative form of a gene found at the
same locus on homologous chromosomes

Homozygous: the presence of two identical alleles at a
particular locus on a pair of homologous chromosomes

Heterozygous: the state of having different alleles at a locus on
homologous chromosomes

Hybrid: individual having two different allele at a locus

4. Some important terminologies (contd..)



Dominant: a trait which is expressed in
individuals who are heterozygous for a particular
allele.

Recessive: a trait which is expressed in
individuals who are homozygous for a particular
allele but not in those who are heterozygous.

Codominance: when both alleles are expressed
in the heterozygote

5. 


Pseudo-dominance: when a recessive trait
expresses in heterozygote state
(hemochromatosis)

Genotype: the genetic constitution of an
individual

Phenotype: the appearance (physical,
biochemical, physiological) of an individual
which results from an interaction of the
environment and the genotype.

6. Some important terminologies (contd..)



Mutant: a gene which has undergone a change or
mutation

Mutation: a permanent change in genetic material
(genomic sequence), either of a single gene, or in the
structure of the chromosomes. A mutation which
occurs in the gametes is inherited, a mutation which
occurs in the somatic cells (somatic mutation) is not
inherited.

Mutagen: substances that cause mutation i.e,
viruses, chemicals, transposon, radiation

7. Mendel’s first law: Law of Uniformity



It states that:
when two homozygotes with different alleles are crossed, all the
offsprings of the F1 (first filial) generation are identical and
heterogygous.
The characteristics do not blend and reappear in the later
generation.

Eg. Pure bred tall (TT) X pure bred short (tt)

F1 generation

8. Mendel’s second law: Law of Segregation



It states that each individual possesses two
genes/allels for a particular characteristic, only one
of which can be transmitted at any one time.
Rare exceptions to this rule can occur when two
allelic genes fail to separate because of
chromosome nondisjunction at the first meiotic
division.
A hereditary disease or trait transmitted by a single
gene is called Mendelian trait.

10. Segregation of allels/genes
Punnett square

11. Mendel’s second law: Law of Segregation (contd..)




Features of a Mendelian trait:
A Mendelian trait is caused by a single gene
Mode of inheritance reveal whether a Mendelian trait is dominant
or recessive and whether the gene that controls it is carried on an
autosome or a sex chrosome.
Mendalian trait or single gene disorder can be inherited in five
ways: autosomal dominant, autosomal recessive, X linked
dominant, X linked recessive and Y linked.
Mendel’s second law which can predict the probability that a
child will inherit a Mendelian trait, applies anew to each child.

12. Key features of an autosomal dominant trait








Both males and females can be affected.
Male and female transmit the trait with equal frequency.
Can have male to male transmission.
Transmitted by affected individuals.
Successive generations are affected.
Transmission stops if a generation arises in which no one is
affected.
Can arise from fresh mutations.
Autosomal dominant inheritance: when a parent is affected and
the other is not, each offspring has a 50% probability of inheriting
the mutant allele and the condition.

13. Some autosomal dominant disorders:










Achondroplasia
Familial hypercholesterolemia
Huntington’s disese
Lactose intolerance
Marfan syndrome
Myotonic dystrophy
Neurofibromatosis I
Polycystic kidney disease
Polydactyly
Porphyria variegate

14. Autosomal dominant trait: achondroplasia

15. Marfan syndrome (mutation of fibrillin-1 gene
in chromosome 15)

16. Neurofibromatosis I

17. Key features of an autosomal recessive trait:








Both males and females are affected
Affected males and females can transmit the trait, unless it
causes death before reproductive age
The trait can skip generation
Parents of affected individual are heterozygous or also have the
trait (carriers)
Commonly seen in consanguineous marriage.
Probability: normal (25%), carrier (50%) and affected (25%)
chance
Genotypic ratio: 1:2:1
Phenotypic ratio: 3:1

19. Autosomal recessive disorders:











Albinism (tyrosine kinase deficiency)
Ataxia telangiectasia
Cystic fibrosis
Familial hypertrophic cardiomyopathy
Gaucher’s disease (glucosylceramide beta glucosidase deficiency)
Hemochromatosis
Phenylketonuria (phenylalanine hydroxylase deficiency)
Sickle cell disease
Tay-Sachs disease (hexosaminidase-A deficiency)
Maple syrup urine disease (branched –chain beta ketoacid
decarboxylase deficiency)
Hurler syndrome (MPS-I, alfa-L-iduronidase deficiency)

20. Albinism

21. Key features of X linked dominant trait:








Males as well as females are affected but often with an excess of
females
Females are less severely affected than males
Affected males can transmit the disorder to their daughters but
not to their sons

X linked domint disorder (trait):
Vitamin D resistant rickets
Charcot-Marie Tooth disease (hereditary sensory and motor
neuropathy)
Alport syndrome
Rett syndrome
Incontinentia pigmenti

22. Key features of X linked recessive trait:



Males are usually only affected
Transmitted through unaffected/ carrier females
Males cannot transmit the disorder to their sons ie,
no male to male transmission can occur.

23. X linked recessive disorder (trait):






Haemophilia
Partial color blindness
Duchenne’s muscular dystrophy
Glucose 6 phosphate dehydrogenase (G6PD)
deficiency
Testicular feminization
Hunter’s syndrome (MPS-II, iduronate sulfate
sulphatase deficiency)

24. Y linked inheritance, also called Holandric
inheritance:



Males are only affected
Affected males must transmit it to their sons

Y linked inheritance (trait):
Porcupine skin, hairy ears, webbed toes.

25. Some diseases may show
different pattern of inheritance

26. 

Ehlers-Danlos syndrome
Autosomal dominant

27. Mendel’s third law: Law of independent assortment





Members of different gene pairs segregate to offspring
independently of one another.
However, genes that are close together on the same
chromosome tend to be inherited together, ie, they are
linked.

Features:
Genes are transmitted in different chromosomes
Transmission of one gene does not influence that of
another
Meiotic events explain independent assortment

28. Mendel’s third law: Law of independent assortment







Example:
if a male having following features –
passing yellow urine (Bb),
colored eyelid (Hh) and
normal fingers (ee)
mates with a female having following features-
passes red urine (bb),
normal eyelids (hh) and
short fingers (Ee);
then the chances of a child having the following features- who
passes red urine (bb) x colored eyelids (Hh) x short fingers (Ee)
are ½ x ½ x1/2 = 1/8.

29. Mitochondrial inheritance






Each cell contains thousands of copies of mitochondrial
DNA.
Mitochondria are exclusively inherited from mother
through the oocyte.
Mitochondrial DNA has a higher rate of spontaneous
mutation than nuclear DNA.
Each mitochondria contains 37 genes.
13 genes are concerned with enzymes related with
oxidative phosphorylation (converting sugar into ATP)
24 genes are concerned with building tRNA, and rRNA.

30. Mitochondrial inheritance (contd..)



Transmitted by affected females to all the
offsprings but affected males cannot transmit
this condition to their offsprings.
Disorders with unusual combinations of
neurological and myopathic features are
characteristic to it.
Examples are: Leigh disease, Leber hereditary
optic neuropathy, Barth syndrome, cytochrome C
oxidase deficiency, age related hearing loss,
MELAS etc.

31. Summary






A hereditary disease or trait transmitted by a single gene
is called Mendelian trait.
Autosomal dominant trait is manfested in successive
generations, and/or fresh mutation.
Autosomal recessive trait skips multiple generations,
commonly seen in consanguinal marriage.
X-linked trait cannot be transmitted by father to son.
Y-linked trait is also known as holandric trait.
Mitochondrial diseases are transmitted by females to all
the offsprings but not by males.

32. thank you.thank you.thank you.thank you.