Modes of Inheritance

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Your genetics load the gun. Your lifestyle

pulls the trigger – Mehmet Oz.

All diseases of Mankind except accidental

injuries have a genetic component to it.

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Applications:

Disease Prediction:

- Counselling for prevention.

- Early diagnosis & treatment.

- Genetic Therapy.

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Genetic Diseases

Single gene disorders

Mutations at specific locus

Sickle cell anemia

Multifactorial Disorders

Mutations at several loci

Diabetes Mellitus

Chromosomal disorders

Physical changes in the chromosomes

Down’s syndrome

Mitochondrial Disorders

Mutations in Mito DNA

Neuropathies

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Gregor Johann Mendel

“The Garden Pea”

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Mendelian Inheritance

1. Autosomal Dominant

2. Autosomal Recessive

3. X linked Dominant

4. X linked Recessive

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The law of segregation

When any individual

produces gametes, the copies

of a gene separate so that each

gamete receives only one copy

(allele). A gamete will receive

one allele or the other.

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The Law of Independent Assortment

The alleles of different genes assort

independently of one another during gamete

formation.

Pair 1: A and aPair 2: B and bPair 3: C and c

No. of Combn. 2n

• a B C

• a B c

• a b C

• a b c

• A B C

• A B c

• A b c

• A b C

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Pedigree Construction

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Autosomal Dominant

Most affected parents are

heterozygous.

Why?

1. Low incidence of the disease

per se (1/10,000).

2. Lethality of homozygous

individuals.

Eg: Achondroplasia,

Marfan’s syndrome.

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Hallmarks:

No skipping of generations - Longitudinal

Inheritance.

No sexual predilection.

Normal offspring don't transmit the disease.

Usually structural proteins are affected.

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Autosomal Dominant

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1. Variable Expressivity.

Eg: Marfan’s syndrome.

2. Late Onset.

Eg: Huntington’s chorea.

3. High Recurrent Mutation Rate.

Eg: Achondroplasia.

4. Incomplete Penetrance.

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Autosomal Dominant with incomplete

penetrance

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Autosomal Recessive

Most affected individuals have

parents heterozygotes (Normal).

Why?

1. Low incidence of the disease

per se (1/10,000).

The likelihood of two affected

persons mating would be1/10,000

x 1/10,000 or 1/100,000,000.

Eg: Cystic fibrosis,

β- Thalassemia.

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Hallmarks:

No sex predilection.

Horizontal Inheritance.

Parents of affected children may be related.

The rarer the trait in the general population, the more

likely a consanguineous mating is involved.

The trait may appear as an isolated (sporadic) event in

small sibships.

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X linked disorders

X-linked genes are never passed from father to son.

An affected female must have an affected father.

A single dose of a mutant allele will produce a mutant phenotype in the male.(Both dom & rec.)

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X linked Dominant

All daughters of an affected male are affected.

All sons of an affected male and a normal female are normal.

Males are usually more severely affected than females.

Females are more likely to be affected than males, even if the disease is not lethal in males.

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X linked Dominant

Eg:

X linked Hypophosphatasia.

Rett’s Syndrome.

Alport’s Syndrome.22

X linked Recessive

Males are affected. Females are carriers.

Oblique mode of transmission.Uncle – Nephew affected.

Never occur in females except:

Turner’s syndrome.

Lyon hypothesis.

Born to affected father & carrier female.

Testicular feminisation syndrome.

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X linked Recessive

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Skipping of generations?

Yes

Recessive

Both males and females involved

X linked recessive

only males affected

Autosomal recessive

Dominant

Father to son?

All daughters of father affected?

Autosomal Dominant

X linked Dominant

No

NoYes

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Mitochondrial inheritance

Maternal transmission.

The ovum -100,000 copies of mtDNA;

The sperm - <100 copies, and these are

probably lost at fertilization.

Eg: Neurological problems,

Lactic acidosis. (MELAS, Kearns Sayre

disease, LHON)

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Multifactorial Disorders

Sir Francis Galton.

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Regression to mediocrity.

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Several loci are involved in the expression of the trait.

There is no dominance or recessivity at each of these loci.

The loci act in concert in an additive fashion, each adding or detracting a small amount from

the phenotype.

Nature and nurture.

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Most affected children have normal parents.

Applicable for traits with continuous distribution.

Consanguinity slightly increases the risk for an affected child.

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Chromosomal

Abnormalities

Numerical

abnormalities

(Aneuploidy)

Monosomy Trisomy

Structural

abnormalities

Deletion

Duplication

Translocation

Inversion

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Deletion Duplication Inversion33

Insertion

Translocation

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Take Home Message

Most diseases have a genetic

component to them.

Mendelian disorders are potential candidates for gene therapy.

Lifestyle modifications have a role to play in preventing Multifactorial diseases.

Meticulous pedigree analysis & counselling can reduce the burden of genetic diseases in the society.

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References & Further Reading

Robbins & Cotran Pathological Basis of Diseases,

8th edn.

http://www.nature.com/scitable/topicpage/gregor-

mendel-and-the-principles-of-inheritance-593 -

Website of Nature Publishing Group.

http://www.uic.edu/classes/bms/bms655/index.html

- Website of Univ. of Illinois at Chicago.

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Thank you !

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