Modes of Autosomal and Sex Linked Inheritance

To MBBS/BDS 1st year

08-01-2017

By Dr. Laxman Khanal

Assistant Prof. (Department of Anatomy)

Gregor Johhan Mendel: 1822-1884

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Law of dominance

An important reason for studying the patternof inheritance of disorders within families isto enable advice to be given to members of afamily regarding the likelihood of theirdeveloping it or passing it on to their children(i.e.genetic counseling)

Why this topic is important ?

Some definitions

Gene: Sequence of nucleotides in DNA which forms specific RNAfollowed by protein which eventually produce some observable trait.

Alleles: Different variants of gene present in specificlocation(locus) of homologous chromosome.

Homologous chromosome: Similar chromosomeinherited from father and mother containing similargenes.

Fibrillin

Chromosome 15

Dominant disorders

Hemoglobin

Chromosome 11

Disease expression occurs

Disease expression occurs

Recessive disorders

Which is more lethal condition ?

Which is manifested earlier ?

Mode of inheritance: Definition

• Its the manner in which a particular genetic trait or disorder is passed from one generation to the next.

Examples:

• Autosomal dominant/ recessive

• Sex-linked dominant/recessive

• Mitochondrial inheritance.

Knowledge is important for the purpose of ‘Genetic Counselling’

22 AA + XX/ XY

Autosomal dominant inheritance

• Both parent can transmit mutant gene to both sons and daughter.

• Male = female affected• Vertical transmission (no generation gap)

• Myotonic muscular dystrophy• Marfan’s syndrome• Achondroplasia• Huntington’s disease• Familiar hypercholesterolemia

Autosomal dominant

• Myotonic muscular dystrophy• Marfan’s syndrome• Achondroplasia• Huntington’s disease• Familiar hypercholesterolemia

• Both parents can transmit mutant gene to both sons and daughter.

• Male = female affected• Vertical transmission (no generation gap)

50% of offspring will be affected ifone of the parent has single mutantallele.

Autosomal dominant inheritance

• Only one copy of a disease allele is necessary for an individual to be susceptible to expressing the phenotype.

• With each pregnancy, there is 50% chance the offspring will inherit the disease allele.

• All affected individuals will have at least one parent who carries the disease allele.

• Vertical inheritance involving all generations.

• Male and females are equally affected.

?

Reduced penetrance

50% chance of being diseased.

• Pleiotropy• Variable expressivity• Reduced penetrance

Autosomal recessive inheritance

• Typically, the parents of an affected individual are not affected but are gene carriers.

• With each pregnancy of carrier parents:

• There is a one in four (25%) chance of having the disease.

• There is a one in two (50%) chance of having carrier

• There is a one in four (25%) chance of having no disease.

• Proportion of affected male and female is equal.

Carrier

• 25%- affected• 50%- carrier• 25%- normal

Autosomal recessive inheritance• Observed more frequently

in consanguineous relationships and in certain ethnicbackgrounds.

• Most of people have 1-5mutant copy of gene forautosomal recessive disorders.

• Sickle cell anemia• Cystic fibrosis• Tay-sachs disease

Sex limited disorders• Limited in one of genders• Mostly genes are in autosome• Examples Male pattern baldnessOvarian carcinoma

Sex linked disorders• Either X or Y linked• Can occurs in both gender (if X linked)• Occurs only in males (if Y linked)• Genes are in sex chromosome

XY XX

Y linked inheritance(Holandric inheritance)

Y linked disorders• Hairy pinna• Only occurs in male

X X X Y

• Father cannot transmit X linked mutant gene to sons.• Mother can transmit X linked mutant gene to both sons and daughters.

xx XY xx XY

X linked inheritance

X X X Y

xx XY xx XY

X linked recessive inheritance

• 50 % of male will be affected• 50% of female will be carrier

XY

xx XY xx XY

X X X Y

xx XY xx XY

X linked recessive inheritance

• 50 % of male will be affected• 50% of female will be carrier

XY

xx XY xx XY

X X X Y

xx XY xx XY

X linked recessive inheritance

Rare situation

Conclusion:Males>> females affectedMostly females act as carriers

• Duchenne muscular dystrophy• Hemophilia A• Color blindness• G6PD deficiency

X-linked recessive inheritance

• Two copies of a disease allele on the X chromosome are required for an individual with two X chromosomes (a female) to be affected.

• Since males are hemizygous for X-linked genes, any male with one copy of disease allele is affected.

• Females are usually carriers because they only have one copy of the disease allele.

• For a carrier female, with each pregnancy there is 50% chance her sons will inherit the disease allele and 50% chance her daughters will be carriers.

X X X Y

xx XY xx XY

X linked dominant inheritance

XY

xx XY xx XY

X X

XY X XX X XY

Females >> males affected.

X-linked recessive inheritance X-linked dominant inheritance

Fragile X syndrome (!!)Vitamin D resistant ricketsCharcot-Marie-Tooth disease

• Males and females are equally affected• Both father and mother can transmit the

mutant gene to both sons and daughter.

YESNO Autosomal inheritanceSex linked inheritance

Vertical transmission +no generation gap

Autosomal dominant

Horizontal transmission +generation gap

Autosomal recessive

Father to sons transmission

Y-Linked

No father to sons transmission

X-Linked

Males >> females – X-recessiveFemales>> males- X-dominant