Modes of Inheritance

Jonathan Wolfe

Wolfson House, room 109

http://www.ucl.ac.uk/~ucbhjow/

Objectives - at the end of this lecture you should be able to:

• Identify dominant and recessive Mendelian modes of inheritance

• Describe reasons why some genetic diseases seem to depart from Mendelian expectations

Mendel’s laws

0. Genes are particulate and come in different forms known as alleles.

• Organisms (peas or humans!) have two copies of each gene but transmit only one to each offspring. Which one is transmitted is chosen at random. i.e. if you are heterozygous for two different alleles, the alleles will segregate from each other in your offspring.

• Where alleles of more than one gene are segregating, segregation at each gene occurs independently of the others.

Autosomal dominant inheritance

• All affected individuals should have an affected parent

• Both sexes should be equally affected

• Roughly 50% of the offspring of an affected individual should also be affected

• Huntington’s disease, Achondroplastic dysplasia, Neurofibromatosis.

A large autosomal dominant pedigree!

Autosomal Recessive Inheritance

• Usually there is no previous family history• The most likely place to find a second affected

child is a sibling of the first

Autosomal recessive

• Inbreeding increases the chance of observing an autosomal recessive condition

• E.g. Cystic fibrosis, sickle cell disease, Tay Sachs disease.

Exceptions to clear cut Mendelian inheritance

• Lethal alleles

T/+ x T/+

T/T T/+ +/+ 1 : 2 : 1 ratio at conception

0 : 2 : 1 ratio at birth

Exceptions to clear cut Mendelian inheritance

• Lethal alleles

• Incomplete dominance

Familial Hypercholesterolemia

+/+ = normal

+/- = death as young adult

-/- = death in childhood

Exceptions to clear cut Mendelian inheritance

• Lethal alleles

• Incomplete dominance

• Codominance

• Silent alleles

Exceptions to clear cut Mendelian inheritance

• Lethal alleles

• Incomplete dominance

• Codominance

• Silent alleles

• Epistasis The Bombay Phenotype:

The ABO blood group genotype cannot be deduced in h/h homozygotes.

Exceptions to clear cut Mendelian inheritance

• Lethal alleles

• Incomplete dominance

• Codominance

• Silent alleles

• Epistasis

• Pleiotropy

• genetic heterogeneity

Exceptions to clear cut Mendelian inheritance

• Lethal alleles

• Incomplete dominance

• Codominance

• Silent alleles

• Epistasis

• Pleiotropy

• genetic heterogeneity

• variable expressivity

• incomplete penetrance

Exceptions to clear cut Mendelian inheritance

• Lethal alleles

• Incomplete dominance

• Codominance

• Silent alleles

• Epistasis

• Pleiotropy

• genetic heterogeneity

• variable expressivity

• incomplete penetrance

• Anticipation

E.g. Myotonic dystrophy

Number of CTGrepeats

phenotype

5 normal

19 - 30 premutant

50 - 100 mildly affected

2,000 or more severely affected

Exceptions to clear cut Mendelian inheritance

• Lethal alleles

• Incomplete dominance

• Codominance

• Silent alleles

• Epistasis

• Pleiotropy

• genetic heterogeneity

• variable expressivity

• incomplete penetrance

• Anticipation

• germline mosaicism

• phenocopies

Phocomelia

• Incomplete ascertainment

• mitochondrial inheritance

Mitochondrial inheritance

Exceptions to clear cut Mendelian inheritance

• Lethal alleles

• Incomplete dominance

• Codominance

• Silent alleles

• Epistasis

• Pleiotropy

• genetic heterogeneity

• variable expressivity

• incomplete penetrance

• Anticipation

• germline mosaicism

• phenocopies

• Incomplete ascertainment

• mitochondrial inheritance

• uniparental disomy

• linkage