1. Modes of Inheritance Jonathan Wolfe Wolfson House, room 109 http://www.ucl.ac.uk/~ucbhjow/

2. 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

3. 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.

4. 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.

5. A large autosomal dominant pedigree!

6. 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

7. Autosomal recessive Inbreeding increases the chance of observing an autosomal recessive condition E.g. Cystic fibrosis, sickle cell disease, Tay Sachs disease.

8. 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

9. Exceptions to clear cut Mendelian inheritance Lethal alleles Incomplete dominance Familial Hypercholesterolemia +/+ = normal +/- = death as young adult -/- = death in childhood

10. Exceptions to clear cut Mendelian inheritance Lethal alleles Incomplete dominance Codominance Silent alleles

11. 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.

12. Exceptions to clear cut Mendelian inheritance Lethal alleles Incomplete dominance Codominance Silent alleles Epistasis Pleiotropy genetic heterogeneity

13. Exceptions to clear cut Mendelian inheritance Lethal alleles Incomplete dominance Codominance Silent alleles Epistasis Pleiotropy genetic heterogeneity variable expressivity incomplete penetrance

14. 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

15. 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

16. Mitochondrial inheritance

17. 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