1. Mendelian Genetics Exceptions
Human Genetics
Mendelian Genetics
Exceptions 1

3. Gene (allele) interactions
Dominance
Recessive
Codominance
Incomplete dominance
Epistasis
Pleiotropy
Linkage
Penetrance
Expressivity
Environmental factors

4. Exceptions to Mendel’s Laws
Mendel chose traits in peas that showed
two distinct forms.
Not all genes exhibit such simple inheritance.
Alleles interact
Genes interact
Non-nuclear genes exist
Segregation of genes on same chromosome

5. Lethal Allele Combinations
Homozygous recessive lethal alleles eliminate a progeny class.
Sometimes this is hard to see in a family- it may result in reduced fertility.

6. Genetic Disease is an Important Component of Childhood Mortality
These lethal genetic combinations could be homozygous recessive, heterozygous dominant, homozygous dominant, chromosomal deletions/duplications or multiple genes interacting
Many Human Geneticists are pediatricians
Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins

7. Age at Expression of Genetic Disease
Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins

8. Lethals can be considered Semidominant
The phenotype of the homozygote is more extreme than the phenotype of the heterozygote.
The normal allele of this gene is expressed in the embryo.
Carriers can have a phenotype but the homozygotes die as early embryos.
Allele is maintained by crosses of heterozygotes and new mutations.

9. Mexican Hairless Dogs

10. Multiple Alleles
A gene can have more than two alleles, but a diploid individual only has one or two of them.
Different allele combinations can produce different phenotypes and different severities of symptoms.

11. Multiple Alleles
An individual has two alleles, but a population can have many alleles within the individual members.
Genes can mutate in many ways at any nucleotide in their DNA sequence.
Eye Color and Hair color are examples of multiple alleles

12. Multiple Alleles in Rabbit Coat Color
Grey
CC or Ccch or Cch or Cc
Chinchilla
cchcch
Himalayan
chc or chch
Light gray
cchch or cchc
Albino cc

13. Codominant Alleles

14. Epistasis
The masking of the action of an allele of one gene by the allelic combinations of another gene.
The interaction of nonallelic genes in the formation of the phenotype.
Common indicator of epistasis: the F2 generation of a dihybrid cross will be a variation of the 9:3:3:1 phenotypic ratio
Example: Flower Color

15. Epistasis in flower color

16. Epistasis in flower color

17. Bombay Phenotype Epistasis
H gene is epistatic to the ABO gene.
H protein attaches the A or B protein to the cell surface.
hh genotype = no H protein.
All ABO genotypes appear as type O.

18. H structure: Mucopolysaccharide found on the surface of RBCs

19. How are Autosomal Dominant Diseases maintained in populations?
Since every mutant allele for an autosomal dominant disease is expressed, and by definition a disease is a deleterious phenotype, shouldn't autosomal diseases be eliminated by natural selection against deleterious phenotypes?
Four phenomena maintain these deleterious alleles in the population:
Variable Expressivity
Late Onset
High Recurrent Mutation Rate
Incomplete Penetrance

20. Incomplete Dominance
Incomplete dominance may lead to a distortion of the apparent ratios or to the creation of unexpected classes of offspring.
Familial Hypercholesterolemia (FH). Here there are three phenotypes:
+/+ = normal
+/- = death as young adult
-/- = death in childhood.
The gene codes for the liver receptor for cholesterol. The number of receptors is directly related to the number of active genes.
If the number of receptors is lowered the level of cholesterol in the blood is elevated and coronary artery disease risk is higher.

21. Familial Hypercholesterolemia
Top number is pedigree number, bottom is age the trait is diagnosed.
Can we say if person II-5 might be a carrier, since they are still young?
Persons III-6, III-7 and III-8 show symptoms early
WV study
Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins

22. Penetrance
Probability that a disease phenotype will appear when a disease-related genotype is present.
Both genetic and environmental factors can affect penetrance. 
DD or Dd 80% polydactyly
DD or Dd 20% no polydactyly
Incomplete penetrance occurs when the disease phenotype is not always observed among individuals carrying the disease-associated genotype.

23. Incomplete or Variable Penetrance
Incomplete penetrance is not the same as variable expressivity.
In diseases with variable expressivity, the patient always expresses some of the symptoms of the disease and varies from very mildly affected to very severely affected.
In autosomal dominant diseases with incomplete penetrance, the person either expresses the disease phenotype or he/she doesn't. Incomplete penetrance and variable expressivity are phenomena associated only with dominant inheritance, never with recessive inheritance.

24. Incomplete Penetrance
The disease is passed from the father (II-3) to the son (III-5), this never happens with X-linked traits. The disease occurs in three consecutive generations, this never happens with recessive traits.
Males and females are affected, with roughly the same probability.
However, II-1 does not express the disease. He must have inherited the mutant allele because he passed it on to two children, III-1 and III-3. II-1 is a classical example of incomplete penetrance, he has the allele for the disease but he does not express it.

25. Von Hippel-Lindau (VHL) disease
OMIM
Dominantly inherited familial cancer syndrome predisposing to various benign or malignant tumors:
central nervous system (CNS)
ocular hemangioblastomas (tumor composed of hemangioblasts, a type of stem cell that normally give rise to blood vessels or blood cells).
renal cell carcinoma (RCC) and/or renal cysts,
pancreatic tumors and cysts.
The birth incidence is estimated to be 1 in 36,000 to 1 in 53,000.
Retinal Hemangioblastoma in von Hippel-Lindau Disease: A Clinical and Molecular Study ()Hélène Dollfus et al. Investigative Ophthalmology and Visual Science. 2002;43:

26. Age at Appearance of first Hemangioblastoma
Retinal Hemangioblastoma in von Hippel-Lindau Disease: A Clinical and Molecular Study ()Hélène Dollfus et al. Investigative Ophthalmology and Visual Science. 2002;43:

27. Several mutations involved, leading to differences in activity of the mutant protein, which is a tumor suppressor.
Retinal Hemangioblastoma in von Hippel-Lindau Disease: A Clinical and Molecular Study ()Hélène Dollfus et al. Investigative Ophthalmology and Visual Science. 2002;43:

28. Factors affecting gene expression
Many genes give consistent and regular patterns of expression.
Some genotypes – the phenotypes may vary.
gene – gene interaction
gene- environment interaction
Examples: temperature, age

29. Various factors, both genetic and environmental can affect the colour of the Siamese cat. As the points and body colour are temperature sensitive, an important factor in the depth of pigmentation is the amount of heat loss from the skin. Colour is affected by climatic conditions, for instance in Australia the Northern Territory's hot climate has a dramatic effect on Seal Point Siamese, whose points become brindled, with cream and seal hairs intermingling. In contrast , studs and other cats kept in an outdoor cattery in Tasmania's winter cold, have dense seal points and are darker in the body.
Theoretically, if we keep our Siamese warm, especially Seal Points, the lighter their body colour should be. But not too warm, as an elevation in temperature can cause brindling, or loss of pigmentation in the points; often seen after the cat has been ill. Siamese grow out darker on the body after surgery, and white hairs can appear on the points when the follicles are damaged. Age is another factor, and the sites of intense pigmentation appear on the shoulders and hips where the skin is closest to the underlying bone structure. The lighter the colour the more sensitive to heat - Chocolate is more sensitive to heat than Seal (Black) - hence the difficulty in breeding a Chocolate Point with perfectly even points.
That temperature alone effects colour is an over-simplification as there are many other genetic factors, including modifiers and polygenes. When visiting theLindisfarne Cattery in Auckland, New Zealand in 1964, I saw the UK import Spotlight Pride, who at 15 years old had a clear cream coat and dense seal points. In stark contrast, their other male Morris Maestro, also IMP UK, was extremely dark all over - almost a self-seal. Both studs were housed under identical conditions, so their disparity of colour must have been genetic. Various factors, both genetic and environmental can affect the colour of the Siamese cat. As the points and body colour are temperature sensitive, an important factor in the depth of pigmentation is the amount of heat loss from the skin. Colour is affected by climatic conditions, for instance in Australia the Northern Territory's hot climate has a dramatic effect on Seal Point Siamese, whose points become brindled, with cream and seal hairs intermingling. In contrast , studs and other cats kept in an outdoor cattery in Tasmania's winter cold, have dense seal points and are darker in the body.
That temperature alone effects colour is an over-simplification as there are many other genetic factors, including modifiers and polygenes. When visiting theLindisfarne Cattery in Auckland, New Zealand in 1964, I saw the UK import Spotlight Pride, who at 15 years old had a clear cream coat and dense seal points. In stark contrast, their other male Morris Maestro, also IMP UK, was extremely dark all over - almost a self-seal. Both studs were housed under identical conditions, so their disparity of colour must have been genetic.

30. How might this Nerve Disorder with Leg Weakness be inherited?
Don is affected and Tom Jr. is concerned that he not pass the disorder on to his children with Alice.
What can we conclude about Tom Sr, who died in a car wreck?
Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins

31. Autosomal Dominant with Variable Age of Onset
50% for Tom
25% chance for child
Don is ill and Tom Jr. is concerned that he not pass the disease on to his children with Alice.
What about Tom Sr, who died in a car wreck?
Tom Sr. had the trait and passed it to Don
Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins

32. Pleiotropy Examples: Marfan Syndrome; Porphyria
The appearance of several apparently unrelated phenotypic effects caused by a single gene
refers to a Mendelian disorder with several symptoms
Different subset of symptoms in different individuals.
Usually means that a genes is involved in multiple processes
Examples: Marfan Syndrome; Porphyria

33. Porphyria Autosomal dominant
Many symptoms due to variety of problems with porphyrin accumulation
Photo © North Wind Picture Archives

34. Marfan Syndrome Inheritance - autosomal dominant
Inheritance - autosomal dominant
Phenotype - tall and thin, with long extremities, deficiencies in the skeletal system, eyes and cardiovascular system.
Defect - defective gene on chromosome 15
Affected gene produces abnormal fibrillin
End result - abnormal connective tissue
Major problem - aorta rupture
1 in occurrence
Both male and females afflicted
25% of cases occur in families with no previous history
Reason - gene undergoes a high mutation rate

35. Normal Marfan Syndrome

36. Marfan’s Syndrome Pedigree

37. The debate over Lincoln
In the early 1960s, Dr. A.M.Gordon addressed the Kentucky State Medical Association suggesting that President Abraham Lincoln had Marfan syndrome.
The diagnosis was based written physical descriptions of Lincoln:
He was much taller than most men of his day,
Long limbs
An abnormally-shaped chest
Loose (lax) joints
Since then, other physicians have disputed a diagnosis of Marfan syndrome for Lincoln.

38. Genetic heterogeneity
Different genes can produce identical phenotypes.
Individuals with identical phenotypes may reflect different genetic causes.
Deafness
Albinism
Cleft palate
Poor blood clotting

39. Autosomal Deafness

40. Phenocopy A trait caused by the environment that appears inherited.
Exposure to teratogens
Thalidomide causes limb defects akin to rare inherited phocomelia.
Infection
Rubella in pregnant mothers causes deafness mimicking inherited forms of deafness.

41. Imprinting Epigenetics has become a huge area of active research
Nova- The Ghost in your genes.