Human Genetics
Mendelian Genetics
Exceptions
Gene (allele) interactions
Dominance RecessiveCodominanceIncomplete
dominanceEpistasis
PleiotropyLinkagePenetranceExpressivityEnvironmental
factors
Mendel chose traits in peas that showed
two distinct forms.
Not all genes exhibit such simple inheritance.
Alleles interactGenes interactNon-nuclear genes existSegregation of genes on same chromosome
Exceptions to Mendel’s Laws
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.
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
Age at Expression of Genetic Disease
Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins
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.
Mexican Hairless Dogs
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.
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
Grey CC or Ccch or Cch or Cc
Albino cc
Light graycchch or cchc
Himalayanchc or chch
Chinchillacchcch
Multiple Alleles in Rabbit Coat Color
Codominant Alleles
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
Epistasis in flower
color
Epistasis in flower color
Bombay PhenotypeEpistasis
hh genotype = no H protein.
All ABO genotypes appear as type O.
H gene is epistatic to the ABO gene.
H protein attaches the A or B protein to the cell surface.
H structure: Mucopolysaccharide found on the surface of RBCs
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
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.
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
Incomplete penetrance occurs when the disease phenotype is not always observed among individuals carrying the disease-associated genotype.
DD or Dd 80% polydactyly
DD or Dd 20% no polydactyly
Probability that a disease phenotype will appear when a disease-related genotype is present.
Both genetic and environmental factors can affect penetrance.
Penetrance
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.
Incomplete Penetrance
Von Hippel-Lindau (VHL) disease
OMIM 193300 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;43:3067-3074
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;43:3067-3074
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;43:3067-3074
Many genes give consistent and regular patterns of expression.
Some genotypes – the phenotypes may vary.
gene – gene interactiongene- environment interaction
Examples: temperature, age
Factors affecting gene expression
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
Autosomal Dominant with Variable Age of Onset
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
50% for Tom25% chance for child
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
Pleiotropy
Porphyria
Autosomal dominant
Many symptoms due to variety of problems with porphyrin accumulation
Photo © North Wind Picture Archives
Marfan Syndrome 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 10000 occurrence Both male and females afflicted 25% of cases occur in families with no previous history Reason - gene undergoes a high mutation rate
Normal Marfan Syndrome
Marfan’s Syndrome Pedigree
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.
Genetic heterogeneity
Individuals with identical phenotypes may reflect different genetic causes. Deafness Albinism Cleft palate Poor blood clotting
Different genes can produce identical phenotypes.
Autosomal Deafness
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.
Imprinting
Epigenetics has become a huge area of active research
Nova- The Ghost in your genes.