Human Genetics
Mendelian Genetics
Exceptions
Gene (allele) interactions
Dominance
Recessive
Codominance
Incomplete
dominance
Epistasis
Pleiotropy
Linkage
Penetrance
Expressivity
Environmental
factors
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
Lethal Allele Combinations
Homozygous recessive lethal alleles
eliminate a progeny class.
Sometimes this is hard to see in a familyit 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
Multiple Alleles in Rabbit Coat
Color
Grey
CC or Ccch or Cch or Cc
Himalayan
chc or chch
Chinchilla
cchcch
Light gray
cchch or cchc
Albino
cc
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 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.
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
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.
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
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
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
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
Pleiotropy
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
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
Different genes can produce identical
phenotypes.
Individuals with identical phenotypes may
reflect different genetic causes.




Deafness
Albinism
Cleft palate
Poor blood clotting
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.