9/26/2008

Human Genetics
Mendelian Genetics
Exceptions

Gene (allele) interactions

Dominance
Recessive
Codominance
Incomplete
dominance
Epistasis

Pleiotropy
Linkage
Penetrance
Expressivity
Environmental
factors

Lethal Allele Combinations

Exceptions to Mendels 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

Genetic Disease is an Important

Component of Childhood Mortality

Homozygous recessive lethal alleles

eliminate a progeny class.
Sometimes this is hard to see in a familyit may result in reduced fertility.
fertility
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

9/26/2008

Age at Expression of Genetic

Disease

Lethals can be considered

Semidominant
The phenotype of the homozygote is
more extreme than the phenotype of the
heterozygote.
gene is
The normal allele of this g
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.

Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins

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.
y at anyy
Genes can mutate in manyy ways
nucleotide in their DNA sequence.
Eye Color and Hair color are examples of
multiple alleles

Multiple Alleles in Rabbit Coat

Color

Greyy
CC or Ccch or Cch or Cc

Himalayan
chc or chch

Chinchilla
cchcch

Light gray
cchch or cchc

Albino
cc

9/26/2008

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

Bombay Phenotype
Epistasis

Epistasis in flower color

H structure: Mucopolysaccharide
found on the surface of RBCs

H gene is epistatic to
the ABO gene.
protein
oe a
attaches
ac es the
e
Hp
A or B protein to the
cell surface.
hh genotype = no H
protein.
All ABO genotypes
appear as type O.

9/26/2008

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

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,
carrier since
they are still young?
Persons III-6, III-7 and
III-8 show symptoms
early
WV study

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.

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.

Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins

Incomplete or Variable Penetrance

Incomplete 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.
ff t d
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.

9/26/2008

Von Hippel-Lindau (VHL) disease

Age at Appearance of first

Hemangioblastoma

OMIM 193300
Dominantly inherited familial cancer syndrome
predisposing to various benign or malignant
tumors:
central nervous system
y
((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 ()Hlne Dollfus et al. Investigative Ophthalmology and Visual
Science. 2002;43:3067-3074

Retinal Hemangioblastoma in von Hippel-Lindau Disease: A Clinical and

Molecular Study ()Hlne 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.

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

Retinal Hemangioblastoma in von Hippel-Lindau Disease: A Clinical and

Molecular Study ()Hlne Dollfus et al. Investigative Ophthalmology and Visual
Science. 2002;43:3067-3074

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

9/26/2008

Autosomal Dominant with Variable

Age of Onset

Pleiotropy
The appearance of several apparently unrelated
phenotypic effects caused by a single gene

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

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

Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins

Porphyria

Marfan Syndrome
Inheritance - autosomal dominant
Phenotype - tall and thin, with long extremities,
deficiencies in the skeletal system, eyes and
cardiovascular system.

Autosomal
dominant
Many symptoms
due to varietyy of
problems with
porphyrin
accumulation

Defect - defective gene on chromosome 15

Affected gene produces abnormal fibrillin
End result - abnormal connective tissue
Major problem - aorta rupture

Photo North Wind Picture Archives

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

Marfans Syndrome Pedigree

Normal

Marfan Syndrome

9/26/2008

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
Th
Thalidomide
lid id causes lilimb
bd
defects
f t akin
ki tto 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.