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Evidence Supporting a
Genetic Basis for a Clinical
Observation
• Family studies reveal a Mendelian inheritance
pattern for a clearly defined clinically
significant trait
• Chromosomal analysis correlates a specific
pattern of clinical symptoms with a specific
chromosomal aberration
• Relative frequency of a specific pattern of
clinical symptoms in genetically related
individuals is higher than less related or
unrelated individuals.
Genotype Relative Risk
• The ratio of individuals with a
given genotype who exhibit a
phenotype relative to an
alternative genotype.
Mendelian Inheritance
Patterns
• High genotype relative risk
• Unique pattern of clinical findings
• High penetrance
Mendelian Inheritance
• DNA sequence variants inherit in a
Mendelian inheritance pattern
essentially 100% of the time
• Medically significant “traits” sometimes
inherit in a Mendelian inheritance
pattern
Why we care if a medically
significant trait shows a
Mendelian inheritance pattern
• Providing genetic counseling
information for patients
• Locating gene for medically important
trait through positional cloning
Implication of a Mendelian
Inheritance Pattern for a
Medically Significant Trait
• There must exist a single site in the
genome where a specific difference in
DNA sequence is present which is the
primary cause of the difference between
affected and unaffected individuals.
Penetrance
• The proportion of individuals with a
given genotype who express the
phenotype under consideration.
• Penetrance has numerical value
between 0 and 1.
• When penetrance is significantly less
than 100% it is referred to as
incomplete.
Age Dependent Penetrance
• The proportion of individuals with a
given genotype who express the
phenotype under consideration as a
function of age.
• Age dependent penetrance can have a
numerical value which rises as a
function of age
Expressivity
• The extent or severity of the phenotype
in individuals of equivalent genotype.
• Expressivity can be referred to as
variable but does not have a
quantitative value.
Autosomal Dominant
• An affected person usually has one
affected parent
• Either sex can transmit to next
generation
• Either sex can be affected
• Children of an affected parent have a
50/50 chance of being affected
Autosomal Dominant
How can autosomal dominant
genes cause severe diseases
in humans?
• The disease occurs later in life, so
reproductive fitness is not severely
reduced
OR
• The gene has a high mutation rate
Autosomal Dominant
• Gain of function
• Loss of function
Many Types of Dominant
Alleles Result from Gain of
Function
• Production of a “dominant negative” form of
polypeptide chain which prevents the normal form of
the polypeptide chain from working properly
• Changes in the control of timing, amount, tissue or
response to signals of the production of the mRNA for
a gene
• Polypeptide chain which carries out a novel function
Dominant alleles caused by
loss of function
• Genes which show sensitivity to gene
dosage
• Tumor suppressor genes
Dominant Negative Mutation
• Original gene …….AAA GGA CCA…
polypeptide chain…LYS GLY PRO
• Dominant negative mutant AAA CGA
GCA polypeptide chain………..
LYS ARG PRO
• Change in amino acid sequence causes
mutant protein to disrupt function of
normal protein
Dominant Negative Mutation
• Example:
– Hypertrophic cardiomyopathy--mutation in
myosin gene causes disruption in function
of normal myosin in heart muscle.
– Contraction of heart muscle abnormal
when one mutant gene and one normal
gene are present.
– Autosomal dominant inheritance pattern
results.
Hypertrophic Cardiomyopathy
Hypertrophic Cardiomyopathy: DOMINANT NEGATIVE
MUTATIONS IN SARCOMERE PROTEINS
Dominant Allele Resulting From Mutation Which Changes the
Control of Timing, Amount, Tissue or Response to Signals of
the Production of the mRNA for a Gene
•
Example: Glucocorticoid
remedial aldosteronism-Unequal crossover during
meiosis leads to the
formation of a chimeric gene
in which the promoter for 11b-hydroxylase enzyme
controling production of
cortisone (flight or flight
hormone) is placed in front
of gene controlling synthesis
of aldosterone (aldosterone
synthase), a hormone
regulating salt balance in the
kidney--results in
hypertension (high blood
pressure)
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
Glucocorticoid remedial
aldosteronism
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
GAIN OF FUNCTION IN
HUNTINGTON’S DISEASE
• Extra amino acids in Huntington’s Disease protein
can cause it to become sticky and bind to itself and
other proteins in the cell
• mRNA…….CCC (CAG)20 CCC…normal allele
polypeptide. PRO (GLN)20 PRO… normal allele
• mRNA… CCC (CAG)50 CCC.. mutant allele
polypeptide PRO (GLN)50 PRO.. mutant allele
Huntington’s Disease is Caused by
an Expanded Polyglutamine Repeat
[CAG]n CAG triplet repeat
40-120
5-35
HD Gene
(Gln)n Polyglutamine repeat
40-120
5-35
[CAG]n CAG triplet repeat
40-120
5-35
HD RNA
Huntingtin protein
AUTOSOMAL DOMINANT
INHERITANCE CAN BE CAUSED BY
LOSS OF FUNCTION
• Retinoblastoma--fatal disease in
childhood
• Until treatment developed no
families possible
• Dominant inheritance caused by
loss of function in one copy of RB1
gene
Knudsen’s Two Hit Hypothesis For Rb
First Hit:
Inherited
A
somatic line
zygote
germ line
B
C
Second Hit:
Somatic
Cells With
Malignant
Potential
SOME MUTATIONS IN THE RB1 GENE CAN CAUSE
RETINOBLASTOMA WITH LOW PENETRANCE