Download Mendelian Genetics II

Human Genetics
Understanding Genetics with
Family Trees
How do we use Mendel’s Observations
about Dominant and Recessive Traits,
Segregation and Independent Assortment
to predict the inheritance of traits in
humans?
Pedigree
- the family tree
- representation of the ancestry of
an individual’s family.
- symbolic representations of family
relationships and inheritance of a
trait
Pedigree Analysis
Parents
Offspring
Unaffected Male
Unaffected Female
Affected male
Affected female
A numbering system is
used to identify individuals
Individuals I1 and III1 express the
unusual trait being studied
Rest have normal phenotypes
Proband
- the first afflicted member of a family
seeking medical attention.
- marked with the an arrow and the letter p
Pedigree
The family tree
representation of the ancestry of an
individual’s family.
 symbolic representations of family
relationships and inheritance of a
trait
Common Pedigree Symbols
Mode of Inheritance determined by
inheritance pattern of mutant phenotype
Autosomal recessive
Autosomal dominant
X-linked recessive
X-linked dominant
Y-linked
mitochondrial
Most common
Criteria for an Autosomal
Recessive Trait
Male and Female are both affected
Affected males and females can transmit
the trait, unless it causes death before
reproductive age
Trait can skip generations
Parents of affected are heterozygous or
have the trait and are homozygous.
Autosomal Recessive Inheritance of
a Disease
Criteria for an Autosomal
Dominant Trait
Male and Female are both affected. Can
have male to male transmission.
Males and females transmit the trait with
equal frequency
Successive generations are affected
Transmission stops if a generation arises
where no individual is affected.
Autosomal Dominant
Inheritance
Dominant
Trait
Distal
symphalangism
is an autosomal
dominant
disorders
characterized by
fusion of the
proximal or distal
interphalangeal
joints.
Comparison of autosomal dominant
and autosomal recessive inheritance
Autosomal
dominant
Autosomal
recessive
Males and females affected?
Yes
Yes
Males and females transmit
the trait?
Yes
Yes
Trait skips generations?
No
Yes
At least one parent of
affected child must be
affected?
Yes
No
Trick Question Alert!
There is a tendency to believe that the
dominant allele is more common than the
recessive allele.
Sometimes that is true, but often it is not.
Dominance and Recessive traits BOTH
can result from lack of expression of a
gene and expression of an incorrect gene
product. Recessive traits simply require
two copies for the effect, while
Dominance requires only one copy.
Some Human Mendelian Traits
Many genes have more then two
alleles- so the gene displays
multiple phenotypes
Gene for blood group in humans has 3 alleles
IA IB and IO
There are only two alleles for each gene
present in a normal diploid individual
Codominance
 Both alleles are expressed equally
 Heterozygotes fully express both alleles
ABO Blood groups
 3 alleles
 6 genotypes
 4 phenotypes
Type AB blood - both the A and the B
antigen are expressed on red blood cells
H structure: Mucopolysaccharide
found on the RBC surface
Blood Types
3 alleles -- IA , IB , and IO
IA and IB are codominant
IO is recessive
Type A blood can be IAIA or IAIO
Type B blood can be IBIB or IBIO
Type AB blood is IAIB - codominant state
Type O blood is IOIO
Incomplete dominance
Heterozygous phenotype is intermediate
between the two parental homozygotes.
The heterozygous phenotype is typically
intermediate to the homozygous phenotype.
Incomplete dominance
If you cross true breeding red
and white snapdragons
F1 are all pink flowers
F2 - 1:2:1 red:pink:white
It takes 2 doses of the red allele to get red
RR- red
Rr – pink rr - white
Independent Assortment in Humans:
Albinism and Deafness
Lets look at some Pedigrees
Dimples
Dimples
Autosomal dominant inheritance
Brachydactyly
Autosomal dominant inheritance
Who could be carriers?
Tay Sach’s Disease
- Autosomal
Recessive Disorder
- II1 and II2 must be
carriers –Who else
could be?
- at least 2 carriers in
generation I
- but all could be
carriers
Or, is it Incomplete Dominance?
The condition is caused by insufficient activity
of an enzyme called hexosaminidase A that
catalyzes the biodegradation of acidic fatty
materials known as gangliosides.
Gangliosides are made and biodegraded
rapidly in early life as the brain develops.
Patients and carriers of Tay-Sachs disease can
be identified by a simple blood test that
measures hexosaminidase A activity.
Albinism
- Autosomal recessive
- Heterozygotes carry the recessive allele but exhibit
the normal skin color (sometimes called wild type
phenotype)
Pedigree Analysis
How do you evaluate a pedigree to
determine the mode of inheritance of a
particular trait?
 form a hypothesis as to how the trait is
inherited
 test the pedigree for consistency with that
hypothesized mode of inheritance
 if consistent with the hypothesized mode of
inheritance, accept your hypothesis only
when all other modes of inheritance can be
been ruled out.
What type of inheritance does
this trait have?
A.Dominance
B.Recessive
C.Dominance or recessive- insufficient data to tell
What type of inheritance does
this trait have?
A.Dominance
B.Recessive
C.Dominance or recessive- insufficient data to tell
Predict inheritance of a
dominant vs recessive?
Offspring 2 marries someone homozygous for
the trait. What will their children be if the trait
is recessive? Dominant- Heterozygote?
Homozygote?
Statistical Genetic Predictions
Ellen’s brother Michael has Ellen and Michael’s parents must be carriers.
A
a
sickle cell anemia, an
autosomal recessive disease.
A AA Aa
What is the chance that Ellen’s
child has a sickle cell anemia
allele (a)?
a
Aa aa
Ellen is not affected and
cannot carry aa genotype
chance Ellen is a carrier = 2/3
chance child inherits sickle cell allele
= 1/2
Ellen Michael
?
Overall chance child carries sickle cell
allele from Ellen = 2/3 x 1/2 = 1/3
Consanguinity
most common – first cousins marriages
- share grandparents - risk passing on
the same recessive alleles to offspring
First Cousin Marriages
Over a billion people worldwide live in
regions where 20%-50% of marriages are
consanguineous - that is where the
partners are descended from the same
ancestor.
What is the risk really?
Dr. Bittles, Director for the Centre for
Human Genetics in Perth, Australia
 Collated data on infant mortality in
children born within first-cousin marriages
from around the world and found that the
extra increased risk of death is 1.2%.
In terms of birth defects, he says, the
risks rise from about 2% in the general
population to 4% when the parents are
closely related.
Data Quality isn’t Good
Born in Bradford Study
 50% of births are Pakistani, and 70% of
Pakistani births in the study so far are from
consanguineous marriages
 150 genetic diseases identified, more than
expected from other cities
British Paediatric Surveillance Unit
 Since 1997, 902 British children born with
neurodegenerative conditions
 8% of those were in Bradford which only has
1% of the population.
Ptolemy Dynasty 323 BC to 30 BC
Preferred marriage was
brother/sister
 Why is so much
inbreeding not fatal?
 It could have an effect,
but the early miscarriages
and diminished fertility
and infant deaths weren’t
recorded.
What are the proposed solutions
and ethical considerations?
Make first cousin marriage illegal?
 This is a strong cultural preference in many
cultures and could be discriminatory
Test pregnancies for genetic defects and
have selective abortions?
 This requires legal abortions and screening
that is as early as possible
Provide parental screening and
counseling?
 This could lead to prejudice against carriers
There are very few life guards at
the gene pool in WV
 Human Genetics Testing
Staff are certified by:
 The American Board of
Medical Genetics
 The American Board of
Genetic Counseling
 The American Board of
Pathology: Molecular
Genetic Pathology
 Sharon L Wenger, PhD
West Virginia University
Dept Pathology