Transcript No Slide Title

Pedigree Workshop
Congenital cataracts
A pedigree
traces the
patterns of
inheritance of
genetic traits
from generation
to generation
within a family.
Generations are numbered with
Roman numerals. Within each
generation, individuals are numbered
from oldest to youngest.
female
male
Affected
individuals
marriage
proband
consanguineous
marriage
diseased
Extra-marital
mating
carrier
progeny
?
Unknown
phenotype
Dizygotic twins
Female carrier of
an x-linked trait
Stillborn
or abortion
identical
(monozygotic)
twins
Autosomal Recessive Traits
Only expressed in individuals that have two copies of
the relevant gene. More frequent with inbreeding,
isolated groups.
Autosomal Dominant Traits
Expressed even if only one copy of the gene is
inherited.
Effects sometimes show up later in life.
Sex-linked Traits
Associated with genes on the X chromosome.
Chromosomal Abnormalities
Deletions, Duplications, Inversions, Translocations
Nondisjunction and Aneuploidy
Extra or missing chromosomes
Complicating factors:
-Sex influenced genes
-Multi-gene traits
-Incomplete penetrance
-Imprinting
-Phenocopies
-Anticipation
-Pleotropy
-Epigenetic effects
Penetrance: Fraction of a
genotype that show the disease
(or trait).
Expressivity: Extent to
which a trait (disease) shows
variablity of expression when
present.
Autosomal dominant (AD)
AD with variable expression
Autosomal recessive (AR)
AD with incomplete penetrance
X-linked dominant (XLD)
AD with delayed age of onset
Characteristics of
autosomal dominant inheritance:
-Direct transmission from an affected
parent to an affected child. (Affected
children always have an affected parent.)
-Transmission can occur from affected
father to affected son.
-Approximately a 1:1 ratio of affected
vs. unaffected progeny with one
affected parent.
Examples of Autosomal
Dominant Traits
Achondroplastic dwarfism
Huntington's disease
Polydactly
One of the wives of Henry VIII had
an extra finger.
Characteristics of
autosomal recessive
inheritance:
-Affected parents can have
affected offspring. (In fact,
affected children typically
do not have affected
parents.)
-Affected progeny are both
male and female.
Examples of autosomal
recessive traits:
Albinism- the lack of pigmentation in skin,
hair, and eyes.
Phenylketonuria (PKU) - sufferers lack the
ability to synthesize an enzyme to convert the
amino acid phenylalanine into tyrosine.
Characteristics of
sex-linked recessive traits:
-More affected males than
affected females.
-Affected grandfather to
affected grandson
transmission through a carrier
female intermediate.
-No male to male transmission.
Examples of sex-linked
recessive traits:
Red and green color blindness.
Color blindness afflicts 8% of
males and 0.04 % of human
females.
Hemophilia A
Duchenne Muscular Dystrophy (DMD)
An example of an xlinked dominant trait.
Hypophosphatemic Rickets
Mitochondrial inheritance:
Affected males do not transmit
the trait to any of their children.
Affected females transmit the
trait to all of their children.
Pedigree Workshop Example
Given the pedigree shown below,
answer the following questions. (Draw
this and label it according to the usual
conventions for pedigree charts.)
Is the pedigree consistent with
autosomal recessive inheritance?
Briefly explain why or why not and
indicate all individuals who must be
heterozygous if this is an AR trait.
Yes. What would exclude AR inheritance is 2 affected
individuals having unaffected children, which is not
the case here. If it is AR, then I-4 and III-2 are aa
and II-1, II-2, II-3, II-4, and II-5 must be Aa
heterozygotes. (The first because he produced an
affected child and the others because their mother
was affected.) In addition, either I-1 or I-2 must be
Aa.
Is it consistent with X-linked
recessive inheritance? Briefly
explain why or why not.
No. The sons of I-4 must be affected if it were XR.
An affected female must be homozygous and would
have to pass the trait on to all her sons.
Is it consistent with
autosomal dominant inheritance?
If so, what assumption must be
made?
Yes, if it is incompletely penetrant. Then II-2 could
have the dominant allele and pass it on to her son,
III-2, but not show the trait herself.
Pedigree Practice
http://www.cellbio.drake.edu/Cancer/CancerBioMail.html
An important goal of science
education is to influence students
to think like scientists.
Case Studies:
1. Queen Victoria, porphoria and hemophilia
in the royal families of Europe
2. The Blue People of Kentucky
3. Construction of a pedigree from
microsatellite analysis
4. Familial, early-onset Alzheimer's disease
5. Fragile “X”
6. “Anticipation” in Huntington’s Disease
7. Li-Fraumeni Syndrome
8. Marfan Case Study
9. Heredity and Deafness
10. Thomas Jefferson’s “Y” chromosome
Your Assignment
1. Prepare a pedigree for your case study. Discuss
possible modes of inheritance and a typical genotype of
an affected individual.
2. Briefly summarize the disease's main symptoms, and
the frequency of occurrence in affected populations or
sub-populations.
3. If known, what is the biochemistry behind this trait?
4. If known, what is the chromosomal location of the
gene?
5. Prepare a very short presentation of your pedigree
with an interactive component for the whole class.
Case 1: A Royal Carrier
Resources: See
handout from
Science
Spectrum and A
Royal Pedigree
http://www.peopl
e.virginia.edu/~rj
h9u/scot.html
Case studies
(Including Queen Victoria and the inheritance of hemophilia)
http://ublib.buffalo.edu/libraries/projects/cases/ubcase.htm
Case 2: The Blue People
of Kentucky
Robert J. Huskey
http://www.people.virginia.
edu/~rjh9u/fugate.html
Luna Fugage and John Stacy
(figure from © Science82:
November, 1982)
Case 3: Microsatellite
marker analysis
Which microsatellite
allele is likely linked to
the disease allele?
http://nitro.biosci.arizona.edu/courses/EEB320/EEB320.html#notes
4. Genetics of Familial,
early-onset Alzheimer's
disease
Genetics
Familial, early-onset Alzheimer's disease
About 5% of people with Alzheimer's disease have a strong
family history of the disease, with several affected family
members and an early age of onset (under the age of 60).
Mutations in three different genes - the amyloid precursor
protein (APP) gene, and the presenilin 1 and 2 (PS1 and PS2)
genes - have been found in different families afflicted with
early-onset familial Alzheimer's disease. The mutations are
dominant, that is, the child of a sufferer has a 50% chance of
inheriting the disease susceptibility. With the possible
exception of PS2, mutations in these genes are highly
penetrant, though the severity of the disease is variable.
Together, mutations in the three genes account for about 2050% of familial cases, suggesting that other gene(s) implicated
in familial Alzheimer's still remain to be found.
The APP gene encodes the beta-amyloid
protein, which shows abnormal accumulation in the
brains of Alzheimer's disease sufferers. The
normal functions of the PS1 and PS2 genes are not
well understood, but the protein products of these
genes interact with proteins known to be involved in
signaling processes within and between cells.There
is some evidence that presenilins may play a role in
targeting some of these proteins to their correct
destinations in the cell.
5. Genetics of Fragile X
Fragile X syndrome affects about 1 in 4000 males
and 1 in 8000 females. The major features are learning
disability of varying severity, behavioral problems such as
hyperactivity and autistic tendencies, and physical
characteristics including long face, protruding ears, lax
joints and (in males) enlarged testes. There is no cure but
there is some evidence that treatment of the associated
behavioural and educational problems can be beneficial.
Understanding Key Protein
in Fragile X Syndrome
http://www.hhmi.org/news/warren.htm
Genetics of Fragile X
Fragile X syndrome is caused by mutation of the FMR-1
gene on the X chromosome. The FMR-1 gene contains a
sequence that consists of a variable number of repeats of the
trinucleotide CGG. This sequence occurs in a part of the gene
that is transcribed but is not translated into protein. The
normal number of CGG repeats varies between 5 and about 50
(average around 30). Individuals with fragile X syndrome
typically have more than 200 of these repeats, a condition
known as a full mutation (FM). The full mutation prevents
transcription of the FMR-1 gene, so that none of its protein
product is made. Males have only one X chromosome, so if they
carry a FM they are always affected. Females have two X
chromosomes and the result of a FM in one chromosome can be
very variable: about 50% of such females show some symptoms
of the syndrome and 20% are severely affected.
The unaffected mothers of fragile X individuals are
invariably found to have an FMR-1 gene containing
between 50 and 199 CGG repeats; this intermediate
number is known as a premutation (PM). The population
frequency of the PM is about 1 in 250. For reasons that
are as yet not understood, the number of repeats in a PM
is potentially unstable and can increase into the FM range
in a child that inherits the affected chromosome from its
mother. The chances of a PM in a mother expanding to a
FM in her child have been estimated at about 10% in the
general population and about 60-80% in known fragile X
families. In contrast to the potential instability of a PM
transmitted from the mother, a PM transmitted from the
father does not expand to a FM in his daughters. This
means that all the children of a male with a PM are
unaffected (his sons do not inherit his X chromosome),
but because all of his daughters inherit the PM they are
at risk of having a child with a FM.
Case Study 6: Li-Fraumeni Syndrome:
http://www.medinfo.cam.ac.uk/phgu/info_database/
Diseases/
MA was worried. There was just too much cancer in her
family and was she next. Her older sister was only 18 years old
when she developed a brain tumor, which required surgical
intervention followed by radiation and chemotherapy. Her
younger brother had died at five years of age from
rhabdomyosarcoma (cancer of muscle) despite being treated
by pre- as well as post-operative chemotherapy accompanied
with resection. Her mother had died of breast cancer at 43
years of age despite mastectomy and chemotherapy at the
time of diagnosis four years earlier. Her anxiety was only
heightened when she considered her maternal family's history:
an aunt with acute leukemia in adolescence, a grandfather who
died from melanoma, and two first cousins who developed
osteosarcomas in adolescence.
The diagnostic criteria for Li-Fraumeni syndrome are:
Presence of sarcoma in proband at <45 years of
age; AND, sarcoma, breast cancer, primary brain tumor,
leukemia or adrenocortical carcinoma in a first degree
relative <45 years of age; AND cancer diagnosed in
another close relative at <45 years old or sarcoma at any
age.
Case 7. HD Pedigree showing
anticipation.
The age of onset is younger with each
generation. How does this happen?
8. Information and Background for Marfan
Case Study
Your medical team has just received the
case of Anne, as 16 year old woman, who is
concerned that she may have Marfan syndrome.
She has heard a news story recently about the
dangers of intense sports to those who suffer
from Marfan syndrome, and feels that her
general characteristics and family history may
indicate Marfan Syndrome. She wants to know if
she is at risk.
http://www.hamline.edu/depts/biology/courses/genetic
s/marfan.html
You need to analyze Anne's family's medical
history, draw a conclusion about the probability of
Marfan Syndrome, and make specific
recommendations to Anne regarding how to deal with
her situation. Should she be concerned at all (or is
she just alarmed at nothing), should she undergo
further testing (if so, specify which tests), should
she receive medical treatment at this time, should
she pursue her athletic goals?
Your team has an appointment with Ann
next week, at which time you should be prepared
to make recommendations to her regarding her
future. You should make a pedigree of Anne's
family, and use this to help explain your
conclusions to her. You will also need to explain
the problems caused by Marfan's syndrome, and
your plan for monitoring, diagnosis and
management. You should give Anne some specific
recommendations for the immediate future.
The members of your team include a
genetic counsellor, a family doctor, and a
cardiologist. If your team has four members, you
should include another medical specialist of your
choice.
Case 9. Heredity and
Deafness
Resources: See handout from Science
article.
What Is Hereditary Deafness?
http://www.medhelp.org/lib/heredeaf.htm
http://www.pbs.org/wgbh/pa
ges/frontline/shows/jeffers
on/etc/genemap.html