Pedigree Analysis
SDK
November 23, 2012
Learning Objectives
– Define common terms used in genetic pedigree
– What are the goals of pedigree analysis
– What a genetic pedigree is
– How to read a genetic pedigree
– How to draw a human genetic pedigree
– Clinical Examples of genetic pedigree
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Terms
Trait – characteristic of an organism
Gene – a heredity unit that codes for a trait.
Allele – different gene forms
Dominant – the gene that is expressed (shown)
whenever it is present
Recessive – the gene that is “hidden”. It is not
expressed unless a homozygous condition
exists for the gene.
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Terms
• Homozygous – two identical (same) alleles
for a given trait (TT) also called purebred.
• Heterozygous – two different (opposite)
alleles for a given trait (Tt), also called
hybrid.
• Gamete – sexual reproductive cell (sperm
& egg).
• Fertilization – the fusion of two gametes.
• Phenotype – physical trait of an organism.
• Genotype – the genes present in the cell.
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Remember
Homozygous = AA or aa = purebred
Heterozygous = Aa = hybrid
Dominant = capital letter (A)
Recessive = lower case letter (a)
Genotype = alleles involved (AA, aa, or Aa)
Phenotype = trait expressed (blue or green)
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What is a Genetic Pedigree?
 Pedigree is a diagram of family relationships that uses symbols to
represent people and lines to represent genetic relationships
 A genetic pedigree is an easy way to track your family traits.
 It looks like a family tree, but also contains information about the
mode of inheritance (dominant, recessive, etc.) of genetic
diseases.
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What is a Genetic Pedigree?
 A doctor or geneticist might draw a family pedigree if some one
had a family history of a particular disease.
 With this information they could see how the disease is inherited
and calculate the probability of passing on the disease to future
children.
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Goals of Pedigree Analysis
1. Determine the mode of inheritance:
1.
2.
3.
4.
5.
Dominant
Recessive
Sex-linked
Autosomal
mitochondrial, maternal effect.
2. Determine the probability of an affected
offspring for a given cross.
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Symbols
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Symbols
 Each of the individuals indicated by a circle is a woman and each
of the squares represents a male family member.
 Individual III:1 is a male.
 Occasionally, the sex of an individual may not be known.
Common reasons for this would be, miscarriages or early death,
babies given up for adoption, a child that has not been born yet.
 These individuals can be noted by using a diamond symbol (
)
instead of a square or circle.
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Symbols
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Symbols
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More Symbols
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Generations
I
1
2
II
2
1
3
III
1
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Generations
 This is an example of a family tree showing 3 generations of family
members.
 The roman numerals (in red) on the left indicate the generation each
person belongs to.
 Each individual in a generation is then numbered (in green).
 Notice it restarts at 1 every new generation.
 Older siblings are on the left and younger siblings are on the
right in descending order.
 Using this system, the individual at the bottom of this pedigree is
III:1.
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“Marriage Lines”
I
1
2
II
2
1
III
1
3
• The lines highlighted in red
indicate individuals that have had
children together. Even though
we call them “marriage lines” it
does not matter if they are
married, were married, or were
never married.
• It is important to realize that time
has no meaning on a genetic
pedigree, therefore we do not
usually indicate if someone has
died or been divorced.
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•
•
“Children Lines”
I
1
2
II
2
1
3
The lines highlighted in red are
“children lines”
– The marriage line that they are
connected to from above indicates
who gave them their genetic traits
rather than who raised them.
– If a couple has more than one
child together then we split the
child line as the green highlighted
line shows. More siblings would
simply require a longer line with
more lines coming down from it.
• Thus II:2 and II:3 are children of I:1
and I:2, but II:1 married into the
family and has different parents. We
also know that II:2 is older than his
sister (read left to right). However,
we don’t know anything about the
relative age of II:1 even though she
is on the left since she married into
the family.
III
1
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Remarriages Half Siblings
I
1
2
3
II
1
2
• This is an example of how to
show a parent who has had
children with more than one
person. It does NOT mean that
they are married to more than
one person at the same time.
• Remember, time has no meaning
in a pedigree.
• In this example, II:1 and II:2 are
half brother and sister. They
share the same mother, but
different fathers.
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Adoptions
I
1
2
II
1
 The red line (dashed) “children lines” to denote a
child that is not related biologically (adopted).
 In this example, the couple adopted a son.
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• Twins are another fairly common
occurrence. However, there are
two kinds and from a genetic
standpoint it is very important to
know the difference.
Twins
– In the case of identical twins, the two
siblings have the same DNA.
– To show this we split the sibling line
at an angle. The red highlighted line
is an example of this.
– In the case of fraternal twins,
although born at the same time, the
siblings are no more related than any
other siblings. Thus, they are drawn
the same as any siblings. The green
highlighted lines show this.
I
1
2
II
1
2
3
4
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A Punnett square
• A Punnett square is a chart which shows/predicts all
possible gene combinations in a cross of parents.
• Punnett Square looks like a two-dimensional table,
where over the square horizontally fit the gametes of
one parent, and the left edge of the square in the
vertical - the gametes of the other parent.
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Steps in Pedigree Analysis
1. Analyze whether the pedigree belongs to a
dominant or recessive group.
1. Recessive
a) Parents will be not affected
b) There will be skip generations
2. Dominant
a) Affected person must have affected parents
b) Every generation will be affected
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Steps in Pedigree Analysis
1. Autosomal . Both boys and girls will be involved.

Dominant




Disease must b in multiple generation.
Disease person must have an affected parents.
Male & female are equally affected
Recessive.



Disease have skip generation.
Disease person must not have an affected parents.
Because autosomes are involved , Male & female are equally affected
2. X-linked

Dominant



Affected male will transmit the character to all daughters but not to sons
Affected female will transmit the character to Half sons and Half daughters.
Recessive.


No male to male transfer
Affected male will be more than female
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1. Autosomal Dominant Inheritance
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Autosomal Dominant Traits
•A
dominant
condition
is
transmitted in unbroken descent
from each generation to the next.
• A typical pedigree might look like
this:
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Autosomal Dominant Traits
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Autosomal Dominant Traits
Dd
dd
dd
dd
Dd
Dd
Dd
Dd
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Dd
DD
dd
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Autosomal Dominant Traits
•
•
•
Huntington disease is a progressive nerve degeneration, usually beginning about
middle age, that results in severe physical and mental disability and ultimately in
death
Every affected person has an affected parent
~1/2 the offspring of an affected individual are affected
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Autosomal Dominant Traits








Huntington's disease
Marfan syndrome
Neurofibromatosis
Retinoblastoma
Familial hypercholestrolemia (LDL receptor defect Type IIa)
Adult polycystic kidney disease
Hereditory spherocytosis
Hypertrophic Obstructive Cardiomyopathy (HOCM)
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How is this trait most likely
inherited?
If individual III4 and III6 have a
child, what’s the probability that the
child will be affected?
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Brain Work
• Neurofibromatosis type 1 is one of the most common autosomal
dominant disorders. A woman with neurofibromatosis type 1 has an
unaffected partner. Which of the following is correct regarding
their children?
A. The probability that each of their children will be affected is 1 in 4.
B. The probability that their second child will be affected if their first child is
affected is 1 in 4.
C. The probability that their third child will be affected if their first two children
are affected is 1 in 2.
D. If their first child is affected then their second child will not be affected.
C. The probability that their third child will be affected if their first
two children are affected is 1 in 2.
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2. Autosomal Recessive Traits
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Autosomal Recessive
• A recessive trait will only show
up when homozygous.
• Most people are heterozygous
carriers
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Autosomal Recessive
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Autosomal Recessive Traits
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Autosomal Recessive
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Autosomal Recessive Traits
• Albinism = absence of pigment in the skin, hair, and iris of the eyes
• Most affected persons have parents who are not themselves affected; the
parents are heterozygous for the recessive allele and are called carriers
• Approximately 1/4 of the children of carriers are
affected
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CYSTIC FIBROSIS
 Cystic fibrosis (CF) is a genetic condition that affects many organs in the
body: especially the lungs, pancreas and sweat glands.
 A build-up of thick, sticky mucus in these organs leads to respiratory
problems, incomplete digestion and increased salt loss from the sweat glands.
 CF most commonly affects people who are of Northern European or UK
descent, is also fairly frequent in people whose ancestry is Southern European
and Middle Eastern.
 In CF the CFTR gene(salt-transport’ gene) that contains the information for the
production of the protein that transports salt in and out of the cells is absent
that result in thick secretions loaded with salt.
 The CFTR gene is located on chromosome 7, an autosome
 This thick secretions block air passages, pancreatic and intestinal ducts will
impair the function of these organs, Indigestion wt loss and increased loss of
Salts.
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CYSTIC FIBROSIS
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Presentation of Disease
Mucous in the airways cannot be easily cleared from the lungs.
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Autosomal Recessive Traits








Abetalipoproteinemia.
Acute fatty liver of pregnancy
Alkaptonuria.
Congenital hepatic fibrosis.
Cystic Fibrosis.
Cystinosis, Cystinuria.
Dubin-Johnson syndrome.
Fanconi Anemia.
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








Leukocyte Adhesion Defect.
Nieman Pick Disease.
Rotor syndrome.
Situs Inversus.
Sickle cell Disease and
Trait.
Thalasemia.
Wilson's Disease.
Xeroderma pigmentosa
Friedrech's Ataxia.
Glycogen storage diseases.
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How is this trait most likely inherited?
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Brain Work 2
• In the below family, a child has been born with
Acheiropodia (congenital absence of hands and feet).
• Assuming that this is a genetic problem, what is the
MOST LIKELY inheritance pattern and how likely is
it that a next child of III3 and III4 will be affected?
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A. X linked recessive; 1 in 2 for a son and 1 in 4
for a daughter
B. Autosomal recessive; 1 in 2
C. Autosomal dominant; 1 in 2
D. Autosomal recessive; 1 in 4
E. Mitochondrial; 1 in 2
D. Autosomal recessive 1 in 4
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3. X-Linked Recessive Inheritance
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X-Linked Recessive T rait
• Characteristics of an X-linked recessive trait
include:
– More affected males than affected females
– No male to male transmission
– Male transmission through female
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X-Linked Recessive T rait
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X-Linked Recessive Trait
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X-Linked Recessive Trait
 Lesch-Nyhan Syndrome
 Duchene Muscular
Dystrophy
 Glucose 6 Phosphate
Dehydrogenase Deficiency
 Hemophilia A and B





Fabry's Disease
Bruton's Aggamaglobulinemia
Color Blindness
Complete Androgen Insensitivity
Congenital Aqueductal stenosis
(hydrocephalus)
 Inherited Nephrogenic Diabetes
Insipidus
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Brain Work
• II3 in the pedigree below has two brothers with hemophilia A, a
bleeding disorder that is inherited as an X-linked recessive trait.
What is the risk of hemophilia for her children?
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A. 1 in 4 for a son, close to zero for a daughter
B. 1 in 2 both for sons and daughters
C. 1 in 2 for a son and 1 in 4 for a daughter
D. 1 in 2 for a son, close to zero for a daughter
E. 1 in 4 both for sons and daughters
A. 1 in 4 for a son, close to zero for a daughter
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Brain Work 2
• II-3 in the below family has two brothers and three sons
with classical hemophilia (factor VIII deficiency).
• Now she is pregnant again. How likely is it that this
child will also have hemophilia?
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A. 100% for a son and 50% for a daughter
B. 100% for a son, zero for a daughter
C. 50% for a son, zero for a daughter
D. 50% for both sons and daughters
E. 25% for a son and zero for a daughter
E. 25% for a son and zero for a daughter
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4. X-Linked Dominant Inheritance
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X-Linked Dominant Inheritance
•
•
Affected males transmit the trait to all of
their daughters and none of their sons.
Affected females transmit the trait to half of
their sons and half of their daughters.
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X-Linked Dominant Inheritance
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X-Linked Dominant Inheritance
•
Affected males transmit the trait to all of
their daughters and none of their sons.
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X-Linked Dominant Inheritance
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X-Linked Dominant Inheritance
 X Linked Hypophosphotemic Rickets.
 Focal Dermal Hypoplasia,
 Orofaciodigital syndrome.
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How is this trait
most likely
inherited?
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Y-Linked Inheritance
• We will now look at how
various kinds of traits are
inherited from a pedigree
point of view.
• Traits on the Y
chromosome are only
found in males, never in
females.
• The father’s traits are
passed to all sons.
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Mitochondrial Genes
 About 20,000 genes in the human genome are located in small compartments
in the cell called the mitochonria.
 The genes found within the mitochondria contain the information that codes
for the production of enzymes that drive the biochemical reactions to produce
energy(ATP).
 The cells in the body, especially in organs such as the brain, heart, muscle,
kidneys and liver, cannot function normally unless they are receiving a
constant supply of energy (ATP).
 Faulty mitochondrial genes can result in absence of these enzymes, or
enzymes that are impaired and do not work properly.
 This leads to a reduction in the supply of ATP, and may result in problems
with the body’s functions .
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Mitochondrial Genes
 The pattern of inheritance of conditions due to faulty
mitochondrial genes is often called maternal inheritance.
 This is because a child inherits the great majority of their
mitochondria from their mother through the ova.
 Usually a mother will have a mixture of mitochondria
containing the working gene copy and others containing the
faulty gene.
 For a condition to develop, the number of mitochondria with
the faulty gene must be above a critical level (the threshold).
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Mitochondrial Genes
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Mitochondrial Genes
 As mitochondria are only
inherited from the mother.
 If a female has a
mitochondrial trait, all of her
offspring inherit it.
 If a male has a mitochondrial
trait, none of his offspring
inherit it.
 If the mother is not affected
but has the faulty genes, than
 Disease will occur depending
up on the levels of faulty
genes.
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Mitochondrial Genes
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Thank You
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