Laboratory #4: Pedigree Exercises
Single-gene disorders are genetic disorders that are caused by mutations in
individual genes. These mutations result in the occurrence of a disease phenotype,
and can be inherited from parent to child. Therefore, we can follow the occurrence
of these diseases through the use of a pedigree. Overall there have been roughly
3917 single-gene disorders characterized. Of these disorders, 3310 are known to
affect only 1990 genes. For the other 600+ disorders, the implicated gene has not
been discovered yet. That means that for some genes there can be different
mutations, and these different mutations can lead to different genetic diseases.
A gene the basic unit of heredity, and is encoded by a specific DNA sequence.
Humans have roughly 18,000 genes, and each gene has its own specific sequence.
The sequence of a particular gene is derived from the combination of nitrogenous
bases, i.e. adenines, thymines, cytosines and guanines, in a particular order. For
instance, the order of nitrogenous bases for the DMPK gene (implicated in myotonic
dystrophy) is different from the Clotting factor VIII gene (implicated in hemophilia).
A mutation is a heritable change in DNA sequence.
Each gene can have multiple variants called alleles. The most common allele
(or variant) in the population is considered the wild-type allele. This allele is
generally considered the normal allele and is not disease causing. Any other allele
(or variant) will have a different DNA sequence and is considered mutant.
Depending on the different alleles being studied, the wild-type (or normal allele) can
either be recessive or dominant.
An individual human has two copies of each gene, with one copy coming from
the mother and the other coming from the father. For each copy, an individual can
have either two wild-type copies (i.e. they are homozygous for the wild-type allele),
two mutant alleles (i.e. they are homozygous for the mutant allele), or they can have
one wild-type and one mutant allele (the individual is heterozygous). The written
combination of alleles is considered the genotype. The outward symptoms that one
can see (i.e. facial deformities, mental retardation etc.) are considered the
phenotype.
As stated previously, both wild-type and mutant alleles can be either
dominant or recessive depending on the disorder being studied. For instance, for
sickle cell anemia, the mutant allele is recessive, whereas the wild-type allele is
dominant. This is opposite of the case for Huntington’s disease, in which the mutant
allele is dominant and the wild-type allele is recessive. When we write these out, we
usually signify the dominant allele with the appropriate capital letter (for instance,
with Huntington’s disease we’ll use H for the mutant allele), and we signify the
recessive allele with the same letter, but in lower case (i.e. for Huntington’s disease,
the wild-type allele is designated with a h). Therefore, the written genotype of a
heterozygote with Huntington’s disease is Hh. A healthy person must have two
recessive alleles with respect to Huntington’s disease and will have the genotype hh.
We generally use this notation when studying genes that are not linked to the Xchromosome.
When we study genes that are linked to the X-chromosome, we use a
slightly different notation. Let’s take the case of the gene that encodes red-green
color vision. The gene for red-green color vision is found on the X-chromosome.
The allele for normal color vision (i.e. the wild-type allele) is dominant, and the
mutant allele that leads to red-green color blindness is recessive. To write a
genotype for a normal female that is homozygous for the wild-type allele we write
her genotype as XC XC. The X stands for the fact that this gene is found on the Xchromosome. The (C) stands for the fact that the wild-type allele is the dominant
allele. If a woman were a heterozygote, then her genotype would be XCXc, etc. What
happens in the case of the male. Well, he only has one X-chromosome, and his Xchromosome pairs with the Y chromosome. So if we have a male that has normal
color vision, his genotype is XCY. Furthermore, if a male has red-green color
blindness he has the genotype XcY. A male always has a hemizygous genotype when
studying genes on the X-chromosome. This is because he has only one copy of each
gene (as he has only one X-chromosome).
As stated previously, we can follow genetic disorders through families
through the use of a pedigree. To use a pedigree, one must become familiar with the
common symbols seen on the pedigree. Each individual pedigree follows a single
family, both immediate and extended. Each individual in the family is designated by
a specific symbol. All males are denoted by a square and all females are denoted by
a circle. An individual where the sex is unknown is denoted by a diamond. If an
individual has a disorder, then he/she will have a shaded symbol. If an individual is
a carrier (i.e. has one disease causing allele, but does not show a disease phenotypealso a heterozygote for a recessive disorder), then he/she will have a shaded dot in
the middle of his/her symbol. For X-linked disorders, only females can be carriers.
Also, note that the individual that brings the family to the attention of the geneticist
is known as the consultand. His/her symbol will have an arrow pointing to it. If the
consultand has the genetic disorder, then he/she is a special type of consultand
called a proband. The proband has a shaded symbol with an arrow pointing to it.
Many genetic disorders result in death. Generally, deceased individuals are noted
on the pedigree with a diagonal line running through their symbol.
The individuals in the pedigree are all related to each other in some sort of
way. To determine the nature of how the individuals are related, lines are drawn
between the symbols. If there is a horizontal line drawn between the symbols, this
denotes a union (in common societal terms, a union is closest to a marriage), which
denotes a mating couple that can produce children. A vertical line down from the
line denoting a union represents children produced from the union. If there are
multiple children produced from that union we see a vertical line down from the
union line that branches to each of the individual children from that union.
Relationships between relatives are measured in degrees. First degree relatives are
considered immediate family members (parents siblings and children). In the
pedigrees we study, we study the relationships with respect to the proband. So, the
immediate family of the proband are first degree relatives. Second degree relatives
are grandparents, grandchildren, aunts, uncles, nephews, nieces and hal-sibs. Third
degree relatives are first cousins.
When working with pedigrees today, we will be studying the nature of how
pedigrees are put together, and we will study the mechanism of how a variety of
disorders are inherited. The four mechanisms of inheritance by which a disease can
be inherited is autosomal dominant, autosomal recessive, X-linked dominant and Xlinked recessive. Below are some important characteristics of each mechanism of
inheritance, and these characteristics will allow you to solve each pedigree.
Autosomal Dominant Inheritance:
1. An autosomal dominant disease phenotype will appear in both sexes with equal
frequency, and will be passed to each sex in the next generation with equal
frequency because it is not linked to any of the sex-chromosomes
2. Most likely, the disease phenotype will be present in each generation, and will not
skip generations because the affected individual needs only one allele that encodes
the disease phenotype
3. Affected individuals will also ALWAYS have an affected parent because he/she
must have received the allele from one of the parents
4. Parents who are unaffected will only have children who are also unaffected
5. You can also determine genotypes of each individual in the pedigree. For affected
individuals, if they give rise to unaffected offspring, then they are heterozygotes. If
they only give rise to affected offspring then they are homozygotes
Autosomal Recessive Inheritance:
1. An autosomal recessive disease phenotype will also appear in both sexes with
equal frequency.
2. Unlike an autosomal dominant disease, the phenotype for a disease transmitted in
an autosomal recessive fashion may not be present in all generations, it may skip a
generation.
3. It is common to see unaffected parent having offspring that are affected, i.e. the
skipping of generations This occurs when two heterozygote carriers mate to
produce offspring.
4. The unaffected parents (heterozygotes) who pass the alleles onto their offspring
are called carriers as they are asymptomatic
X-linked Recessive Inheritance:
1. More males than females must be affected
a. Males are hemizygous and only need one disease causing allele to have the
disease
b. Females need two disease causing alleles to have the disease
2. Affected sons are usually born to unaffected mothers
3. These unaffected mothers carrying the disease causing allele are known as
obligate carriers
4. The disease is never passed from father to son
5. All females who are affected MUST ALWAYS have an affected father
X-linked Dominant Inheritance:
1. For an X-linked dominant disease, both males and females will be affected
2. As well, since the disease will be inherited in a dominant fashion, we do not see
the disease usually skipping generations
3. Usually there will be at least one family member who has the disease in each
generation
4. In order to determine whether the disease you are studying is X-linked dominant,
look at affected individuals and their offspring
a. Affected fathers will pass the disease to their daughters only
b. Affected mothers will pass the disease onto ½ of their sons and ½ of their
daughters
Laboratory Procedures/Questions
Go to http://www.ucl.ac.uk/~ucbhjow/medicine/FHD/pedigree_exercise/index.html
This online tool allows for drawing and analysis of pedigrees. Do only exercises 1
and 2.
For Exercise 1
1. For the first question, read the description of the family in the paragraph above
the question. Below, pick the pedigree that best fits the description being asked by
the first question. Draw out the pedigree.
2. Read the second question, pls. pick the pedigree that best fits the description
given in this question. Please draw out the pedigree.
3. Read the third question, pls. attempt to draw the pedigree to the best of your
abilities.
For Exercise 2:
1. Look at the pedigree, pick the most likely mechanism of inheritance.
2. Read the question, and draw out the pedigree shown. Pick out the two individuals
in the pedigree the question is describing (i.e. the obligate carriers).
Now go to
http://www.sciencecourseware.org/blol/
Go to the biology online link on the left and click to register for the 1 day trial
Click on the pedigree exercise.
For each of the disease state the mechanism of inheritance, and explain why you
believe this is the case based on the data in the pedigree.
1. Disease 1:
Description:
Mechanism of Inheritance:
Rationale:
2. Disease 2:
Description:
Mechanism of Inheritance
Rationale:
3. Disease 3:
Description:
Mechanism of Inheritance:
Rationale:
4. Disease 4:
Description:
Mechanism of Inheritance:
Rationale:
5. Disease 5:
Description:
Mechanism of Inheritance:
Rationale:
6. Disease 6:
Description:
Mechanism of Inheritance:
Rationale: