Pedigree analysis

Pedigree analysis

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Pedigree analysis


A pedigree is a diagram of family relationships that uses symbols to represent people and
lines to represent genetic relationships. These diagrams make it easier to visualize
relationships within families, particularly large extended families. Pedigrees are often used
to determine the mode of inheritance (dominant, recessive, etc.) of genetic diseases.

If more than one individual in a family is afflicted with a disease, it is a clue that the
disease may be inherited. A doctor needs to look at the family history to determine
whether the disease is indeed inherited and, if it is, to establish the mode of inheritance.
This information can then be used to predict recurrence risk in future generations.

A basic method for determining the pattern of inheritance of any trait (which may be a
physical attribute like eye color or a serious disease like Marfan syndrome) is to look at its
occurrence in several individuals within a family, spanning as many generations as
possible. For a disease trait, a doctor has to examine existing family members to
determine who is affected and who is not. The same information may be difficult to obtain
about more distant relatives, and is often incomplete. In a pedigree, squares represent
males and circles represent females. Horizontal lines connecting a male and female
represent mating.
Vertical lines extending downward from a couple represent their children. Subsequent
generations are therefore written underneath the parental generations and the oldest
individuals are found at the top of the pedigree. If the purpose of a pedigree is to analyze
the pattern of inheritance of a particular trait, it is customary to shade in the symbol of all
individuals that possess this trait. Generations are numbered from the top of the pedigree
in uppercase. Roman numerals, I, II, III etc. Individuals in each generation are numbered
from the left in Arab numerals as subscripts, III1, III2, III3 etc.

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 Modes of inheritance
Most human genes are inherited in a Mendelian manner. It is usually unaware of the
existence unless a variant form is present in the population which causes an abnormal (or
at least different) phenotype. One can follow the inheritance of the abnormal phenotype
and deduce whether the variant allele is dominant or recessive.
Using genetic principles, the information presented in a pedigree can be analyzed to
determine whether a given physical trait is inherited or not and what the pattern of
inheritance is. In simple terms, traits can be either dominant or recessive. A dominant trait
is passed on to a son or daughter from only one parent. Characteristics of a dominant
pedigree are:

o Every affected individual has at least one affected parent;
o Affected individuals who mate with unaffected individuals have a 50% chance of
transmitting the trait to each child; and
o Two affected individuals may have unaffected children.

Recessive traits are passed on to children from both parents, although the parents may
seem perfectly "normal." Characteristics of recessive pedigrees are:
 An individual who is affected may have parents who are not affected;
 All the children of two affected individuals are affected; and
 In pedigrees involving rare traits, the unaffected parents of an affected individual
may be related to each other.

 Penetrance and expressivity
Penetrance is the probability that a disease will appear in an individual when a disease-
allele is present. For example, if all the individuals who have the disease causing allele for
a dominant disorder have the disease, the allele is said to have 100% penetrance. If only a
quarter of individuals carrying the disease-causing allele show symptoms of the disease,
the penetrance is 25%. Expressivity, on the other hand, refers to the range of symptoms
that are possible for a given disease. For example, an inherited disease like Marfan
syndrome can have either severe or mild symptoms, making it difficult to diagnose.
 Non-inherited traits
Not all diseases that occur in families are inherited. Other factors that can cause diseases
to cluster within a family are viral infections or exposure to disease causing agents (for
example, asbestos). The first clue that a disease is not inherited is that it does not show a
pattern of inheritance that is consistent with genetic principles (in other words, it does not
look anything like a dominant or recessive pedigree).

Autosomal dominant
A dominant condition is transmitted in unbroken descent from each generation to the next.
Most mating will be of the form M/m x m/m, i.e. heterozygote to homozygous recessive.
Therefore, it is expected that every child of such a mating to have a 50% chance of
receiving the mutant gene and thus of being affected. A typical pedigree might look like
this (Figure 3.2):

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Examples of autosomal dominant conditions include:
o Tuberous sclerosis,
o neurofibromatosis and many other cancer causing mutations such as
retinoblastoma

Autosomal recessive
A recessive trait will only manifest itself when homozygous. If it is a severe condition it will
be unlikely that homozygotes will live to reproduce and thus most occurrences of the
condition will be in mating between two heterozygotes (or carriers). An autosomal
recessive condition may be transmitted through a long line of carriers before, by ill chance
two carrier’s mate. Then there will be a ¼ chance that any child will be affected. The
pedigree will therefore often only have one 'sibship' with affected members.
























If the parents are related to each other, perhaps by being cousins, there is an increased
risk that any gene present in a child may have two alleles identical by descent. The degree
of risk that both alleles of a pair in a person are descended from the same recent common
ancestor is the degree of inbreeding of the person. Let us examine b) in the figure above.
Considering any child of a first cousin mating, one can trace through the pedigree the
chance that the other allele is the same by common descent.
Let us consider any child of generation IV, any gene which came from the father, III3 had a
half chance of having come from grandmother II2, a further half chance of being also
present in her sister, grandmother II4 a further half a chance of having been passed to
mother III4 and finally a half chance of being transmitted into the same child we started
from. A total risk of ½ x ½ x ½ x ½ = 1/16 .

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This figure, which can be thought of as either
 the chance that both maternal and paternal alleles at one locus are identical by
descent, or
 the proportion of all the individual's genes that are homozygous because of identity
by common descent, is known as the coefficient of inbreeding and is usually given
the symbol F.
Once phenotypic data is collected from several generations and the pedigree is drawn,
careful analysis will allow you to determine whether the trait is dominant or recessive. Here
are some rules to follow. For those traits exhibiting dominant gene action:
- affected individuals have at least one affected parent
- the phenotype generally appears every generation
- two unaffected parents only have unaffected offspring

The following is the pedigree of a trait contolled by dominant gene action. And for those
traits exhibiting recessive gene action:















- unaffected parents can have affected offspring
- affected progeny are both male and female
The following is the pedigree of a trait contolled by recessive gene action.

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Mitochondrial inheritance
Mitochondria are cellular organelles involved in energy production and conversion. They
have a small amount of their own mitochondrial DNA (mtDNA). Though it is a relatively
small portion of our total DNA, it is still subject to mutation and several diseases
associated with mutations in mtDNA have been found. The inheritance patterns of mtDNA
are unique. Mitochondrial DNA is inherited maternally.

Each person inherits the mtDNA of their mother, but none of their father’s. This is because
the relatively large ovum has many copies of mitochondrial DNA but the sperm has very
few and these are lost during fertilization. Due to this unique feature of mitochondrial DNA
inheritance, there are some constraints on the inheritance patterns of mitochondrial DNA
disorders. These include:
- All children of affected males will not inherit the disease.
- All children of affected females will inherit it.

An example of this type of disease is Leber’s optic atrophy, a progressive loss of vision in
the central visual field due to degeneration of the optic nerve. There are relatively few
human genetic diseases caused by mitochondrial mutations but, because of their maternal
transmission, they have a very distinctive pattern of inheritance. A mitochondrial
inheritance pedigree is that all the children of an affected female but none of the children
of an affected male will inherit the disease.

Uniparental disomy
Although it is not possible to make a viable human embryo with two complete haploid sets
of chromosomes from the same sex parent it is sometimes possible that both copies of a
single chromosome may be inherited from the same parent (along with no copies of the
corresponding chromosome from the other parent.) Rare cases of cystic fibrosis (a
common autosomal recessive disease) have occurred in which one parent was a
heterozygous carrier of the disease but the second parent had two wild type alleles. The
child had received two copies of the mutant chromosome 7 from the carrier parent and no
chromosome 7 from the unaffected parent.

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a-

b-

c
d

e