An autosomal dominant gene is one that occurs on
an autosomal (non-sex determining) chromosome. As it is dominant,
the phenotype it gives will be expressed even if the gene is
heterozygous. This contrasts with recessive genes, which need to
be homozygous to be expressed.
The chances of an autosomal dominant disorder being inherited are
50% if one parent is heterozygous for the mutant gene and the
other is homozygous for the normal, or 'wild-type', gene. This is
because the offspring will always inherit a normal gene from the
parent carrying the wild-type genes, and will have a 50% chance of
inheriting the mutant gene from the other parent. If the mutant
gene is inherited, the offspring will be heterozygous for the
mutant gene, and will suffer from the disorder. If the parent with
the disorder is homozygous for the gene, the offspring produced
from mating with an unaffected parent will always have the
disorder.
Autosomal dominant
inheritance would be much preferred to a recessive inheritance
because we will be able to eliminate those Dobermans that have the
gene from our breeding programs. Based on this, in just a
few generations, we could eradicate DCM. If it were a recessive it
would take many more generations.
Autosomal Dominant
Autosomal dominant
(AD) disorders are those in which Heterozygotes and homozygous
dominant individuals show the abnormal phenotype. One copy of the
mutant gene is sufficient for expression of the abnormal
phenotype. In fact, in many AD diseases the homozygous genotype
is incompatible with life. Some examples of AD disease include
familial hypercholesterolemia, Huntington’s disease,
achondroplasia, and Marfan’s.
Several distinct
characteristics of AD inheritance include:
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Every individual has
an affected parent (except in cases of new mutations or incomplete
penetrance).
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Males and females are
equally likely to inherit the allele and be affected. This is
because these are genes on autosomes, of which each male and
female has two copies. Sex-linked disorders show different
patterns in this respect since males are XY and females are XX.
This is discussed in the X-linked disorders lecture.
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Recurrence risk (the
probability that a genetic disorder that is present in a patient
will recur in another member of the family) for each child of an
affected parent is ½. For a dominant disorder, only one copy is
necessary for development of the disease. If one parent is a
heterozygote for a particular gene, their offspring will either
inherit the gene or they will not, with each outcome equally
likely.
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Normal siblings of
affected individuals do not pass the trait on to their offspring.
If an affected individual’s siblings are not affected, they do not
carry the mutation and cannot pass it on to their own offspring.
Structural
proteins are usually the defective gene product. Structural
proteins are disrupted to the extent of clinical disease when only
one copy of the gene is non-functional. If the proteins produced
by one mutant gene try to combine with the normal proteins, it can
lead to a disruption of structural organization and integrity,
which can manifest itself as clinical disease. This is in
contrast to autosomal recessive diseases, which usually involve
key enzymes in a biochemical pathway.
In the figure below, 2
normal copies of the gene yields a normal structure. 1 normal
gene plus 1 mutated gene leads to a disruption of structural
integrity.
The following pedigree
demonstrates characteristics of autosomal dominant inheritance.
In this pedigree,
every affected child has an affected parent. Males and females
are affected with equal likelihood. Normal siblings of affected
individuals have not passed the gene on to their offspring (e.g.
II-3). The recurrence risk for each child of an affected
individual is 1/2 (e.g. the offspring of II-1 and II-8). This
type of pedigree could be seen in a family with a disease such as
familial hypercholesterolemia.
Since many of these AD
disease are so deleterious, one would expect that over time they
would disappear from the population due to natural selection.
However, there are several phenomena that can lead to maintenance
of these alleles in the population.
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Variable expressivity: the variable severity of a genetic
trait. Different individuals with the same mutation will
develop different degrees of the disorder due to difference in
environment and the modifying effects of other genes. Because
of this, a mutation that leads to a relatively mild form of
the disease in one individual stands a good chance of being
passed on and maintained in the population. The same mutation
in another individual may lead to such a severe manifestation
that the affected individual is unable to propagate the
mutation to the next generation. This demonstrates very well
the fact that genetic disease results as combination of
genetic and environmental influences.
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Late
onset: when a disease has an onset later in life, affected
individuals may have passed the gene to their offspring before
the y even knew they carried it themselves. One example of
this is Huntington’s disease, a late onset neuro-degenerative
disorder. It is now possible to receive genetic testing for
this disorder, a practice that leads to many complex issues
for the family undergoing the testing.
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High
recurrent mutation rate: 85% of cases of achondroplasia, a
major cause of dwarfism, are the result of new mutations.
Some segments of the genome are subject to higher than normal
rates of mutation, which can lead to the maintenance of the
disease in the population even if both parents were normal.
This is particularly true of diseases that affect fertility.
If the disease is invariably lethal at a young age, before
reproduction is possible, the only source of the disease would
be new mutations.
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Incomplete penetrance: phenomena where a portion of
individuals with a disease-associated genotype do not develop
a disease. If only 30 people out of 50 who have a
disease-associated mutation actually develop the disease, it
is incompletely penetrant. A disease that is 75% penetrant is
one in which 75% of those who carry the disease-associated
mutation eventually develop the disease. The rest do not.
Do not confuse
incomplete penetrance with variable expressivity. Incomplete
penetrance is an all-or-none phenomenon—either they develop it or
they do not. Variable expressivity occurs when all develop the
disease in some manner but to varying degrees. These are only
associated with AD diseases.