Non-Mendelian Inheritance Patterns, by Dr. Bruce Korf. In collaboration with the University
of Alabama at Birmingham.
My name is Bruce Korf. I'm a Medical Geneticist at University of Alabama at Birmingham. This
lecture will focus on non-Mendelian inheritance patterns. This lecture will explain the following
ideas: sex-limited inheritance, epistasis, digenic inheritance, anticipation in the role
of triplet repeat expansion mutations, genomic imprinting, and mitochondrial inheritance.
In sex-limited expression, a phenotype is only seen either in males or females but not
in both. The example here is that of male pattern baldness, which is typically expressed
only in males. It is an autosomal dominant trait, but females have a low likelihood of
manifestation. In this case then, a female has transmitted the trait and could be said
to be non-penetrant having an affected father and an affected son. Other examples of sex-limited
expression would be hereditary breast and ovarian cancer, where obviously ovarian cancer
does not occur in men, and breast cancer only rarely does.
Epistasis involves the influence of one gene on the expression of another. The classic
example involves the ABO blood group system. This system is a two-allele system in which
individuals with the A allele produce an antigen on red blood cells called A, and those with
the B allele, an antigen called B. Heterozygotes, who have an A and a B allele will produce
both antigens. If you look at the pedigree above, you see a male with type A blood and
a partner with type O blood had a child with type AB. This would seem to be impossible,
because the mother does not have a B allele to transmit in this pedigree.
What actually is going on though is an example of an epistatic interaction. The enzymes that
are the product of the A or the B allele act on a substrate, the H substance, which is
a precursor either to A or B. H itself is the product of another enzymatic reaction
from a previous precursor. Individuals who have what is called the Bombay phenotype fail
to produce H because of a deficiency of the enzyme required to go from the precursor to
the H substance.
These individuals then fail to make either the A or the B antigen, but not because they
lack the A or the B enzyme, but rather because they lack the H substance. So one can presume
that the mother in this case has this phenotype due to mutation in an enzyme upstream of the
A or the B enzymes. In this case, therefore, the enzyme that would act to produce H substance
acts in an epistatic manner to produce a phenotype similar to deficiency of the A or B enzyme.
Digenic inheritance is a relatively recently discovered phenomenon in which heterozygosity
for two distinct genes can produce a phenotype that otherwise would require homozygosity
for one or the other gene. Consider this pedigree where there are two gene loci, and this individual
is heterozygous for a mutation in locus 1, and this individual heterozygous for a mutation
in locus 2. Notice that this child inherits the locus 1 and locus 2 mutations and is affected,
even though he is not homozygous for either one.
There are a number of disorders where this digenic inheritance pattern has been identified,
most notably retinitis pigmentosum. Neither allele, if heterozygous by itself, would be
sufficient to produce the phenotype. This tends to occur when the gene products interact
with one another and when a partial deficiency of one compounded with a partial deficiency
of another leads to inadequate function and, hence, a phenotype.
The phenomenon of anticipation is described as the increasing severity of a phenotype
from one generation to the next, and earlier and earlier age of onset. So in this pedigree,
a relatively mild individual has offspring who are slightly more severely affected. He,
in turn, has offspring who are a bit more severely affected, and finally, this individual
has a child who's quite severely affected.
Anticipation tends to occur in triplet repeat expansion disorders. These are conditions
in which a particular triplet of DNA bases is repeated multiple times normally, and where
expansion of that repeat underlines the pathology. This is a generic gene. It's not meant to
be any one particular gene. In one gene, a CGG repeat in the promoter region leads to
Fragile X syndrome, a form of X-linked intellectual disability. In another gene, a CAG repeat
within an exon, which encodes a polyglutamine repeat causes Huntington disease, and there
are various other genes associated with spinocerebellar ataxia that have a similar type of mutation.
In the condition myotonic dystrophy, a CTG repeat in the three prime untranslated region
leads to that condition. Friedreich ataxia is associated with a GAA repeat that occurs
within an intron. This diagram below shows a detail of what happens in myotonic dystrophy,
where there is normally a CTG repeat expanded multiple times, but significant expansion
of this CTG repeat leads to the condition myotonic dystrophy. The reason for anticipation
is that the longer the repeat; first of all, the earlier the onset of the condition, and
the more severe it is, and secondly, the longer the repeat, the more unstable it is with a
tendency to expand even further in the next generation.
The phenomenon of genomic imprinting implies differential expression of the maternal and
paternal alleles. Whether it's the mother's copy or the father's copy that is expressed
will be a characteristic of each specific imprinted locus. Most genes are not imprinted,
but a subset, the exact size of which is at present unknown, are subject to this phenomenon.
In this example, let's assume that it's the maternal copy that's expressed, so consider
this pedigree. This copy is expressed in this individual, which must be what he inherited
from his mother. This copy in this individual, which she must have inherited from her mother.
In the next generation, it's the green copy that's expressed in this individual, because
it's the one that he inherited from his mother. But now look at this lower generation. Father
passes the green copy to his daughter. It was expressed in him, but no longer is it
expressed in the daughter. Where she inherits the pink copy from her mother, which was not
expressed in her mother, but now is expressed in her, because she inherited it from her
mother.
The key point is that when germ cells are formed-- sperm or egg-- the imprint is completely
erased so that the maternal and paternal copies of the gene are not distinguishable in the
sperm or egg cells until they are mature, at which point if it's a sperm cell for this
particular gene, that gene will be turned off, and if it's an egg cell, that gene will
be turned on.
Here's an example of a condition, hereditary paraganglioma, that is subject to genomic
imprinting. It's an autosomal dominant, but notice that this affected woman passes the
gene to two offspring, and you know they must have inherited the gene, because his daughter
or her granddaughter are affected. But notice that neither of these individuals is affected,
and when she transmits it to a son, he is also not affected.
But finally, when he transmits it to a daughter, she is. In this case, when the father transmits
to a daughter, she's affected. It's not relevant here that only females are affected. What
is relevant is that the gene is only expressed in terms of a phenotype when it's inherited
from a male. This tells us that this gene must be active only in the male-inherited
copy, and if that copy carries a mutation, then that mutation will be seen phenotypically.
Finally, let's turn attention to maternal inheritance. This would be a prototypical
pedigree, where an affected female has transmitted the trait to all of her offspring, and males
transmit to none. Maternal inheritance is a characteristic due to the presence of the
mitochondrial genome. The mitochondrial genome consists of a 16.5 thousand base pair circular
double-stranded DNA molecule, present in multiple copies per mitochondrion, and encoding 13
subunits of mitochondrial proteins and a full set of transfer and ribosomal RNAs. It's important
to remember that the majority of mitochondrial proteins are encoded in the nucleus, not in
the mitochondria.
The reason for maternal inheritance is that the sperm mitochondria, which are present
proximal to the head attached to the tail, are shed at the time of fertilization, so
all of the mitochondria are maternally derived. Unlike the nuclear genome, where each gene
is replicated and faithfully transmitted to each daughter cell, mitochondrial DNA segregates
at random during mitosis or meiosis. And this in principle can lead to big discrepancies
in the proportion of mutant versus non-mutant mitochondria if there is a mixture in a given
cell. This is referred to as heteroplasmy, and it can cause very significant differences
in phenotype from one cell or tissue to another or from one member of a family to another.
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