In our final lecture on single gene inheritance, we’ll be looking at expansions and mitochondrial inheritance.
Now, what are expansions? I brought them up very briefly in an earlier lecture. Trinucleotide repeat
expansions are what we’re talking about. If you don’t recall anything about expansions previously,
you can probably get from the title trinucleotide, three nucleotides and repeat, they keep repeating
and they keep expanding. These are dynamic mutations. They change from generation to generation.
As it’s passed down from one parent to their offspring, the number of repeats almost generally will increase.
We don’t really notice it when it’s decreasing. They are expanding repeats. The repeats are normal
in the population, regular number. At a certain number, they become abnormal and result in some
phenotypic problems. Again, they’re expanding as they go from generation to generation. You can recall
very easily from the title exactly what’s going on because they’re named appropriately. There are two
main diseases that we’ll be considering: Huntington’s disease which is a polyglutamine disease,
meaning we get many more glutamine residues in a particular gene than we would like to have.
Then Fragile X, I brought that up when we were talking about X-linked disorders because indeed,
it is an X-linked disorder. Let’s take a look first at Huntington’s disease, a polyglutamine disease.
It’s an expanding repeat. It’s an expanding repeat of C, A, and G, so CAG, CAG, CAG. It’s normal to have
about 25 repeats of this in the Huntington gene which is on chromosome 4. It’s not a sex-linked disease.
This is an autosomally inherited disease. The CAG from uneven crossing over or from maybe translocations
but either way, the CAG repeat, replication causes these extra repeats. Once an individual has more than
40 repeats, we see expression of Huntington’s disease. What the repeats end up doing is having multiple
glutamines added to the chain. Those glutamines end up forming a dysfunctional Huntington protein.
We’ll talk a lot more about the manifestations of Huntington’s disease in the aging lectures
where we’ll look at disorders of aging. But for here, we’ll just look at this expanding CAG repeat causing
multiple glutamines. Now, anticipation is the concept of having the disease display progressively
earlier and earlier in the family line. The longer the repeat, the earlier the disease is expressed.
So, it is anticipated from generation to generation. We also note a paternal transmission bias.
If an individual has more than 25 but less than 40, we call this a premutation. That premutation is called
a premutation because it can continue to expand as it is passed down from generation to generation.
A paternal transmission bias means that it is transmitted and elongated more through the paternal line
than it is through the maternal line. A father that has a premutation could pass on an allele that would
become mutated in the next generation. Not that it couldn’t happen from a female parent but it is biased
towards the male parent having the premutation turn into a full-on mutation. Again, that’s when
it reaches about 40 different sequential CAG repeats. Too many glutamines causes dysfunctional protein.
Here is a pedigree showing Huntington’s disease. Below it, you can see a Southern blot analysis.
Recall that in Southern blotting, as we talked about in molecular genetics, involves moving DNA
through a gel and then making a radioactive print of that. The further through the gel that the fragments move,
the shorter the pieces because shorter things are going to go through faster. Here you can see
that the individual number 2 all the way over on the right in the first generation homozygous
has only one length fragment for the normal length of CAG repeats which is about 25. You can also see
that for individual 3. Now, you’ll see noted beneath each individual the number of repeats that they have.
For a moment, knowing what you know that the larger the repeat, the earlier the condition shows,
which individual in this pedigree is likely to display Huntington’s disease at an earlier age?
Okay, you’re right. The one with 103 below it, generation 2, individual number 5 is going to have
the earliest onset and perhaps the most severe symptoms of Huntington’s disease. That’s what we call
the age dependent penetrance. As note at the time of this pedigree, individual with 42 repeats at age 50
did not yet display Huntington’s but it’s expected because he has more than 40 that he will display
the symptoms of Huntington’s later in life. Take a look at this figure and think for a moment
what is it showing. It’s really a great figure because it summarizes everything that I’ve talked about
with the polyglutamine disease of Huntington’s. You can see on the X axis, we’re talking about the number of
CAG repeats and age and what’s going on in this blue area. Why don’t we see anything all the way over here
on the left side? We don’t see anything because we need to have 40 repeats. Once we have 40 repeats
or around 40, we may have expression. You know that the more repeats we have,
the earlier the age of expression. This graph does a really nice job of summarizing the concepts
that we’ve learned in Huntington’s disease. Good one to keep in mind.