[Instructor] Hello, and welcome
to the second lecture in Module 4,
called Chromosomal Abnormalities.
In this lecture we're going to talk
about chromosomal abnormalities.
And by that I mean changes in chromosome structure
that will affect gene expression
or can affect gene expression
for genes in the region of the chromosome
that has an abnormality.
This is different from aneuploidy in that aneuploidy
is the incorrect number of the copies of chromosomes
present in a cell.
Either an extra copy or one fewer copies
of an entire chromosome would be aneuploidy.
Chromosomal abnormalities will be looking
at a segment of a chromosome
as opposed to an entire chromosome.
So just one last quick review,
you saw this in the previous lecture as well.
Looking at a karyotype, this is a karyotype of a male
who has one X and one Y chromosome.
And just as a reminder,
there are a specific set of genes,
specific set of genes on each of these chromosomes,
one through 22, X and Y,
and each of these genes is located
in a specific location along its chromosome.
And what I mean by that is, say for example,
a gene related to eye color,
and let's say that gene happens to be on chromosome eight.
Well, it's on chromosome eight,
it will always be on chromosome eight.
And let's say it's on chromosome eight,
and it's always, let's say it's always located right here.
So you can think of it as an address.
So each gene has its specific address
where it lives on a chromosome,
and that gene is always in that particular location.
And if it is not in that location,
this can affect the gene expression.
And as you recall from the previous lecture,
any changes in gene expression
can have some significant clinical implications.
So let's dissect the anatomy of a chromosome here.
So a chromosome, and if you recall here,
this would be a chromosome which has been duplicated.
So there are two sister chromatids, one and two.
At either end of the chromosome
is a region called a telomere.
A telomere is just simply the end caps for chromatids.
When we look at a chromosome,
there's the portion of the chromosome
where the two sister chromatids come together
and are attached, and this is at the centromere.
Typically, it's around the center of the chromosome,
but in some of the shorter chromosomes,
it can actually be very close to the top of the chromosome.
This leaves two what are called arms for each chromatid.
And these are gonna be on either side of the centromere.
The short arm of the chromosome
is always going to be designated
as the p arm, or for petite.
The q arm is going to be the longer arm of the chromosome.
This is important to know
because it will help in defining that specific address
where a gene or a abnormality on a chromosome lies.
And remember, as I mentioned in the previous slide,
genes are always located on the same place
along the chromosome called the gene's locus.
So the locus is sort of like its specific address.
And an example of that would be the beta globin gene
is always located on chromosome 11 on the p arm.
Just wanted to give you a reminder
of the perspective of what a chromosome is.
As you recall, if you zoom into a chromosome,
you can actually see it's double-stranded DNA
wrapped around histones.
They're not showing histones in this particular picture,
but as you recall it, they wind around histones.
And as you zoom in further and further,
you see the double-stranded,
the double strands which are base paired together
along the nucleotide bases, C, T, A and G,
and they base pair together across the two strands.
All right, so there are some common designations
for locations that we'll use.
And you don't need to necessarily memorize all of these,
it's just more for a point of reference
so that you can have an understanding
when you read some of the shorthand designations
for particular chromosomal abnormalities
or even locations of normally functioning genes,
you can have an understanding of what they're talking about.
So if we look at, let's say this is, you know,
this is a chromatid from a chromosome.
Again, as I mentioned, you have the centromere,
which is that center point, which is the constricted part,
generally more towards the center of the chromosome,
the short arm, which would be the p arm,
the long arm, which is the q arm,
and then within that, you have different banding patterns
which appear when chromosomes are stained
with a particular dye called Giemsa.
And this is used by cytogeneticists
who will analyze chromosomes
and put together karyotypes to make diagnoses
of genetic conditions.
There are regular banding patterns
which appear on karyotypes of chromosomes,
which, and these are used
to define the physical location of a region on a chromosome.
If you remember from looking at those karyotypes,
let's go back for a moment,
you can see there are regions which are darker
and regions which are lighter.
These are the bands that we're referring to.
And these are consistent between individuals,
so they will always stain in this particular manner,
which is very helpful because it allows us
to have a way to standardize location along the chromosome.
Alright, so if we look at this,
the way that we're starting to designate locations
in this particular chromosome,
and for shorter chromosomes or longer chromosomes,
you may have more or fewer of these particular designations,
but this is generally the way it works.
It will be written with the chromosome number first.
So let's say this is chromosome 12,
it would be written as 12.
So let's say the region we're trying to get to
is the p22.1 band, so let's say we're trying
to describe this particular region here.
So what we would describe it as is it's on the p arm, right?
It's on the short arm relative to the centromere.
Within that, the region between regions one and two,
well, it's located in region two, so it would be p2.
Within region two, it's located in sub region two,
so it would be two two.
And then within that, it's located on band one.
So it would be identified as,
since it's chromosome 12, would be 12 p,
it's on the p arm, 2, 2.1.
This is the band location that you're looking for.
So if we do this again as the address,
it would be like giving your location as the United States,
which would be like chromosome 12.
So now you know which of the chromosomes it's on,
which of the countries you're in, United States.
Then you would say Vermont, which is the p arm,
so you know, within the United States, it's in Vermont.
So let's say this is, you know,
it's getting you closer and closer on the p arm.
Within Vermont, where are you?
You're located in Burlington.
That's like saying you're located in region two.
Within Burlington, where are you located?
You're located in sub region two.
So you know it's in this portion here somewhere.
Okay, we're getting closer and closer,
and now we know that okay, on sub region two,
which is like saying you're on Main Street,
where are you in 32 Main Street?
Well, you're in apartment four.
So we know now that not only are you on the p arm,
you're in region two, you're in sub region two,
you're in band one.
So this would be p22.1.
So that's like giving your address
and getting closer and closer and closer
into your actual location.
Chromosomal rearrangements, these actually can occur
as a result of damage to chromosomes and to DNA
that make up chromosomes
when the DNA has a double-strand break.
And what I mean by that is that the DNA is actually severed
between both strands with both strands of the DNA.
That can allow for some improper structures that result.
Similarly, improper DNA replication
or improper attachment to other chromosomes
can also result in these abnormalities.
Segments of chromosomes may break off and become lost.
This is called deletion.
They may attach to other chromosomes.
This is a translocation.
They could duplicate a specific region.
This is a duplication or flip around
and which is an inversion,
and we'll look at each of these separately.
These can each result in improper gene expression
of the genes on those segments and can lead to disease.
Let's start with deletion.
This is probably one of the easier ones to understand.
So if we're looking at this as like a chromatid, right,
one of a chromosome,
let's say this particular region here,
there's a double-strand break on this side
and there's a double-strand break on this side.
And the result is that, potentially, what can happen
is that this entire segment
between those two double-strand breaks gets lost
in a process called deletion,
and the chromosome will actually reattach itself
without that particular segment being there,
and it will try to continue on as as best as possible.
But many times this is quite problematic to the cell
because you're actually losing genetic material.
In duplication, a portion of the chromosome is duplicated
during an error in DNA replication.
A portion of the chromosome is duplicated
during an error in DNA replication,
resulting in genes in that region being duplicated
and likely misexpressed.
So what do we mean by that?
So if you have, let's say this particular segment,
and as part of DNA replication,
the DNA replication machinery accidentally duplicates this.
So it goes over it, and it makes this particular region,
but then it actually goes back over it,
makes it again, that's a problem.
Then you have twice as much
of this particular region on the chromosome.
And so you have these genes in this particular segment
replicated, represented in higher copy number.
And inversion can occur if there's, again,
a double-stranded break on either side of a segment,
and then when you could have it basically reattaching,
but instead of it just totally reattaching back
and forming the chromosome
before it was the DNA breakage occurred,
there's actually the piece of chromosome
flips around 180 degrees and reattaches.
But now the segment that was down here
closer to the end of the q arm is now up here
closer to the centromere.
There are two different kinds of inversions.
It's not really that important for you to know,
but basically there can be an inversion
just solely along the arm of a chromosome,
which would be paracentric,
which means not involving the centromere,
or a pericentric inversion,
which basically means an inversion between the p and q arms
of a segment that involves the centromere.
A translocation is interesting
because here you basically have a double-strand break
between two different chromosomes.
So these are not homologous chromosomes,
these are two different chromosomes,
like chromosome nine and three, let's say,
that both of those chromosomes
each had a double-strand break occur.
And now what happens is that instead of them reattaching
back to their original chromosome,
they actually get swapped around.
So now a piece of, say, chromosome nine gets stuck
under the bottom of chromosome three and vice versa.
And this can be a problem because the different chromosome
each kind of have their own signatures of gene regulation.
So this can definitely kind of mess things up
when we're talking about that delicate balance
of gene expression.
So let's talk about some of the nomenclature
to designate some of these different types
of chromosomal abnormalities.
So for a deletion, it would be noted as D-E-L or Del,
and duplication would be D-U-P or Dup,
along with the chromosome number
and location of the deletion or duplication
by its arm, p or q, and its band number.
So this would result in, let's look at a couple of examples.
I think it's easiest just to look at a few examples.
So if we're looking at something
that's designated Del 17 q11.2,
that would be a deletion on the q arm of chromosome 17
at band location 11.2.
So that would be region one, sub region one, band two
along chromosome 17.
Another example, Dup 11 q15 would be a duplication
on the q arm of chromosome 11 at location 15.
For translocations, these are noted as t for translocation,
and then in parentheses, the two chromosomes
in which the translocation has occurred between
and then following that in parentheses,
the locations for each of those.
So an example of a translocation of chromosome 12 p22
and chromosome 22 q21 will be denoted
as t for translocation, parentheses 12 and 22,
these are the two chromosomes
which have participated in this translocation.
Then you'd have q22, which would be the location
of the first chromosome designated here
that has been swapped with this location
of the second chromosome.
Chromosome 22 would be q21.
So it would be t(12;22)(q22;q21)
And I know it seems like a little bit like gibberish,
but hopefully it's really just to raise your awareness
of how to interpret these.
It's not as though I'm expecting you
to really memorize them,
just to functionally understand when you look at one,
when you look at a designation like this,
you can start to understand what they're referring to.
An inversion is noted as inv for inversion
and in parentheses the chromosome number,
and then following that, the, in parentheses,
the location of the inversion.
Example, an inversion on chromosome four
between p12 and q21, which would be a pericentric inversion
because it's crossing the p and q arm,
so therefore, it must be crossing a centromere.
This would be denoted as inv for inversion,
parentheses 4 because it's on chromosome four,
and then parentheses p12 q21
because it is an inversion between p12 and q21.
So let's look at some diagnosis.
And this can occur through cytogenetic analysis.
And a common approach for this
is called fluorescence in situ hybridization,
or shorthand is called FISH.
And this stains specific regions of chromosomes
with different colors for detection.
Blue dye stains all the chromosomes.
So all that you're seeing here that's blue,
that's just a general dye for any chromosomes.
The green dots in this particular FISH,
the green dots mark the ends of chromosome 22.
And the red dots mark the q11.2 region on chromosome 22.
And the reason why they would be looking for this
is a common chromosomal abnormality
is chromosome 22, a deletion of the q11.2 band.
And here you can actually see a patient
where that's the case.
So what we're looking at is this particular chromosome
and this chromosome are both chromosome 22,
and we know that because they each have the green dots,
and the green dots represent
basically anywhere on chromosome 22.
So it represents the end of chromosome 22.
So we know these are both chromosome 22,
and then the red or this pinkish color
is going to be where the q11.2 band would be.
So you can see it just fine on this chromosome 22,
but on this chromosome 22, there's no red dot.
And that basically is telling us
that this patient has a deletion of the q11.2,
and this person would have a diagnosis
of the 22 q11.2 deletion syndrome.
Here's another example of a cytogenetic analysis
and being able to diagnose another chromosomal abnormality.
In this case, it's a translocation.
This happens more so in diagnosis of tumors,
so might happen specifically in certain cells in the body
in which a cancer will develop
as opposed to it happening from birth.
So each chromosome in what we're looking at here,
this is a little bit different,
each chromosome is stained with a different color
to make it easy to see translocation,
so a piece of one chromosome
being stuck on another chromosome and vice versa.
In this case, the end of q arm of chromosome nine
is translocated with the end of the q arm of chromosome 22.
This resulted in a patient developing lymphoma.
So here you can see this chromosome nine
should be this darker red color.
And chromosome 22 is this lighter pink color.
And what you can see is that there's a little piece
of pink chromosome on the end of chromosome nine
and that the chunk of chromosome nine that's missing
is actually now on chromosome 22 and vice versa.
So here we have a translocation.
All right, so let's switch gears just for a moment here.
And I want to mention the importance
of a particular genetic phenomenon that occurs.
And the reason being it can actually significantly influence
the outcome of patients, depending upon the parent
who contributed one of these types
of chromosomal abnormalities.
This is called imprinting, imprinting.
Imprinted genes are genes expressed
only from one of the two homologous chromosomes,
either the maternal or paternal.
Only a few hundred of our 25,000 genes are imprinted.
The parental copy that is silenced
is methylated in the fertilized egg
and remains methylated and shut off forever.
So what do we mean by this?
Basically what we're saying is that in certain genes,
only, let's say the paternal copy is ever expressed,
and the maternal copy is permanently shut off,
and in other genes, only the maternal copy is ever expressed
and the paternal copy is shut off.
So only the copy of the gene
that you got from your mom might be expressed,
or the copy that you got from your dad might be expressed,
and the other one would be shut off by being methylated.
Most imprinted genes are related to growth and metabolism.
And why would that be?
Well, it's actually
kind of an interesting evolutionary story.
It's part of the battle of the sexes for maternal resources
for the man's baby.
So let's think about this for a minute.
Paternal imprinted genes, genes that are only expressed
from the copy received from the father,
generally promote big babies, big baby.
So why would the father wanna have a big baby?
Well, in part it's because he wants to make sure
his offspring have all of the resources of the mother.
And the mother, on the other hand, wants to balance this.
So maternal imprinted genes,
genes only expressed from the copy received from the mother,
generally promote normal sized babies.
Why would she want to have a normal sized baby?
Well, in part because it conveys less harm to the mother
to have a normal sized baby,
and it also allows her to provide her resources
to her other children instead of just the one child
from this particular father.
So the father is really trying to promote the passing on
of his genes ahead of others
because, and in doing that,
he's doing that, basically, by trying to ensure
his baby's going to be the biggest and the strongest.
So we have, as a result of this,
this crazy battle of the sexes has been waged
in species long before there were actually humans,
that as a result of this, we have a subset of genes,
again, not all of them, not by long shot,
only a few hundred over 25,000 genes
are regulated in this way,
that only one copy, either the mother's copy
or the father's copy, depending on the gene,
would be expressed and the other one would be shut off.
So why do we care about this?
Basically, there can be differences in the outcome,
depending upon whether the chromosomal abnormality
was inherited from the mother or the father.
And let's look an example of this.
We'll take a peek at a couple
of different chromosomal abnormalities here.
And the first couple we'll look at
actually involve regions of a chromosome
which contain imprinted genes,
and as a result, it matters whether the, as a result,
the actual symptoms related to the disorder
are very different
depending upon whether they're inherited
from the mother or the father.
And they're so different
that they're actually called two different names
for the different syndromes,
the first being Angelman syndrome.
This is a deletion of chromosome 15 on the q arm in band 12,
and Angelman syndrome only happens,
Angelman syndrome only happens if this deletion
was inherited from the mother.
It occurs in one in 12,000 to 20,000 live births,
and it primarily affects the nervous system
with characteristic features of delayed development,
intellectual disability,
severe speech impairment and ataxia.
Most affected children also have epilepsy and microcephaly.
Delayed development becomes noticeable
by the age of six to 12 months.
And other common signs and symptoms
usually appear in early childhood.
Children typically have a happy excitable demeanor
with frequent smiling laughter and hand flapping movements.
It's also associated with hyperactivity,
a short attention span and a fascination with water.
Most affected children also have difficulty sleeping
and need less sleep than usual.
Here are a few pictures of a couple of individuals
with Angelman syndrome.
So remember, this is a deletion
in a portion of chromosome 15
if it was inherited from the mother.
If, on the other hand, this very same deletion
was inherited from the father, from the father,
it will result in a child having Prader-Willi syndrome.
This occurs in about one to 10,000 to 30,000 live births,
and in infancy, it's characterized
by hypotonia, feeding difficulties,
poor growth and delayed development.
Beginning in childhood, affected individuals
develop an insatiable appetite
which leads to chronic overeating and obesity.
Some also develop type 2 diabetes as a result.
Associated with mild to moderate intellectual impairment
and learning disabilities, behavioral problems are common,
including temper outbursts, stubbornness
and compulsive behavior such as picking at the skin.
Additional features of this condition
include distinctive facial features such as narrow forehead,
almond-shaped eyes and a triangular mouth,
short stature and small hands and feet.
Both affected males and females
have underdeveloped genitals.
Puberty is delayed or incomplete,
and most affected individuals are infertile.
So remember, there are two different syndromes
that can come from the very same deletion.
It just depends upon whether it was inherited
from mom or from dad.
So you can have Angelman syndrome
in males and females, right,
but it was just in Angelman syndrome
the deletion was inherited from the mom's copy.
And in Prader-Willi syndrome, the very same deletion
was inherited from the father,
but it gives very different clinical manifestations.
And so imprinting can have a big impact
on the clinical manifestations of a chromosomal abnormality.
This is the 22q11.2 deletion syndrome
that I mentioned and showed you the fluorescence
and C2 hybridization for, with the, you know,
the green dots and the red dots.
This is also commonly called VCFS
or sometimes called DiGeorge syndrome.
There's actually a number of different names
for the very same condition.
It's a, again, a deletion within chromosome 22
of the q11 portion.
It occurs in about one in 4,000 live births,
and the features vary widely.
Common signs include heart abnormalities
that are often present from birth, cleft palate
and distinctive facial features.
You can sort of see between these two individuals
who have 22q11 deletion syndrome,
you can start to see some similarities
in slightly wider set eyes, similar nose and mouth shape
and smaller and low-set ears.
It often causes recurrent infections
caused by problems with the immune system,
and affected individuals may also have breathing problems,
kidney abnormalities, low levels of calcium in the blood,
thrombocytopenia, significant feeding difficulties,
gastrointestinal problems and hearing loss.
Children may have developmental delays
including delayed growth and speech development
and learning disabilities.
And later in life, they're at increased risk
of developing mental illness such as schizophrenia,
depression, anxiety and bipolar disorder.
Beckwith Wiedemann syndrome is a duplication
in chromosome 11 on the q15 band.
And this only comes from the paternal inheritance,
so only if the individual inherited this from their father.
Occurs in one in 12,000 live births,
and it results in an overgrowth syndrome,
with macrosomia and continued growth
at an unusual rate during childhood.
Growth slows by age eight,
and adults with this condition are not unusually tall.
May be born with an opening in the wall of the abdomen
that allows the abdominal organs
to protrude through the navel.
Most infants have an abnormally large tongue,
abnormally large abdominal organs,
creases or pits in the skin near the ears,
hypoglycemia and kidney abnormalities.
Increased risk of developing several types of cancerous
and non-cancerous tumors,
and this is, again, related to the overgrowth condition.
Tumors develop in about 10% of people with this condition
and almost always appear in childhood.
About one in five infants dies early in life.
So why this, I think this is a good example
of that battle of the sexes that I mentioned,
with imprinting being related
primarily to genes which regulate growth.
So here, this is inherited from the father
if there's a duplication of this particular region
of the chromosome from the father.
Basically, this is what would happen
if you didn't have the female balance
to the male contribution.
Male contributions being,
"I want a really, I want a big baby."
And the female saying, "Well, we need
to dial that back a little bit."
Unfortunately, if there is an abnormality,
say a duplication in the father's copy,
then the genes that he's contributed
will be overexpressed
relative to the maternally contributed genes
and will result in overgrowth conditions
such as Beckwith-Wiedemann syndrome.
So what about the risks of chromosomal abnormalities?
Well, these are very similar
to the risks associated with aneuploidy.
Advanced maternal age is a significant risk,
especially over the age of 45.
And it's very similar to what we talked about
before with aneuploidy.
It's just an accumulation of damage
to the cells over time
and specifically damage to the DNA,
which can result in increased breakage.
Similarly, exposure to toxins
and carcinogens prior to conception can lead to DNA breakage
in either sperm or egg.
Previous chromosomal abnormality, birth
or spontaneous abortions may indicate
a parent has chromosomal abnormality in the germline,
so in cells which are precursors to egg and sperm.
So, in basically all of their egg
or sperm that they produce,
this chromosomal abnormality may exist.
So let's do a quick summary here.
Chromosomes must have their genes in the right locations
and right numbers for proper gene expression.
I keep hammering you over the head with this,
and I apologize, but it's actually very, very important
that you understand this.
It's not even that there's necessarily a specific problem
in the sequence of the genes.
It's just that there are too many or too few of them
that can result in significant health problems.
DNA damage can result in chromosomes with deletions,
duplications, inversions or translocations,
all of which can lead to health issues.
Certain genes are only expressed from the maternal
or paternal chromosomes,
and these are called imprinted genes.
So outcomes may vary with the same chromosomal abnormality,
depending on whether it was inherited
from the mother or father.
Think of the Angelman syndrome and Prader-Willi syndrome,
same chromosomal abnormality, different outcomes
depending on whether it was inherited from mom or dad.
Chromosomal abnormalities generally result
in a wide range of symptoms,
and the risks for chromosomal abnormalities
are similar to risks for aneuploidy.
All right, so what's next in this module?
We'll finish it off with a rather brief discussion
on the concept of mosaicism.
So I will talk with you in the next lecture.
I look forward to hearing your thoughts
and any comments that you might have about this lecture
or anything else in this module.
I will talk with you soon.