[Lecturer] Hello and welcome to the third
and final lecture in Module 4.
In this lecture, we're going to discuss mosaicism
and how timing of when a non-disjunction event,
which could result in aneuploidy
or a chromosomal abnormality occurs,
how the timing of when that occurs can dramatically impact
the presentation of the disease
and whether or not a person will pass it on
to their offspring and many other implications
that might exist.
So just a quick review of what we've talked about so far.
Aneuploidy is having an improper number of chromosomes,
either too many or too few.
So that's the whole chromosome.
Chromosomal abnormalities are changes in the structure
of one or more chromosomes
with a segment being deleted, duplicated,
inverted, or translocated.
Any of these can cause significant disruptions
of the normal balance of gene expression in a cell.
Thus far, we have talked about these occurring in meiosis
during the formation of egg and sperm,
so it's the offspring that is affected.
But what if this happens in a somatic cell?
So what if this happens, for example,
in aneuploidy during mitosis,
or what if this chromosomal abnormality just happens
to randomly occur in a somatic cell?
Well, first we need to understand the idea of mosaicism.
So mosaicism is basically like a mosaic,
or you know, sort of like having patches
of one type versus another.
A good example of mosaicism that happens
that's actually very, very visual,
so that, and something you may have heard of before,
is in female cats that have a calico coloring.
So one of the genes that determines coat color in cats
is on the X chromosome.
Female cats who inherit an orange coat color gene
from one parent and a black coat color gene
from another parent will have patches of black and orange,
depending on which X chromosome was inactivated
in the skin cells in that area.
This makes the cat have mosaicism,
which is just essentially like patches of cells
that have one x inactivated and patches that have another.
So let's look at what I'm actually talking about here
with cats at least, and then we can extend this into humans.
In cats with orange and we're just really looking
at the orange and black coat colors.
There are other coat color genes,
and it becomes kind of complicated,
and they're on other chromosomes,
but let's just focus on the orange and black.
That's located on a gene on the X chromosome.
In males, as you remember, you know,
males only have one X chromosome.
Same thing is true in cats, by the way.
They, males have one x chromosome and one y chromosome.
So in males, if a male cat inherits from its,
it would inherit from its mother.
Think about that, right?
I mean, any male,
all males inherited their X chromosome from their mothers
because they inherited their Y chromosome
from their fathers.
So if their mother donated an X chromosome
with the orange coat color,
then the male cat will be all orange.
If they inherited a black coat color gene
from their mother, then the male cats will be all black.
In females, it's a little bit more complicated.
If they inherit both black color coats from both parents,
then they'll of course be fully black in coat color,
and if they inherit orange coat color from both parents,
they'll also be orange.
Now what this is showing is,
remember when I talked about X inactivation
in the previous lecture, why do we need X inactivation?
It's because we've adapted
to only have one active X chromosome
so that males that have the natural XY chromosome,
so just one x chromosome, will have the same level
of gene expression as from the X chromosome
as females who have two X chromosomes.
Because in females, there is an inactivation
of one of the two x chromosomes.
This actually occurs randomly,
and it occurs differently in different cells.
And as a result, you can start to see patches
of certain cells that will be expressing the gene
that was inherited from the mother
versus the one that was inherited from the father.
And you get these patches.
So in the case of a female calico cat,
which is inheriting an orange coat color
from one of its parents and a black coat color
from the other parent, in some cells
it will inactivate the X chromosome,
had the gene coding for an orange coat color.
And in some cells within the same individual,
it will actually inactivate the X chromosome
that has the black coat color gene on it.
As a result, you get cells, some cells, skin cells
that are expressing black coat color,
some that are expressing orange.
And so you get these different patches.
And it's the same thing in humans.
If we look at, for example,
let's say we're looking at a female, right?
How do we know this is a female?
I know they're not numbered, but you can kind of start
to tell these are chromosomes.
One, two, three, four, five.
Very much aligned like a typical karyotype.
And this is through chromosome 22.
And then this would be,
these would be the two X chromosomes.
If certain cells lose one of these X chromosomes,
this would be a monosomy.
Or you would say, for example, if this were the case
in all of the cells in this person's body,
this woman would have Turner syndrome
because she would be monosomic for the X chromosome.
However, in this particular case,
this individual lost one of her X chromosomes,
but only in a subset of her cells, not in all of them.
Started out as a fertilized egg
with the normal compliment of chromosomes,
so all 46 chromosomes,
but somewhere along the way, one of her cells lost one
of the X chromosomes, and it didn't die.
That cell continued to grow and divide.
And all of the cells that came from that original cell
that lost one of its X chromosomes contributed
to certain parts of her body.
And so, if you take a tissue sample, for example,
from this portion of her, you would see,
oh, well all of her chromosomes seem to be in order.
If, however, you were to take a another sample
and you could do a karyotype, you would see,
oh, well perhaps she has some,
oh, perhaps she has Turner syndrome.
So it can be kind of complicated for individuals
who have mosaicism.
You can also imagine that the implications
from the clinical perspective might be quite different
for someone with mosaic form of aneuploidy
versus someone who has complete aneuploidy.
And that would be that most likely mosaic individual
is going to have less severe symptoms
because they will have some of their cells,
some parts of their bodies will be made up of cells
that have the normal amount of chromosomes,
while other parts of their bodies
that came from a cell which lost or gained a chromosome
somewhere along the way would have the inappropriate number.
So there can be some compensation in the body
if some of the cells are normal.
So as I mentioned, this means
that aneuploidy is occurring from mitosis.
We were really focusing on meiosis aneuploidy,
so non-disjunction in meiosis,
which resulted in full aneuploidy of the offspring
of a person who had a non-disjunction event in meiosis.
But now let's talk about within an individual
who, say, the fertilized egg had all 46 chromosomes,
but at a later stage in development,
some stage in development,
one of their cells undergoing mitosis, say for example,
loses or gains a chromosome.
The result can affect any of the tissues
that those cells go on to produce.
Aneuploidy in mitosis affects only cells which come
from the original cell in which the error occurred.
This is not passed on to children if it does not occur
in a germline cell,
a cell which will become an egg or sperm cell.
So keep that in mind.
And for an individual who has a mosaic genetic disorder,
it is not necessarily something that will be passed on,
and that's something which can be checked
through cytogenetic testing to see if the person's egg
or sperm cells actually do contain
whatever the genetic abnormality is
that the person's concerned about passing on
to their children.
Sister chromatids do not separate properly,
leading to one daughter cell with 47 chromosomes
and one daughter cell with 45 chromosomes.
Most of the time these cells cannot survive
and initiate a process called apoptosis.
Apoptosis is essentially cell suicide.
So a cell recognizes in itself
that something has gone terribly wrong
and that if it continues its life,
it's going to somehow screw up something majorly
for the person.
As a result, cells are programmed
to kill themselves if they do detect a sufficient amount
of abnormalities within themselves.
This doesn't always work.
It's not always a hundred percent the case,
as we will talk about when we talk about cancer,
which is really just a disease of cells,
not of damaged cells not being able to kill themselves.
But most of the time,
cells will actually undergo apoptosis
if aneuploidy does occur in mitosis.
Early mitotic aneuploidy,
so in the first week of development,
can result in presentation of an aneuploidy syndrome.
And by that, I mean if this is happening early enough
so that say in the, you know,
8-16 cell stage of development,
eight or 16 cell stage of development,
if it happens in one of those cells at that point,
then all the cells and all of the tissues
and organs that result
from those early, early on developmental,
from those early developmental cells
will have this disorder.
So a greater percentage of the person's total body
and the cells in their body will have the disorder,
and as a result, there's a greater likelihood
that the symptoms will be more severe.
Mitotic aneuploidies in cells which do not undergo apoptosis
can lead to cancer formation.
Again, we'll talk more on this later.
So the timing of chromosomal abnormalities
really does matter.
Similar to aneuploidy, the earlier events
of chromosomal abnormalities, so happening in an early stage
of fetal development, will have greater impact on health
because it will be incorporated into more cells.
So let's say, for example,
a chromosomal abnormality happens down here.
So what we're showing here
is basically one cell becoming two, two becoming four,
four becoming eight, eight becoming 16,
and so on and so on and so on.
And this is how we go from one cell to 50 trillion cells.
So if a chromosomal abnormality
happens in, say, a stage in which,
you know, we've reached 25 trillion cells,
and it happens in just one of those cells,
it's unlikely to really cause a major problem
because that's not going to be contributing
to much by way of the total body's makeup.
However, if one of these happens,
if one of these abnormalities happens, let's say,
at this stage, let's say at the two cell stage,
then all of the cells that come from this cell
will also inherit that abnormality.
So all of these cells, all of these, all of these,
essentially half of the body will have
that particular abnormality.
So it really does matter.
The earlier that these abnormalities happen in a cell,
the earlier that these abnormalities happen
during development, the greater the negative impact
it will have on the individual who develops.
Germline versus somatic cell occurrence.
So chromosomal disorders, be it aneuploidy
or chromosomal abnormalities can occur in any cell.
If it occurs in a germline cell,
so a cell which will go on to become an egg or sperm,
it affects the individual's offspring
but not the individual, him or herself.
They're more of a carrier.
So what am I talking about?
Well, if, let's talk about the,
let's go back to the non-disjunction in meiosis.
So if, say, a woman is producing an egg,
so this is going through a process of meiosis,
and there's a non-disjunction event that occurs,
and it produces an egg
with two copies of, say, chromosome 21.
Well, she will not have Down syndrome,
the mother, the woman who's produced the cell
will not have Down syndrome, but her children,
but the child who would result from fertilization
of this egg would have Down syndrome.
Similarly, any kind of chromosomal abnormality
that might happen, if it doesn't happen in a cell
that will become an egg or sperm cell,
it will not get passed on to the child.
So only the events that happen in egg or sperm
will be passed on to future generations.
Otherwise, it just affects the individual
in his or her lifespan.
If it occurs in a germline cell,
it affects the individual's offspring
but not the individual, him or herself.
So they're really just a carrier for it.
If it occurs in a somatic cell and not a germline cell,
the individual will not pass that particular disorder on
to his or her children, but he or she may be symptomatic.
So what I mean by that is if, say,
a chromosomal abnormality, let's say a deletion
of a particular chromosome happens
within a person and leads to cancer for them,
deletion is not necessarily going to be passed on
to their children if it did not occur early enough
in development where it actually was passed on
to those germline cells.
Remember, germline cells are set very early in development.
So if the mutation,
if the, so the chromosomal abnormality happened
in a somatic cell, say, really any other cell in the body,
and those cells do not become germline cells, right?
So those are just somatic cells.
Then it does not get passed on.
It basically will affect that individual potentially,
but it will not be passed on to their children.
People who inherit a chromosomal disorder from a parent
will be both affected by any associated conditions
and can pass it on to their children.
That's because they started out from day one,
from cell one, with that mutation.
So every single cell in their body
will have that particular disorder
and will have that particular abnormality.
And as a result, that would include their germline cells
as well as their somatic cells.
So all of their egg and sperm cells
will also have this abnormality
as well as all cells in their body.
And so because all the cells in their body have it,
they will be affected by the disease,
but then they'll also be able
to pass it on to their children
because their germline cells were affected.
All right, let's do a quick summary here.
So timing matters.
And what I mean by that is the time
when a chromosomal abnormality happens, timing matters.
Aneuploidy or chromosomal abnormalities
occurring in somatic cells will only affect cells
which come from the cell in which the event occurred.
These are not passed on to future generations
unless they occur in a gamete precursor or germline cell.
Most somatic cells with mitotic aneuploidy
or chromosomal abnormalities will die
through a process called apoptosis,
and mitotic aneuploidy or chromosomal abnormalities,
which happen in early development, present a risk
of detrimental impact on the embryo's health.
So that'll wrap it up for module four.
There are some interesting stories
that I've posted in the required reading folder
that are basically, so these are real life stories
that are posted from interviews done
with patients or family members
who have chromosomal abnormalities or aneuploidy
and gives a patient-centered experience of what that's like.
So I'm asking you to read those.
There's an assignment associated with that.
And hopefully, it'll start to put this
in more of a personal and clinical perspective for you,
all that we've been talking about so far.
So what's in the next module?
I'm sure you're wondering.
So module five, we're going
to go over patterns of inheritance.
So here, we're going to start talking about terms
that you've probably heard before, like dominant,
recessive, autosomal, sex-linked,
all of these types of different genetic diseases.
So specific genetic diseases, how they're inherited,
and how you actually go from a genotype to a phenotype.
So we will talk about all of that in the next module.
Thanks so much.
And I look forward to reading your posts
on the discussion board.