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[Lecturer] Hello and welcome to the third

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and final lecture in Module 4.

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In this lecture, we're
going to discuss mosaicism

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and how timing of when
a non-disjunction event,

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which could result in aneuploidy

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or a chromosomal abnormality occurs,

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how the timing of when that
occurs can dramatically impact

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the presentation of the disease

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and whether or not a
person will pass it on

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to their offspring and
many other implications

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that might exist.

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So just a quick review of what
we've talked about so far.

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Aneuploidy is having an
improper number of chromosomes,

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either too many or too few.

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So that's the whole chromosome.

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Chromosomal abnormalities
are changes in the structure

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of one or more chromosomes

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with a segment being deleted, duplicated,

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inverted, or translocated.

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Any of these can cause
significant disruptions

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of the normal balance of
gene expression in a cell.

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Thus far, we have talked about
these occurring in meiosis

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during the formation of egg and sperm,

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so it's the offspring that is affected.

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But what if this happens
in a somatic cell?

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So what if this happens, for example,

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in aneuploidy during mitosis,

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or what if this chromosomal
abnormality just happens

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to randomly occur in a somatic cell?

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Well, first we need to
understand the idea of mosaicism.

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So mosaicism is basically like a mosaic,

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or you know, sort of like having patches

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of one type versus another.

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A good example of mosaicism that happens

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that's actually very, very visual,

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so that, and something you
may have heard of before,

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is in female cats that
have a calico coloring.

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So one of the genes that
determines coat color in cats

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is on the X chromosome.

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Female cats who inherit
an orange coat color gene

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from one parent and a
black coat color gene

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from another parent will have
patches of black and orange,

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depending on which X
chromosome was inactivated

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in the skin cells in that area.

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This makes the cat have mosaicism,

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which is just essentially
like patches of cells

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that have one x inactivated
and patches that have another.

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So let's look at what I'm
actually talking about here

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with cats at least, and then
we can extend this into humans.

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In cats with orange and
we're just really looking

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at the orange and black coat colors.

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There are other coat color genes,

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and it becomes kind of complicated,

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and they're on other chromosomes,

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but let's just focus on
the orange and black.

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That's located on a gene
on the X chromosome.

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In males, as you remember, you know,

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males only have one X chromosome.

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Same thing is true in cats, by the way.

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They, males have one x
chromosome and one y chromosome.

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So in males, if a male
cat inherits from its,

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it would inherit from its mother.

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Think about that, right?

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I mean, any male,

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all males inherited their X
chromosome from their mothers

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because they inherited their Y chromosome

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from their fathers.

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So if their mother donated an X chromosome

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with the orange coat color,

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then the male cat will be all orange.

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If they inherited a black coat color gene

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from their mother, then the
male cats will be all black.

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In females, it's a little
bit more complicated.

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If they inherit both black
color coats from both parents,

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then they'll of course be
fully black in coat color,

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and if they inherit orange
coat color from both parents,

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they'll also be orange.

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Now what this is showing is,

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remember when I talked
about X inactivation

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in the previous lecture, why
do we need X inactivation?

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It's because we've adapted

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to only have one active X chromosome

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so that males that have
the natural XY chromosome,

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so just one x chromosome,
will have the same level

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of gene expression as
from the X chromosome

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as females who have two X chromosomes.

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Because in females,
there is an inactivation

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of one of the two x chromosomes.

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This actually occurs randomly,

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and it occurs differently
in different cells.

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And as a result, you
can start to see patches

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of certain cells that will
be expressing the gene

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that was inherited from the mother

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versus the one that was
inherited from the father.

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And you get these patches.

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So in the case of a female calico cat,

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which is inheriting an orange coat color

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from one of its parents
and a black coat color

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from the other parent, in some cells

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it will inactivate the X chromosome,

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had the gene coding for
an orange coat color.

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And in some cells within
the same individual,

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it will actually
inactivate the X chromosome

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that has the black coat color gene on it.

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As a result, you get cells,
some cells, skin cells

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that are expressing black coat color,

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some that are expressing orange.

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And so you get these different patches.

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And it's the same thing in humans.

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If we look at, for example,

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let's say we're looking
at a female, right?

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How do we know this is a female?

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I know they're not numbered,
but you can kind of start

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to tell these are chromosomes.

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One, two, three, four, five.

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Very much aligned like
a typical karyotype.

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And this is through chromosome 22.

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And then this would be,

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these would be the two X chromosomes.

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If certain cells lose one
of these X chromosomes,

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this would be a monosomy.

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Or you would say, for
example, if this were the case

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in all of the cells in this person's body,

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this woman would have Turner syndrome

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because she would be monosomic
for the X chromosome.

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However, in this particular case,

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this individual lost one
of her X chromosomes,

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but only in a subset of her
cells, not in all of them.

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Started out as a fertilized egg

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with the normal compliment of chromosomes,

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so all 46 chromosomes,

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but somewhere along the way,
one of her cells lost one

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of the X chromosomes, and it didn't die.

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That cell continued to grow and divide.

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And all of the cells that
came from that original cell

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that lost one of its X
chromosomes contributed

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to certain parts of her body.

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And so, if you take a
tissue sample, for example,

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from this portion of her, you would see,

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oh, well all of her chromosomes
seem to be in order.

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If, however, you were
to take a another sample

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and you could do a
karyotype, you would see,

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oh, well perhaps she has some,

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oh, perhaps she has Turner syndrome.

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So it can be kind of
complicated for individuals

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who have mosaicism.

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You can also imagine that the implications

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from the clinical perspective
might be quite different

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for someone with mosaic form of aneuploidy

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versus someone who has
complete aneuploidy.

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And that would be that most
likely mosaic individual

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is going to have less severe symptoms

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because they will have
some of their cells,

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some parts of their bodies
will be made up of cells

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that have the normal
amount of chromosomes,

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while other parts of their bodies

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that came from a cell which
lost or gained a chromosome

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somewhere along the way would
have the inappropriate number.

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So there can be some
compensation in the body

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if some of the cells are normal.

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So as I mentioned, this means

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that aneuploidy is occurring from mitosis.

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We were really focusing
on meiosis aneuploidy,

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so non-disjunction in meiosis,

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which resulted in full
aneuploidy of the offspring

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of a person who had a
non-disjunction event in meiosis.

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But now let's talk about
within an individual

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who, say, the fertilized
egg had all 46 chromosomes,

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but at a later stage in development,

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some stage in development,

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one of their cells undergoing
mitosis, say for example,

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loses or gains a chromosome.

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The result can affect any of the tissues

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that those cells go on to produce.

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Aneuploidy in mitosis
affects only cells which come

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from the original cell in
which the error occurred.

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This is not passed on to
children if it does not occur

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in a germline cell,

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a cell which will become
an egg or sperm cell.

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So keep that in mind.

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And for an individual who has
a mosaic genetic disorder,

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it is not necessarily something
that will be passed on,

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and that's something which can be checked

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through cytogenetic testing
to see if the person's egg

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or sperm cells actually do contain

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whatever the genetic abnormality is

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that the person's
concerned about passing on

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to their children.

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Sister chromatids do
not separate properly,

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leading to one daughter
cell with 47 chromosomes

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and one daughter cell with 45 chromosomes.

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Most of the time these
cells cannot survive

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and initiate a process called apoptosis.

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Apoptosis is essentially cell suicide.

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So a cell recognizes in itself

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that something has gone terribly wrong

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and that if it continues its life,

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it's going to somehow
screw up something majorly

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for the person.

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As a result, cells are programmed

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to kill themselves if they
do detect a sufficient amount

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of abnormalities within themselves.

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This doesn't always work.

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It's not always a
hundred percent the case,

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as we will talk about
when we talk about cancer,

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which is really just a disease of cells,

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not of damaged cells not
being able to kill themselves.

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But most of the time,

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cells will actually undergo apoptosis

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if aneuploidy does occur in mitosis.

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Early mitotic aneuploidy,

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so in the first week of development,

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can result in presentation
of an aneuploidy syndrome.

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And by that, I mean if this
is happening early enough

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so that say in the, you know,

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8-16 cell stage of development,

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eight or 16 cell stage of development,

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if it happens in one of
those cells at that point,

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then all the cells and all of the tissues

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and organs that result

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from those early, early on developmental,

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from those early developmental cells

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will have this disorder.

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So a greater percentage
of the person's total body

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and the cells in their body
will have the disorder,

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and as a result, there's
a greater likelihood

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that the symptoms will be more severe.

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Mitotic aneuploidies in cells
which do not undergo apoptosis

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can lead to cancer formation.

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Again, we'll talk more on this later.

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So the timing of chromosomal abnormalities

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really does matter.

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Similar to aneuploidy, the earlier events

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of chromosomal abnormalities,
so happening in an early stage

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of fetal development, will
have greater impact on health

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because it will be
incorporated into more cells.

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So let's say, for example,

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a chromosomal abnormality
happens down here.

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So what we're showing here

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is basically one cell becoming
two, two becoming four,

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four becoming eight, eight becoming 16,

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and so on and so on and so on.

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And this is how we go from
one cell to 50 trillion cells.

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So if a chromosomal abnormality

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happens in, say, a stage in which,

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you know, we've reached 25 trillion cells,

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and it happens in just one of those cells,

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it's unlikely to really
cause a major problem

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because that's not
going to be contributing

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to much by way of the total body's makeup.

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However, if one of these happens,

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if one of these abnormalities
happens, let's say,

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at this stage, let's say
at the two cell stage,

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then all of the cells
that come from this cell

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will also inherit that abnormality.

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So all of these cells, all
of these, all of these,

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essentially half of the body will have

258
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that particular abnormality.

259
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So it really does matter.

260
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The earlier that these
abnormalities happen in a cell,

261
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the earlier that these
abnormalities happen

262
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during development, the
greater the negative impact

263
00:11:40,860 --> 00:11:44,463
it will have on the
individual who develops.

264
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Germline versus somatic cell occurrence.

265
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So chromosomal disorders, be it aneuploidy

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or chromosomal abnormalities
can occur in any cell.

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If it occurs in a germline cell,

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so a cell which will go on
to become an egg or sperm,

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it affects the individual's offspring

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but not the individual, him or herself.

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They're more of a carrier.

272
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So what am I talking about?

273
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Well, if, let's talk about the,

274
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let's go back to the
non-disjunction in meiosis.

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So if, say, a woman is producing an egg,

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so this is going through
a process of meiosis,

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and there's a non-disjunction
event that occurs,

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and it produces an egg

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with two copies of, say, chromosome 21.

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Well, she will not have Down syndrome,

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the mother, the woman
who's produced the cell

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00:12:33,270 --> 00:12:36,016
will not have Down
syndrome, but her children,

283
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but the child who would
result from fertilization

284
00:12:39,390 --> 00:12:41,610
of this egg would have Down syndrome.

285
00:12:41,610 --> 00:12:44,130
Similarly, any kind of
chromosomal abnormality

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00:12:44,130 --> 00:12:47,910
that might happen, if it
doesn't happen in a cell

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that will become an egg or sperm cell,

288
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it will not get passed on to the child.

289
00:12:53,370 --> 00:12:56,790
So only the events that
happen in egg or sperm

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00:12:56,790 --> 00:12:58,680
will be passed on to future generations.

291
00:12:58,680 --> 00:13:00,780
Otherwise, it just affects the individual

292
00:13:00,780 --> 00:13:02,310
in his or her lifespan.

293
00:13:02,310 --> 00:13:04,380
If it occurs in a germline cell,

294
00:13:04,380 --> 00:13:06,480
it affects the individual's offspring

295
00:13:06,480 --> 00:13:08,190
but not the individual, him or herself.

296
00:13:08,190 --> 00:13:10,560
So they're really just a carrier for it.

297
00:13:10,560 --> 00:13:13,590
If it occurs in a somatic
cell and not a germline cell,

298
00:13:13,590 --> 00:13:16,530
the individual will not pass
that particular disorder on

299
00:13:16,530 --> 00:13:20,400
to his or her children, but
he or she may be symptomatic.

300
00:13:20,400 --> 00:13:22,740
So what I mean by that is if, say,

301
00:13:22,740 --> 00:13:25,047
a chromosomal abnormality,
let's say a deletion

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00:13:25,047 --> 00:13:27,660
of a particular chromosome happens

303
00:13:27,660 --> 00:13:32,640
within a person and
leads to cancer for them,

304
00:13:32,640 --> 00:13:35,867
deletion is not necessarily
going to be passed on

305
00:13:35,867 --> 00:13:39,420
to their children if it
did not occur early enough

306
00:13:39,420 --> 00:13:41,880
in development where it
actually was passed on

307
00:13:41,880 --> 00:13:43,170
to those germline cells.

308
00:13:43,170 --> 00:13:46,470
Remember, germline cells are
set very early in development.

309
00:13:46,470 --> 00:13:48,330
So if the mutation,

310
00:13:48,330 --> 00:13:51,480
if the, so the chromosomal
abnormality happened

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00:13:51,480 --> 00:13:55,590
in a somatic cell, say, really
any other cell in the body,

312
00:13:55,590 --> 00:13:58,620
and those cells do not
become germline cells, right?

313
00:13:58,620 --> 00:14:00,600
So those are just somatic cells.

314
00:14:00,600 --> 00:14:02,370
Then it does not get passed on.

315
00:14:02,370 --> 00:14:04,830
It basically will affect
that individual potentially,

316
00:14:04,830 --> 00:14:07,323
but it will not be passed
on to their children.

317
00:14:08,520 --> 00:14:11,730
People who inherit a chromosomal
disorder from a parent

318
00:14:11,730 --> 00:14:14,730
will be both affected by
any associated conditions

319
00:14:14,730 --> 00:14:16,920
and can pass it on to their children.

320
00:14:16,920 --> 00:14:19,290
That's because they
started out from day one,

321
00:14:19,290 --> 00:14:21,840
from cell one, with that mutation.

322
00:14:21,840 --> 00:14:23,910
So every single cell in their body

323
00:14:23,910 --> 00:14:26,816
will have that particular disorder

324
00:14:26,816 --> 00:14:30,090
and will have that particular abnormality.

325
00:14:30,090 --> 00:14:33,930
And as a result, that would
include their germline cells

326
00:14:33,930 --> 00:14:35,280
as well as their somatic cells.

327
00:14:35,280 --> 00:14:36,960
So all of their egg and sperm cells

328
00:14:36,960 --> 00:14:39,690
will also have this abnormality

329
00:14:39,690 --> 00:14:41,130
as well as all cells in their body.

330
00:14:41,130 --> 00:14:43,320
And so because all the
cells in their body have it,

331
00:14:43,320 --> 00:14:45,750
they will be affected by the disease,

332
00:14:45,750 --> 00:14:46,950
but then they'll also be able

333
00:14:46,950 --> 00:14:48,390
to pass it on to their children

334
00:14:48,390 --> 00:14:50,540
because their germline
cells were affected.

335
00:14:52,020 --> 00:14:53,820
All right, let's do a quick summary here.

336
00:14:53,820 --> 00:14:55,440
So timing matters.

337
00:14:55,440 --> 00:14:56,875
And what I mean by that is the time

338
00:14:56,875 --> 00:15:01,590
when a chromosomal abnormality
happens, timing matters.

339
00:15:01,590 --> 00:15:03,780
Aneuploidy or chromosomal abnormalities

340
00:15:03,780 --> 00:15:06,150
occurring in somatic cells
will only affect cells

341
00:15:06,150 --> 00:15:09,720
which come from the cell in
which the event occurred.

342
00:15:09,720 --> 00:15:12,240
These are not passed on
to future generations

343
00:15:12,240 --> 00:15:16,470
unless they occur in a gamete
precursor or germline cell.

344
00:15:16,470 --> 00:15:19,320
Most somatic cells with mitotic aneuploidy

345
00:15:19,320 --> 00:15:21,240
or chromosomal abnormalities will die

346
00:15:21,240 --> 00:15:23,730
through a process called apoptosis,

347
00:15:23,730 --> 00:15:26,640
and mitotic aneuploidy or
chromosomal abnormalities,

348
00:15:26,640 --> 00:15:29,130
which happen in early
development, present a risk

349
00:15:29,130 --> 00:15:31,803
of detrimental impact
on the embryo's health.

350
00:15:33,780 --> 00:15:36,690
So that'll wrap it up for module four.

351
00:15:36,690 --> 00:15:39,600
There are some interesting stories

352
00:15:39,600 --> 00:15:44,310
that I've posted in the
required reading folder

353
00:15:44,310 --> 00:15:48,390
that are basically, so
these are real life stories

354
00:15:48,390 --> 00:15:52,620
that are posted from interviews done

355
00:15:52,620 --> 00:15:54,540
with patients or family members

356
00:15:54,540 --> 00:15:58,380
who have chromosomal
abnormalities or aneuploidy

357
00:15:58,380 --> 00:16:03,210
and gives a patient-centered
experience of what that's like.

358
00:16:03,210 --> 00:16:05,130
So I'm asking you to read those.

359
00:16:05,130 --> 00:16:06,900
There's an assignment
associated with that.

360
00:16:06,900 --> 00:16:08,880
And hopefully, it'll start to put this

361
00:16:08,880 --> 00:16:12,300
in more of a personal and
clinical perspective for you,

362
00:16:12,300 --> 00:16:14,433
all that we've been talking about so far.

363
00:16:15,630 --> 00:16:17,010
So what's in the next module?

364
00:16:17,010 --> 00:16:18,540
I'm sure you're wondering.

365
00:16:18,540 --> 00:16:20,040
So module five, we're going

366
00:16:20,040 --> 00:16:22,950
to go over patterns of inheritance.

367
00:16:22,950 --> 00:16:25,950
So here, we're going to
start talking about terms

368
00:16:25,950 --> 00:16:28,500
that you've probably heard
before, like dominant,

369
00:16:28,500 --> 00:16:32,760
recessive, autosomal, sex-linked,

370
00:16:32,760 --> 00:16:36,300
all of these types of
different genetic diseases.

371
00:16:36,300 --> 00:16:39,030
So specific genetic diseases,
how they're inherited,

372
00:16:39,030 --> 00:16:43,170
and how you actually go from
a genotype to a phenotype.

373
00:16:43,170 --> 00:16:46,170
So we will talk about all
of that in the next module.

374
00:16:46,170 --> 00:16:47,010
Thanks so much.

375
00:16:47,010 --> 00:16:49,500
And I look forward to reading your posts

376
00:16:49,500 --> 00:16:50,700
on the discussion board.