[Lecturer] Hello, all right, well, in this module,
as you heard from the intro video,
we are going to take some time to review Modules 2-5
so that we make sure we are all clear on those concepts
before the midterm take home exam is given out
and also before we move on to topics
that build on what you've learned
in these first five modules.
So what we really need, right?
It's like after you've eaten a big Thanksgiving dinner,
you just need some time to digest.
I've given you a lot of information
and you have learned an extraordinary amount
and over a relatively short period of time
and I think it is beneficial to our comprehension
and to, again, to ensure that we have
all of these main concepts down before we move on.
It just take some time to digest, let things sink in,
maybe go back over them again even if you think
you've got it, go back over again just to make sure.
You may see something in a different light than you did
the first time you went over it
now that you have more knowledge
and more experience with this, going back and looking
at some of that earlier material might help it to fit
into place a little bit better.
So what I'm going to do here in these slides
is I've pulled some images from some figures
from some of the past slides
or like a greatest hits (laughs) highlight reel,
if you will, of past lectures
and there aren't very many words on these slides
because I'm primarily just going to talk through them
and I would encourage you to, you know,
if you're interested in getting some of the details
around these concepts again,
go back to the PowerPoint slides
for each of those separate lectures
and each of those modules and revisit those
because all the details are there.
Whether it's just in the PowerPoint slide
or if you go back and listen to the lectures again,
either way, you'll get that information.
This is just a review of, as I said,
some of the highlights of what we've covered.
So let's start back at Module 2
where we all began with the cell.
Remember our first look at the cell, basic cell anatomy,
this image here on the left,
and this is just to show you, reminder that, you know,
we're made up of about 50 trillion cells,
each one of these looks a bit different, you know,
one from another and they may have different functions
and exist in different areas of the body,
but generally, they all have a plasma membrane,
which is that outer shell,
and then on the inside, you have cytoplasm,
which is sort of the goo inside of the cell
where you have proteins,
you have all sorts of things kind of moving around
and you have individual what are called organelles
or these separate structures that you see here.
It's not really important that you know
what each of those does, just that they do have
individual functions, and you can see in the center there
the nucleus.
That's important, as we talked about...
That has its own separate membrane to protect the DNA
from any potential damage.
It also helps to kind of keep it in one location.
The exception to this, of course, is during mitosis
when in a very short period of time
during mitosis when the DNA...
When your chromosomes are actually separating
from one another.
In order to allow that to happen and form two new cells,
the nuclear membrane has to actually dissolve
and then it will reform two nuclear membranes
around each set of the genomes so that way,
each cell has one set of...
One complete set of DNA.
So that's the basic cell anatomy,
and then also remember, as I said, you know,
you have many different types of cells
that perform specific functions
and that's a product of cell differentiation.
As you can see down there, there's a few examples
of what types of cells come from the mesoderm
and the endoderm from early stages of development
of an embryo and that would include cells, you know,
you have muscle cells, blood cells, kidney cells,
thyroid cells, pancreatic cells, all sorts
of different cells that look different
from one another form different functions.
However, they all actually have, as you remember,
they all have the same genetic material,
they all have the same genome.
Yet they perform very different functions
and look very different from one another,
so how does that happen?
Well, it ties into what we learned in a different module,
which has to do with gene expression.
So which genes are on, which genes are off,
and for the ones that are on,
to what extent they're on, remember that?
So all that regulation from transcription factors
and other factors that play a role
in determining the expression of a specific subset of genes,
how these can be different from...
In one cell type to another cell type.
Now, taking a peek at the structure of DNA,
looking first on the left here, as you remember,
the molecular structure of DNA, it's two strands,
and you can see there's the deoxyribose sugar backbone,
the sugar phosphate backbone,
the sugars are connected by phosphates
and that provides the backbone...
That's homogenous, you know, that's the same
all the way through each strand.
The different part is the part that you...
That picture here in the middle, which is the actual bases,
so that's the A, T, G, or C.
Remember there's complementarity.
So A and T bind together,
A and T have hydrogen bonds together
across those two strands,
and G and C bond together, they have three hydrogen bonds
across the double strands and that's what holds
those two strands together, is the complementarity
and the binding, the hydrogen bonding,
between complementary bases across the way there.
So these are your nucleotides,
as you can see outlined in red there,
that would be a single nucleotide,
which would include the base
and the sugar phosphate backbone, all right?
And typically, we just refer to when we actually are looking
at sequence, we just refer to the bases,
so we would say As, Ts, Cs, or Gs
because the sugar phosphate backbone is going
to really be the same throughout the entire strand of DNA,
and as you can see here on the right, higher order structure
when we zoom out a bit, so that's the...
Really zoomed in really close view on the left
the molecular structure, if we start to zoom out a bit,
and now, we're just looking at it sort
of from a bit farther distance,
you can see the double strands here and remember
that they wrap around these proteins called histones,
which is like the spools around which thread would wrap
and that helps to compact the DNA and keep it organized
and protected because otherwise, you know,
one long strand would be really susceptible to breakage
because it's, you know, it's a really thin strand.
So a wrap around these systems helps keep it protected,
helps to keep it sort of compact and in one place
and that further compacts down
into the chromosome structure.
This would be duplicated chromosome
because it has the X shape.
So two sister chromatids attached at the centromere
with the short or p arm on the long or q arm,
as you can see here and, again, it only compacts down
into this shape before mitosis or meiosis.
Normally, it's sort of a little more relaxed
in order for those histones to get out of the way of,
as you remember, and as we learned in another module,
so the histones can kind of get out the way
of the transcription factors coming
in and activating expression of genes.
In order for that to happen, the chromosome has to sort
of loosen up a bit, relax, and take a more loose structure,
which it does more like that bowl of spaghetti kind
of structure.
The X shape as shown here, this is a very convenient shape
because it...
You can easily separate one chromosome from another
and that's why when you would say,
"Send a sample out for karyotyping,"
they would look for cells that are undergoing mitosis
so that way they would be able to see the chromosomes
in their condensed form and be able to tell
one from another so they can see does this individual have
the correct number of chromosomes
and are there any, you know, major chromosome abnormalities
that could be detected?
That's what you're seeing here,
that's sort of the higher order structure
and remember, you know, like if you zoom in a little bit
into this double stranded structure,
we would read the sequence, we would only read
one of the strands 'cause the other strand's going
to be just exactly complementary to that,
so you only need to know the sequence
of one of those strands and that would be your sequence
of bases, so ACCGTG, whatever,
reading all the way through, okay?
And so that's where that comes from,
and a gene would be located along a segment of a chromosome
like a stretch of a chromosome might constitute a gene
and as we'll talk about momentarily, you know,
that would have a start and a stop codon to it for...
And as well as a promoter region to help align the machinery
for transcription to form mRNA, right?
Because the gene is a unit of DNA that encodes
the instructions for making a protein,
and in order for that to happen,
it has to be transcribed into mRNA.
So it has to have all of that in place.
It has to have a promoter, it has to have the,
you know, the start sequence, it has to have a stop codon,
and that whole space between the start and stop,
that is going to be your gene,
and you'll have many genes along the length of a chromosome
and you'll also have spaces in between genes
that are actually quite large
and these are the non-coding regions.
Remember we talked about those non-coding regions
as being...
Actually, a lot of our whole genome,
98% of our genome is actually non-coding,
which means likely spaces between genes, right?
It would include both spaces between genes,
as well as the regions within genes that are not going
to code for a protein.
So those would be the introns, those are also non-coding.
Just a little reminder there.
All right, so let's see what we have next.
Well, here's the flow of information, the central dogma.
We know it, we love it, let's review it one more time.
So that's the, again, the flow of information,
which we start from DNA and that gets transcribed into mRNA,
which is single stranded and is complementary
to the antisense strand of the DNA,
from which it was transcribed,
and it's complementary with the exception
that the T is now replaced with U or uracil.
So thymine is now replaced with uracil
and that allows the mRNA to leave the nucleus
and in doing that, because you can not have translation
within the nucleus, you don't have translation
in the nucleus, translation happens outside of the nucleus
where you have all this machinery ready,
the ribosome and other machinery, the tRNA as well,
ready to kind of swoop in and decode the mRNA
into the proper order of amino acids
and assemble those amino acids along to make the protein,
and that's translation.
Right, so the first step is transcription into mRNA,
that mRNA leaves the nucleus, and then is picked up
by the translational machinery, the ribosome,
and the ribosome helps in the proper tRNA binding
to its complementary codon in the mRNA.
This tRNA has attached to it this specific amino acid
that is code for by this codon to which it is complementary
and that then brings in that amino acid
and adds it to the chain and then they move down the line,
so then you'll move down to the next three bases,
which is a codon remember that?
Moves to the next three bases and brings in the next tRNA
that was called charged or has the amino acid on it
that is associated with that particular codon
and then the tRNA attaches its amino acid to the chain
of amino acids and then once it reaches the stop codon,
there's no tRNA that actually is complementary
to the stop codon, so then basically, the ribosome says,
"Well, okay, I guess we're done here,"
and the machinery falls apart
and you have your fully formed protein now,
and the protein, remember is just a specific sequence
of amino acids.
All right, so then remember here's your codon table
and this is the way that we would read and know
which amino acid is coded for by which codon in the mRNA.
So if for example, the mRNA were to read GUU,
we would know that would be coded for by a valine.
So the tRNA that's complementary to GUU would be attached
to valine and it would deliver that valine
to the chain of forming amino acids.
So let's take a peek at regulation of expression.
So that's the basic idea of how expression is happening.
Now, how is it actually regulated?
How's transcription regulated?
Well, if we're looking at a depiction of a gene here,
let's say, and then we have this stretch of...
This is non-coding DNA, but it's really essential
for the regulation of expression of a particular gene.
So while it doesn't actually encode for a protein,
its sequence is necessary and important to be specific
to allow for transcription factors to bind there.
Transcription factors you remember
are these specific proteins that are in the nucleus
that will bind to specific sites in the promoter
to allow for the transcription to actually happen
of a particular gene.
So let's take a peek at that.
Transcription factors bounce on in and they bind to...
They locate their specific spot in the promoter,
their sequence, they bind there
and then that allows for scaffolding proteins to bind.
So RNA polymerase comes in and now can bind,
is lined up properly in order to perform its function,
which is to help to make the complementary mRNA
for that gene.
Okay, so the mRNA is transcribed
and this means that the gene is on.
If, however, if for whatever reason
one of these steps does not happen properly
and it's most likely the transcription factor's not binding,
then the gene would not be transcribed,
the gene would be considered off.
So what could possibly cause the transcription factors
to not bind?
Well, there could be any number of reasons,
but the main reasons would include
that the transcription factors are not present
in the nucleus and that could be due to the regulation
of where that transcription factor is located.
So moving it from the cytoplasm, for example,
into the nucleus, that could be a highly regulated event
depending upon some external factor in the environment.
So the cell is able to respond to something
in its environment by basically modifying the location
of its transcription factor, whether it's in the cytoplasm
or if it's moved to the nucleus.
It can also be that the transcription factor needs to bind
to another protein in order to make it
in the right confirmation, it's in the right shape,
basically, so that that transcription factor can bind
to the promoter properly and allow for transcription.
There are many, many different ways
in which transcription factors are regulated,
but you can think of them as, really, the primary way
in which cells will be responsive in terms
of their gene expression to changes in their environment.
So another way that transcription factors may be blocked
from binding to their promoter
is through epigenetic modifications.
So remember with the two main ones that we learned
about are histone modifications and DNA methylation.
So histone modifications, as you can see here on the bottom,
depending upon the particular types of modifications,
they can result in a loosening of the histones
around the strand of DNA and that basically leaves open
larger stretches of DNA.
That basically makes room for this transcription factors
to be able to come in and the other machinery to be able
to come in and bind and transcribe that gene
or particular modifications to histones could cause it
to tighten up and to just really become really tight
and condensed, which wouldn't allow much to get in there
by way of transcription factors
or other machinery, transcriptional machinery.
DNA methylation is basically adding a methyl group
to cytosine and those cytosines, if they're in the promoter,
it's possible that if they're specifically in a site
in the promoter that is necessary for a transcription factor
to recognize and bind there,
that when that cytosine is methylated,
the transcription factor very well might not bind
to that promoter anymore because it's blocking it,
the methyl group is actually blocking
the transcription factor from recognizing its sight
and binding there.
Both of these kinds of modifications are regulated
themselves through a number of different mechanisms
and can be responsive to environmental factors,
and we talked a little bit about...
Actually, these types of modifications can be responsive
to stress, to diet, to all sorts of other factors
that are related to general health and can accumulate
over our lifetimes in our cells,
so we can actually accumulate
more and more epigenetic modifications that could cause...
Could be detrimental in the long run to our health
and are actually thought to be related
to the processes of aging.
Another way that we can regulate the proteins
that are found in our cells is not necessarily
just through transcription, so you could transcribe an mRNA,
but it's through that next step of splicing.
So remember splicing is removing the introns,
those non-coding sequences in between exons,
which are coding.
Introns are non-coding and so they are removed,
but you can also have alternative splicing,
which basically means some of the exons could be removed.
If for example, a particular version or form of a protein
is needed one say maybe one version over another in response
to something in the cell's environment,
the cell needs to adapt to that,
it needs a particular version of a protein
of one type more than another,
it may induce alternative splicing such that it will create
mRNAs that after being spliced that contain
a specific set of axons.
So here's an example of a specific example
of an environmental factor.
This is estrogen, we know it, we love it,
some of us have it. (laughs)
So estrogen is a molecule that is sort of floating around,
sometimes more of it around than others
and in some tissues more than others,
but the estrogen molecule, there's a receptor
that we have to estrogen,
and when estrogen enters the cell and binds to the receptor,
that receptor will actually act as a transcription factor,
but only when it's bound to estrogen.
So this is an example of a transcription factor changing
its conformation or its shape in order to be able to bind
to the promoter and initiate transcription
and turn a gene on initiate transcription,
but only when there's some kind of incentive
for it to do that.
In this case, the presence of estrogen,
the molecule of estrogen binding to it causes it
to change shape such that now, it can bind to the promoter
and activate expression of...
Actually, a number of different genes will have an estrogen,
what's called an estrogen response element.
When the estrogen receptor is in its confirmation
such that it can bind to those promoters will activate
expression of those genes and those specific genes
that are activated in the case of estrogen receptor...
Responsive genes, those tend to be those genes
that will induce cell proliferation, cell division,
and the reason why that's the case is that in breast tissue
and in uterine tissue that will prepare the uterus
and the breast tissue potentially for a potential pregnancy.
Let's take a peek at DNA replication.
So remember that is what's called semi-conservative method
of replication, which means that the...
You have your original double strand
and it sort of forks off and each one of those strands goes
to form one strand of a new double stranded DNA.
So the complementary strand is formed off of that,
two new strands are formed and just, again, a quick peek
at what it actually looks like, say if you're looking
at a karyotype and what we have here, this...
Let's say this is chromosome 1.
We're looking at here are duplicated chromosomes
and so these are sister chromatids
as you can see labeled here
and these are homologous chromosomes,
homologous to one another.
So that indicates, if we're looking at this karyotype,
this happened after DNA replication,
but before mitosis has completed here,
so you have duplicated chromosomes.
All right, let's take a look at the cell cycle.
So in the cell cycle, we have multiple stages.
So starting here with G1 phase,
this is growth and is preparing for DNA synthesis
and then S phase, that's synthesis phase or DNA...
Where DNA replication actually happens
and that's in preparation for the cell to divide.
In G2, that's what's happening
after DNA has been replicated, you have preparation
for mitosis, which would include, you know, basically making
all of those proteins that are going to be needed
during mitosis and immediately after mitosis is that...
You remember the four stages of mitosis,
prophase, metaphase, anaphase, and telophase
in order to essentially that the process is basically
to line up and evenly distribute the chromosomes
into each one of two new forming cells,
and then on the right-hand side, we see meiosis,
which is what's happening in only in those cells
that are going to form germ cells or egg or sperm cells.
Remember, the goal of meiosis is to create a cell
that has haploid.
Remember, haploid means that it has only one copy
of each chromosome in order to basically allow for it
to fuse with its complementary derm cell
and form an embryo that has if the diploid
or two copies of each chromosome.
All right, now, sometimes problems can happen, right?
Sometimes bad things happen and this is an example,
an aneuploidy, where during meiosis where you can...
Where you're actually in meiosis 1 separating
homologous chromosomes, meiosis 2 separating duplicated
or sister chromatids, you can have non-disjunction occur.
Non-disjunction means that they don't let go
of one another properly and the chromosomes,
whether they're homologous chromosomes
or the sister chromatids, two of them go to the same cell
and so that means one of the cells has zero copies
of that and the other cell will have two
or duplicate copies of that and you can see the net result
down at the bottom of the gametes.
You might have one too many or one too few copies
of the chromosomes and if that...
So here's a karyotype that we're looking at here.
This actually, if you look at this karyotype, what stage
of cell cycle would this karyotype have come from?
Well, we're looking at it, what do you notice?
Do they look like Xs?
Nope, they look like single columns, right?
So they look like just one line for each.
There's a pair of each, right?
But that makes sense because we have
two copies of each chromosome, but what you don't see
is that X shape where they're being held together
at the center.
Remember that those would be the sister chromatids
or the duplicated, the identical chromosomes have been
duplicated in S phase of the cell cycles.
So we would say in this karyotype that it was from cells
that had not yet undergone S phase.
Probably where they got these was just immediately following
mitosis because they're still condensed
and they haven't relaxed yet,
but it was probably cells that had...
From a cell that had recently completed mitosis.
So if we're looking at this karyotype, what do we notice?
What would we diagnose here?
Well, it looks like we have the normal expected pair
of chromosomes for each of the autosomes, chromosomes 1-22,
then we have two X chromosomes, okay, great,
but then we also have a Y chromosome.
That would give us the diagnosis of Klinefelter syndrome
or 47 because there are now 47 chromosomes XXY, okay?
All right, now, let's think
about some of those chromosomal abnormalities.
There's a number of them that can happen
and you're looking here on the left,
remember that's the ideogram of how we look
at and designate specific areas of a chromosome.
You may wanna go back and take a peek
at how we designate specific chromosomal abnormalities.
I'm not gonna talk about that here 'cause I think
it's in pretty good detail in your lecture notes,
but you can have a deletion where a segment
is deleted, removed.
You could have a duplication where that particular region
is duplicated and added in.
So now, you'll have double copies
of that in that one chromosome, which is a problem,
potentially, depending upon the genes
that are in the location.
You could have inversions.
So you can have paracentric with an A
and that's an inversion that's in within one arm
or you can have pericentric inversion, which is an inversion
that involves the centromere,
so between the p and the q arms and this can actually wreak
more havoc than you might think.
Well, you might say, "Well, you're not losing
or gaining any genetic material, you're just flip-flopping
it around a little bit, so why should that matter?"
Well, a couple things can matter.
One is if that flip-flop, if where it's being cut
on either side is within an important region,
either regulatory region for regulating gene expression
or within a gene itself, you've just disrupted that gene
or the regulation of the gene that is associated
with that regulatory region.
It could also kind of screw up local regulation
within those regions.
So you can have regions of chromosome that have a lot
of non-coding DNA in them and those stretches tend
to be really compacted by histones.
If you start flip-flopping things around,
you might put a region that has genes in it,
that needs to be active, in an active part of the chromosome
into a region that is inactive
and then those genes might not be expressed.
So it can really cause some problems,
and then you also have similarly a translocation,
which would be flip-flopping bits and pieces
between two different chromosomes.
Here is an example of a fluorescence in C2 hybridization
or fish and each one of the chromosomes is colored
with a different color fluorescent marker
and they do this in order to see some of these inversions
and translocations and things like that.
So you can see that that piece
of chromosome 22 has been flip-flopped
with the piece of chromosome 9 and that can cause
some issues for the individual, again,
depending upon the genes that are involved there
and the region, specifically the regions that are affected.
All right, and either of these chromosomal abnormalities
or aneuploidies, they can occur in every cell in the body
and if that happened, it was likely that the aneuploidy
or chromosomal abnormality happened in the gamete,
so either the egg or the sperm.
So from moment time zero, you know, from second one
the embryo had the fertilized egg, which then became
the embryo, had those chromosomal abnormalities
or aneuploidy in every single cell.
Every single cell, completely, all of it 100%.
You can also have situations
in which there are certain patches of a person.
Certain, I mean, this would include tissues, organs,
it could be patches of skin, it could be patches of...
It could be, you know, percentage of blood or lymph.
Any parts of the body could be mosaic or, you know,
some parts may be normal and some parts may have aneuploidy
or may have a chromosomal abnormality
and that would be due to likely...
It could be due to really either one of two situations.
The first situation is that the aneuploidy
or chromosomal abnormality was...
Happened in the embryo or in the individual
at some stage in their life after conception
and then it only was passed on to those cells
that came from that initial cell that had
that aneuploidy or chromosomal abnormality,
so it wouldn't be everywhere.
The other possibility is what's called a rescue
and that would be in an individual, let's say their...
One of the gametes did have an aneuploidy
and formed a fertilized egg.
So you know, we have this single cell embryo that will form,
you know, will form an embryo that's say has an aneuploidy.
At some early stage in development, one of the cells could
actually spit out the extra chromosome,
let's say it's trisomy 21, which you saw an example
of that, a mosaic trisomy 21 in one of your assignments,
let's say that one of the cells was able to actually remove
the extra chromosome from itself, then all of the cells
that that cell will develop into would have
the normal number of chromosomes.
All right, now, let's talk about some of these different
kinds of mutations that can happen.
So we're getting smaller and smaller with aneuploidy,
which is the wrong number of chromosomes sort
of very large scale chromosomal abnormalities,
which is within a chromosome you can have
some of these large scale issues.
Now, let's look even smaller into the sequence level.
You could have mutations that could result
in different effects and one effect is basically no effect,
which means while the base itself is changed in a mutation,
it doesn't have any effect on the protein
that it's being coded for because it still codes
for the same protein.
As you remember from your codon table,
there are multiple codons that code for the same amino acid.
So you could have a change and actually still code
for the same amino acid.
That doesn't have any detrimental effect
on the individual whatsoever
'cause it's the exact same protein that's forming
and these are called silent, no effect.
This sense mutations, what happens here is that you have...
So what they're showing here is a T instead of a C
in the mutated version down below.
So we'll change that codon from, instead of it being
GGC encoding for glycine, it's now AGC encodes for serine.
So you get a different amino acid.
So the protein is one amino acid different,
and you might think, "Well, big deal, you know,
it's like one amino acid."
It might not be a problem or it might be a big problem.
It depends upon where in the protein
this amino acid substitution is happening
and the type of substitution that has occurred.
If it's changing to a completely different amino acid,
it might totally screw up the normal function
of this protein.
If it's happening in a region in the protein
that's really necessary for that protein's function,
it could screw it up.
Nonsense mutation is what would happen if you change a codon
and it now is, instead of whatever it was coding
for a normal amino acid, it's now a stop codon,
a stop codon.
So you see down below an A instead of a T in this one spot.
So now, that codon, instead of it being
AAG encoding for lysine, it's now UAG encodes for nothing,
encodes for a stop.
So then the protein is truncated, which basically means
it's not going to be the full length.
If that happens like really close to the end of the protein,
it might not be a problem, but if it happens midway
through or at the very beginning of the protein,
you essentially could have no function
for that protein whatsoever.
Now, let's talk about inserting or deleting
a number of bases.
So we were talking about substituting or mutation,
so this instead of that, but let's say you take out a chunk.
Well, if you're taking out a chunk that's a multiple
of three, and why do I say multiple of three?
Because three is the number of codon...
Is the number of bases in a codon
If you do that, then it would be
an in-frame insertion or deletion
and that would basically affect just that one amino acid,
either deleting an amino acid or adding an amino acid,
so that's your in-frame insertion,
same thing in-frame deletion, okay?
Frame shift is the bigger problem
and this is gonna be more likely if you're adding
or deleting bases because, you know,
that's basically anything that's not a multiple of three.
So that gets everything off kilter
and remember, back from that lecture I was talking about,
looking at at words and, you know, the red...
I forget what it was.
The red bug bit the dog or something like that,
and if you move that over just by one letter,
it becomes gibberish and that's kind of what happens
in frameshift mutations as well.
It shifts everything over by a base
and that screws up everything
and the protein's completely different.
So that could be an insertion or a deletion, all right.
All right, let's switch gears here.
Keep going, we're just gonna power on through.
We're gonna switch gears and talk
about modes of inheritance,
and so we have a number of different common ones
and these are autosomal dominant, autosomal recessive,
X-linked dominant, and X-linked recessive.
Remember, these are Mendelian inheritance,
which means that it is a phenotype associated with one gene.
So let's look at the case of autosomal dominant.
Remember how we designate each of these?
So uppercase indicates the dominant allele
and lowercase indicates the recessive allele.
Whether the uppercase dominant
or the lowercase recessive alleles are disease alleles
or wild type alleles depends upon the disease,
whether the disease is dominant or the disease is recessive.
Here, we're showing in the top left corner,
autosomal dominant.
If you have, let's say a...
Let's say we're talking about Huntington's disease
and the father has Huntington's disease
and let's say he's heterozygous for it,
which means he has one copy, that's the disease copy
that's indicated by the big H, uppercase H, right?
Because that's the dominant version that happens
to be the disease version, in this case.
Lowercase h 'cause he's heterozygous,
and let's say the mother doesn't have Huntington's disease.
So both of her copies, both of her alleles are wild type,
and since this, again, wild type is recessive,
we would show it as lowercase h.
When we do our Punnett square and we see
all the combinations, the possible combinations
for their offspring.
Since this is an autosomal condition,
which means that the Huntington gene exists on an autosome,
we look at all the combinations that could happen here.
We have big H, little h, little h, little h, big H,
little H, little H, little h,
and we can count them up and we would say
two out of the four possible combinations
of these alleles would give us little h, little h,
or both wild type alleles
and so those would be unaffected children.
However, we would also note that two of the four would have
one copy of the disease or big H alleles,
so that would be big H, little h.
So these two out of the four would have
Huntington's disease.
As you know from statistics, that does not mean
if a family...
If let's say this couple has four children,
it's guaranteed that two of the four are going
to have Huntington's disease and two of the four are not.
It's for each individual there's a 50% chance
or two out of four, there's a 50% chance
that each child they have would have Huntington's disease.
No matter how many children they end up having,
each child...
It's like flipping a coin.
Each time you flip the coin, it's 50% chance it'll be heads
or tails no matter how many times you flip the coin.
Autosomal recessive, as you can see
on the right-hand side there, let's say there
are two carriers, the mother and the father
are both carriers of this condition, say cystic fibrosis.
So we would say they're big F, little f.
So neither parent has cystic fibrosis,
they're both carriers for it.
In order to calculate the risk that they would have a child
with cystic fibrosis or a child that is a carrier,
we would do the Punnett square and we would see
that one out of four possibilities would be big F, big F,
or both wild type.
In this case, big F represents wild type
because that's the dominant allele.
So this in the one out of four would be unaffected,
completely unaffected.
So they wouldn't be carrier, they wouldn't have the disease,
so there's a 25% chance for each of their children
that they would be completely unaffected.
There is a two out of four or 50% chance for each child
that they would be carriers that they would've inherited
one disease allele from one parent and one wild type allele
from the other parent.
There's a 25% chance for each one of their children
that they would...
That that child would have cystic fibrosis
or would have inherited the disease allele from each parent.
Okay, X-linked dominant and recessive conditions.
So now, we're talking about X-linked
and males only have one X, females have two
so we have to look at things a little bit differently.
In X-linked dominant conditions, again,
you only have one allele from the father,
you have two alleles from the mother.
Let's say that the mother has this condition and so...
And she's heterozygous for it,
so she would have one disease allele,
which is designated as uppercase, again, big R.
Let's say this is like Rett syndrome
and she would have a wild type or normal allele
as the other allele.
Let's look at all the combinations thereof.
So she could have for daughters, which would be those
that would've inherited an X chromosome from the father,
she would have...
50% of her daughters would have Rett
and 50% of her daughters would be completely unaffected
and for her sons, all of her sons will inherit
one of her two X chromosomes and a Y chromosome
from the father, so we don't...
He doesn't have a second allele,
so we would just look here, these are the sons.
So 50% of her sons would have inherited
the disease allele and in the case of Rett syndrome,
that would be lethal, so it would it...
That son would not make it to term
because having one copy and no normal copy
is lethal in this case and then...
So essentially, what would end up happening
if we look at live births from these two parents,
we would see that 50%, again,
50% of the daughters would have Rett,
50% would be unaffected, and then what we would see actually
is that 100% of the sons would be unaffected.
Why do I say that?
Because the sons that would've inherited her disease allele,
her X chromosome with the disease allele would not have
survived and not have made it to term.
So X-linked recessive conditions, similarly, again,
you know, you only have one allele from the father,
you get two alleles from the mother.
Let's say we have a father that's unaffected
and we have a mother that's a carrier for an X-linked,
let's say it's a hemophilia's example that we gave.
So we would look at the daughters.
50% of the daughters would be unaffected
and 50% would be carriers.
She would not have any daughters
who would have the condition,
assuming that the father does not have the condition
and out of the sons, we would have 50% that are unaffected
because they inherited the wild type allele
and 50% that would have hemophilia of her sons, right?
50% of her sons would have hemophilia
'cause they would've inherited the disease, the X chromosome
with the disease allele on it.
Let's move on then to some exceptions to Mendel,
and these would include different dominance relationships.
It doesn't come up too much in the clinical context,
you might see someone talking
about incomplete or co-dominance so it's included here,
I wouldn't worry about it too much,
but, you know, the idea is that incomplete dominance,
you have sort of a blended phenotype
between both homozygous parents.
In co-dominant situation, you would have patches
or representation of both in the heterozygous child,
which is a result of a cross
between two homozygous parents.
All right, now, let's look at pleiotropy
and genetic heterogeneity.
So a couple of phenomena that I think are actually
more relevant to the clinical context.
Pleiotropy, that is one mutation causing
lots of different phenotypes, and so the example here
is PKU, is a mutation in one gene, the PAH gene,
which results in all these different kinds of phenotypes,
which might appear to be unrelated to one another,
but clearly, the protein encoded by this gene is involved
in pathways that affect each of these kinds of phenotypes,
so that's pleiotropy, one gene, multiple phenotypes.
Genetic heterogeneity is almost kinda like the opposite
of that where you have one phenotype,
in this case, polycystic kidney disease, which would be...
Which could be caused by mutation
in a number of different genes.
Doesn't mean it requires a mutation in each of those genes,
it just means a mutation
in any one of those genes could cause the same phenotype,
which would be a polycystic kidney,
and then finally, we have penetrance and expressivity
as our last two phenomena to talk about,
and I'm just designating these as like in a sort
of abstract colors to look at just maybe a different way
to think about it other than, you know, in addition
to what we had in our slides from the lectures there,
but penetrance you can think of as,
let's say you have this population here
and all of these circles represent people that have
a genotype that indicates they should have
a particular disease, right?
So they have a genotype for Huntington's disease.
All of these people should develop Huntington's disease,
but let's say these two white circles
that are represented in the field of blue circles,
they never actually end up developing Huntington's disease.
That would be incomplete penetrance.
Incomplete penetrance is the...
Basically indicates that there are some members
of the population who have the genotype,
but don't ever end up developing the phenotype.
Expressivity is sort of like the rainbow of possibilities
of different outcomes that you could see associated
with the disease.
So it could be severity of the condition, it could be onset,
you know, whether it's earlier or late onset.
So here, I'm representing it by a bunch of different shades
of, you know, blue that you could see in the disease.
So they all have the disease,
they'll all have some phenotypes of the disease,
it's just that those phenotypes might be different
from one to the other even though their genotypes
are the same.
So that's variable expressivity.
Okay, well, that wraps it up.
Whew, that was a whirlwind, that was a whirlwind.
Okay, so what's in the next module?
Well, we're going to talk about health history
and risk assessment, basically, where do we go from here
and how do we take patient information
and start to turn that into pedigrees
and start to analyze that, so taking us to the next step.
All right, well, with that, I will say goodbye.
Please let me know if you have any questions
and let's, you know, get Blackboard up and running.
If there's some questions that you have along the way
that you want some help with or just want to raise
for discussion, that would be great.
All right, I will talk with you soon, take care.