[Instructor] All right, you made it
to the last lecture in module five.
Well, here we're gonna talk about some exceptions
to the rule, as you know.
I mean, I think genetics is,
it's an interesting field of study
because there are so many rules
and it can be quite black and white,
but then for every rule, there's at least one exception.
And sometimes those are pretty important
and you'll actually see them quite often.
And so, as clear-cut as it was
to explain Mendelian inheritance,
and you can draw up these Punnett squares
and that's wonderful, you can estimate risk,
there are exceptions to each of those
and it can become kind of confusing at times
when you're looking at a pedigree and you're thinking,
well, according to Mendelian inheritance,
it should look like this, but it actually looks like that.
And so, trying to understand why that might be the case
where there would be some exceptions
and what those exceptions are
and giving you a few examples of that.
So, that's the goal for this lecture.
So, along with that, there's gonna be
a number of different terms I'm going to use
and wanted to provide you with a list of definitions
right up here at the front.
And I'm actually not gonna talk
through each of these right now
because I'm going to talk through each of them
as I go through them in their slides,
but wanted you to have a list
so you can refer back to those,
maybe keep it handy beside you
if I'm starting to use a term
that falls into one of these categories,
you can look it up rather quickly.
Let's first talk about dominance relationships.
So, we categorized dominant or recessive
as you have two alleles,
and one of them is going to be dominant to the other, right?
And it's the dominant one that you actually,
that actually impacts the phenotype.
So, you see that the phenotype come through.
So, if it's recessive,
the only way you're seeing the phenotype
is if both alleles are the same recessive allele.
Well, that, and that is the case the majority of the time.
There are some exceptions to that,
and you may hear these terms,
and I just wanna make sure that it's clear
what they're referring to.
And these are just different dominance relationships.
So, yes, dominant recessive
is the main kind of relationship you'll see
for single gene disorders or for single gene traits,
but there are some others that do come up,
and these would include incomplete dominance
and codominance.
So, what do I mean by that?
Well, some way to visualize it that I find helpful
is actually just sort of looking at colors as a phenotype,
and actually several of these kinds of genetic phenomena
that we're going to talk about in this lecture
were first categorized by looking in plants and in flowers
that were expressing different types of traits.
It could easily be logged.
So, you could look at a plant and its flower
and see, well, what is the color of the flower?
What is the size, the shape?
And so, plants were used to help us better understand
some of these genetic concepts.
Plus, plants don't generally complain when you cross them,
and when you say,
I'm going to cross this plant with this plant,
they don't put up much of a fight.
They're just going to go with it.
Humans, on the other hand,
it's notoriously difficult to get two humans to cross
just to see what happens,
and I'm pretty sure none of us would want to do that.
So, a lot of what we know, we know initially from plants.
And so, I find this to be a helpful way to demonstrate it
just by looking at color as a type of phenotype output,
but you can apply this to different diseases
and other human traits as well,
and I'll give you some examples of those
in some subsequent slides.
But just to get us all on the same page here,
when you see different dominance relationships,
you see those primarily when you have a cross
between two parents that are both homozygous, right?
So, both of their alleles are the same,
and the two parents are different from one another.
So, this one parent is homozygous,
let's say, for the A1 allele,
if that was one of the alleles.
Let's say the other allele is the A2 allele,
and we're calling them this
instead of uppercase and lowercase,
because, let's say, for the sake of argument,
we don't actually know which of these two alleles,
the green allele or the white allele,
is actually going to be dominant to the other one.
So, what we're just going to designate them
as A1 for the white one, and A2 is the green allele, okay?
If you had a cross between,
again, let's think of this in terms of plants,
because it's going to sound weird
if we start thinking that I'm saying
we're crossing two humans together.
So, let's just assume we're talking about plants here, okay?
So, let's say we're crossing a white flower plant
with a green flower plant,
and the resulting cross gives us a offspring or child,
if we're thinking about humans, that is white,
that demonstrates the phenotype
that is associated with one of the two parents.
That tells us that A1 allele is dominant to A2,
just straight up dominant,
just like what we've been talking about
in the previous lecture.
If, on the other hand, you cross the white flower plant
with the green flower plant,
and you get a green flower offspring,
that tells us that the A2 allele,
which the green flower parent was homozygous for,
is actually dominant to the A1 allele,
or the allele that the white flower parent plant had.
So, we know that these two,
these first two cases are complete dominants,
and that's the sort of the traditional
dominant recessive relationship.
If, however, you cross a white flower
with a green flower plant,
and you get some color in between white and green,
so like this sort of yellowish, light green color,
so it doesn't look like either one
of the two original homozygous parents.
Well, it's sort of a blended phenotype,
so the phenotype looks like sort of a spectrum,
it's somewhere in between the two parents,
and that's an incomplete dominance,
so that's known as incomplete dominance.
Codominant would be if you're crossing
a white flower plant with a green flower plant,
and you get a flower from the offspring
that has green stripes and white stripes,
so portions of it look just like one parent,
and other portions of it look just like the other parent,
so you actually have distinct domains, parts of each,
that represent each of the two,
look like each of the two homozygous parents.
That's codominant, so they're dominant together,
like they're both sort of demonstrating
a type of dominance in different regions of the offspring.
Basically, you're able to see the phenotype
of both parents in the offspring.
All right, let's take a peek
at what this actually looks like in humans.
Moving from plants to humans, so in codominance,
both alleles individually contribute to the phenotype,
and you can see both of those in the phenotype.
The classic example of this is blood type, right?
So you know there's type A, type B, AB, and O,
so you either have the A allele, a B allele,
or an O allele, and some combination of those two,
and individuals that have an A allele,
A is dominant to the O allele,
so they would have type A blood.
If someone has a B allele, a B is dominant to the O allele.
O is basically like a fully recessive allele.
Then that person would have type B blood
if their genotype is B-O.
Now let's look at a cross between an A-O and B-O individual,
and what we see is that you get A-O offspring, right,
and that's going to be type A because A is dominant to O.
You get children that have B-O genotype,
and they would be type B blood,
and then those that are O-O,
so that would be type O blood,
again, because O is recessive to both A and B.
If you have two copies of O,
then they're going to have type O blood.
A is dominant to O, B is dominant to O,
but what about when you get one of each of the A and B?
Which one wins out?
Well, in this case, there actually isn't a single winner.
They both share dominance.
It's codominant, so you would have blood type A, B,
blood type A, B, and that's going to be caused
by having these two sort of,
you can think of it as like fighters,
and those dominant alleles will knock out
the recessive allele,
and so they'll be the last one standing, right?
So if you have A and O, it's like A versus O,
A is going to win out.
If you have B versus O, B is going to win out
in terms of the phenotype,
and so that's going to be dominant.
If you have A and B, it's like having fighters
that are both equally good as one another,
and so they just kind of both exist together.
Neither one ever really knocks out the other,
and you see both together.
That's giving you something
that is a codominant relationship.
Okay, so we kind of talked through that,
and again, A and B alleles are codominants.
So the dominance relationship is established
between any two alleles.
You're going to have a relationship established,
and again, like the fighter analogy,
if A is stronger than O,
let's say fighter A is stronger than fighter O,
it's going to knock it out,
and it's going to be dominant to O
in that situation when it's A versus O.
However, when it's A versus B,
or A and B are together,
and they're trying to figure out
which one gets the phenotype,
well, they're both equally strong,
and so they're actually codominant to one another,
and if you have two Os in the ring, right,
if it's O versus O, it's like the lightweight match,
then it's going to be a type O blood type,
and that's going to be your phenotype
because it's recessive.
It doesn't really beat out anything,
but if there's nothing else left to fight it,
if it's just two of the same O in the ring, so to speak,
then you're going to get a blood type of O
because it's recessive.
So just think about that for a little bit.
It's all about relationships between two alleles,
so A is dominant to O, B is dominant to O,
and A and B are codominant to each other.
All right, incomplete dominance.
Let's look at an example of that.
Both alleles contribute to a mixed phenotype.
Disease allele is usually severe
when homozygous and less severe,
but not nonexistent when heterozygous.
An example of this is sickle cell trait.
So if you have an individual,
let's say the father has sickle cell anemia
and the mother is wild type, is not a carrier,
doesn't have the condition,
and let's say they have children with one another.
So what does that mean?
If the mother is wild type,
she does not have a disease allele.
Sickle cell anemia is recessive.
That means the father has both copies are disease allele.
That means all of their children are going to have,
are going to be carriers, right?
So what we define as carriers,
which is they have one dominant wild type allele
and one recessive disease allele.
Well, in the case of sickle cell disease,
it's not quite so cut and dry
as it being a completely recessive condition.
It is indeed, sickle cell anemia is recessive.
So you would have to have both alleles
be the disease allele.
However, there is an intermediate phenotype in the carriers.
These are carriers,
but they're not completely asymptomatic.
In individuals who are carriers for sickle cell disease,
this would be someone who would be diagnosed
having sickle cell trait.
That means that they, under certain stress conditions,
they may actually be symptomatic.
And it can be rather problematic for individuals
who say are participating in athletic events
or under some kind of physical stress
or dehydration.
They might actually start to display
some of the disease phenotype of sickle cell disease.
So they don't actually have full sickle cell disease,
but they might show some symptoms,
some mild symptoms, something in between, right?
So like it's between perfectly healthy
and having sickle cell disease or sickle cell anemia
is this middle place where many of the carriers
actually will be slightly symptomatic.
So this does not,
this fit the definition of fully dominant or recessive.
All right.
Now let's think about a couple of other phenomena.
And we've been talking about one gene, one phenotype.
And that is a really nice and convenient way
to think about it.
However, in reality, there are certain genes
that when mutated can affect multiple different traits
simply because the function of the protein
that's encoded for by the carrier
by that gene is such that it may work
in multiple systems of the body.
It may maybe express at different times in development
and that could lead to multiple different
seemingly unrelated phenotypes.
And one good example of this is phenylketonuria or PKU,
which is one of the more common single gene disorders
that's diagnosed and it's part of newborn screening
to look for it.
It's the results of a mutation in one gene
and this can cause multiple phenotypic traits
that may appear unrelated.
As you can see here on the right-hand side,
this is a young man with untreated phenylketonuria
and he is in a wheelchair.
He also experiences intellectual disability, epilepsy.
He has fair skin.
As you can see down here, a mutation in the PAH gene,
which leads to PKU can result in a number
of different phenotypes that are often characteristic
of untreated PKU.
And this is a really severe condition
that can be treated by a specific diet.
Inheritance still follows Mendelian patterns,
but it is because it is from one gene.
And however, the difficulty can come
from looking at the patient.
That's what you look at as the patient.
You're seeing all these different kinds of traits
and symptoms and you're thinking, you know,
it could be related to maybe more of an aneuploidy
or something in the environment or something like that
as opposed to being the result of a single gene,
one gene being mutated.
However, that certainly can be the case
and when that is the case, it's called pleiotropy.
This indicates the protein encoded
by this gene likely functions in different systems,
as I said, and at different times,
potentially in development.
Genetic heterogeneity.
One good example of genetic heterogeneity
is polycystic kidney disease,
which I'm showing you a picture of polycystic kidneys
on the right-hand side here.
And what that is is almost like the opposite of pleiotropy.
So pleiotropy is mutations in one gene
affecting multiple different phenotypes.
This would be like seeing one phenotype,
in this case, polycystic kidneys,
and that could be caused by mutations
in a number of different genes.
Now, this is not polygenic.
It does not mean that you need a mutation
in each one of these genes to get polycystic kidney disease.
It does not mean that.
Genetic heterogeneity does mean that a mutation
in any one of these genes here,
in this case, for polycystic kidney disease,
any one of these three genes and mutation in those,
a disease mutation in those,
would result in this condition.
So you don't need mutations in all of them.
It's just in any one of them could give you this disease.
Now, what does that mean?
Well, it could potentially impact
when you're looking at what you would expect
from Mendelian inheritance for genetic heterogeneity,
you would expect to see, for example,
if this is an autosomal recessive condition, let's say,
and you have two parents that are both affected.
When they have children, you expect all of their children
to have polycystic kidney disease.
However, that's not necessarily going to be the case
if, say, one of the parents had a mutation
in the PKD1 gene and the other parent had mutations,
say, in the PKHD1 gene.
So then their children would actually be heterozygous
for mutations in each of those genes
and could be perfectly normal
if it's a recessive disease,
all that is causing the disease.
So I don't want to make this too confusing,
but just wanted to give you a sense
that it's not always so black and white.
So again, one phenotype may be caused by mutations
in any one of those different genes.
And a patient with PKD could have a mutation
in any one of those three genes
with the same disease presentation.
And you can also, it's important to keep in mind
that disease mutations in these different genes
may have different patterns of inheritance.
In this case, they do.
PKD1 and PKD2 mutations are dominantly inherited
while PKHD1 mutations are recessively inherited.
And often what is the molecular cause
of having a mutation in any one
of a number of different genes causing the same disease
is that these genes code for proteins
that are actually involved in the same pathway,
same molecular pathway, play a role,
maybe slightly different roles,
but all sort of lead to the same effect.
And so if you're interfering with any one of them,
you could basically shut down the whole normal function
and result in disease.
All right, let's talk about penetrance and expressivity.
So penetrance is the proportion of individuals
with a mutation causing a particular disorder
who exhibit clinical symptoms of that disorder.
So let's think of it a different way.
Percentage of the people who quote unquote
should have a disease based on genotype
that actually end up having it.
So what do I mean by that?
Well, sometimes with some diseases,
you can have the genotype for the disease,
but actually never develop the disease itself.
So disease with reduced penetrance,
it implies a patient with a genetic test result
indicates they will have,
or they have the genotype for the disease,
but actually don't develop the disease ever necessarily.
Some percentage of them may not ever develop it.
A very common example of this is the BRCA1/2 mutations.
And so these are related to breast cancer,
increase the likelihood of developing breast cancer.
So BRCA1/2 mutations,
they're actually dominantly inherited.
So if you inherit one copy from the mother or father,
then that increases your,
substantially increases your likelihood
that you will develop breast cancer
at some point in your lifetime.
However, it does not guarantee it.
So there are certainly some individuals
who never develop breast cancer.
And you can think for, in this case in particular,
well, what are some possible reasons for that?
Well, in the case of breast cancer,
as you're probably very aware,
that your likelihood of developing cancer
is strongly linked to lifestyle choices,
including diet and exercise, getting regular screenings.
So these can reduce the chances
of ever developing full-on breast cancer.
Some diseases that have a,
that are genetic diseases actually are not fully,
what would be considered fully penetrant.
They have reduced penetrance.
And so there isn't necessarily a guarantee
that the person will actually develop the disease,
even if they have the genotype for it.
So expressivity, what does expressivity mean?
Well, that means the extent to which you have symptoms
or the phenotype of a disease might vary.
So variation in the extent to
which a phenotype is expressed.
So this would be the extent to which an individual
who has a genetic disease expresses the symptoms,
mild, moderate, severe, and also the stage of onset,
whether it's early onset or late onset.
So variable expressivity is just
how a disease will play out.
A person does have the disease.
And so let's contrast this with penetrance
because oftentimes these two get confused,
these two concepts.
Penetrance is do you have the disease, yes or no, right?
Penetrance is a yes, no question.
If you, in diseases that have reduced penetrance,
there's a certain percentage of the population of people
who have the genotype who no,
do not ever develop the disease.
So that's sort of the yes, no question.
Expressivity is the extent to which you have a disease.
Do you have a bad case of it,
or sort of a less severe case of it?
Do you develop it early in life, later in life?
It's sort of how the disease plays out,
but you do have the disease.
All right, so disease with variable expressivity
implies patients with the disease
have variable degrees of symptoms,
severity, and presentation.
Example is shown here on the right.
Patients with neurofibromatosis,
an NF1 mutation will develop neurofibromatosis, they will,
but some will have mild freckling or cafe au lait spots,
as you can see here in this top picture,
and others will have life-threatening CNS tumors
and tumors all over the body,
as you can see in this picture on the bottom here.
So both of these individuals
have potentially the same mutation in the NF1 gene
that would result in neurofibromatosis,
but it plays out very differently
from one person to the next.
Remember, penetrance is the percentage of people
who actually end up developing the disease.
You have the genotype for it.
Expressivity is the degree or the extent
to which that disease is more or less severe,
earlier or late onset, how the disease plays out,
but a person does have the disease with expressivity.
So what causes incomplete penetrance
and variable expressivity?
Well, one reason is another concept called epistasis.
Epistasis is the effect of one gene's alleles
on another gene's alleles.
So this basically means we're not all,
they're not just a combination of single genes
and they all perform one single function.
No, no, no, it's a community going on inside of your cells,
and epistasis is quite common,
which basically means your genetic background.
Other genes that you, you know,
other mutations that you might have might be,
and other genes might be affecting
the way a particular disease mutation
that you've inherited is playing out.
It could also be influenced by the environment.
So this would include nutrition, stress,
any comorbidities you have, general health and wellbeing.
As you all know very, very well
that you see in your patients,
you can have two patients that are diagnosed
with the exact same disease
and it plays out quite differently.
And many times a lot of that has to do
with just how healthy a person is more generally.
How well do they take care of themselves?
What's their nutrition like?
What's their level of stress?
What other diseases do they have?
And sometimes a disease was present
but not diagnosed in a family member.
So when you're actually taking the family history
and looking at a pedigree,
it appears to be incomplete penetrance,
but actually it might not be.
It may just be that either someone passed away
before a disease would have presented itself.
So that's something that you might see.
Someone might say, well,
my grandfather had this dominant disease,
had Huntington's disease,
and then my dad didn't have it, so I'm okay.
Well, maybe or maybe not.
If say the father died,
if that person's father died
before he would have started presenting
with Huntington's disease symptoms,
it may appear to be incomplete penetrance,
but really it was just never diagnosed
because the person didn't live long enough
to have the disease express itself.
And similarly, it could just be that in some people,
they were just never diagnosed
and lived with a disease
or had a more mild form of a disease.
All right, so what are some of the implications?
Not all single gene diseases
will demonstrate the expected pattern
of inheritance based on phenotype
and be prepared to interpret
seemingly contradictory information
through those principles of types of dominance,
pleiotropy, genetic heterogeneity,
penetrance, and expressivity.
All right, so let's take a quick summary here.
Some alleles are not fully dominant to other alleles,
leading children to have a mixed phenotype.
So whether that's the blended phenotype
of incomplete dominance
or the sort of patchwork phenotype,
you can think of it as codominance.
One disease mutation in a single gene
can sometimes result in different traits
or phenotypes, this is pleiotropy,
and mutations in different genes
can sometimes result in the same trait.
And this is genetic heterogeneity,
sort of like the other side of the coin of pleiotropy.
Phenotypes may vary in presentation and severity
due to variable expressivity.
Remember that variable expressivity
is really the extent to which a disease,
how a disease plays out, basically.
A person has a disease and how it plays out
is variable expressivity.
Phenotypes may appear to skip presenting
in some individuals due to incomplete penetrance.
Incomplete penetrance means the percentage of individuals
who do not develop the disease
but do have the genotype for it.
Okay, so I think that's a pretty good list
of some exceptions that are important to stay aware of.
And so that wraps up this fifth module.
And what we're going to move on to
is some traits of non-Mendelian inheritance.
And here we're also going to start talking
about multifactorial genetic disease.
And so it gets a little bit more complicated
with actually a multifactorial genetic disease.
These are like what we would consider everyday conditions
of heart disease, diabetes, cancer.
Many of these are multifactorial genetic diseases
and they're incredibly important
for us to better understand.
So that's gonna be what's up next.
In the next module,
that's going to be in the next new material module.
I am going to give you in module six,
what we're going to do in the next week after this
is we're going to take a beat
and just absorb everything that you've learned,
not just in this module
but all the previous modules up until now.
It's a tremendous amount of material
and you're doing fantastic with it.
And I just want to make sure we take a moment
to absorb it all and make sure that it's all registering.
You'll have a chance to do your midterm exam
which will be based upon these first five modules
that you've learned as the foundation
for what we're gonna do in the second half of the course.
Yeah, with that, I will say goodbye
and I look forward to talking with you soon.