OK. We are wrapping up our segment on genetics today,
Genetics 4. We're going to talk about human disease genetics,
modes of inheritance for human diseased genes.
And then we'll transition next time into molecular biology,
which is the next blank square here. And then recombinant DNA cell
biology and beyond. I wanted to start today by clearing
up a couple of things. Firstly, the term F1,
in the last lecture I gave you a list of terms,
and I used this definition of the first filial generation,
the F1 generation as the product of crosses between two homozygous
individuals, homozygous for different alleles such that the
offspring were always heterozygous, big A, little A at that particular
gene. Well, it turns out that some people
use the term F1 to refer to the offspring of any cross.
So you have the parents and you have the F1s regardless of the
genotype of the parents. So that's a looser definition of
the term F1. And it's been used in Section and so on,
so I didn't want to confuse you. The strict definition is the one I
told you, but don't get hung up on that. We're always going to give
you the relevant genotypes so you'll be able to figure out what the
genotypes of the offspring are. Also, near the end of the last
lecture, I talked about crosses involving linked genes.
If you remember the Y and D gene controlling color and density,
I think, of peas. And I told you that they were linked,
and we carried out a test cross. And we then worked out what the
percentages of the different phenotypes and genotypes would be.
Well, in that example, I assumed that the Y allele and the
D allele were together on the same chromosome. But importantly if
you're just given the genotype as it's written here,
you actually cannot know that. The big Y might be on the opposite
chromosome from the big D. So to avoid confusion about that
sort of thing, in future examples and in problems,
problems, that is test questions, we'll always show you the
chromosomes so you'll know that the genes are together on the same
chromosome or on opposite. Yeah. And in the absence of this,
if the question is to tell us what the alleles must look like and they
give you the phenotype, you have to conclude the genotype.
If the question is tell us what the alleles must look like then we're
not going to give you the answer, but in other situations where
there's ambiguity about what the alignment might be, we'll
tell you what that is. OK? We also had a question from a
student, actually an emailed question, those are also welcome,
email question from a student. It was good question because in our
discussion of dominance and recessiveness,
we really haven't dealt with the molecular nature of that.
And that was this individual's interest. Why is an allele dominant
over another one? Why is a trait dominant over
another one? And I gave an example to him,
which I will give to you, which I think covers most of the examples
that we've been discussing in class. And it also is an opportunity for
me to reinforce the notions related to chromosomes,
genes, DNA and proteins, because apparently there are some of
you who are still a little fuzzy on those relationships.
So let's imagine a gene which is present on a chromosome.
Chromosome shown here. Gene shown here. And it's the S gene that
we've talked about before that controls smooth versus
wrinkled pea texture. So here's the S gene.
It's made up of DNA. And based on the sequence of that DNA within the
gene, therein lies the information to produce a protein.
And we're going to call this protein, in our example,
this is a hypothetical example, the starch synthase protein. It's
an enzyme that controls a reaction, that catalyzes a reaction from some
sugar substrate into some starch. And if you make enough of that
starch product then you have a smooth shape.
OK? This enzyme controls shape because it produces this product
which is involved in the shape of a pea. OK? So this is the normal
situation. The big S allele produces a functional starch
synthase enzyme which produces enough product to give the pea its
smooth shape. In this example, the little S allele, which is the
recessive one, has a mutation within the coding
sequence of the gene. We won't talk about the nature of
that mutation just yet, what it is, why it causes what it
does because you're going to get that in the next segment.
Just suffice to say that it's a mutation, an alteration of the DNA
such that the protein that's produced from this allele is
nonfunctional. You might be able to see I've
inserted a little X there. It's actually quite little and
invisible on your handout, but you might want to just circle it
if you look carefully. There's a little X there which is
the result of this mutation. And that X causes the protein to be
nonfunctional. The enzyme now does not catalyze
the production of this starch product, so no starch product is
produced. If you don't make the starch product you don't have a
smooth shape, you have a wrinkled shape. OK? If the genotype of the
pea is little S, little S then none of this enzyme is
produced such that none of the starch product is produced such that
the pea is wrinkled. OK? Now what happens if you're big
S, little S, the heterozygote? Well, for many biochemical reactions,
having just one copy of the gene that encodes the functional enzyme
is enough. For many biochemical reactions that's true.
And so in a situation where big S is dominant over little S,
we assume that having one copy of big S makes enough of the starch
synthase protein to make enough of that starch product to give the pea
its smooth shape. OK? So that's a simple example of why
big S is dominant over little S, why you only see the phenotype
associated with the little S allele, the wrinkled phenotype when you have
two copies of the little S allele. OK? So I hope that helps clarify
the situation for you and actually is useful as we talk about human
disease genes as well. So this is a slide from your book
which allows us to transition from concepts of inheritance
to real-life stuff. Genes that regulate how your body
functions normally or in response to various environmental stresses.
We're now in an era where we can relatively easily figure out whether
a disease has a genetic component by looking at families that might have
that disease, and based on that information and using mapping
techniques like I described to you last time, we can isolate where that
gene might lie on all of your chromosomes.
And then using molecular techniques, which we'll talk about in future
lectures, we can actually isolate that gene, determine its sequence,
and based on that produce lots of various valuable things like better
ways to diagnose the disease, better ways to understand how the
disease process takes place such that we can then perhaps prevent the
disease from occurring in the first place or treating it more
effectively by replacing the gene with a new copy or producing a drug
that can replace the gene in other ways.
So this is what we're after. So we need to understand diseased
genes and how they behave in such affected families.
So there are a number of diseases which have a genetic component.
And these diseases have various modes of inheritance.
Some of them are autosomal dominant.
The diseased gene is dominant over the wild type gene,
and I'll give you examples of that. And the term autosomal means that
it's not sex linked. That is the disease gene is carried
on chromosomes 1 through 22, one of the those chromosomes,
not on the X or the Y. It doesn't matter if your father,
whether the disease gene is coming from a male or a female,
passed on to a daughter or a son. There's no sex linkage for these
autosomal dominant diseases. There another class of genes,
disease genes which follow autosomal recessive inheritance patterns.
Here the disease gene is recessive to wild type.
You only see the disease phenotype when you're homozygous for the
mutant allele. And, again, autosomal because it's
not sex linked. There are X linked diseases which
are dominant. In this case, the disease gene is on the X
chromosome. There are also X linked diseases that are recessive.
There are very few,
but for the sake of completeness, Y linked diseases. But there are so
few that we're actually not going to talk about them at all in this class.
And, finally, there's a class of diseases that
we're also not going to talk about but get inherited not from the genes
that are in the nucleus of the cell along your chromosomes but rather
get inherited from the mitochondria.
And since we haven't talked about mitochondria with you really at all
we're not going to expect you to know about those diseases,
but just have in the back of your minds that those are relatively
important. Autosomal dominant diseases are not terribly common.
There are about 200 known. Autosomal recessive diseases are
actually much more common, though not very frequent in the
population. There are about 2,
00 of these known. And together I would estimate there are about 25
sex linked diseases. So we've used the term autosomal
dominant, autosomal recessive, sex linked. What does this really
look like in terms of the genes and the alleles?
Well, just as in the case of peas,
a dominant disease allele will cause disease regardless of the nature of
the other allele. It's dominant over the normal
common version of the gene. So if we call this allele the
disease allele of some gene --
-- and this allele the commonly found on in the population,
and we refer to these often as the wild type --
-- in an individual who has this
genotype for a dominant disease gene, will they develop disease?
Yes, because the disease allele is dominant over the normal copy of the
gene. So these individuals will develop disease.
For recessive disease alleles you
need to have both copies, both alleles be mutant in order to
manifest the disease. So here's another gene,
which we'll call the H gene, which has a disease allele. This
individual is homozygous for the disease allele.
Will this individual develop disease?
There might be other people in the
population who are heterozygous for that allele and have a wild type
allele on the other chromosome. Will they develop disease? No.
These individuals are called heterozygous carriers.
They carry the disease allele,
but because they also carry a wild type allele they don't develop the
disease. They're normal. They're normal in the sense of their
phenotype. They have an abnormal genotype in the sense that they have
a disease allele, but they're normal in the sense of
their genotype, phenotype. Now,
for X linked genes, sorry, before I do that let me --
Let me review for you sex determination.
We talked about this briefly. In order to understand the
inheritance pattern for X linked genes you need to remember this.
That males of course have one X chromosome and one Y chromosome.
Females have two X chromosomes. If you think of a Punnett Square
related to the inheritance of chromosomes males will pass along an
X or a Y at 50% each, females will pass along one of their
two Xs.
Will produce an equal number of males and females from such crosses.
But it's important to think about where the X chromosomes come from,
specifically males and the Y chromosomes.
Males transmit their only Y, their only Y to all of their sons.
If you're the son then you've gotten your father's only Y.
Males transmit their only X chromosome to all of
their daughters.
If you're the daughter, when you're the daughter of a male,
you have inherited his X chromosome. OK?
Females transmit either X to each
daughter or son. In the case of the female X,
you can be a male who got this X chromosome or a male who got this X
chromosome. You can be a female who got this X chromosome or a female
who got this X chromosome. And that's important for
understanding the disease genetics. So let's imagine a dominant disease
involving the X chromosome.
A gene, we'll call it Q. Males only have one X chromosome.
They only have one X chromosome, therefore if they carry the disease
gene they're going to get disease.
Females have two X chromosomes. They might carry the disease allele
on one but a normal copy on the other. In this scenario,
will they develop disease? Yes, because it's a dominant
disease allele.
For recessive X linked disease, once again, males only have one X.
Are they going to get disease? Yes. Females have two X chromosomes.
If they carry a disease allele on one they are likely to carry a wild
type copy on the other. Are they going to get disease?
No. They're going to be heterozygous carriers.
And you'll see how this plays out
towards the end of the lecture.
OK. So let's look at some examples. We're going to start with recessive
diseases first, recessive autosomal diseases first.
And one you've already seen before,
and that's PKU, phenylketonuria. If you recall, this is a disease which
is associated with failure to make an enzyme that converts
phenylalanine to tyrosine. It's an enzyme called phenylalanine
hydroxylase. If you don't have that enzyme then you produce too much of
this byproduct, phenylpyruvic acid which is toxic
and leads to brain damage and retardation.
This can be avoided, the disease can be avoided by
limiting your amount of dietary phenylalanine.
And that's why such patients are not supposed to have Equal,
as we discussed before. The disease, PKU, is autosomal recessive.
The incidence is rare, about one in 10,000 to 15,000 individuals have
PKU. As I talked to you about last time, the mutant allele has a single
amino acid chain change in the active site of this enzyme which
changes an arginine residue to a tryptophan residue.
And that makes the enzyme inactive. This is an autosomal recessive
disease. So if you have one mutant allele and one normal copy of the
phenylalanine hydroxylase gene, do you have the disease? No. You
would be a carrier but you would not have the disease symptoms.
Because again, as in the other hypothetical example,
most of the time, if you have a single normal copy of an enzyme that
carries out some biochemical reaction that's enough and your
phenotype is normal. Here's another common example,
cystic fibrosis. This is actually a more common disease.
It affects about one in 2, 00 to 3,000 individuals. That's not
an insignificant number. So there are a lot of people with
cystic fibrosis in this country. Again, it's autosomal recessive.
Patients present with the disease at birth.
They have problems both in their intestinal system as well as in
their lungs. It tends to be the lung symptoms that ultimately kills
the patient due to inability to breathe properly,
but actually more importantly persistent infections which
ultimately are so severe that they lead to death.
And these patients tend to die within the first two to three
decades of life. The gene encoded by the disease,
the gene responsible for this disease is a chloride channel.
When it functions properly it allows chloride ions to move through,
and this achieves a proper water balance inside the cells.
When the disease allele is present in both copies,
this channel is not formed properly, and therefore the water balance in
such cells is not correct and it leads to the build up of this kind
of mucousy sticky substance both in the lungs and in the intestines.
These individuals, as you can see, have a very hard time breathing, and
they have to get this mucous cleared from their lungs periodically.
And they also often have to have respirators to allow them to breath.
OK. So that's some examples of autosomal recessive diseases.
Let's think about the genetics. And we'll talk about CF
specifically. Let's imagine the disease allele of CF.
We'll call it CFD. There are actually many different disease
alleles for this disease, but we'll just lump them together.
Here are two individuals with this
genotype. Do these individuals manifest the disease?
Yes or no? Do they manifest the disease? No, because this is an
autosomal recessive disease and they have a wild type copy.
But if we think about the offspring that they could produce,
this individual will produce gametes that carry the D allele and the wild
type allele, likewise this individual, the D allele and the
wild type allele, such that the offspring will either
be DD, wild type D, wild type, wild type or wild type,
D. Right? So you'll have one wild type,
wild type individual produced out of such a cross. And this individual
now has no disease allele present. This individual is both
genotypically and phenotypically normal. No more issues about cystic
fibrosis for this person or his or her descendants.
There will be two individuals who are heterozygous,
and these individuals are carriers. They don't have the disease but they
do have a mutant allele. So depending on whom they marry,
I shouldn't generalize, depending on whom they have children with they
may or may not have to worry about the fact that they have a mutant CF
allele. And one, on average, out of four will have
two disease alleles and develop CF. OK?
So we're going to now think about
these diseases in inheritance looking at pedigrees,
which I think are probably familiar to most of you.
They're described in your book as well. But I just want to make sure
you understand what the symbols mean before we get into it.
Females are represented as circles. Males are represented as squares.
Seems appropriate. Lines between them represent a
mating, they have mated. And the offspring are represented
below.
If the symbol is left open then the individual is normal,
genotypically and phenotypically. If the individual has a shaded
symbol they are affected, they show disease symptoms.
And if the symbol is partially shaded, I usually fill in half the
symbol, the book will sometimes put a little circle inside the circle
then they are carriers. They're heterozygous carriers.
OK? So let's look and think about this example up here.
We talked about two individuals who were both heterozygous for the
disease allele, so they were carriers.
Their genotype was CFD, CF wild type.
They mated. They had
four children.
There were four possible genotypes, rather three possible genotypes.
And, in fact, we observe all three genotypes in this generation.
We have one individual over here who doesn't have her symbol filled.
We have another whose symbol is fully filled.
And then we have two whose symbols are partially filled.
What's the genotype of this individual? Wild type,
wild type. This one? D, D. This one? D, wild type.
And this one? Same thing. OK? So that's what pedigrees look like.
Let me show you a larger pedigree and give you some of the rules that
apply to autosomal recessive diseases. So here's a large
pedigree involving an autosomal recessive gene,
disease gene. Again, the two parents are heterozygous.
They had many, many offspring all here. Roughly a quarter of them
will carry both copies of the disease gene and develop disease.
Among the rest there will be unaffected individuals but of two
classes, ones that don't have the disease gene at all and ones who are
heterozygous carriers. Two-thirds of those unaffected
offspring are themselves carriers, two-thirds. Two-thirds of the
unaffected offspring are themselves carriers.
Among those half of the offspring of a carrier are themselves carriers,
as shown here. So if this individual came to you at a genetics
clinic and wanted to know what is my likelihood of carrying the D mutant
allele, you'd be able to say, without knowing the genotype of his
mother you would be able to say that it's half of a half
or a quarter. OK? Now, every once in a while two
affected individuals, two homozygotes have children,
as shown here. And you can see in that scenario all of the offspring
have disease because the only alleles that are present are the
mutant alleles. That has to be true because these
are both affected, and therefore all of the offspring
will also only inherit mutant alleles and develop the disease
themselves. OK? And importantly because the disease
gene is coming in on chromosomes 1 to 22, one of those and not the X or
the Y, there is no gender associations here.
Mothers can pass the disease to their daughters and their sons.
Fathers can pass the disease to their daughters and their sons.
There are no gender associations with this scenario.
OK. Disease alleles are present in different frequencies in the
population. Some of them are extremely rare,
but some of them are actually rather common.
So we're talking about the allele
frequency, the percentage of alleles among all of our chromosomes that
are the disease type. For PKU it depends a lot on where
you're from. For example, in Turkey it's actually
rather common, one in 206,000 alleles of this gene
are mutant in this population, but in Japan it's much less common.
One in 220,000 Japanese carry this allele.
Exactly why this is we're not entirely sure,
although I'll give you some speculation in a little while about
what controls the frequency of these actually rather deleterious alleles.
CF is fairly frequent. One in 25 alleles are CF.
One in 25. There are as maybe 200 of you in this room,
so that's some number of mutant alleles among you. It's
a fairly high number. You're sitting there carrying a
mutant copy of the CF allele. This is actually relevant to
European descendancy. I'm not entirely sure whether it
applies to all descendencies but let's just say that it's roughly
that number. And another disease that you might have heard of
Tay-Sachs disease in the Ashkenazi Jewish population --
-- is also quite common.
One in 25. It's so common, in fact, that in certain parts of
the world individuals undergo genetic testing before they decide
whom to date because they want to avoid the risk that they're going to
date somebody else who carries such a mutation.
This is actually a very horrible disease. I shouldn't joke about it.
So they want to avoid ever having to face the problem of having a
child who has Tay-Sachs disease. So they undergo, in a sense,
pre-marriage counseling to figure out their genotype to decide whether
or not to date. And you can also imagine with
similar tests we could figure out whether or not individuals carry
mutations in these genes to let them know what their risks of developing
disease are or whether or not to maintain a pregnancy of a child who
may or may not be affected and so on.
So they're very serious societal implications for these kinds of
disease alleles. Now, some of the alleles are very
rare. Here's one example in the Japanese population of PKU.
The likelihood that two individuals would randomly get together who had
mutant alleles of a phenylalanine hydroxylase gene and have a child is
exceedingly small. And so in these situations,
where the allele frequency is extremely rare,
when you find an affected individual it's almost always a sure sign of
inbreeding. Consanguinity is the term used in genetics where cousins
or other relatives marry and have children. And since they are
related and have a higher allele frequency within their families of a
particular allele then the likelihood that they'll have an
offspring who has two copies of the allele is much higher.
And so when you see a pattern such as this, it's a fairly clear
indication that you're dealing with an autosomal recessive disease
involving consanguineous mating. Here are two cousins who are
producing offspring both of whom are affected. And when you see a
pattern like this you can actually figure out, or at least figure out
pretty well who were the carriers in this scenario,
who were the carriers in this family. Since both, since the children have
two mutant copies then both of their parents must be heterozygous
carriers. OK? That goes without saying.
They're heterozygous. Since this individual is heterozygous and the
allele was passed on from their grandparents then his mother must
also carry the allele inherited from one of the two grandparents.
Likewise this woman's father must carry the mutant allele.
And in this generation we actually don't know whether it's the male or
the female who carries the mutation. It could be either. And it's been
passed along to both sides of this family tree and reduced to
homozygocity in this generation. OK? You can also begin to figure
out what the likelihood of other members of the family tree
is being heterozygous. So this individual here has a one in
two chance. One of these two parents is definitely a heterozygote,
and so the likelihood that he's a heterozygote is one in two.
And among his children you could say they have a one in four chance.
If he has a one in two chance then there's a one in two chance that
he'll pass it onto them, so overall there's a one in four
chance that they will be themselves carriers.
And this, again, this kind of genetic testing is done
frequently to figure out what your relative risk of developing a
particular disease are. Now, as I said, for other disease
alleles like CF and Tay-Sachs, the allele frequency is actually
strikingly high. And yet if you're homozygous for
these mutations you're dead. Not necessarily right away but not
for very long. It clearly reduces your
reproductive fitness. And so why would these alleles be
present in our population at all? Why wouldn't they be removed
through natural selection? We're not going to get into this in
great detail, but there are theories out there and some evidence to
support them that there might be actually an advantage in certain
circumstances for being heterozygous wild type over mutant.
And there are theories both related to Tay-Sachs disease,
sickle cell disease and cystic fibrosis such that if you are
heterozygous you actually survive better in the face of certain
pathogenic exposure than do people who are wild type for both alleles.
And that's the argument for why these alleles actually built up,
at least in the past, over the evolution of our species.
OK. Let's transition now to autosomal dominant diseases.
This is a famous example, Huntington's disease,
otherwise called Huntington's chorea. Relatively rare.
About one in 10, 00 to 25,000 individuals affected.
It exhibits an autosomal dominant pattern of inheritance,
as you'll see in a moment. The age of onset is about 35 to 40
years of age. These individuals actually are totally normal for the
first three to four decades. You wouldn't know that they had a
disease. But starting at that time they begin to develop symptoms which
involve both effects on their personalities but more importantly
effects on their movements. That's what you first begin to see.
That's what chorea means. It's sort of this dance-like movement.
And then that gets much, much more severe and stereotypical.
And eventually, in addition to that, there's death of cells in the brain.
And the combination of these affects leads to the death of the
individual by about the fourth or fifth decade of life.
This is actually a movie of an individual who has Huntington's
disease. He's being told to hold his arms
straight out, but because of this neurogenerative process that's
taking place within his brain and also other parts of his nervous
system he's unable to do so. And this is sort of the
stereotypical presentation of Huntington's chorea.
They have this wave-like movement and also their limbs get stuck in
particular postures, as you can see this individual here.
At the molecular level the problem in these individuals is that their
brain cells are dying, particular ones, actually,
within a particular region of the brain surrounding this ventricle
here. And this is a normal space in a normal brain.
And there are various sets of neurons on either side of those
ventricles. And in HD patients those cells are progressively lost
over time, and when those cells are lost you lose motor control and you
also develop rather severe dementia.
And the reason that those cells are being lost is that the mutant
protein, the mutant form of this protein called Huntington,
the mutant form builds up inside of those cells and aggregates and
causes the cells to die. OK? And this is why this is an
autosomal dominant disease. If you have the disease allele then
you will get the aggregation of the protein and you will develop
the disease.
So let's take another example of a cross between an individual who is
normal, two normal copies of HD and an individual who has a disease
allele and a wild type allele who is heterozygous. Is this
individual diseased? He either is already or he will be
in the case of HD. It's an autosomal dominant disease.
If you have the disease allele you will develop disease.
If we look at a Punnett Square, this individual will always transmit
the wild type allele, this individual will transmit the
mutant allele half the time the wild type allele of the other.
These individuals will be wild type D, wild type D,
wild type, wild type, wild type, wild type.
So you'll get half diseased, half normal. OK? A rather
different picture than we saw previously. And importantly,
as I mentioned, the presence, the mere presence of the D allele leads
to the production of this toxic protein.
And ultimately brain damage. And that's why it's dominant.
OK. So let's look at a pedigree of an autosomal dominant disorder.
Here's an affected individual, a female who marries,
who has children with an unaffected male.
They have four children. On average half of them will
inherit the defective allele and therefore develop disease.
Half of the offspring of an affected parent will be affected.
Importantly, the unaffected offspring of an affected parent have
unaffected offspring. If you are normal, you do not
inherit the disease allele, you're scot-free. Your children will
no longer have to worry about this disease.
But in this case, in this individual,
again roughly half, in this example two-thirds of the offspring do
develop the disease. This is another really important
case of genetic testing. This guy might have wanted to know
that he was going to develop Huntington's disease in order to
decide whether to have children in the first place.
This individual here likewise might want to know before the disease
actually manifested itself what would happen in order to make
lifestyle decisions. Am I going to quit work and have a
good time for the next ten years? Because pretty soon I'm actually
not going to be able to. So genetic testing actually can
make an extremely important set of decisions for individuals affected
in this way. And there's actually a subtlety here,
too. Sometimes people don't want to know because there's actually
nothing to be done for them. In the case of Huntington's disease
that's true. We don't have a cure for it.
So Arlo Guthrie who is the son of Woody Guthrie,
who died of Huntington's disease, apparently doesn't want to know
because if he learns that he's going to get it he's just going to be
depressed. If he learns that he didn't get it he might be relieved,
but he doesn't want to take that chance so he's just leading life in
hopes that he doesn't have the disease allele.
Now, I actually don't know in his case whether he has children or not.
He has children, so he actually made that decision almost for his
children as well. So important implications for these
kinds of genetic diseases. Now, here's an interesting pattern
that I want to share with you. And this relates to a phenomenon
called penetrance.
Penetrance. Penetrance is a number which reflects the percentage of
individuals who have the disease genotype who end up getting the
disease. I've been telling you about examples where that's 100%.
If you have the disease genotype you get the disease.
But that's not always true. Sometimes you can have the disease
genotype, but because of other factors like environmental factors,
what you eat, what you get exposed to you actually don't
develop the disease. Or maybe you just got lucky because
some of these diseases are stochastic in nature.
And you might have been one of the lucky ones. That would be an
example of lack of penetrance. You have the disease genotype but
you don't have the disease itself. And this can lead to the
development of individuals in pedigrees, such as the one I'm going
to show you, who are obligate carriers, obligate carriers.
We call them obligate carriers because they have a child who is
affected but they themselves were not affected. And they have a
parent who likewise was affected. So the simplest explanation for a
pedigree such as this is that this mother passed along the disease
allele to her daughter but she did not manifest the disease,
an example of lack of penetrance, but she still had the disease allele
which she passed onto her daughter who developed disease.
OK? And we call these individuals obligate carriers.
Even though they don't manifest the disease they must be carriers.
And in that sense this circle should be shaded.
We haven't shaded it because actually there are other
explanations for how you can get this pattern. Sometimes,
for example, the disease is such that there are non-familial forms of
the disease which complicate the analysis. Heart disease is a good
example. There are familial forms of heart disease and there is
sporadic heart disease. Maybe this woman doesn't have the
predisposing mutation and her daughter just developed heart
disease. That can happen. Another example is that maybe she
picked up a new mutation. Her mother is actually clean but
she picked up her own mutation in the development of the sperm or egg
that gave rise to her, and then she has the disease.
That would be rare but not unprecedented.
And the final example, which is the most interesting,
is so-called non-paternity or even non-maternity.
So we're making an assumption here based on what the family has
provided us in terms of this pedigree that this girl is the
daughter of this mating, this woman and this man. But about
10% of kids born in this country actually have a father who isn't
their father. It's a shocking statistic, I know,
but it's true. This is called non-paternity.
So it might be the case that this woman actually doesn't have the
mutation. It's just that her father, her mate, the father of this girl
[LAUGHTER] is not that guy. And this is sick but true, most
often in situations like this it's Uncle Bob or brother Steve.
I know it's disgusting but this is often an example,
the explanation for examples such as this.
And another interesting example is non-maternity.
We're assuming that this is the mother of this child but sometimes
families don't want to admit, for example, that this girl had a
baby. And so they give it to Aunt Sue. And now Aunt Sue's child gets
the disease, but it's not because of Aunt Sue's genes.
It's because of her cousin. OK? So here are some examples.
Now, I have one more minute, and I need to riffle through the
slides because I'm going to leave you for a few days.
And I want to just remind you that there are X linked diseases that
affect, that are both dominant and recessive. Most of them are
recessive. And here's a classic example, an X linked recessive
disease involving hemophilia in the royal families of Europe.
Importantly, when you look at X linked disease pedigrees,
and here's Duchenne muscular dystrophy, another familiar disease,
again X linked recessive, there are certain rules that dictate the
development of the disease over the generations.
They're summarized here. And you should look in your book
for more information. And, finally, there are rare
examples of X linked dominant diseases, and their rules of
inheritance are somewhat different. So you should familiarize yourself
with X linked modes of inheritance.