In our final podcast on basic genetics, we're going to talk about working with
pedigrees. There are actually several websites that you can go to to help you
design your own pedigrees. So, I clicked on this one just to show you an example
and I'm going to click on the English translation. You can use this to design
pedigrees. I'm going to go back now to our podcast.
What you need to do is learn how to read pedigrees and you want to know what
first-degree relatives are, second-degree relatives, third degree relatives. I'm not
going to go over the symbols on this chart, you should be able to learn these
on your own. First thing you might ask is about degrees of relationships or what
percentage of genes do people share in common. So, if I asked you what percentage
of genes do these two people, that are highlighted by the arrows, share in
common, I hope you'd be able to calculate, through the pedigree, that they contain
approximately 0.8% of their genes in common. The first thing to say is can
you realize that the third cousins? Here would be first cousins, here would be
second cousins, and here would be third cousins. Now, when you're looking at a
pedigree like this, the first thing to do is exclude people that are not really in
the family. So, in this instance, this person is not in the family except by
marriage. But then, if you want to figure out what percentage of genes do these
third cousins share in common, you can calculate back and you can say from that
person to that person they share half of their genes in common. Then, this person
to this person, half the genes in common. This person to that person, half the
genes in common. I hope you see what I'm doing. I'm trying to draw a straight line
from one person to the other through the family tree. Half in common, again, half to
half. Half in common. Half in common. So, you can multiply all of this out 1/2
times 1/2 times 1/2 times 1/2 times 1/2 times 1/2 times 1/2 is approximately
this fraction 1/128 or 0.8% of their genes in common. So, what did I
do? I'm looking at the coefficient of
relationship. Sometimes you can talk about consanguinity and the coefficient
of relationship, but if you want to know what percentage
of genes the individuals share in common, one way to do it is to just draw these
direct connections through the family tree, from one person to the other going
through the related people. So, from this person to that person, half of the genes
are in common. From this person to that person, half of the genes are in common.
From that person to that person, half of the genes are in common. That's the
simple way to do it. The other is to actually calculate the coefficient of
relationship. And what you would do is you would say, what is the relationship
between A and E to each beginning point on the family tree? So, A shares half of
the genes in common with B, B shares half of the genes in common with F, that
grandparent, F shares in half of the genes in common with D, D shares half of the genes
in common with E. And then, do the same thing for the other side of the family
tree going to that grandparent. So, you got 1/2 times 1/2 times 1/2 times the
half that's 1/16 plus 1/2 times 1/2 times 1/2 times 1/2 is a 16th. So, 1/16 plus
1/16 the 2/16 or 1/8. So, the simple way to do it is just draw the
direct line between the individuals in the family tree, and for our course it is
okay to do that. You'd have to be careful here in the sense of saying the pedigree
is actually reflecting what the true family history is. For that we would mean,
for example, that there's not a different relationship in the family. It is
sometimes useful to know the degree of relationship between people in a family.
Clearly, identical twins share 100% genetic identity. Maybe 20,000
genes in common. First degree relative as a parent to a child or a brother and a
sister, 50% of the genes in common. Second-degree relatives grandparent to
grandchild aunt or uncle to niece nephew or half sibs, 25%, and you can go
down and see what first cousins share in common, first cousins once removed, second
cousins, etc. It's interesting to realize that the background
risk for any birth defect in a population is something like 3%. So, you
think about it, if second cousins marrying are not necessarily at a higher risk for
any given birth defect than what's in the general population. Now, you do have
to understand that if there's rare autosomal recessive diseases in a family
those diseases may be manifest. How close a relation can you marry? Well, it turns
out that second cousins can legally marry in all 50 states in the United
States. Here's an example a brother and a sister, here, show symptoms of a genetic
condition that's not seen in the family before, so what type of inheritance is
this? Well, the first thing to note is consanguinity in a relationship and
consanguinity in a relationship, if you've never seen the disease before,
suggests they may be an autosomal recessive mutation in the family. I've
purposely pointed out that these individuals are carriers. So, again, makes
the point that there's an autosomal recessive condition in the family. What
is the risk that these two parents, who happen to be cousins, will have another
affected child? See, they have two affect the children, what if they have a fifth
child, what's the risk that that child will be affected? Well, you can do the
punnett square and you'd say, for example: Aa
crossed Aa. What it would say is there's the 25% risk that the next
child would also have the genetic condition as the two children they've
already had. What percentage of genes do they share in common?
Well, again, you can look at the degree of relationship, they're cousins
so it would be 1/8. So, I go from this person to that person as 1/2, from this
person to this person is 1/2, so 1/2 times 1/2 is 1/4 and this person to this
person as 1/2, so 1/2 times 1/2 times 1/2 is 1/8 or 12% of the genes they share in
common. This pedigree represents a family with a genetic disease.
What can you conclude about the disease-causing mutation? Is it for
example an x-linked disease, is it an autosomal dominant disease is it an
autosomal recessive disease, or a mitochondrial disease? Looking at the
pedigree, it suggests that there's vertical transmission. The disease is
appearing in each generation. It's appearing in both men and women. It
suggests that it's an autosomal dominant disease. So, now, another question. If the
person in the third generation labeled at A marries an unaffected person not
related to her, what is the risk that her child will have the same disorder that
her cousins have? And we're going to assume here that it's complete
penetrance. If it's an autosomal dominant condition with complete penetrants, she
does not have the disease. That means she does not have the mutation. She marries
someone not related to her, then her children would have the background risk
of having this disease. In other words, whatever the spontaneous mutation rate
is they would not have the risk that their cousins have of having the disease,
indeed they probably wouldn't have the disease if it's a relatively rare
disease. All of the individuals indicated here have the same genetic disease. What
can you say about individual one in the second generation. Does he carry a
recessive gene, a dominant gene, an x-linked gene, or does he not carry a
disease-causing gene? Well, this one becomes rather interesting because you
can see on this side of the family it looks like autosomal dominant
inheritance and it looks like it's a vertical inheritance pattern. But here,
you wonder if no disease his brother is showing the disease he's not, but then he
has two children with the disease? Is he a germline mosaic? Potentially. Well, maybe
he carries an autosomal dominant condition that shows reduced penetrance.
And without any other clinical information, that would be the most
likely conclude in this case. You know, we're not saying
any family history other than that. We're not giving you any indication of what
the disease is. So, he's likely got an autosomal dominant
condition. He's inherited the disease gene, but it's showing reduced penetrants.
What about the two individuals in the third generation that are unaffected. Do
they contain normal genes, mutant genes, or are they heterozygous? You can really say
is that these individuals have a normal phenotype. They could indeed have
inherited the diseased or mutant gene and depending on how penetrant it is, one
would need to do genetic testing on these individuals to know if they have a
likelihood of passing the disease to their offspring.
What pattern of inheritance is shown here? An autosomal dominant, an autosomal
recessive, an x-linked dominant, a x-linked recessive, or a y-linked disease?
It's interesting, we see only females affected. This suggests that it's an
x-linked disease and since we see a lot of aborted fetuses, it's probably an
x-linked dominant disease and the males probably died in utero. What type of
inheritance pattern is shown in this pedigree? Here we're seeing inheritance
only through the maternal individuals. This is likely a mitochondrial
inheritance pattern. Here's another situation.
This family has hemophilia A and so we're indicating individuals with the
disease. This individual happens to be deceased.These individuals are carriers.
What is the risk that the unborn child is going to have this disease? So, the
first question to ask hemophilia A, how is it inherited? Well, we know it's
inherited in an x-linked manner, so can this child's mother be a carrier and if
so, what's your risk of being a carrier? You can work the punnett square. She
certainly could be a carrier. We know that her mother was a carrier, so we can
say well, her mother, carrier, represented like this, mating with her father.
We know that she has a 50% chance of being a
carrier. So, if mom is a carrier, what's the likelihood that she passes the disease
to her child? Well, it's a half, but you got to consider it's a half risk that
she passes the disease to her child, but it's a half risk that she's a carrier so
it's a half times a half. But then, since it's an x-linked recessive gene, the
person showing the disease has to be a boy, so it's 1/2 times 1/2 times 1/2. So,
it's a 1/8 chance that this unborn child is going to have the disease. Is a
genetic disease in the family, what's the likelihood that the unborn child, shown
with the red question mark, has the same condition as the proband. The proband
is this individual marked with the arrow. This is the answer 1/32 and this is
finally working out the pedigree. What I'm going to do is work back and tell you
how I would have come to that conclusion. So, the first question I would ask is
what kind of inheritance or disease does the proband have? And if I look at the
pedigree, the first thing I see is he has some type of a disease and his parents
are in a consanguineous relationship. That suggests an autosomal recessive
disease because it hasn't appeared anywhere else in the family. So, I'll say
he's aa. The proband's parents must be carriers. I'll say they're
Aa and I can represent them that way.
The proband's grandfathers are also most likely carriers Aa, so I can
represent them like that. I don't know anything about the individuals they
married. I'm going to assume, as you should assume in any situation when you're
trying to do a calculation, assume people that are outside the family are normal
and not carriers. So, I'm going to assume that this person's mate was normal AA,
likewise, she's normal AA, likewise, these
individuals are normal AA. We'll use that as kind of a ground rule if
you're trying to solve a problem for our course. One of the proband's
great-grandparents is also likely to be a carrier. I haven't put it in on this
pedigree because I don't know which one would be the carrier and it really isn't
relevant to me trying to solve the question I'm asking, that is what's the
likelihood that the unborn child has the same condition as the proband. What I
can do is start working some punnett squares. We can say well, if you cross a
carrier or the normal individual, so I'm looking at this individual, for example,
Aa cross with AA that means this person has a 1/2 chance
of being a carrier. That person shares one-half of their genes in common with
that person. This person shares one-half of their genes in common with that
person. And that person shares one half of their genes in common with that
person, that's this half of the pedigree. Now, I'm going to say this person going
to here, aa with AA, I know that this person must be a
carrier. Do the punnett square. That person has to be a carrier. This person
is a carrier and shares one-half of the genes in common with that person. So,
therefore, I would say 1/2 times 1/2 times 1/2 times 1/2 times 1 is not
relevant, times 1/2 is 1/32 . So, the likelihood that the unborn child shares
the same condition as the proband is 1 out of 32. And that's fortuitously
interesting, because 1/32 is approximately 3% and as you
remember, 3% is the background risk that any child has for having any birth
defect.