WEBVTT

00:00:01.000 --> 00:00:03.000
I want to go back a second to the
end of last time because in the

00:00:03.000 --> 00:00:06.000
closing moments there, we, or
at least I, got a little bit

00:00:06.000 --> 00:00:09.000
lost, and where
the plusses and

00:00:09.000 --> 00:00:12.000
minuses were at
a certain table.

00:00:12.000 --> 00:00:18.000
And, I want to go back and make
sure we've got that straight.

00:00:18.000 --> 00:00:22.000
We were talking about a situation
where we were trying to use genetics,

00:00:22.000 --> 00:00:27.000
and the phenotypes that might
be observed in mutants to try to

00:00:27.000 --> 00:00:32.000
understand the biochemical pathway
because we're beginning to try to

00:00:32.000 --> 00:00:36.000
unite the geneticist's point of
view who looks only at mutants,

00:00:36.000 --> 00:00:40.000
and the biochemist's point of view
who looks at pathways and proteins.

00:00:40.000 --> 00:00:44.000
And, I had hypothesized that there
was some biochemists who had thought

00:00:44.000 --> 00:00:49.000
up a possible pathway for the
synthesis of arginine that involved

00:00:49.000 --> 00:00:53.000
some precursor,
alpha, beta, gamma,

00:00:53.000 --> 00:00:57.000
where alpha is turned into beta;
beta is turned into gamma; and gamma

00:00:57.000 --> 00:01:02.000
is used to turn into
arginine. And, hypothetically,

00:01:02.000 --> 00:01:06.000
there would be some enzymes:
enzyme A that converts alpha,

00:01:06.000 --> 00:01:10.000
enzyme B that converts beta,
and enzyme C that converts gamma.

00:01:10.000 --> 00:01:14.000
And, we were just thinking about,
what would the phenotypes look like

00:01:14.000 --> 00:01:18.000
of different arginine auxotrophs
that had blocks at different stages

00:01:18.000 --> 00:01:22.000
in the pathway. If I had
an arginine auxotroph that

00:01:22.000 --> 00:01:26.000
had a block here because let's say
a mutation in a gene affecting this

00:01:26.000 --> 00:01:30.000
enzyme, or at a block here
at a mutation affecting, say,

00:01:30.000 --> 00:01:34.000
the gene that encodes enzyme C,
how would I be able to tell very

00:01:34.000 --> 00:01:38.000
simply that they were in
different genes? Last time,

00:01:38.000 --> 00:01:42.000
we found that we could tell they
were in different genes by doing a

00:01:42.000 --> 00:01:46.000
cross between a mutant
that had the first mutation,

00:01:46.000 --> 00:01:50.000
and a mutant that had the second
mutation, and looking at the double

00:01:50.000 --> 00:01:54.000
heterozygote, right? And,
if in the double heterozygote

00:01:54.000 --> 00:01:58.000
you had a wild type or a normal
phenotype, then they had to be in

00:01:58.000 --> 00:02:03.000
different genes,
OK? Remember that?

00:02:03.000 --> 00:02:06.000
That was called a test
of complementation.

00:02:06.000 --> 00:02:09.000
That was how we were able to sort
out which mutations were in the same

00:02:09.000 --> 00:02:12.000
gene, and which mutations
were in different genes.

00:02:12.000 --> 00:02:15.000
Now we can go a step further.
When we've established that they're

00:02:15.000 --> 00:02:18.000
in different genes, we
can try to begin to think,

00:02:18.000 --> 00:02:21.000
how do these genes relate
to a biochemical pathway?

00:02:21.000 --> 00:02:24.000
I wanted to begin to introduce,
because it'll be relevant for today,

00:02:24.000 --> 00:02:27.000
this notion: so, suppose I had a
mutation that affected enzyme A so

00:02:27.000 --> 00:02:31.000
that this enzymatic step
couldn't be carried out.

00:02:31.000 --> 00:02:35.000
Such a mutant, when I
just try to grow it on

00:02:35.000 --> 00:02:40.000
minimal medium won't be able to grow.
If I give it the substrate alpha,

00:02:40.000 --> 00:02:45.000
it doesn't do it any good because
it hasn't got the enzyme to convert

00:02:45.000 --> 00:02:50.000
alpha. So, given alpha, it
won't grow. But if I give it

00:02:50.000 --> 00:02:55.000
beta, what will happen? It
can grow because I've bypassed

00:02:55.000 --> 00:03:00.000
the defect. What about if
I give it gamma? Arginine?

00:03:00.000 --> 00:03:18.000
Now, if instead the mutation were
affecting enzymatic step here,

00:03:18.000 --> 00:03:36.000
then if I give it
on minimal or medium

00:03:36.000 --> 00:03:40.000
but it can grow on gamma.
What about this last line?

00:03:40.000 --> 00:03:44.000
If I have a mutation and
the last enzymatic step,

00:03:44.000 --> 00:03:49.000
minimal medium can't grow with
alpha, can't grow with beta,

00:03:49.000 --> 00:03:53.000
can't even grow with gamma.
But, it can grow with arginine

00:03:53.000 --> 00:03:57.000
because I've bypassed that step.
So, I get a different phenotype,

00:03:57.000 --> 00:04:02.000
the inability to
grow even on gamma,

00:04:02.000 --> 00:04:08.000
but I can grow on arginine. Now,
here, if I put together those

00:04:08.000 --> 00:04:13.000
mutants and make a double mutant,
a double homozygote, let's say,

00:04:13.000 --> 00:04:19.000
that's defective in both A and B,
which will it look like? Will it be

00:04:19.000 --> 00:04:24.000
able to grow on minimal medium?
Will it be able to grow on alpha?

00:04:24.000 --> 00:04:30.000
Will it be able
to grow on beta?

00:04:30.000 --> 00:04:36.000
Will it be able to grow on gamma
and arginine? What about if I have a

00:04:36.000 --> 00:04:43.000
double mutant in B and C,
minus, minus, minus, minus,

00:04:43.000 --> 00:04:49.000
plus? So this looks the same as
that. This looks the same as that.

00:04:49.000 --> 00:04:56.000
And so, by looking at
different mutant combinations,

00:04:56.000 --> 00:05:02.000
I can see that the phenotype of B
here is what occurs in the double

00:05:02.000 --> 00:05:08.000
mutant. So, this phenotype is
epistatic to this phenotype.

00:05:08.000 --> 00:05:13.000
Epistatic means stands upon,
OK? So, phenotypes, just like

00:05:13.000 --> 00:05:19.000
phenotypes can be recessive or
dominant, you can also speak about

00:05:19.000 --> 00:05:24.000
them being epistatic. And
epistatic means when you have

00:05:24.000 --> 00:05:30.000
both of two mutations
together at the epistatic

00:05:30.000 --> 00:05:33.000
then one of them is epistatic
to the other, perhaps.

00:05:33.000 --> 00:05:36.000
It will, in fact, be
the one that is present.

00:05:36.000 --> 00:05:39.000
So, this is not so easy to do
in many cases because if I take

00:05:39.000 --> 00:05:43.000
different kinds of mutation
affecting wing development,

00:05:43.000 --> 00:05:46.000
and I put them together in the same
fly, I may just get a very messed up

00:05:46.000 --> 00:05:49.000
wing, and it's very hard to
tell that the double mutant has a

00:05:49.000 --> 00:05:53.000
phenotype that looks like
either of the two single mutants.

00:05:53.000 --> 00:05:56.000
But sometimes, if they fall very
nicely in a pathway where this

00:05:56.000 --> 00:06:00.000
affects the first step,
this affects the second step

00:06:00.000 --> 00:06:04.000
this affects the third step,
this affects the fourth step,

00:06:04.000 --> 00:06:08.000
then the double mutant
will look like one of those,

00:06:08.000 --> 00:06:12.000
OK? And, that way you can somehow
order things in a biochemical

00:06:12.000 --> 00:06:16.000
pathway. Now, notice,
this is all indirect,

00:06:16.000 --> 00:06:20.000
right? This is what geneticists did
in the middle of the 20th century to

00:06:20.000 --> 00:06:24.000
try to figure out how to connect
up mutants to biochemistry.

00:06:24.000 --> 00:06:28.000
Actually, that's not true.
It's what geneticists still do

00:06:28.000 --> 00:06:31.000
today because you might think
that Well, we don't need to do this

00:06:31.000 --> 00:06:34.000
anymore, but in fact geneticists
constantly are looking at mutants

00:06:34.000 --> 00:06:38.000
and making connections trying to
say, what does this double combination

00:06:38.000 --> 00:06:41.000
look like? What does that
double combination look like,

00:06:41.000 --> 00:06:44.000
and how does that tell us
about the developmental pathway,

00:06:44.000 --> 00:06:48.000
which cell signals which cell?
This turns out to be one of the

00:06:48.000 --> 00:06:51.000
most powerful ways to figure out
what mutations do by saying the

00:06:51.000 --> 00:06:54.000
combination of two mutations
looks like the same as one of them,

00:06:54.000 --> 00:06:58.000
allowing you to order the
mutations in a pathway.

00:06:58.000 --> 00:07:02.000
And, there's no general way to
grind up a cell and order things in a

00:07:02.000 --> 00:07:06.000
pathway. Genetics is a very
powerful tool for doing that.

00:07:06.000 --> 00:07:10.000
Now, there are some ways to
grind up cells and order things,

00:07:10.000 --> 00:07:15.000
but you need both of these
techniques to believe stuff.

00:07:15.000 --> 00:07:19.000
Anyway, I wanted to go over that,
because it is an important concept,

00:07:19.000 --> 00:07:23.000
the concept of epistasis, the
concept of relating mutations to

00:07:23.000 --> 00:07:27.000
steps and pathways, but what
I mostly want to do today

00:07:27.000 --> 00:07:33.000
is go on now to talk about genetics
not in organisms like yeast or fruit

00:07:33.000 --> 00:07:39.000
flies or even peas,
but genetics in humans.

00:07:39.000 --> 00:07:46.000
So, what's different about genetics
in humans than genetics in yeast?

00:07:46.000 --> 00:07:53.000
You can't choose who mates
with whom. Well, you can.

00:07:53.000 --> 00:08:00.000
I mean, in the days of arranged
marriages maybe you couldn't,

00:08:00.000 --> 00:08:04.000
but you can choose who mates
with whom, but only for yourself,

00:08:04.000 --> 00:08:08.000
right? What you can't do is
arrange other crosses in the human

00:08:08.000 --> 00:08:12.000
population as an experimentalist.
Now, your own choice of mating,

00:08:12.000 --> 00:08:16.000
unfortunately or fortunately perhaps
produces too few progeny to be

00:08:16.000 --> 00:08:20.000
statistically significant. As
a parent of three, I think about

00:08:20.000 --> 00:08:24.000
what it would take to raise a
statistically significant number of

00:08:24.000 --> 00:08:28.000
offspring to draw any conclusions,
and I don't think I could do that.

00:08:28.000 --> 00:08:32.000
So, you're absolutely right. We
can't arrange the matings that

00:08:32.000 --> 00:08:36.000
we want in the human population.
So, that's the big difference.

00:08:36.000 --> 00:08:40.000
So, can we do genetics anyway?
How do we do genetics even though

00:08:40.000 --> 00:08:45.000
we can't arrange the matings
the way we'd like to? Sorry?

00:08:45.000 --> 00:08:49.000
Well, family trees. We have to
take the matings as we find them in

00:08:49.000 --> 00:08:54.000
the human population. You
can talk to somebody who might

00:08:54.000 --> 00:08:59.000
have an interesting phenotype,
I don't know, attached earlobes,

00:08:59.000 --> 00:09:02.000
or very early heart disease,
or some unusual color of eyes,

00:09:02.000 --> 00:09:05.000
and begin to collect a
family history on that person.

00:09:05.000 --> 00:09:08.000
It's a little bit of a dodgy thing
because you might just be relying on

00:09:08.000 --> 00:09:12.000
that person's recollection. So,
if you were really industrious

00:09:12.000 --> 00:09:15.000
about this, you'd go check out each
of their family members and test for

00:09:15.000 --> 00:09:18.000
yourself whether they have the
phenotype. People who do serious

00:09:18.000 --> 00:09:21.000
human genetic studies often go and
do that. They have to go confirm,

00:09:21.000 --> 00:09:25.000
either by getting hospital records
or interviewing the other members of

00:09:25.000 --> 00:09:28.000
the family, etc. So, this
is not as easy as plating

00:09:28.000 --> 00:09:39.000
out lots of yeasts
on a Petri plate.

00:09:39.000 --> 00:09:58.000
And then you get pedigrees. And
the pedigrees look like this.

00:09:58.000 --> 00:10:18.000
Here's a pedigree. Tell
me what you make of it.

00:10:18.000 --> 00:10:26.000
Now, symbols: squares are males,
circles are females by convention,

00:10:26.000 --> 00:10:32.000
a colored in symbol means
the phenotype that we're

00:10:32.000 --> 00:10:36.000
interested in studying at the
moment. So, in any given problem,

00:10:36.000 --> 00:10:41.000
somebody will tell you, well,
we're studying some interesting

00:10:41.000 --> 00:10:46.000
phenotype. You often have
an index case or a proband,

00:10:46.000 --> 00:10:50.000
meaning the person who
comes to clinical attention,

00:10:50.000 --> 00:10:55.000
and then you chase back in the
pedigree and try to reconstruct.

00:10:55.000 --> 00:11:00.000
So, suppose I saw a
pedigree like this.

00:11:00.000 --> 00:11:22.000
What conclusions could I draw?
Sorry? Recessive, sex link trait;

00:11:22.000 --> 00:11:35.000
why sex link trait? So,
let's see if we can get your

00:11:35.000 --> 00:11:40.000
model up here. You think
that this represents

00:11:40.000 --> 00:11:46.000
sex-linked inheritance. So,
what would the genotype be of

00:11:46.000 --> 00:11:51.000
this male here? Mutant:
I'll use M to denote a

00:11:51.000 --> 00:11:56.000
mutant carried on the X chromosome,
and a Y on the opposite chromosome.

00:11:56.000 --> 00:12:02.000
What's the genotype
of the female here?

00:12:02.000 --> 00:12:06.000
So, it's plus over plus where I'll
use plus to denote the gene carried

00:12:06.000 --> 00:12:10.000
on the normal X chromosome.
OK, and then what do you think

00:12:10.000 --> 00:12:14.000
happened over here?
So, mutant over plus,

00:12:14.000 --> 00:12:18.000
you mate to this male who is plus
over plus. Why is that male plus

00:12:18.000 --> 00:12:22.000
over plus? Oh,
right, good point.

00:12:22.000 --> 00:12:26.000
It's not plus over plus. It's
plus over Y. Why is that male

00:12:26.000 --> 00:12:30.000
plus over Y as opposed
to mutant over Y?

00:12:30.000 --> 00:12:35.000
He'd have the mutant phenotype.
So, he doesn't have the mutant

00:12:35.000 --> 00:12:40.000
phenotype so he can infer he's plus
over Y. OK, and then what happens

00:12:40.000 --> 00:12:46.000
here? Mutant over Y; this is plus
over Y. How did this person get

00:12:46.000 --> 00:12:51.000
plus over Y? They just the
plus for mom, and the daughters,

00:12:51.000 --> 00:12:57.000
Y from dad, and a plus from mom.
That's cool. Now, what about the

00:12:57.000 --> 00:13:02.000
daughters there?
They're plus over plus,

00:13:02.000 --> 00:13:06.000
or M over plus? Is one,
one, and one the other? Well,

00:13:06.000 --> 00:13:11.000
in textbooks it's always plus
over plus and M over plus,

00:13:11.000 --> 00:13:16.000
but in real life? We don't know,
right? So, this could be plus over

00:13:16.000 --> 00:13:20.000
plus, or M over plus,
we don't know, OK? Now,

00:13:20.000 --> 00:13:25.000
what about on this side
of the pedigree here?

00:13:25.000 --> 00:13:30.000
What's the genotype
here? Plus over Y, OK.

00:13:30.000 --> 00:13:36.000
Why not mutant over Y?
Because if they got the mutant,

00:13:36.000 --> 00:13:42.000
it would have to come from the, OK,
so here, plus over plus, and then

00:13:42.000 --> 00:13:48.000
here, everybody is normal because
there's no mutant allele segregated.

00:13:48.000 --> 00:13:54.000
Yes? Yeah, couldn't there
just be recessive? I mean,

00:13:54.000 --> 00:14:00.000
it's a nice story
about the sex link

00:14:00.000 --> 00:14:07.000
but couldn't it be recessive?
So, walk me through it being

00:14:07.000 --> 00:14:15.000
recessive. M over plus,
plus over plus. Wait, wait,

00:14:15.000 --> 00:14:22.000
wait, hang on. Could this be M over
plus, and that person be affected?

00:14:22.000 --> 00:14:30.000
It's got to be M over M,
right so mutants over mutants

00:14:30.000 --> 00:14:37.000
but that's possible. Yeah,
OK. So, what would this

00:14:37.000 --> 00:14:44.000
person be? Plus over plus,
let's say, come over here. Now,

00:14:44.000 --> 00:14:51.000
what would this person be? M plus.
It has to be M plus because, OK,

00:14:51.000 --> 00:14:58.000
and what about this person
here? M plus, now what about the

00:14:58.000 --> 00:15:05.000
offspring? So, one
of them is M over M,

00:15:05.000 --> 00:15:11.000
plus over plus, and two M pluses.
Does it always work out like that?

00:15:11.000 --> 00:15:17.000
[LAUGHTER] No, it doesn't
always work out like that at all.

00:15:17.000 --> 00:15:23.000
So, I'm just going to write
plus over plus here just to say,

00:15:23.000 --> 00:15:29.000
tough, right? In real life, it
doesn't always come out like that.

00:15:29.000 --> 00:15:35.000
What about over here? It would
have to be plus over plus.

00:15:35.000 --> 00:15:39.000
Why not? It doesn't because it
could be M over plus and have no

00:15:39.000 --> 00:15:44.000
effect at offspring by chance,
right? But, you were going to say

00:15:44.000 --> 00:15:48.000
it's plus over plus because in the
textbooks it's always plus over plus

00:15:48.000 --> 00:15:53.000
in pictures like this, right?
And then, it all turns out

00:15:53.000 --> 00:15:57.000
to be pluses and mutants, and
pluses and mutants, and all that,

00:15:57.000 --> 00:16:02.000
right? Well, which
picture's right?

00:16:02.000 --> 00:16:08.000
Sorry? You don't know. So,
that's not good. There's supposed

00:16:08.000 --> 00:16:14.000
to be answers to these things.
Could either be true? Which is

00:16:14.000 --> 00:16:19.000
more likely? The one on the left?
Why? More statistically probable,

00:16:19.000 --> 00:16:25.000
how come? Because it is. It
may not quite suffice as a fully

00:16:25.000 --> 00:16:31.000
complete scientific
answer though.

00:16:31.000 --> 00:16:48.000
Yes? Yep. Well, but I have
somebody who is affected

00:16:48.000 --> 00:17:05.000
here. So, given that I've gotten
affected person in the family --

00:17:05.000 --> 00:17:08.000
yeah, so it is actually, you're
right, statistically somewhat

00:17:08.000 --> 00:17:12.000
less likely that you would have two
independent M's entering the same

00:17:12.000 --> 00:17:16.000
pedigree particularly
if M is relatively rare.

00:17:16.000 --> 00:17:20.000
If M is quite common, however,
suppose M were something

00:17:20.000 --> 00:17:24.000
was a 20% frequency in the
population, then it actually might

00:17:24.000 --> 00:17:28.000
be quite reasonable that this could
happen. So, what would you really

00:17:28.000 --> 00:17:33.000
want to do to test this? Sorry?
Well, if you found any females here

00:17:33.000 --> 00:17:39.000
maybe you'd be able to conclude that
it was autosomal recessive because

00:17:39.000 --> 00:17:46.000
females never show a
sex-linked trait. Is that true?

00:17:46.000 --> 00:17:53.000
No, that's not true. Why not?
You're right. So, you just have to

00:17:53.000 --> 00:18:00.000
be homozygous for it on
the X. So, having a single

00:18:00.000 --> 00:18:09.000
female won't, I mean, she's
not going to take that as

00:18:09.000 --> 00:18:18.000
evidence. Get an affected female
and demonstrate that all of her male

00:18:18.000 --> 00:18:28.000
offspring show the trait.
Cross her with, wait, wait.

00:18:28.000 --> 00:18:31.000
This is a human pedigree guys
[LAUGHTER]. Whew! There are issues

00:18:31.000 --> 00:18:35.000
involved here, right? You
could introduce her to a

00:18:35.000 --> 00:18:39.000
normal guy, [LAUGHTER] but whether
you can cross her to a normal guy is

00:18:39.000 --> 00:18:43.000
not actually allowed. So,
you see, these are exactly the

00:18:43.000 --> 00:18:46.000
issues in making sense
out of pedigrees like this.

00:18:46.000 --> 00:18:50.000
So, what you have to do is you
have to collect a lot of data,

00:18:50.000 --> 00:18:54.000
and the kinds of characteristics
that you look for in a pedigree,

00:18:54.000 --> 00:18:58.000
but they are statistical
characteristics, and

00:18:58.000 --> 00:19:02.000
notwithstanding -- So, this
could be colorblindness or

00:19:02.000 --> 00:19:06.000
something, but notwithstanding
the pictures in the textbook of

00:19:06.000 --> 00:19:10.000
colorblindness and all that, you
really do have to take a look at

00:19:10.000 --> 00:19:14.000
a number of properties.
What are some properties?

00:19:14.000 --> 00:19:19.000
One you've already referred to
which is there's a predominance in

00:19:19.000 --> 00:19:23.000
males if it's X-linked. Why
is there a predominance in

00:19:23.000 --> 00:19:27.000
males? Well, there's a
predominance in males because if I

00:19:27.000 --> 00:19:32.000
have an X over Y and I've
got a mutation paired on

00:19:32.000 --> 00:19:36.000
this X chromosome, males
only have to get it on one.

00:19:36.000 --> 00:19:40.000
Females have to get it on both, and
therefore it's statistically more

00:19:40.000 --> 00:19:44.000
likely that males will get it.
So, for example, the frequency of

00:19:44.000 --> 00:19:48.000
colorblindness amongst males
is what? Yeah, it's 8-10%,

00:19:48.000 --> 00:19:52.000
something like that. I
think it's about 8% or so.

00:19:52.000 --> 00:19:56.000
And, amongst females,
well, if it's 8% to get one,

00:19:56.000 --> 00:20:00.000
what's the chance
you're going to get two?

00:20:00.000 --> 00:20:08.000
It's 8% times 8% is a
little less than 1% right?

00:20:08.000 --> 00:20:17.000
It's 0.64%, OK, in females.
So, we'll just go 8%

00:20:17.000 --> 00:20:25.000
squared. So in males, 8% in
females, less than one percent.

00:20:25.000 --> 00:20:33.000
So, there is a
predominance in males

00:20:33.000 --> 00:20:39.000
of these sex-linked traits. Other
things: affected males do not

00:20:39.000 --> 00:20:46.000
transmit the trait to the kids,
in particular do not transmit it to

00:20:46.000 --> 00:20:53.000
their sons, right, because
they are always sending the

00:20:53.000 --> 00:21:00.000
Y chromosomes to their
songs. Carrier females

00:21:00.000 --> 00:21:10.000
transmit to half of their sons,
and affected females transmit to all

00:21:10.000 --> 00:21:20.000
of their sons. And, the
trait appears to skip

00:21:20.000 --> 00:21:30.000
generations, although I
don't like this terminology.

00:21:30.000 --> 00:21:35.000
It skips generations. These
are the kinds of properties

00:21:35.000 --> 00:21:40.000
that you have.
So, hemophilia,

00:21:40.000 --> 00:21:45.000
a good example of this, if I
have a child with hemophilia,

00:21:45.000 --> 00:21:50.000
male with hemophilia, would you
be surprised if his uncle had

00:21:50.000 --> 00:21:55.000
hemophilia? Which uncle would
it be, maternal or paternal?

00:21:55.000 --> 00:22:00.000
The maternal uncle would
have hemophilia most likely.

00:22:00.000 --> 00:22:04.000
It's always possible it could be
paternal. This is the problem with

00:22:04.000 --> 00:22:08.000
human genetics is you've got to
get enough families so the pattern

00:22:08.000 --> 00:22:12.000
becomes overwhelmingly clear,
OK, because otherwise, as you can

00:22:12.000 --> 00:22:16.000
see with small numbers, it's
tough to be absolutely certain.

00:22:16.000 --> 00:22:20.000
So, these are properties
of X linked traits.

00:22:20.000 --> 00:22:24.000
How about baldness? Is
baldness, that's a sex-linked

00:22:24.000 --> 00:22:28.000
trait? How come? You don't
see a lot of bald females.

00:22:28.000 --> 00:22:32.000
Does that prove it's sex linked?
Sorry? Guys are stressed more.

00:22:32.000 --> 00:22:37.000
[LAUGHTER] Is there evidence that
it has anything to do with stress?

00:22:37.000 --> 00:22:41.000
Actually, it has to do with
excess testosterone it turns out,

00:22:41.000 --> 00:22:46.000
that high levels of testosterone
are correlated with male pattern

00:22:46.000 --> 00:22:51.000
baldness, but does the fact that
males become bald indicate that this

00:22:51.000 --> 00:22:56.000
is a sex linked trait? No.
Just because it's predominant

00:22:56.000 --> 00:23:01.000
in male, we have to check
these other properties.

00:23:01.000 --> 00:23:05.000
Is it the case that bald
fathers tend to have bald sons?

00:23:05.000 --> 00:23:09.000
Any evidence on this point?
Common-sensical evidence from

00:23:09.000 --> 00:23:14.000
observation? It's pretty clear.
It's very clearly not a sex-linked

00:23:14.000 --> 00:23:18.000
trait. It's a sex-limited trait,
because in order to show this you

00:23:18.000 --> 00:23:23.000
need to be male because the high
levels of testosterone are not found

00:23:23.000 --> 00:23:27.000
in females even if they have the
genotype that might predispose them

00:23:27.000 --> 00:23:33.000
to become bald if they were male.
So, it actually is not a sex-linked

00:23:33.000 --> 00:23:40.000
trait at all, and it's very clear
that male pattern baldness does run

00:23:40.000 --> 00:23:48.000
in families more vertically. So,
you've got to be careful about

00:23:48.000 --> 00:23:55.000
the difference between
sex linked and sex limited,

00:23:55.000 --> 00:24:02.000
and sex linked you can really pick
out from transmission and families.

00:24:02.000 --> 00:24:10.000
OK, here's another
one. New pedigree.

00:24:10.000 --> 00:24:43.000
She married twice here.
OK, what do we got?

00:24:43.000 --> 00:24:53.000
Yep? She married again. She
married twice. She didn't have

00:24:53.000 --> 00:25:01.000
any offspring the second
time. But that happens,

00:25:01.000 --> 00:25:06.000
and you have to be able
to draw it in the pedigree.

00:25:06.000 --> 00:25:12.000
She's entitled, all right.
OK, so she got married again,

00:25:12.000 --> 00:25:17.000
no offspring from this marriage.
That's her legal symbol. You guys

00:25:17.000 --> 00:25:22.000
think that's funny.
It's real, you know?

00:25:22.000 --> 00:25:28.000
OK, that doesn't mean she's married
to two people at the same time.

00:25:28.000 --> 00:25:33.000
This is not a temporal picture.
So, what do we got here? Yep?

00:25:33.000 --> 00:25:38.000
Sorry, of this person? Well,
I'm drawing them as an empty

00:25:38.000 --> 00:25:44.000
symbol here, indicating that we
do not think they have the trait.

00:25:44.000 --> 00:25:50.000
They're not carriers. How do
you propose to find that out?

00:25:50.000 --> 00:25:56.000
Look at the children. Well,
the children are affected. They

00:25:56.000 --> 00:26:02.000
could be carriers. The
data are what they are.

00:26:02.000 --> 00:26:09.000
You've got to interpret it.
Does this person have to be a

00:26:09.000 --> 00:26:16.000
carrier? What kind of
trait do you think this is?

00:26:16.000 --> 00:26:23.000
Dominant? Does this look like
autosomal dominant to you?

00:26:23.000 --> 00:26:30.000
Yep? Oh, not all the
kids have the trait

00:26:30.000 --> 00:26:34.000
in the first generation,
and if this was dominant,

00:26:34.000 --> 00:26:38.000
they'd all have it? What's a
possible genotype for this person?

00:26:38.000 --> 00:26:42.000
Mutant over plus. And, these
kids could be mutant over plus.

00:26:42.000 --> 00:26:46.000
This could be plus over plus,
and this could be plus over plus,

00:26:46.000 --> 00:26:50.000
mutant over plus, plus
over plus, mutant over plus,

00:26:50.000 --> 00:26:54.000
and plus over plus would be
one possibility. On average,

00:26:54.000 --> 00:26:58.000
what fraction of the kids
should get the trait? About half

00:26:58.000 --> 00:27:06.000
the kids, right? So, let's
see what characteristics

00:27:06.000 --> 00:27:18.000
we have here. We see the
trait in every generation.

00:27:18.000 --> 00:27:30.000
On average, half the
kids get the trait.

00:27:30.000 --> 00:27:42.000
Half of the offspring of an
affected individual are affected.

00:27:42.000 --> 00:27:54.000
What else? Males and females?
Roughly equal in males and females?

00:27:54.000 --> 00:28:02.000
Sorry? One,
two, three,

00:28:02.000 --> 00:28:08.000
four, five to two.
So, it's a 5:2 ratio?

00:28:08.000 --> 00:28:13.000
Oh, in the offspring it's a 2:1
ratio. So, this is like Mendel.

00:28:13.000 --> 00:28:19.000
You see this number and you say,
OK, 2:1. Isn't that trying to tell

00:28:19.000 --> 00:28:24.000
me something? Not with six
offspring. That's the problem is

00:28:24.000 --> 00:28:30.000
with six offspring, 2:1 might
be trying to tell you 1:1.

00:28:30.000 --> 00:28:34.000
And it is. If I had a dominantly
inherited trait where there's a

00:28:34.000 --> 00:28:39.000
50/50 chance of each offspring
getting the disease and it was

00:28:39.000 --> 00:28:44.000
autosomal, not sex linked,
there would be very good odds of

00:28:44.000 --> 00:28:48.000
getting two males and one female
because it happens: flip coins and

00:28:48.000 --> 00:28:53.000
it happens. So, you have
to take that into account,

00:28:53.000 --> 00:28:58.000
and here you see what else we have.
Roughly equal numbers of males and

00:28:58.000 --> 00:29:03.000
females, they transmit equally,
and unaffecteds never transmit.

00:29:03.000 --> 00:29:07.000
This would be the classic
autosomal dominant trait.

00:29:07.000 --> 00:29:11.000
Right, here this mutant
would go mutant over plus,

00:29:11.000 --> 00:29:15.000
mutant over plus, plus over plus,
mutant over plus, plus over plus,

00:29:15.000 --> 00:29:19.000
plus over plus, and you'd
see here that three out of

00:29:19.000 --> 00:29:23.000
the five here, and one,
two, three out of the six

00:29:23.000 --> 00:29:27.000
there: that's a little more
than half but it's small numbers

00:29:27.000 --> 00:29:33.000
here, right? This is a
classic autosomal dominant

00:29:33.000 --> 00:29:39.000
as in the textbooks. Yes?
Turns out not to make too

00:29:39.000 --> 00:29:46.000
much of a difference. It
turns out that there's lots of

00:29:46.000 --> 00:29:53.000
genome that's on either. And
so, it is true that males are

00:29:53.000 --> 00:30:00.000
more susceptible to
certain genetic diseases.

00:30:00.000 --> 00:30:04.000
So, it'll be some excess,
but it won't matter for this.

00:30:04.000 --> 00:30:09.000
Now, in real life it doesn't
always work so beautifully.

00:30:09.000 --> 00:30:13.000
We'll take an example: colon cancer.
There are particular autosomal

00:30:13.000 --> 00:30:18.000
dominant mutations here that
cause a high risk of colon cancer.

00:30:18.000 --> 00:30:23.000
People who have mutations
in a certain gene, MLH-1,

00:30:23.000 --> 00:30:27.000
have about a 70% risk of getting
colon cancer in their life.

00:30:27.000 --> 00:30:33.000
But notice, it's not 100%. You
might have incomplete penetrance.

00:30:33.000 --> 00:30:41.000
Incompletely penetrance means not
everybody who gets the genotype gets

00:30:41.000 --> 00:30:48.000
the phenotype. Not all
people with the M over plus

00:30:48.000 --> 00:30:56.000
genotype show the phenotype.
Once you do that, it messes up our

00:30:56.000 --> 00:31:03.000
picture colossally,
because, tell me,

00:31:03.000 --> 00:31:09.000
how do we know that this person over
here is not actually M over plus.

00:31:09.000 --> 00:31:15.000
Maybe they're cryptic. They
haven't shown the phenotype.

00:31:15.000 --> 00:31:21.000
And maybe, it'll appear in the
next generation. That'll screw up

00:31:21.000 --> 00:31:27.000
everything. It screws up our rule
about not transmitting through

00:31:27.000 --> 00:31:32.000
unaffected, it screws up the
rule about not being shown in

00:31:32.000 --> 00:31:36.000
every generation, and it
will even screw up our 50/50

00:31:36.000 --> 00:31:41.000
ratio because if half the
offspring get M over plus,

00:31:41.000 --> 00:31:46.000
but only 70% of that half show
the phenotype, then only 35% of the

00:31:46.000 --> 00:31:50.000
offspring will show the phenotype.
Unfortunately, this is real life.

00:31:50.000 --> 00:31:55.000
When human geneticists really
look at traits, many mutations,

00:31:55.000 --> 00:32:00.000
most except the most severe
are incompletely penetrant.

00:32:00.000 --> 00:32:04.000
And so you have to really begin to
gather a lot of data to demonstrate

00:32:04.000 --> 00:32:08.000
that you're dealing with an
autosomal dominant trait that's

00:32:08.000 --> 00:32:12.000
incompletely penetrant. And
then there are other issues.

00:32:12.000 --> 00:32:16.000
There's a gene on chromosome
number 17 called BRCA-1,

00:32:16.000 --> 00:32:20.000
mutations in which predisposed to a
very high risk of breast cancer but

00:32:20.000 --> 00:32:24.000
only in women. Males carry
the mutation and do not

00:32:24.000 --> 00:32:28.000
have breast cancer. There
are other mutations that do

00:32:28.000 --> 00:32:32.000
cause breast cancer in males.
Males have breast tissue,

00:32:32.000 --> 00:32:36.000
and can have breast cancer, but
the one on chromosome 17 does

00:32:36.000 --> 00:32:40.000
not. And so, there you would only
see this transmitted through females.

00:32:40.000 --> 00:32:45.000
It would skip into males
without showing a phenotype,

00:32:45.000 --> 00:32:49.000
etc. So, in real life,
life's a bit more complicated.

00:32:49.000 --> 00:32:53.000
All right, so autosomal dominance.
Now, let's take one more pedigree.

00:32:53.000 --> 00:32:58.000
Sorry? Sex limited,
but not sex linked.

00:32:58.000 --> 00:33:03.000
So, on chromosome 17, which
is a bona fide autosome,

00:33:03.000 --> 00:33:08.000
but it's sex limited in that
phenotype can only show itself in an

00:33:08.000 --> 00:33:13.000
individual who happens to be female.
Yes? Sorry? How come autosomal

00:33:13.000 --> 00:33:19.000
recessive? So, if that
left guy up there is

00:33:19.000 --> 00:33:24.000
actually a heterozygote,
and up there that individual,

00:33:24.000 --> 00:33:30.000
so if we had a homozygote,
homozygote, heterozygote,

00:33:30.000 --> 00:33:33.000
homozygote, ooh, you can
interpret that pedigree if

00:33:33.000 --> 00:33:37.000
you want to as an autosomal
recessive, provided that M is pretty

00:33:37.000 --> 00:33:40.000
frequent in the population.
That's right. Human geneticists,

00:33:40.000 --> 00:33:44.000
in fact, to really prove that
they've got the right model,

00:33:44.000 --> 00:33:48.000
collect a lot of pedigrees
and run a computer model.

00:33:48.000 --> 00:33:51.000
The computer model first
tries out autosomal recessive,

00:33:51.000 --> 00:33:55.000
tries out autosomal dominant,
tries out dominant with incomplete

00:33:55.000 --> 00:33:59.000
penetrance, and for every possible
model figures out the statistical

00:33:59.000 --> 00:34:03.000
probability that you would
see such data under that model.

00:34:03.000 --> 00:34:05.000
And when the data become
overwhelming and you say,

00:34:05.000 --> 00:34:08.000
yeah, with one pedigree, any
pedigree I draw on the board,

00:34:08.000 --> 00:34:11.000
it could actually fit almost any for
the models. It doesn't say this in

00:34:11.000 --> 00:34:14.000
the textbooks, but
it's true. I get enough

00:34:14.000 --> 00:34:17.000
pedigrees, and eventually I say the
odds are 105 times more likely that

00:34:17.000 --> 00:34:20.000
this collection of pedigrees would
arise from autosomal dominance,

00:34:20.000 --> 00:34:22.000
inheritance with incomplete
penetrance of about 80%.

00:34:22.000 --> 00:34:25.000
Then, from autosomal recessive
inheritance, then I get to write a

00:34:25.000 --> 00:34:28.000
paper about it. That's
really what human

00:34:28.000 --> 00:34:32.000
geneticists do is they
have to collect enough,

00:34:32.000 --> 00:34:36.000
now, any other organism,
you'd just set up a cross,

00:34:36.000 --> 00:34:41.000
but you can't. And, as long
as we have nontrivial models,

00:34:41.000 --> 00:34:46.000
we really have to collect a lot of
data. Let's take the next pedigree,

00:34:46.000 --> 00:34:50.000
great, that you're thinking
like a human geneticist.

00:34:50.000 --> 00:34:55.000
It's very good. Here's the
next pedigree. Actually,

00:34:55.000 --> 00:35:00.000
I'm going to reverse
it. There we go.

00:35:00.000 --> 00:35:03.000
What's that? Who knows? You
can't tell. Good, I've got you

00:35:03.000 --> 00:35:07.000
up to training to the point where,
but in textbooks, this would be

00:35:07.000 --> 00:35:11.000
autosomal recessive.
Or it could be anything.

00:35:11.000 --> 00:35:15.000
You know that, right? But the
textbooks would show you this

00:35:15.000 --> 00:35:18.000
picture as an autosomal recessive.
But of course, what else could it

00:35:18.000 --> 00:35:22.000
be? It could be an autosomal
dominant with incomplete penetrance.

00:35:22.000 --> 00:35:26.000
It could be sex linked. It
could be a lot of things.

00:35:26.000 --> 00:35:30.000
It could also be, I haven't
told you the phenotype.

00:35:30.000 --> 00:35:34.000
What if the phenotype here
was getting hit by a truck?

00:35:34.000 --> 00:35:38.000
[LAUGHTER] Would you
tend to observe this? Yep,

00:35:38.000 --> 00:35:42.000
so getting hit by a truck, for
example, if someone gets hit by

00:35:42.000 --> 00:35:46.000
a truck, it's unlikely either
their parents were hit by a truck,

00:35:46.000 --> 00:35:50.000
or going back several generations
that their grandparents were hit by

00:35:50.000 --> 00:35:54.000
a truck. So, how do you tell
being hit by a truck from,

00:35:54.000 --> 00:35:58.000
I mean, that is to say, how
do you know that something's

00:35:58.000 --> 00:36:01.000
genetic at all? When it's
relatively rare and it

00:36:01.000 --> 00:36:04.000
pops up in a pedigree, how
do you know it's genetic?

00:36:04.000 --> 00:36:07.000
Because of the DNA. But, I mean,
it takes a lot of work to find the

00:36:07.000 --> 00:36:10.000
gene and all that as we'll come to
the course. You might want a little

00:36:10.000 --> 00:36:13.000
bit of assurance before you go write
the grant to the NIH and say I'm

00:36:13.000 --> 00:36:16.000
going to find the gene for this
because you write it and say I'm

00:36:16.000 --> 00:36:19.000
going to find the gene
for getting hit by a truck,

00:36:19.000 --> 00:36:22.000
and they're going to write back and
say show me that it's worth spending

00:36:22.000 --> 00:36:25.000
money to find that gene.
Show me that it's true. So,

00:36:25.000 --> 00:36:28.000
what kind of things would we look
for? If we wanted to show something

00:36:28.000 --> 00:36:32.000
was autosomal recessive in a
population, what would we do?

00:36:32.000 --> 00:36:40.000
More data. So, we
collect a lot of families,

00:36:40.000 --> 00:36:48.000
and what would we see? As we
collected more and more families,

00:36:48.000 --> 00:36:56.000
we begin to see what things?
Sometimes we might see families like

00:36:56.000 --> 00:37:04.000
this, or we might see
families like this. [LAUGHTER]

00:37:04.000 --> 00:37:08.000
If both parents were mutants,
all the children would be mutant,

00:37:08.000 --> 00:37:13.000
right? We'd color them in mutant.
Is that true? Well, first off, it

00:37:13.000 --> 00:37:18.000
depends. Some of the things we
want to study are extremely severe

00:37:18.000 --> 00:37:23.000
medical genetical phenotypes,
and they're not going to live to

00:37:23.000 --> 00:37:28.000
have children. So, that's
an issue that you have

00:37:28.000 --> 00:37:33.000
to deal with. But, it
is true that if it was

00:37:33.000 --> 00:37:37.000
autosomal recessive, a mating
between two homozygotes for

00:37:37.000 --> 00:37:42.000
that gene would transmit.
[LAUGHTER] What if they were all in

00:37:42.000 --> 00:37:46.000
the same car? Which is
a very important part,

00:37:46.000 --> 00:37:51.000
because we joke about the car,
but diet, things like that, are

00:37:51.000 --> 00:37:55.000
familial correlated environmental
factors. There are environmental

00:37:55.000 --> 00:38:00.000
factors that correlate
within a family.

00:38:00.000 --> 00:38:04.000
And so, it's not trivial
to make this point. So,

00:38:04.000 --> 00:38:09.000
all right, we'll be able to
demonstrate what's the real proof of

00:38:09.000 --> 00:38:14.000
Mendelian inheritance here?
Because they could all be in the

00:38:14.000 --> 00:38:19.000
same car, or they all eat the same
kind of food or something like that,

00:38:19.000 --> 00:38:24.000
which predisposes them a certain way.
So, we're going to want some better

00:38:24.000 --> 00:38:29.000
proofs of these things.
How about Mendelian ratios?

00:38:29.000 --> 00:38:34.000
Mendelian ratios anyone? No,
because it could be incomplete

00:38:34.000 --> 00:38:38.000
autosomal dominance. I
don't want to mess you up.

00:38:38.000 --> 00:38:42.000
On the exams, you guys can think
cleanly about simple things.

00:38:42.000 --> 00:38:46.000
But, this could be dominant
with incomplete penetrance,

00:38:46.000 --> 00:38:50.000
though the TA's are going to hate
me because I'm telling you that,

00:38:50.000 --> 00:38:54.000
anyway, what about Mendelian ratios?
How about something that's a pretty

00:38:54.000 --> 00:38:58.000
good prediction? What
fraction of the offspring will

00:38:58.000 --> 00:39:02.000
be affected? We get
a lot of families,

00:39:02.000 --> 00:39:07.000
line them all up. What
fraction of the offspring?

00:39:07.000 --> 00:39:12.000
A quarter. Now, that's a
hard and fast prediction.

00:39:12.000 --> 00:39:17.000
One quarter of the offspring are
effective. When I have a mating

00:39:17.000 --> 00:39:22.000
between two homozygotes,
so what am I going to do?

00:39:22.000 --> 00:39:28.000
I'm going to go out. I'm going
to collect a lot of families.

00:39:28.000 --> 00:39:31.000
Maybe I'll collect 100 families
because it'll be a particular

00:39:31.000 --> 00:39:35.000
disease, diastrophic dysplasia
or something like that,

00:39:35.000 --> 00:39:39.000
xeroderma pygmentosa,
ataxia teleangiectasia,

00:39:39.000 --> 00:39:43.000
and I will go to the disease
foundation, and I will get all the

00:39:43.000 --> 00:39:46.000
pedigrees for all the families,
and I'll see how many times it was

00:39:46.000 --> 00:39:50.000
one affected, two affected, three
affected, etc. And on average,

00:39:50.000 --> 00:39:54.000
the proportion affecteds will be
a quarter, except it's not true.

00:39:54.000 --> 00:39:58.000
If I actually do that, I find that
the ratio of affecteds is typically

00:39:58.000 --> 00:40:03.000
more like a third.
It isn't a quarter.

00:40:03.000 --> 00:40:09.000
Now, this should disturb you
greatly because you know full well

00:40:09.000 --> 00:40:16.000
that M over plus by M over plus
should give you a quarter affecteds.

00:40:16.000 --> 00:40:23.000
But when you actually look
at human families, it's not.

00:40:23.000 --> 00:40:30.000
Why? In other words, when
we count up all the matings

00:40:30.000 --> 00:40:33.000
between heterozygotes, we'll
collect all the matings that

00:40:33.000 --> 00:40:37.000
produce one affected child.
We'll collect all the matings that

00:40:37.000 --> 00:40:41.000
produce two affected children.
We'll collect all the matings that

00:40:41.000 --> 00:40:45.000
produce three affected children.
But, we will fail to collect those

00:40:45.000 --> 00:40:48.000
matings between homozygotes that
produce zero affected children.

00:40:48.000 --> 00:40:52.000
And so, we will systematically
overestimate the proportion.

00:40:52.000 --> 00:40:56.000
Of course, what we really have to
do is go out and get all of those

00:40:56.000 --> 00:41:00.000
couples who were both carriers,
but because they had a small number

00:41:00.000 --> 00:41:04.000
of children didn't happen
to have an affected child.

00:41:04.000 --> 00:41:08.000
That's not very easy to do
especially when you don't know the

00:41:08.000 --> 00:41:12.000
gene in advance. So, when
human geneticists try to

00:41:12.000 --> 00:41:16.000
go out and measure the
one-quarter Mendelian ratio,

00:41:16.000 --> 00:41:21.000
you can't. But what you
can do is the following,

00:41:21.000 --> 00:41:25.000
conditional on the first trial
being affected, now what will be the

00:41:25.000 --> 00:41:30.000
proportion of subsequent
children who are affected?

00:41:30.000 --> 00:41:33.000
A quarter. If I make it conditional,
conditioning on having a first child

00:41:33.000 --> 00:41:37.000
who's affected, number
one child who's affected,

00:41:37.000 --> 00:41:40.000
then I know I've got a
mating between heterozygotes.

00:41:40.000 --> 00:41:44.000
Subsequent offspring now
do not have that bias.

00:41:44.000 --> 00:41:47.000
And so, as a matter of fact, you
think this pretty cool thought,

00:41:47.000 --> 00:41:51.000
right? You've got a condition on
one. It turns out there's a very

00:41:51.000 --> 00:41:54.000
famous paper about cystic fibrosis
where somebody forgot this point and

00:41:54.000 --> 00:41:58.000
made a huge big deal in the
literature about the fact that a

00:41:58.000 --> 00:42:02.000
third of the kids on average
had cystic fibrosis in these

00:42:02.000 --> 00:42:06.000
families, and proposed all sorts
of models about how cystic fibrosis

00:42:06.000 --> 00:42:11.000
might be advantageous and would lead
to fertility increases and all that.

00:42:11.000 --> 00:42:16.000
In fact, it was just a failure to
correct for this little statistical

00:42:16.000 --> 00:42:20.000
bias. OK, this is what human
geneticists do is they've got to

00:42:20.000 --> 00:42:25.000
deal with the popular, now,
there's one other trick that

00:42:25.000 --> 00:42:30.000
you can use to know that
something is autosomal recessive.

00:42:30.000 --> 00:42:37.000
That trick is this.
To site this trick,

00:42:37.000 --> 00:42:45.000
I have to go back to a person
called Archibald Garrett.

00:42:45.000 --> 00:42:53.000
Archibald Garrett was a
physician in London around 1900.

00:42:53.000 --> 00:43:01.000
Garrett studied children
with the trait alkoptonuria.

00:43:01.000 --> 00:43:06.000
Alkoptonuria was what alkopton
means black. Uria means urine.

00:43:06.000 --> 00:43:11.000
They had black urine. This was
evident because their urine turned

00:43:11.000 --> 00:43:16.000
black on treatment with alkaline.
How would you treat urine with

00:43:16.000 --> 00:43:22.000
alkaline. How would people know
this? Sorry? Outhouses with lime,

00:43:22.000 --> 00:43:27.000
yeah, and who's going to look at
the children's urine, or something

00:43:27.000 --> 00:43:32.000
like that? But you're
on the right track.

00:43:32.000 --> 00:43:38.000
How about diapers? You
wash diapers, cloth diapers,

00:43:38.000 --> 00:43:43.000
in alkaline. They turn black. This
was evident from black diapers.

00:43:43.000 --> 00:43:49.000
The kids' urine would turn black.
So, he observed this, and you know

00:43:49.000 --> 00:43:54.000
what Garrett noticed is when he
studied, children alkoptonuria,

00:43:54.000 --> 00:44:00.000
he found that a very
large fraction of affected

00:44:00.000 --> 00:44:10.000
offspring were in fact produced
from matings of first cousins.

00:44:10.000 --> 00:44:20.000
Consanguineous matings: now you
laugh, but in fact consanguinity has

00:44:20.000 --> 00:44:30.000
been something that has been
favored in many societies,

00:44:30.000 --> 00:44:35.000
and in Britain, particularly
amongst the upper class

00:44:35.000 --> 00:44:40.000
in Britain in 1900, marriage
or first cousins was quite

00:44:40.000 --> 00:44:45.000
common, but not as common as he
observed. He found that eight out

00:44:45.000 --> 00:44:50.000
of 17 alkoptonuria patients were the
products of first cousin marriages.

00:44:50.000 --> 00:44:55.000
That's way off the charts
because it's nearly a half,

00:44:55.000 --> 00:45:00.000
when in fact the typical rate in
Britain might have been about 5%.

00:45:00.000 --> 00:45:03.000
So, on the basis of that in the
early 1900's, Garrett was able to

00:45:03.000 --> 00:45:07.000
show only a few years after the
rediscovery of Mendel's work that

00:45:07.000 --> 00:45:11.000
this property of recessive traits,
enrichment in the offspring of

00:45:11.000 --> 00:45:15.000
consanguineous marriages,
was a clear demonstration of

00:45:15.000 --> 00:45:18.000
Mendelian inheritance.
Not only did he do that,

00:45:18.000 --> 00:45:22.000
but Garrett knew because of
the work of some biochemists,

00:45:22.000 --> 00:45:26.000
and this is way cool, that
the problem with the urine was

00:45:26.000 --> 00:45:30.000
that these patients put out in
their urine a lot of what's called

00:45:30.000 --> 00:45:42.000
homogentisic acid, HGA,
which basically is a phenolic

00:45:42.000 --> 00:45:54.000
ring. What Garrett did was he,
and that stuff turns black on

00:45:54.000 --> 00:46:02.000
exposure to air. What might
produce from the things

00:46:02.000 --> 00:46:07.000
you've learned already
some kind of ring like that?

00:46:07.000 --> 00:46:12.000
What building blocks do you know
have rings like that of things

00:46:12.000 --> 00:46:17.000
you've studied already?
Phenylalanine, tyrosine both have

00:46:17.000 --> 00:46:22.000
rings. Suppose somebody had
problems breaking down homogentisic

00:46:22.000 --> 00:46:27.000
acid. Suppose there was some
pathway where proteins were

00:46:27.000 --> 00:46:32.000
broken down into amino
acids including phenylalanine

00:46:32.000 --> 00:46:37.000
and tyrosine. And, they
were broken down into

00:46:37.000 --> 00:46:42.000
homogentisic acid. And
they were broken down into I

00:46:42.000 --> 00:46:47.000
don't know what. And,
suppose like we had up there,

00:46:47.000 --> 00:46:52.000
patients had a mutation in that
enzyme. What would happen if I fed

00:46:52.000 --> 00:46:57.000
patients a lot of protein? In
their urine, you would recover

00:46:57.000 --> 00:47:01.000
lots of homogentisic acid. Suppose
I fed them a lot of tyrosine.

00:47:01.000 --> 00:47:05.000
I'd get a lot of homogentisic acid
because the body couldn't break it

00:47:05.000 --> 00:47:09.000
down. Suppose I fed them
a lot of phenylalanine.

00:47:09.000 --> 00:47:13.000
They would excrete a
lot of homogentisic acid.

00:47:13.000 --> 00:47:16.000
Suppose I fed them homogentisic
acid. I would get quantitative

00:47:16.000 --> 00:47:20.000
amounts of homogentisic acid.
Garrett did this. These are the

00:47:20.000 --> 00:47:24.000
days before institutional
review boards, you know,

00:47:24.000 --> 00:47:28.000
informed consent. It turns out it's
harmless feeding them proteins and

00:47:28.000 --> 00:47:33.000
things like that.
But in fact, Garrett,

00:47:33.000 --> 00:47:39.000
in 1911, worked out that this trait
had to be recessive because of its

00:47:39.000 --> 00:47:46.000
population genetics, and
inferred a biochemical pathway

00:47:46.000 --> 00:47:53.000
by feeding different things along
the way and was able to connect a

00:47:53.000 --> 00:48:00.000
mutation in a gene to a problem
with a specific biochemical pathway.

00:48:00.000 --> 00:48:05.000
Sorry, 1908: this was his
Croonian Lecture in 1908.

00:48:05.000 --> 00:48:10.000
Eight years after the rediscovery
of Mendel, he's able to connect

00:48:10.000 --> 00:48:15.000
genetic defect, showing
it's genetic by transmission,

00:48:15.000 --> 00:48:20.000
to biochemical defect showing that
he has a pathway that he can feed

00:48:20.000 --> 00:48:25.000
things into. And, it all
blocks up at the inability to

00:48:25.000 --> 00:48:30.000
metabolize homogentisic acid. He
has connected gene to enzyme by

00:48:30.000 --> 00:48:35.000
1908. What do you
think the reaction to

00:48:35.000 --> 00:48:39.000
this was? Polite bewilderment,
and it sunk like a stone. Nobody

00:48:39.000 --> 00:48:43.000
was prepared to hear this. This
is very much like Mendel in my

00:48:43.000 --> 00:48:47.000
opinion. Now, he was a
distinguished professor.

00:48:47.000 --> 00:48:52.000
It was the Croonian Lecture. He
got lots of accolades and all that,

00:48:52.000 --> 00:48:56.000
and people said, what a
lovely lecture that was,

00:48:56.000 --> 00:49:00.000
and proceeded to completely forget
this connection between genes and

00:49:00.000 --> 00:49:05.000
enzymes, genes and proteins. It
was not until 40 years later or

00:49:05.000 --> 00:49:09.000
so that Beadle and Tatum,
working with a fungus, actually

00:49:09.000 --> 00:49:13.000
rosper not yeast, demonstrated
that all these mutants

00:49:13.000 --> 00:49:17.000
interfered with the ability to
digest or to make particular amino

00:49:17.000 --> 00:49:21.000
acids, and wrote this up as the one
gene, one enzyme hypothesis of how

00:49:21.000 --> 00:49:25.000
genes encode enzymes, and
won the Nobel Prize for this

00:49:25.000 --> 00:49:30.000
work, but in fact in
their Nobel address,

00:49:30.000 --> 00:49:34.000
Beetle and Tatum noted, actually,
you know, Garrett kind of

00:49:34.000 --> 00:49:39.000
knew all this. But,
people weren't ready,

00:49:39.000 --> 00:49:43.000
yet, to digest it. Genetics
had just come along,

00:49:43.000 --> 00:49:48.000
Biochemistry had just really been
invented in the last ten years,

00:49:48.000 --> 00:49:52.000
and the idea of uniting genetics
and biochemistry was just something

00:49:52.000 --> 00:49:57.000
people weren't prepared
for yet. More next time.