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ERIC LANDER: Let's talk about
what Mendel really did in his
experiments.
So section one, Mendel's
experiments.
Mendel did a lot of really
cool things.
The first thing he did was, in
order to study heredity, that
was his assignment as a monk--
go study heredity--
he had to get some material
to work with.
He decided to use peas.
Why peas?
Well, there are a lot of
varieties of peas in the
market, many different
kinds of peas.
And you could breed
them together.
There were tall peas, short
peas, green peas, yellow peas,
round peas, wrinkled peas, all
kinds of peas that you could
find in the market.
They grew very well
in the garden.
And when you're done with the
experiment, you could feed
them to the monks.
So the first thing he did
was he got his material.
And did he immediately start
crossing his peas together?
No.
What did he do?
AUDIENCE: [INAUDIBLE].
ERIC LANDER: Sorry?
AUDIENCE: He grew
them separately.
ERIC LANDER: He first grew
them separately.
Because he wanted to see if he
was going to study how traits
were inherited, he first had to
do the control experiment.
He first had to show that if he
took each variety of peas,
they would breed true.
So the first thing is,
Mendel did controls.
That's an important thing
we learned from Mendel.
He took round peas.
He took wrinkled peas.
And he bred them with
themselves.
And they always came
out round.
And he took wrinkled peas and he
bred them with themselves.
And they came out wrinkled.
And if they hadn't always come
out round or hadn't always
come out wrinkled, it would've
been a much harder experiment
to interpret later.
So that was incredibly important
thing to do, was do
the controls, round
and wrinkled.
Then, when he was satisfied that
he had pure breeding or
true breeding plants, then and
only then did he do an
experiment.
What experiment did he do?
You all know Mendel.
The truth is, this is not
like a surprise here.
So what did he do?
He crossed the round
and the wrinkled.
I'm trying to draw out the new
things here, but some of the
old ones you know.
And when he crossed round
and wrinkled--
We'll call this the
F 0 generation.
In the F 1 generation,
what did he see?
Round.
You all know this.
He saw all round.
He didn't see puckered,
slightly puckered or
anything like that.
He didn't see any wrinkles.
They were all every bit as round
as the rounds in the
parental generation.
That was an extremely important
point, because of
course, a competing theory of
inheritance was blending
inheritance, where the
offspring would be
intermediates.
And the truth is almost every
experiment that you do when
you take plants and you cross
them, or animals and you cross
them, despite your biology
textbook, shows blending
inheritance.
A tall plant and a short
plant, you breed them.
Almost always is
a middle plant.
But not for the peas.
The peas were a beautiful
system.
And Mendel very lucky to have
chosen it, because truth is,
there was only one gene
difference that was
controlling these traits.
If there'd been 10 genes
controlling this, you'd get
some blending, blah,
blah, blah.
But Mendel got a situation
with really clean
experimental data.
The round was every
bit as round.
And so that said, no blending.
Now what did he do?
Next, what Mendel does is he
crosses these round peas to
themselves.
He selfs them.
So we're going to
self the peas.
The peas can be selfed.
They have both male and female
reproductive parts.
And when he selfs them,
they self pollinate.
And what do they produce?
Peas.
That's good.
They produce peas.
And what does he notice?
He notices that now they're
not all round.
Some of them are wrinkled.
And the wrinkleds are every
bit as wrinkled as the
wrinkleds were in the parental
generation F 0.
And the round were every
bit as round.
So suddenly wrinkled
had gone away.
And what had happened?
Sorry.
Wrinkled had gone away
in this generation.
And now it had reappeared.
The trait reappears.
It's quantal.
It's discrete.
It's not blended
out in any way.
It's not blended.
It's not imperfect.
It's the same wrinkled that
was there before.
That's a big qualitative
observation.
This whole blending notion can't
be right, at least for
this experiment.
Discreteness rules.
So that was his experiment.
Mendel could've written it up
and said, wow, the traits
don't blend.
They're discrete.
But Mendel, being an MIT kind
of monk, went further.
What did he do?
Sorry?
AUDIENCE: He repeated it.
ERIC LANDER: He repeated it.
And it still showed
some rounds and
wrinkleds and all that.
But he was a very quantitative
MIT monk.
He counted them, which seems
obvious, but ain't so obvious.
He counted them.
And what did he find?
A fixed proportion?
What?
AUDIENCE: A ratio.
ERIC LANDER: A ratio.
AUDIENCE: Wasn't there 1:3?
ERIC LANDER: 1:3 or 3:1 or
something like that?
No.
No.
Nope.
No, he counted.
He counted.
And what he found was
rounds: 5,474.
Wrinkleds: 1,850.
Ratio, not 3:1 at all.
2.96:1.
No, no, no.
But you see, you say because
your books all tell you 3:1,
that it's obvious if you
do that, you say,
that must be 3:1.
It not must be 3:1.
It's 2.96:1.
And if you do it again,
you might get 2.87:1.
And it actually takes quite an
imagination to say, it's
trying to be 3.
Just think about it.
You come to this experiment
and you say, it's
trying to be 3.
That's a separate leap and
an important leap.
He counted.
And he got numbers, 2.96:1.
And he got other numbers.
He then, as you've done so
quickly, made a hypothesis.
That hypothesis was that, in
fact, this was trying to be
3:1, that it quote "wanted to
be 3:1." It was near 3:1.
And that really the reason
it was trying
to be 3:1 was because--
Well, there was a pretty
nice explanation here.
His cool explanation was, the
round plants and the wrinkled
plants, well he made
up a model.
These guys had two particles of
inheritance, big R big R,
little r little r.
When you cross them together,
these guys were
big R, little r.
And when you self them, if you
randomly chose one particle
from the sperm and one particle
from the egg, ovule,
you would have big R, big R, big
R, little r, little r, big
R, and little r, little r,
all as possibilities.
And that these guys, big R, big
R, they would be round.
Why would they be round?
Well because that's what the
parental generation here was.
The little r little r, they
would be wrinkled.
Because that's the parental
generation there.
And these guys that have one of
each, what would they be?
Round, because we saw that in
the F1 generation, one of each
makes it round.
So we had a model, a hypothesis,
a model.
Pretty cool.
You can come up with this
model by saying, the
contribution from the male,
the contribution from the
female, this is the male
gametes, the female gametes.
You get this nice little thing
sometimes referred to as a
Punnett square.
Although he didn't use
Punnett squares.
And Punnett wasn't born yet.
Now what do you do?
Mendel went out and got
experimental material.
He did controls.
He did an experiment.
He counted.
He then made this creative leap
to say, I see something
cool going on.
Integers are what's going on.
And made up a model.
What does a scientist
do at that point?
Sorry?
Oh come on.
In this modern world, if you got
a result this cool, what
would you be doing?
Sorry?
AUDIENCE: Publish it.
ERIC LANDER: Publish it right?
You're going to get out there
quickly and publish it.
Mendel whips off an email to
Nature in London, saying--
Or whatever the 1865 emails.
Actually it wasn't Nature.
It gets published in the
Proceedings of the Royal
Society of Brun.
But forgive me.
I'll use Nature, OK.
So he whips off an email to
Nature, which is what we do
today, telling the editor, we
have this really cool result.
I think it'll be of
broad interest to
the readers of Nature.
We're going to try to send
you a paper next week,
et cetera, et cetera.
Are you interested?
They write back, oh yeah.
We'd love to see your
paper Gregor.
And Mendel whips together
a paper.
What happens when Mendel whips
together this paper and it
goes off to London, to Nature,
the offices of Nature?
What does Nature do with it?
They just set it and type
and say, here it is?
What's the scientific process?
Peer review.
Before you go print this thing,
you've got to send it
out to some other scientists
as anonymous reviewers and
say, we've received this paper,
this correspondence
from Brother Mendel
in Moravia.
Would you review it for the
journal Nature and tell us
your candid opinion?
And they write it up.
And they send it
back to Nature.
And Nature makes a decision
whether to publish the paper.
So you're the reviewers.
Should we publish
Mendel's paper?
Who says yes?
Who says no?
Why no?
AUDIENCE: He needs
more examples.
ERIC LANDER: Needs
more examples.
So you're right.
One lousy trait.
Mendel actually had seven
traits in the paper.
It turns out I didn't tell you
them all, green and yellow,
and tall and short.
And they're all in the paper.
He actually has seven separate
examples that
show the same thing.
Should we publish it?
Why not?
It's just peas.
Oh boy, you're churlish there.
I mean, come on.
It's peas.
People eat a lot of peas.
It's a result.
It'll get others in the
scientific community
interested.
AUDIENCE: Who are the
peer reviewers?
ERIC LANDER: You.
I've assigned you as
peer reviewers.
I'm asking you, should we
publish this thing?
We got seven traits we're
going to publish.
And it's pretty cool.
Nobody's ever reported this
3:1 ratio in this model.
AUDIENCE: That's true.
But I wasn't the peer
reviewer back then.
ERIC LANDER: You are now.
AUDIENCE: Then yes, I
would publish it.
ERIC LANDER: You'd publish it.
OK.
He'd publish it.
Because nobody's
reported this.
It's pretty cool.
The model perfectly
fits the data.
Yes.
AUDIENCE: It's got to
make predictions.
ERIC LANDER: It's going
to make predictions.
But the model fits the data.
AUDIENCE: The model needs to
make predictions [INAUDIBLE]
data.
ERIC LANDER: Are you saying
that we made up the model
after we saw the data?
And that it's not a surprise
that the model fits the data?
Yeah, that's right, isn't it.
That's a real problem.
If you make up models after they
fit the data, they tend
to fit the data.
Well they do.
That's a real problem.
So the reviewers write back to
Mendel and say, Mendel-- this
isn't actually how it happened,
you understand.
But anyway, they write
back to Mendel.
They write back to the
journal Nature.
And they anonymously say, we
would like to see some
predictions of this model to
see if this is really true.
And Nature writes
back to Mendel.
And the email says, could
you just show us some
predictions from this?
So to help Mendel out, what
predictions can we make?
What surprising predictions
could you make for Mendel's
experiment?
Well, this experiment, round
by wrinkled, gives round,
gives some rounds and some
wrinkles, which we think are
big R, big R, big R, little
r little r, big R,
little r, little r.
And that this is big R, big R.
How could we prove something's
going on in this generation?
AUDIENCE: Self them.
ERIC LANDER: Self them.
If we pick out a round
and self it,
what's going to happen?
Sorry?
AUDIENCE: It depends
on which round.
ERIC LANDER: So how do I know
which round to pick.
They all look the same.
AUDIENCE: You just
try all of them.
ERIC LANDER: Try all of them.
If I try to all of them,
what am I going to see?
AUDIENCE: You'll see some that
only produce rounds.
ERIC LANDER: Produce rounds.
About what fraction of them
will only produce rounds?
1/3.
And what fraction will produce
rounds and wrinkleds?
AUDIENCE: 2/3.
ERIC LANDER: 2/3.
We have a prediction.
Thank you.
The prediction is,
test the rounds.
And although we don't know which
are which, 1/3 of them
will give rise to only rounds,
whereas 2/3 of them will give
rise to our 3:1 ratio.
That is a non-obvious
prediction.
If this model weren't right,
it's very surprising if you
would have nailed
that prediction.
Nice.
What other predictions
can you make?
What other crosses could
you set up to test it?
AUDIENCE: Wrinkleds
by wrinkleds.
ERIC LANDER: The wrinkleds
by themselves
will only give wrinkles.
And that's true.
Bingo.
So we're doing well.
What else?
AUDIENCE: Wrinkleds
with rounds.
ERIC LANDER: Wrinkleds
with rounds.
So I could take these three
rounds here and I can cross
them to wrinkleds.
What'll happen here?
If this was rounds, rounds over
wrinkled, wrinkled, it's
going to give rise to what?
AUDIENCE: Rounds.
ERIC LANDER: All rounds.
But if this is round wrinkled,
what would it give rise to?
AUDIENCE: Half and half.
ERIC LANDER: 50:50.
Half and half.
Now we're cooking.
There are all these predictions
that start
dropping out, because your model
tells you things you
haven't yet seen.
Mendel writes back and says,
I did all the experiments.
I did what the referees
requested.
The referees get
the paper back.
They say, yes indeed, Mendel's
done the experiments.
We recommend publication.
Nature publishes it.
They put out a press release
and all that.
Mendel's on the evening news,
that kind of thing.
It didn't really happen
that way exactly.
But anyway, you get the point.
That's the process
of doing science.
It's a cool process.
And it's a back and forth.
And it's a process of convincing
people, and you
convince them by predictions.
And you can think of
the kinds of cool
predictions you could make.
And that's what's fun about
working in a lab, is making
those kind of predictions.
Now all right.
I need to give you a
few definitions.
A gene.
When I refer to a gene for the
moment, I mean a discrete
factor of inheritance, discrete
particle, factor of
inheritance, something
like that.
Because geneticists early on had
no idea what genes were.
You know perfectly well a
gene is a DNA sequence,
blah blah blah blah.
But it's useful to be
able to think about
a gene in the abstract.
It's the thing that controls a
particular inheritance of a
particular trait.
Variant forms of a gene,
alternative forms of a gene,
are called alleles.
When I write big R, little r,
they are alleles of the gene
for roundness.
Allele, from the Greek meaning
other or alternative.
When I write genotype, I mean
the combination of alleles
that an individual has.
Like when I write big R, big
R, that's a genotype.
Or big R, little
r, or little r,
little r, that's a genotype.
When I say the word phenotype,
what do I mean?
A trait, an appearance.
What are the traits under
discussion here?
Round and wrinkled.
Geneticists are like
mathematicians.
They're very precise
about their words.
Now comes the ones that people
always have trouble with,
dominant and recessive.
Phenotype 1 is dominant to
phenotype 2 if the--
Oops, sorry.
I meant to add two words here.
Heterozygote, homozygote,
words you know as well.
Heterozygote, having
different alleles.
Homozygote, having
the same alleles.
Different, same alleles.
So a phenotype, phenotype 1 is
dominant to phenotype 2 if the
F1 heterozygote, the cross
between them, has phenotype 1.
Why did I write this in this
wacky mathematical way?
That says round is dominant to
wrinkled if when I cross round
to wrinkled, the offspring
are round.
So which is dominant,
round or wrinkled?
Which is dominant, big
R, or little r?
No.
Big R is an allele.
We said phenotypes are dominant,
not alleles.
We don't say big R is dominant
to little r.
We say round is dominant
to wrinkled.
Now this will bother
you greatly.
And it will bother about 95%
of my biology colleagues.
But geneticists who are careful
use the word dominant
and recessive to refer to
phenotypes, not alleles.
Why do I care?
I care because big R, as a
molecular allele, as a variant
of a gene, might end up
controlling three or five
different traits.
Some of the traits that big R
controls could be dominant.
Some of them could
be recessive.
Sickle cell anemia, there's
a sickle cell mutation.
Is that recessive or dominant?
Sickle cell anemia
is a recessive
trait, a recessive phenotype.
But sickle cell trait, the
tendency for blood cells to
sickle at low oxygen tension,
is a dominant phenotype.
The allele that causes sickle
cell anemia causes a recessive
trait, anemia, and a dominant
trait that can be measured in
heterzygotes.
You'll forget this.
Everyone will forget this.
But I've at least told you
once that alleles could
control multiple phenotypes
and do control multiple
phenotypes.
And that's why geneticists
obsess about using the words
recessive and dominant to refer
to the phenotype, not
the genotype.
I've made my plea.
Like all of my colleagues in
the biology department, you
will continue to misuse
the word.
But there's a better chance
you'll get it right because
I've made my little
stand here.
Recessive is the opposite
of this.
Good.
This is mostly to say,
geneticists try to think
carefully about their words.
Those are the definitions.
You should be able to use the
words gene, allele, genotype,
heterzygote, homozygote,
phenotype, dominant, recessive
in a good way.
