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I just got the feedback from the one
minute things just a few minutes

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before class, so I think I may defer
commenting on the couple of them

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until the beginning of next lecture.
But there are a couple of things

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that I think I can say.
One is, several people were

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wondering, how does the cell decide
whether to do mitosis or meiosis?

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But the mitosis, which is ordinary
cell division is what happens

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everywhere in your body,
in your intestine, on your skin,

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in your eye, anywhere except, since
that I you make all the different

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cells you have.
The meiosis, which creates the sex

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sells, or gametes,
happens in a very specific place,

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either in the testes if you are male
or the ovary if you are a female.

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So, there's a dedicated place where
meiosis takes place,

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and just your knowledge of human
anatomy and physiology can make a

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pretty good guess as to where that
is.  Everywhere else, it's mitosis.

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There's a very special place where
that happens.  A couple of you still

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got confused when I was talking
about meiosis and I were showing you

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a progression through,
and I put a double headed arrow,

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meaning that's was with that period
was called.  The process is

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unidirectional.
It only goes in one way.

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It's not a reversible process.
There were some questions about the

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chiasmata or the chiasma: why is
there a crossover in chiasma in

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meiosis but not mitosis?
I will tell you about that today

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very specifically.
Why was there a tall and a short

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pair of chromosomes?
That was arbitrary.  I made up a

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simple cell for us to consider these
properties in,

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one with a long,
and what with a short,

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nothing else.  I wasn't trying to
represent any particular organism.

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And I'll pick up on a couple of
other things.  I just want to

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quickly mention something.
Since I've seen you, I flew out to

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San Diego, gave a talk yesterday
morning at a major meeting,

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hopped on a plane, got back at
midnight, and here and again.

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As part of being a scientist,
come teacher, at a place like MIT,

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you guys tend not to see, but my
research life goes on

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while I'm teaching.
And I just want to briefly mentioned

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one thing I talked about yesterday,
because just in my own life it

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captures a couple of things that
I've been trying to tell you,

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that the textbook is not the
ultimate authority.

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That's just what we think up until
today.  A new finding to change the

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way you think about things,
and what I'm telling you, and some

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of your frustrated at,
that I'm not just parroting back the

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textbook is because this is the way
it is.  If you guys are going to be

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leaders in whatever field you're in,
you're going to be dealing with this

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process of shifting sands as we gain
new knowledge.

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So, in fact what I was talking about
has some relationship to the cell

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cycle that I talked about.
Lee Hartwell particularly helped us

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understand that there is what's
called a G1 phase,

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which you could think of as a
preparation for DNA synthesis for

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what's known as the S-phase where
DNA synthesis actually occurs.

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And now, you're at 4N.  You've
doubled the DNA content,

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and there's G2 where it cleans up
from S-phase, gets ready for mitosis,

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and mitosis is what you,
then, separate the daughter

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chromatids, go back to 2N,
and then ultimately the cell divides.

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And we are back to 2N.
And what we were talking about DNA

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replication, I told you how
replicative DNA polymerases test for

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Watson-Crick shape,
and remember that little movie I

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showed you where they flipped the
base pair into a very narrow slot in

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the protein, and they check that
it's there.  And they said at that

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time, that's why polymerases have a
problem when they hit a lesion such

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as a thymine dimer that we get we go
out into the sun.

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And then one of the recent pieces of
excitement in the DNA repair field

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that I work in,
was the discovery of a whole class

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of translesion DNA polymerases that
are very flexible,

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active sites and we are able to copy
over a lesion.

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Right at this point,
you will find in the literature all

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sorts of reviews about polymerase
switching, where people are

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envisioning the replicate of
polymerase coming along.

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It hits a lesion, gets stuck.
It recruits one of these translesion

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polymerases that comes in,
copies of the lesion; it switches

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back to the replica of polymerase,
[and then it goes?].  And there are

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reviews like that coming out in the
literature.  So,

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one of the genes that's needed for
this sort of error prone kind of

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translesion synthesis in yeast and
in humans is a gene called [rev-1?

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.  You don't have to notice for the
exam, this bit.

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But if you knock out the function of
that gene, the yeast aren't mutated

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by UV or chemicals anymore.
So, you know it has an essential

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function somehow in this process of
translesion synthesis.

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So, one of our big surprises was I
was trying it.

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We were trying to actually fish out
partners that might interact with it

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cause we thought it would be
regulated.  And we were surprised.

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The experiments revealed something
we hadn't expected.

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We found out that this protein that
was critical for mutagenesis was

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extremely strongly cell
cycle regulated.

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Well, given the reviews I've told
you, or if somebody you're writing a

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textbook today,
this is what they would tell you:

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polymerase switching during S-phase.
So you might have thought it would

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be high and S-phase,
but it isn't.  We can barely detect

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it during S-phase.
But instead, the rev-1 levels are

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at least 50 times in the G2M phase.
Actually, it goes right through

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this part of the cell cycle,
50 times what they are during

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S-phase.
And so, there's a couple of

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possibilities right now.
Either these very tiny amounts that

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are doing S-phase are what everybody
thinks and current models would

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predict: you're getting polymerase
switching.  And it makes 50 fold

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more during this phase for something
else.  If so, I don't know what that

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is.  The other possibility is that
we have to rethink our model,

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and that it isn't polymerase
switching during replication.

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Actually, the replication for it
just keeps moving,

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and it leaves behind little masses.
And when the cell is busy starting

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to line up as chromosomes,
and even while it's pulling them

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apart, that's when this translesion
synthesis stuff comes in,

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and it cleans up the damage.
Now, I don't know what the right

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answer is.  That was one of the
things I was talking about yesterday

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morning.  But it's an example of how
something that you guys can now

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hopefully at least understand in
principle is being debated

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right now.
And the finding from my lab changed

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the way I'd been thinking about it
at least.  I can now see another

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very real possibility.
So, just to move on, so we are

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going back to Mendel now,
who did an awful lot more than I

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told you.  A few of you thought it
was pretty frustrating and it had

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all that.  But Mendel was doing
other things.  You already know what

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he could do.  He knew how to do
crosses.  He knew how to count.

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And he could think, which was
really important.

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And he's our ratios instead of just
numbers.  So it was another class of

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experiment that he could do,
and that was he could do a cross

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where he looked at more than one
trait at once.

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And he didn't have all that many
options for things he could do,

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but he did what are known as
dihybrid crosses,

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where he followed two traits at once.
And I showed you some of the traits

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that he studied.
In fact, that picture I showed you

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is actually a cross that we can
think of right now.

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He's got smooth, and yellow,
wrinkled, and green, and yellow,

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and you'll see them in all four
combinations.  So,

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an example of the kind of crust that
Mendel carried out,

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then, was he took smooth yellow,
which actually is the dominant

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allele, and [both?
, which he learned from his other

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crosses.
And he crossed it with wrinkled

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green, which I'll represent as a
little s, little s,

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little y, little y,  where he
previously known the little s and

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little y alleles,
the wrinkled and green were the

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recessive alleles.
And then, the F1 generation,

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wouldn't be surprising to you at
this point, I think,

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that they were all smooth,
yellow.  And, they all were ss yy.

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And if you think about the possible
gametes you get out of this,

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you could only get a big S, big Y
out of this one,

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and little s, little y out of that
one.

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So if they came together,
it would have to be that.  So then,

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what he did the self crossed the F1,
and what he got out of that was the

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kind of mixture of things
that he saw there.

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He saw smooth yellow,
smooth green, wrinkled yellow,

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and wrinkled green.  In doing the
same kind of experiments that we

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talked about before,
he counted them, he looked to see if

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he saw characteristic
ratios.  He did.

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The ratios he saw were 9:3:3:1.
So, I think we know how his head

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worked at this point.
He was try to figure out if he

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could explain these results by the
kind of model that he was developing

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where hereditary information came in,
in particles.  And he could.

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But he had to make a critical
assumption.

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And if you've just seen the next
square going to draw,

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without realizing the assumption
underlies it, then you've missed a

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great deal of his thinking.
And that was that the two genes of

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sort, or the two traits anyway,
because he didn't know they were

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genes yet independently.
And the way we could see that would

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be to think about what were the kind
of gametes that you could make from

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those F1s.  So,
we could get a big S and a big Y

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from here, or a big S and a little y,
or a little s and a big Y,

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or a little s and a little y.
And, since this is [selfing?

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, it's the same thing.  So I won't
fill this whole thing in,

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but we get two S's, two big Y's here.
Down here we'd have little s,

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little y like that.  I'll fill in a
couple up here where we've got big S,

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big S, big Y, and a little Y.
Here we have big S,

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big S, but two little Y's.
Here we'd have big S, little s,

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big Y little y.  And over here we'd
have big S, little S,

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two little y's.  So, if you were to
make out [then?

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a table or a chart like this that
showed the phenotypes,

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you'll find that all of these wild
type, we can see it here.

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However, this one would be smooth.
But it's got the two alleles.  So

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it would be green.
This one would be smooth and yellow.

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And this, again,
would be smooth but green.

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And down on the corner it is the
wrinkled green.

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And if you follow that out,
draw out the rest of that, you'll

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discover there the 9:3:3:1 ratios.
That was what Mendel observed in

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all of his experiments.
But he was particularly bothered by

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it because he'd shown particular
information.  The fact [they sorted?

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randomly wasn't an issue.  However,
that was before people knew about

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the chromosomes,
which we spent quite a bit of time

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talking about the other day.
As I said, when people saw those

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chromosomes that gave rise to what's
known as the chromosomal

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theory of inheritance.
And what was interesting about

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chromosomal theory of inheritance
was that it predicted a different

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outcome depending on whether the
traits you were studying were

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encoded by genes on the same
chromosome or by genes on different

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chromosomes.  Now,
as it happened, what I think Mendel

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did was he found traits that were
well behaved and he could study.

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And those all happened to be on
separate chromosomes.

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So, his results didn't disclose
this issue that was raised by the

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discovery of chromosomes.
The chromosomal theory of

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inheritance gives,
as I said, predicts different

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outcomes depending whether things
are on the same or different

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chromosomes.
So let's consider that by taking the

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F1.  So, say they are on separate
chromosomes.  And let's take the F1

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from the previous cross over here.
So, big S., little s, big Y, little

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y, and then we'll cross it with the
homozygous recessive parent.

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That was a cross that I mentioned
the first lecture was very important.

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It's important enough that it's
given a special name.

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It's called a test across.
Well, here we are using it here.

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Well what are the possible outcomes
that could come from this sort of

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thing?  Well, I think the way you
could think about it most easily is,

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what kind of gametes or sex cells
could we get out of this?

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Well, from here we could get a big S
and a big Y.  Or,

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we could get a big S.
and the little y, a little S and a

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big Y, or a little S and a little y.
So, we could get four different

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types of sex cells.
The gametes we can get out of this

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sign, there's only one type.
So, if we start combining those,

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I think you can see what the outcome
would be.

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It's so simple.
We don't even need to draw out the

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00:16:38 --> 00:16:44
square.  If we had big S,
big Y over, they're all going to be

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00:16:44 --> 00:16:50
over.  Well actually,
I'll draw up this way because I

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00:16:50 --> 00:16:56
think it's a little easier to see.
So, there would be four possible

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00:16:56 --> 00:17:02
things that would come out
of this test cross.

210
00:17:02 --> 00:17:06
This would be the smooth and yellow.
Here would be, what have I done

211
00:17:06 --> 00:17:11
wrong here?  No,
this is right.  This should be

212
00:17:11 --> 00:17:16
smooth and green.
This would be wrinkled and yellow.

213
00:17:16 --> 00:17:21
And this would be wrinkled and
green.  And, do you see what the

214
00:17:21 --> 00:17:26
ratio would be?
It would be 1:1:1:1 because we have

215
00:17:26 --> 00:17:31
an equal probability of
making any of those.

216
00:17:31 --> 00:17:36
And, I'm going to rearrange these
because the way that it'll help us

217
00:17:36 --> 00:17:41
think about it,
this is one of the types that we've

218
00:17:41 --> 00:17:46
found in the original cross.
That's a parental phenotype,

219
00:17:46 --> 00:17:52
smooth and yellow.  It was one of
the parents up there.

220
00:17:52 --> 00:17:57
This is the other one that looks
like one of the original parents.

221
00:17:57 --> 00:18:03
So, I can divide these into
parental or nonparental phenotypes.

222
00:18:03 --> 00:18:09
These are 1:1,
and then these others were ones

223
00:18:09 --> 00:18:16
where the progeny differed from the
parent.  And they're all 1:1:1:1.

224
00:18:16 --> 00:18:22
Now, that's what the chromosomal
theory of inheritance would predict

225
00:18:22 --> 00:18:29
if they were on separate chromosomes.
That's what Mendel saw when he was

226
00:18:29 --> 00:18:36
doing his crosses.
What if they were on the same

227
00:18:36 --> 00:18:44
chromosome?  So,
we are going to have to go back to

228
00:18:44 --> 00:18:52
the original cross now to think this
one through.  So,

229
00:18:52 --> 00:19:00
what Mendel started with was a
smooth, yellow parent.

230
00:19:00 --> 00:19:05
So that was SYSY.
But because these are on the same

231
00:19:05 --> 00:19:10
chromosome, I'm going to depict them
this way so we can see they're going

232
00:19:10 --> 00:19:15
to travel as a unit.
So that was then crossed with the

233
00:19:15 --> 00:19:20
wrinkled green,
which would be a little s,

234
00:19:20 --> 00:19:25
little y.  In each case,
[UNINTELLIGIBLE] should be F1 in

235
00:19:25 --> 00:19:30
this case will be all
smooth and yellow.

236
00:19:30 --> 00:19:33
The recessive traits disappear,
but this time they're only, what the

237
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progeny will have,
they will have gotten one of the

238
00:19:37 --> 00:19:41
possible alleles from this one,
which would be the SY on the same

239
00:19:41 --> 00:19:45
chromosome, and one from the other
parent, the little s,

240
00:19:45 --> 00:19:48
little y again on the same
chromosome and one from the other

241
00:19:48 --> 00:19:52
parent, the little s and y,
again, on the same chromosome.

242
00:19:52 --> 00:19:56
So now if you start to ask, what
will happen if I do a test cross,

243
00:19:56 --> 00:20:00
you're going to get a different
outcome.  So here's the test

244
00:20:00 --> 00:20:04
cross in this case.
So, we've got this F1.

245
00:20:04 --> 00:20:08
It's smooth and yellow,
but it's actually at the chromosomal

246
00:20:08 --> 00:20:12
level now.  It's like this,
and we're crossing it with the

247
00:20:12 --> 00:20:17
homozygous recessive parent that's
now going to look like that.

248
00:20:17 --> 00:20:21
So if you think through, what kind
of gametes could we get out of this?

249
00:20:21 --> 00:20:25
Well, there's only two
possibilities.

250
00:20:25 --> 00:20:30
We could get this one or this one.

251
00:20:30 --> 00:20:36
And over here,
the kind of gametes we could get,

252
00:20:36 --> 00:20:43
there's only one type.  So, what are
we going to get out of this cross?

253
00:20:43 --> 00:20:50
What we'll end up getting is big SY,
over the little sy,

254
00:20:50 --> 00:20:57
or little sy over the little sy like
that.  That's smooth and yellow,

255
00:20:57 --> 00:21:04
wrinkled and green, the ratio of
these 1:1.

256
00:21:04 --> 00:21:06
But you see the difference from what
we saw before?

257
00:21:06 --> 00:21:08
These are the parental phenotypes.

258
00:21:08 --> 00:21:22
The chromosomal theory of

259
00:21:22 --> 00:21:26
inheritance doesn't predict that you
will get, or it predicts that you

260
00:21:26 --> 00:21:30
will not get the nonparental
phenotypes.  So,

261
00:21:30 --> 00:21:34
if you wanted to distinguish between
these two hypotheses,

262
00:21:34 --> 00:21:38
and figure out where your genes were,
you'd do the experiment.

263
00:21:38 --> 00:21:42
And what happened when this was
done, again, what often happens in

264
00:21:42 --> 00:21:46
science, you think you've got it
straightened out.

265
00:21:46 --> 00:21:50
You got hypothesis A and hypothesis
B, and you do experiment planning to

266
00:21:50 --> 00:21:54
do the scientific method and show it.
And you get a result that isn't

267
00:21:54 --> 00:21:58
what you expected with either model.
And that's in fact what happened in

268
00:21:58 --> 00:22:03
this case.
And it led to the discovery of

269
00:22:03 --> 00:22:07
genetic recombination.
And to show you actually the

270
00:22:07 --> 00:22:11
experiments where that was
discovered, I'm going to switch to

271
00:22:11 --> 00:22:15
another widely used genetic model,
which is the Drosophila melanogaster,

272
00:22:15 --> 00:22:20
or the fruit fly,
which you see in the summer around

273
00:22:20 --> 00:22:24
rotting fruit.
Or if you're in the biology

274
00:22:24 --> 00:22:28
building, one is apt to land on your
sandwich because there's just a few

275
00:22:28 --> 00:22:33
stragglers that get out of the
Drosophila genetics labs.

276
00:22:33 --> 00:22:37
But the one thing you can see from
this is the eyes,

277
00:22:37 --> 00:22:41
pretty cool.  It's got red.
The wild type is a red eye,

278
00:22:41 --> 00:22:45
and the body's brown.  And, you can
see the red eyes.

279
00:22:45 --> 00:22:50
If you look at a fruit fly
carefully, you'll be able to see,

280
00:22:50 --> 00:22:54
the summer if you take a look,
you'll see that they have red eyes.

281
00:22:54 --> 00:22:58
So, they've been a very useful
model organism for genetics partly

282
00:22:58 --> 00:23:03
because they grow pretty fast and
they are easy to handle in a lab.

283
00:23:03 --> 00:23:09
And so, I'll introduce you to a
couple of features.

284
00:23:09 --> 00:23:16
So, the wild type you find in
nature is a brown body.

285
00:23:16 --> 00:23:23
We'll call it a plus, and it has
normal wings, and which I'll refer

286
00:23:23 --> 00:23:30
to as plus.  And some mutant
phenotypes that geneticists have

287
00:23:30 --> 00:23:37
been able to find is a black body
which I'll refer to as little b.

288
00:23:37 --> 00:23:42
And vestigial wings,
which I'll refer to as VG.

289
00:23:42 --> 00:23:47
So, these are fairly easy to score.
They look like little tiny wings.

290
00:23:47 --> 00:23:53
It's fairly easy if you're crossing
Drosophila, and that looking at

291
00:23:53 --> 00:23:58
progeny to go through and score,
what color are their eyes?  And do

292
00:23:58 --> 00:24:04
they have ordinary wings
or little wings?

293
00:24:04 --> 00:24:08
So, this is the kind of cross that
was carried out.

294
00:24:08 --> 00:24:12
We are going to switch now to an
organism that has male and female.

295
00:24:12 --> 00:24:16
Up until now, plants are both.
They make pollen,

296
00:24:16 --> 00:24:20
and they have the eggs that are
going to develop into the seeds once

297
00:24:20 --> 00:24:24
they're fertilized.
But, Drosophila are more like us.

298
00:24:24 --> 00:24:28
They come in males and females.  So,
we're going to have to specify which

299
00:24:28 --> 00:24:32
is which.  And I think most of you
are probably familiar with

300
00:24:32 --> 00:24:37
this terminology.
This is the symbol geneticists use

301
00:24:37 --> 00:24:41
for female.  And this is the one
that is used for male.

302
00:24:41 --> 00:24:46
So, in this case, let's set up
exactly the same kind of thing that

303
00:24:46 --> 00:24:51
we start here.
We're going to cross a homozygous

304
00:24:51 --> 00:24:55
parent versus a homozygous recessive
parent.  That's just exactly the

305
00:24:55 --> 00:25:00
kind of thing we have up here.
But I'm going to do at this time

306
00:25:00 --> 00:25:05
using Drosophila genetics speak.
And so, we'll be taking female whose

307
00:25:05 --> 00:25:10
wild type for both traits,
we're going to cross with a male

308
00:25:10 --> 00:25:15
that's homozygous recessive for both
traits.  This is the way Drosophila

309
00:25:15 --> 00:25:21
geneticists tend to represent this
kind of thing.

310
00:25:21 --> 00:25:26
So it's exactly the same kind of
cross we got before.

311
00:25:26 --> 00:25:31
And at this point, what we get out
of the F1, it shouldn't

312
00:25:31 --> 00:25:36
be news for you.
You can see genetically what it's

313
00:25:36 --> 00:25:41
going to be.  They'll have to get
one allele from here,

314
00:25:41 --> 00:25:45
one allele from there.
So, by definition, the only

315
00:25:45 --> 00:25:50
possibility that you can get out of
this, the F1s,

316
00:25:50 --> 00:25:55
will all have one allele dominant,
and one recessive allele just like

317
00:25:55 --> 00:26:00
up there.  And this will be,
since the wild type is the dominant

318
00:26:00 --> 00:26:05
allele, this will be brown and
normal, and normal wings.

319
00:26:05 --> 00:26:12
And then, at this point they then
will set up a test cross,

320
00:26:12 --> 00:26:19
exactly the same idea.  We're going
to take the F1.

321
00:26:19 --> 00:26:26
And in this case,
we'll take a female whose got this,

322
00:26:26 --> 00:26:34
and we'll cross her with a male who
is homozygous recessive.

323
00:26:34 --> 00:26:40
So that will be black over black,
and vestigial over vestigial.  And

324
00:26:40 --> 00:26:47
out of this, there are four
possibilities.

325
00:26:47 --> 00:26:54
We can get parental phenotypes.
So, there will be, from that, black

326
00:26:54 --> 00:27:00
over, if you look to the various
combinations of how these things

327
00:27:00 --> 00:27:07
could go together,
you'll find we can get vestigial

328
00:27:07 --> 00:27:13
plus.
Or, we can get black over black,

329
00:27:13 --> 00:27:17
and vestigial over vestigial.  For
example, this one,

330
00:27:17 --> 00:27:21
coming from those two getting
together, and this one coming from

331
00:27:21 --> 00:27:25
this one and this one getting
together.  So this is just exactly

332
00:27:25 --> 00:27:30
the same kind of thing we've done
but done using Drosophila traits.

333
00:27:30 --> 00:27:38
And then, nonparental,
so now we get, for example,

334
00:27:38 --> 00:27:46
black over black, and vestigial over
plus, black but normal wings,

335
00:27:46 --> 00:27:54
or we could have black over plus,
vestigial over vestigial, which

336
00:27:54 --> 00:28:02
would be a brown body,
but with vestigial wings.

337
00:28:02 --> 00:28:06
So, if we were trying to do this
kind of cross,

338
00:28:06 --> 00:28:11
we are doing this kind of cross,
and we are trying to see what the

339
00:28:11 --> 00:28:15
outcome would be,
Mendel, every trait [assorts?

340
00:28:15 --> 00:28:20
independently would predict the
1:1:1:1.  And the chromosomal theory

341
00:28:20 --> 00:28:24
of inheritance would predict we'd
get 1:1 here, and we wouldn't see

342
00:28:24 --> 00:28:29
those at all.  Instead,
what happened when this experiment

343
00:28:29 --> 00:28:34
was done where numbers that
didn't really fit.

344
00:28:34 --> 00:28:39
This part works pretty well.
These are numbers from an

345
00:28:39 --> 00:28:45
experiment of this type.
So these are pretty close to 1:1.

346
00:28:45 --> 00:28:50
That's OK.  That fits with both of
the models.  The surprise is over

347
00:28:50 --> 00:28:56
here where there is [2/6 to 185?
.  So, these are in the ballpark of

348
00:28:56 --> 00:29:02
1:1.  But what you can see is the
result is not what was predicted

349
00:29:02 --> 00:29:06
by the model.
This is the kind of thing I've sort

350
00:29:06 --> 00:29:09
of been trying to tell you through
the course.  It keeps happening in

351
00:29:09 --> 00:29:13
biology.  It's not a QED sort of
thing where you can work it out by

352
00:29:13 --> 00:29:16
logic.  Very often,
you do an experiment,

353
00:29:16 --> 00:29:19
you get a result that doesn't fit
within your current framework.

354
00:29:19 --> 00:29:23
And then you have to go back and
redo your thinking.

355
00:29:23 --> 00:29:26
So what was going on here,
as it turned out, and it all got

356
00:29:26 --> 00:29:30
sorted out, was scientists had just
discovered genetic recombination.

357
00:29:30 --> 00:29:40
And here is where,
what was going on.  So when we

358
00:29:40 --> 00:29:50
talked about Meiosis I,
and we had duplicated the DNA,

359
00:29:50 --> 00:30:00
so we now had to chromatids, and I
showed you the chiasma when it was

360
00:30:00 --> 00:30:11
drying, it looked sort
of like this.

361
00:30:11 --> 00:30:15
And, I said that you always sought
these physical attachments that once

362
00:30:15 --> 00:30:19
the homologous pairs were duplicated,
they would always be in contact.

363
00:30:19 --> 00:30:23
And I said there was actually a
physical interaction going on there.

364
00:30:23 --> 00:30:27
Well what was going on in there was
an exchange, a recombination event

365
00:30:27 --> 00:30:31
at the DNA level that's just exactly
equivalent to what was happening

366
00:30:31 --> 00:30:35
when I showed you the
phage cross.

367
00:30:35 --> 00:30:41
Remember, we had a phage cross,
and if we got a recombination in

368
00:30:41 --> 00:30:47
between the two genes,
then we could get progeny that were

369
00:30:47 --> 00:30:53
a mixture of the two traits.
So, if we were plus plus, for

370
00:30:53 --> 00:30:59
example, these are on the same
chromosome.  And the other one is

371
00:30:59 --> 00:31:06
like this, black,
vestigial, black, and vestigial.

372
00:31:06 --> 00:31:10
If we get a genetic recombination
going on here where these two

373
00:31:10 --> 00:31:15
intersect and recombine in between
these two genes,

374
00:31:15 --> 00:31:20
what you get out of that,
then, is this chromatid is still the

375
00:31:20 --> 00:31:24
same.  It's got both wild type
alleles.  But in this case,

376
00:31:24 --> 00:31:29
now, the black allele has moved from
here to the tip of this one,

377
00:31:29 --> 00:31:34
pairing it with that.
And the other chromatid over here,

378
00:31:34 --> 00:31:39
the other homologous pair, now has
the plus together with the vestigial

379
00:31:39 --> 00:31:45
here and then here.
So, if you, then, draw out the

380
00:31:45 --> 00:31:50
possible gametes one will look like
one parent.  One will look like the

381
00:31:50 --> 00:31:55
other parent.  This one can give
rise to a nonparental phenotype in a

382
00:31:55 --> 00:32:01
test cross.  And that one can give
rise to a nonparental phenotype

383
00:32:01 --> 00:32:07
and a test cross.
And that's what's going on in this

384
00:32:07 --> 00:32:14
experiment I've described.
But the nice thing about this since

385
00:32:14 --> 00:32:22
this sort of thing is happening is
one can calculate,

386
00:32:22 --> 00:32:29
then, a recombination frequency in
just the same way that we calculated

387
00:32:29 --> 00:32:36
it when we were doing phage cross.
And in this case,

388
00:32:36 --> 00:32:44
it was the recombinants,
which in this context I'm referring

389
00:32:44 --> 00:32:52
to the nonparentals,
the recombinants over the total of

390
00:32:52 --> 00:33:00
the parental types and
the nonparental.

391
00:33:00 --> 00:33:05
So in this case,
this would be 206 plus 185 over 965

392
00:33:05 --> 00:33:11
plus 944 plus 206 plus 185.
And if I haven't blown the

393
00:33:11 --> 00:33:16
arithmetic, that would be a
recombination frequency of 17%.

394
00:33:16 --> 00:33:22
Now, we were back talking about
that phage cross.

395
00:33:22 --> 00:33:27
Remember, we did a pair of crosses
between gene one and two,

396
00:33:27 --> 00:33:33
and between two and three,
and then we were trying to figure

397
00:33:33 --> 00:33:39
out if they were in the linear order,
how we could explain it.

398
00:33:39 --> 00:33:43
And we finally worked out the order
by crossing allele one and three.

399
00:33:43 --> 00:33:48
And we made a little genetic map
that could show the order of gene 1,

400
00:33:48 --> 00:33:52
2, and 3, based on nothing more than
the recombination frequency.

401
00:33:52 --> 00:33:57
So, that's exactly what people were
able to do by this kind

402
00:33:57 --> 00:34:02
of measurement.
And that, then,

403
00:34:02 --> 00:34:07
led to the generation of chromosome
maps.  This is a publication from

404
00:34:07 --> 00:34:12
Science in 1994.
This is before the human genome was

405
00:34:12 --> 00:34:16
done.  And they were mapping a kind
of genetic marker that we'll talk

406
00:34:16 --> 00:34:21
about [when?] we do restriction
enzymes.  But they were able to

407
00:34:21 --> 00:34:26
associate it with [banning?
patterns they had seen on the

408
00:34:26 --> 00:34:31
chromosome.
This is the sort of thing that

409
00:34:31 --> 00:34:36
cytologists saw,
and as scientists were working this

410
00:34:36 --> 00:34:41
out, then they were able to
associate these genetic maps of loci,

411
00:34:41 --> 00:34:46
and begin to associate them with the
physical maps of banning patterns

412
00:34:46 --> 00:34:51
[in?] chromosomes.
Now we have the sort of ultimate

413
00:34:51 --> 00:34:56
genetic map, which is the sequence
of the human chromosomes.

414
00:34:56 --> 00:35:01
So now we know exactly, to the base
pair, how far different genes are.

415
00:35:01 --> 00:35:05
Part of the way that the human
genome was assembled from all these

416
00:35:05 --> 00:35:09
little tiny fragments of DNA that
were sequenced were taking advantage

417
00:35:09 --> 00:35:13
of these kind of maps that told the
scientists assembling all these

418
00:35:13 --> 00:35:17
little fragments of DNA sequence
what order they had to be in,

419
00:35:17 --> 00:35:21
what part of the chromosome they
were on, and that kind of thing.

420
00:35:21 --> 00:35:25
There is, this, then, leads us,
though, to other issues since I've

421
00:35:25 --> 00:35:29
now started to talk about
chromosomes.  And one more thing,

422
00:35:29 --> 00:35:33
let me just say before I leave this.
So, from this kind of thing,

423
00:35:33 --> 00:35:39
if the recombination frequency is
much less than 50%,

424
00:35:39 --> 00:35:45
then they're on the same chromosome.
And the word geneticists use to

425
00:35:45 --> 00:35:51
describe  this is they say genes are
linked.  If the recombination

426
00:35:51 --> 00:35:57
frequency is 50%,
then they are on different

427
00:35:57 --> 00:36:01
chromosomes.
At this point,

428
00:36:01 --> 00:36:05
it's just random assortment.
[You go?] one way or the other [as

429
00:36:05 --> 00:36:09
you get?] a number of 50% if you do
this kind of calculation.

430
00:36:09 --> 00:36:13
And these are referred to as
unlinked.  And those of you who are

431
00:36:13 --> 00:36:16
thinking about it can probably
imagine that there might be a

432
00:36:16 --> 00:36:20
problem, that if you had a very long
chromosome, so the two genes you are

433
00:36:20 --> 00:36:24
studying were very far apart,
you might get so many recombination

434
00:36:24 --> 00:36:28
events in between that it would
begin to look,

435
00:36:28 --> 00:36:32
the recombination frequency might
come close to 50%.

436
00:36:32 --> 00:36:36
And you would perhaps have a
difficult time in that genetic cross

437
00:36:36 --> 00:36:41
telling whether the genes are really
unlinked.  They were on separate

438
00:36:41 --> 00:36:45
chromosomes, or they were linked but
very far apart.

439
00:36:45 --> 00:36:50
So this kind of thing could be a
little hard to resolve that kind of

440
00:36:50 --> 00:36:55
situation.  But there are other
things you can do to look at that.

441
00:36:55 --> 00:36:59
So, the chromosomes we've been
talking about are what are

442
00:36:59 --> 00:37:04
known as autosomes.
These are identical pairs.

443
00:37:04 --> 00:37:10
But there's an exception.  And
those are the genes that are

444
00:37:10 --> 00:37:16
involved in sex determination.
It's the chromosomes that are

445
00:37:16 --> 00:37:22
involved in sex determination.
These are known as heterozomes.

446
00:37:22 --> 00:37:28
And, they're on this picture that I
showed you where they used this

447
00:37:28 --> 00:37:34
technique of chromosome
painting to show it.

448
00:37:34 --> 00:37:40
You can see how all these autosomes
are in identical pairs.

449
00:37:40 --> 00:37:46
But this is a male, obviously,
because there's the Y-chromosome,

450
00:37:46 --> 00:37:52
and there is an X.  If you're a
female, you'd have two copies of the

451
00:37:52 --> 00:37:58
X, something I think most of you
know.  So, if we think about how

452
00:37:58 --> 00:38:04
this works in humans,
females have two X's, and males have

453
00:38:04 --> 00:38:10
an X and a Y.
In Drosophila,

454
00:38:10 --> 00:38:16
the fruit fly, it's the same thing.
Males have two X.  Females have two

455
00:38:16 --> 00:38:21
X's, and males have an XY.
But there isn't anything magic in

456
00:38:21 --> 00:38:26
nature about females having two of
the same, and males having one of

457
00:38:26 --> 00:38:32
each because in birds where it's
different enough they use

458
00:38:32 --> 00:38:38
different notation.
The females have one of each.

459
00:38:38 --> 00:38:44
And let me make sure I got my
notation right.

460
00:38:44 --> 00:38:50
I think it's ZZ,
excuse me.  And the females have one

461
00:38:50 --> 00:38:56
of each.  So, nature tends to use
these differences as far

462
00:38:56 --> 00:39:01
as sex determination.
And this, then,

463
00:39:01 --> 00:39:06
poses a new kind of problem.
And that is, what would happen if

464
00:39:06 --> 00:39:10
you were doing a cross,
and the allele that you are studying

465
00:39:10 --> 00:39:15
happened to be a sex chromosome
instead of one of these?

466
00:39:15 --> 00:39:20
You might guess that since females
have two of one and males have one

467
00:39:20 --> 00:39:24
of each that I would not give the
results that are predicted by what

468
00:39:24 --> 00:39:29
we've talked about so far.
And so, this led to the discovery

469
00:39:29 --> 00:39:35
of what's known as sex linkage.
And that's important.

470
00:39:35 --> 00:39:41
And in fact, as you'll see in a
minute, affects stuff that we are

471
00:39:41 --> 00:39:47
familiar with in our lives.
I want to just quickly introduce

472
00:39:47 --> 00:39:53
you to this, and show you how it was
discovered.  It was done by Thomas

473
00:39:53 --> 00:39:59
Morgan in 1910 actually,
this discovery.  What he was doing

474
00:39:59 --> 00:40:05
was he took a white eyed male,
crossed it with a red eyed female

475
00:40:05 --> 00:40:11
wild type, and yet the expected
result that the F1s

476
00:40:11 --> 00:40:18
were all red eye.
But then when he took the F1 female,

477
00:40:18 --> 00:40:25
which was red, and crossed it with a
red eyed male,

478
00:40:25 --> 00:40:32
you got something that was very
puzzling at the time.

479
00:40:32 --> 00:40:37
The females were all red.
The males, half of them had red

480
00:40:37 --> 00:40:42
eyes, and half of them had white
eyes.  If you followed the logic up

481
00:40:42 --> 00:40:47
until now, where you try to work
this out, you would find that you

482
00:40:47 --> 00:40:52
couldn't generate this pattern by
the stuff that we've talked about

483
00:40:52 --> 00:40:57
now.  So once again,
this led to the need to create a new

484
00:40:57 --> 00:41:03
model, something that expanded
our thinking.

485
00:41:03 --> 00:41:07
So, the way the thinking went was,
well, there must be something to do

486
00:41:07 --> 00:41:11
with the sex of the fruit fly in
this.  And so,

487
00:41:11 --> 00:41:15
here was the hypothesis,
and that was that the white eyed

488
00:41:15 --> 00:41:20
male had this genotype.
They had an allele that caused the

489
00:41:20 --> 00:41:24
white eyeness.
But it was located on the X

490
00:41:24 --> 00:41:28
chromosome so that the male would
have had a Y chromosome

491
00:41:28 --> 00:41:34
paired with that.
And, the red eyed female used in the

492
00:41:34 --> 00:41:40
first cross would have a wild type
allele on both X chromosomes.

493
00:41:40 --> 00:41:46
And so, if that were the model,
what's going to happen to them when

494
00:41:46 --> 00:41:53
we do this cross that we've
described here?

495
00:41:53 --> 00:41:59
Well, let's think it through.
So, we've got female whose X plus.

496
00:41:59 --> 00:42:09
We're crossing with the male who's

497
00:42:09 --> 00:42:21
got the X with the white allele over
the Y.  So, the females can either

498
00:42:21 --> 00:42:34
be, they'll get an X plus XW,
and the males, yeah, right.

499
00:42:34 --> 00:42:40
The males are going to get,
they will get this allele for Y.

500
00:42:40 --> 00:42:46
So now, if he takes us red eyed
female, that was the F1 from the

501
00:42:46 --> 00:42:52
cross up here,
which will be this,

502
00:42:52 --> 00:42:58
and crossed with a red eyed male.
Now, that means the male has to

503
00:42:58 --> 00:43:05
have the good allele.
What are we going to get?

504
00:43:05 --> 00:43:11
Well, for the females in this cross,
we've got a couple of possibilities.

505
00:43:11 --> 00:43:17
This one, we could get just the
wild type female back,

506
00:43:17 --> 00:43:23
or we could get this one pairing
with this one,

507
00:43:23 --> 00:43:30
which will give us this.
So, these are all red that fit.

508
00:43:30 --> 00:43:34
But, the males,
then, if you see what happens,

509
00:43:34 --> 00:43:38
they have to have, each have to have
a Y, and then they can either get

510
00:43:38 --> 00:43:42
this allele or that allele.
If they get this allele, they're

511
00:43:42 --> 00:43:47
red.  If this allele,
they're white.  If you stand back

512
00:43:47 --> 00:43:51
and look at that,
you will see that is the outcome

513
00:43:51 --> 00:43:55
that was observed.
Females were all red.

514
00:43:55 --> 00:44:00
The males are half red,
half white.

515
00:44:00 --> 00:44:06
Well, this is a characteristic of,
this would be an X-linked trait.

516
00:44:06 --> 00:44:12
And I want to just point out one
thing.  This female,

517
00:44:12 --> 00:44:18
excuse me, wrong female.
This female here is what's referred

518
00:44:18 --> 00:44:24
to as a carrier.
She's got this allele that causes a

519
00:44:24 --> 00:44:30
white guy, but she's not expressing
it herself.

520
00:44:30 --> 00:44:34
But she's able to transmit it to her
sons.  And when she has progeny,

521
00:44:34 --> 00:44:39
on average, half of her sons will
have the trait.

522
00:44:39 --> 00:44:43
And now, X-linked traits,
there are a number of them that we

523
00:44:43 --> 00:44:48
know about.  Some of you may know
hemophilia.  Queen Victoria was a

524
00:44:48 --> 00:44:53
carrier of this gene causing
hemophilia, where there is a problem

525
00:44:53 --> 00:44:57
with the clotting mechanism.
And if you get a cut, then you can

526
00:44:57 --> 00:45:02
bleed a lot.
So, some of her sons had this.

527
00:45:02 --> 00:45:06
A more common one, which has to
apply to some people in this room,

528
00:45:06 --> 00:45:10
is red-green color blindness.  If
you're a male,

529
00:45:10 --> 00:45:15
you have a much higher probability
of being colorblind because it's an

530
00:45:15 --> 00:45:19
X-linked trait.
And I want to just close by showing

531
00:45:19 --> 00:45:23
you how human geneticists think
about the sort of thing.

532
00:45:23 --> 00:45:28
And we have to think about things
differently if we are doing human

533
00:45:28 --> 00:45:32
genetics because as most of you know,
I think all of us would be very

534
00:45:32 --> 00:45:37
uncooperative subjects in a kind of
genetic cross that a fruit fly

535
00:45:37 --> 00:45:41
geneticist [or most?
geneticists would like to have us

536
00:45:41 --> 00:45:45
do, in which we'd be put in a cage
with a member of the other

537
00:45:45 --> 00:45:49
sex and say, mate.
That was your choice in life.

538
00:45:49 --> 00:45:53
Well, that would be a different
kind of existence for us all.

539
00:45:53 --> 00:45:56
So, human geneticists don't have
that luxury of having pure breeding

540
00:45:56 --> 00:46:00
strains and doing controlled
crosses.

541
00:46:00 --> 00:46:04
We all have very strong feelings
about the kind of crosses that we

542
00:46:04 --> 00:46:08
want to engage in.
And so, what they have to do,

543
00:46:08 --> 00:46:12
they have to make use with what they
find.  And they use a couple of

544
00:46:12 --> 00:46:16
symbols here that I'll just show you.
They look at pedigrees,

545
00:46:16 --> 00:46:21
and then they look for patterns.
And, they use a little shorthand

546
00:46:21 --> 00:46:25
for doing this.
Males are squares,

547
00:46:25 --> 00:46:29
which I don't know if there's any
symbolism to that or not,

548
00:46:29 --> 00:46:33
but if they are affected they show
it as a shaded square,

549
00:46:33 --> 00:46:38
and unaffected as an open symbol.
So, affected males are solid squares.

550
00:46:38 --> 00:46:43
Affected females are solid circles.
So, let's take a look at the sort

551
00:46:43 --> 00:46:47
of pedigree that human geneticists
might see.  And let's consider

552
00:46:47 --> 00:46:52
something.  Let's consider red-green
color blindness,

553
00:46:52 --> 00:46:57
which is an X-linked trait.
So, let's take a male, which there

554
00:46:57 --> 00:47:02
is probably one in this room at
least, maybe more, who have this.

555
00:47:02 --> 00:47:06
So, since the colorblindness trait
is on the X chromosome since he's a

556
00:47:06 --> 00:47:10
male, the other pair will be Y.
That means if you're a male and

557
00:47:10 --> 00:47:14
you've got it,
you're going to display the

558
00:47:14 --> 00:47:18
phenotypes.  So this is,
George, let's say, who is colorblind.

559
00:47:18 --> 00:47:22
They leave a lot of the romance out
of these things,

560
00:47:22 --> 00:47:26
as you'll see, who had progeny with
Mary.  Let's say,

561
00:47:26 --> 00:47:30
they got married after they
graduated from MIT.

562
00:47:30 --> 00:47:35
It was very happy.
They had a, let's see,

563
00:47:35 --> 00:47:41
son.  He had to get the Y from dad.
So, he had to get a good allele

564
00:47:41 --> 00:47:48
from his mother.
But they also had a daughter,

565
00:47:48 --> 00:47:55
and she had to get the color
blindness allele on an X chromosome

566
00:47:55 --> 00:48:02
because the dad only had one of them,
and then a good one from her mom.

567
00:48:02 --> 00:48:08
So at this point,
everybody's normal.

568
00:48:08 --> 00:48:15
But you'll notice, this daughter
has this trait of being a carrier

569
00:48:15 --> 00:48:21
because even though she doesn't
display the trait herself,

570
00:48:21 --> 00:48:28
she's got it in her genome.
So, let's say, [UNINTELLIGIBLE

571
00:48:28 --> 00:48:35
PHRASE], a woman who doesn't have
any colorblindness allele.

572
00:48:35 --> 00:48:39
So, if we have,
let's say, a daughter,

573
00:48:39 --> 00:48:43
and a son, a daughter, and a son,
this is not much happening over on

574
00:48:43 --> 00:48:48
the part of the pedigree.
Everybody would be normal.

575
00:48:48 --> 00:48:52
Yeah, did I miss something?
Pardon?  Oh, it's over Y.  Excuse

576
00:48:52 --> 00:48:57
me, yep, I'm going too fast here.
Over Y, here we go.  I don't need

577
00:48:57 --> 00:49:01
to introduce any genetic
abnormalities on top of what we're

578
00:49:01 --> 00:49:06
already trying to do here.
This is complicated enough.

579
00:49:06 --> 00:49:10
OK, so what happens,
let's say then that the daughter

580
00:49:10 --> 00:49:14
that married a guy,
and they had four children.

581
00:49:14 --> 00:49:18
I'm going to help us with the
genetics of it,

582
00:49:18 --> 00:49:22
from the geneticist,
that sort of a perfect family in

583
00:49:22 --> 00:49:26
this case would be four kids
representing all four possibilities.

584
00:49:26 --> 00:49:30
And so, first off let's think what
would happen with the daughters.

585
00:49:30 --> 00:49:37
Well, the daughters could either
have the colorblindness allele

586
00:49:37 --> 00:49:45
paired with this one.
Or, they could get a wild type

587
00:49:45 --> 00:49:52
allele with this one.
So actually, I'd better put this in.

588
00:49:52 --> 00:50:00
So this is a daughter.
So this would be [CB?] over plus,

589
00:50:00 --> 00:50:06
or it could be plus over plus.
This one would,

590
00:50:06 --> 00:50:12
again, be a carrier.
Now, with the sons, they're both

591
00:50:12 --> 00:50:18
going to get the Y since they're
male.  But there's a possibility of

592
00:50:18 --> 00:50:24
either getting the good allele,
which means he'll be unaffected.

593
00:50:24 --> 00:50:30
But, if you get the other one,
he'll be affected.

594
00:50:30 --> 00:50:33
Now, this would be sort of a typical
pedigree.  And you realize,

595
00:50:33 --> 00:50:36
depending on the number of kids,
you might or might not see this.

596
00:50:36 --> 00:50:39
But this, you're going to get to do
some more of these and to do some

597
00:50:39 --> 00:50:42
other traits.  But let me just sort
of point out, if you're a human

598
00:50:42 --> 00:50:45
geneticist, what you would recognize
here, the trait's more frequent in

599
00:50:45 --> 00:50:48
males.  The frequency of color
blindness is about 8% on the X

600
00:50:48 --> 00:50:51
chromosome.  So,
if you're a female,

601
00:50:51 --> 00:50:54
you've got to have two of them.
So that means, you've got 0.64%

602
00:50:54 --> 00:50:57
because you've got to get two
together.  It's a much smaller

603
00:50:57 --> 00:51:01
probability.  The trait skips a
generation, [you'd often say?].

604
00:51:01 --> 00:51:04
You see it here.
You see here. But you don't see it

605
00:51:04 --> 00:51:08
in between, and that's because you
have this carrier.

606
00:51:08 --> 00:51:11
The affected males don't transmit
to their sons because what they give

607
00:51:11 --> 00:51:15
to their sons is the Y.
So, they [kept giving?] the

608
00:51:15 --> 00:51:18
colorblindness thing.
And then, the heterozygous females

609
00:51:18 --> 00:51:22
who are carriers will transmit the
trait to their sons about half the

610
00:51:22 --> 00:51:25
time.  And that's a pattern that a
human geneticist would look for.

611
00:51:25 --> 00:51:29
And they'd say, ah-ha, it must be
an X-linked trait.

612
00:51:29 --> 00:51:33
And you'll see in your problem sets
and [recitation?

613
00:51:33 --> 00:51:36
sections are the patterns.
OK, I'll see you on Friday.