Stanford University.
Let's see.
Various announcements.
I am out of town tomorrow,
so no office hours.
I managed effortlessly to
confuse a whole bunch of people
Monday about positive selection
versus stabilizing selection.
All of that on the Q&A
part of the course works.
I've pulled out the paragraphs
from the extended readings
that explain that coherently, as
opposed to what happened here.
And Monday-- Monday I discovered
that somebody sitting in this
room, who I cannot
spot at the moment,
has a spectacular tattoo
illustrating the central dogma
of life, or at least one person.
If there's two, it's
really something.
So amazing demonstration
of DNA to RNA to protein.
So if the person doesn't
have a class afterward,
he will be standing up
on top of this counter
here displaying
it for everybody's
educational purposes.
So besides finding about that
guy, what else happened Monday?
Monday we introduced
two concepts
and, with great
dramatic foreshadowing,
started to trash both.
The first one being
this huge emphasis
in all of the preceding lectures
on the evolution of behavior--
not only this emphasis
on adaptation,
not only this emphasis on
inferring a genetic basis
through that roundabout--
here's a story
and until you make up
a better one, I win.
But also that emphasis
on gradualism,
that slow evolutionary change.
What we focused
on there was what
would be the mechanisms,
the molecular mechanisms,
for classic gradualist
evolutionary change,
microevolution, the whole world
of point mutations-- deletion,
insertion, all of that, the
whole world of mutations
potentially being big news,
knocking a protein completely
out of business
and suddenly you've
got a different gender than
you actually are chromosomally,
but a world, none the less,
where for our soundbite,
micromutations are affecting
how readily a protein does
its job-- how strongly,
how potently, how long,
what its job is,
all of that, that
as sort of the grist for the
microevolutionary change.
What we then transitioned
to was the huge, huge attack
on the gradualism that
came with this view
of punctuated
equilibrium, this notion
that most of the time, nothing
exciting was happening,
long periods of stasis, and
then sudden, dramatic change
proposed by Gould, other
evolutionary people.
And what we saw was
the huge implication.
There it was.
If most of the time,
nothing interesting
is happening in terms
of evolutionary shift,
there goes
gradualism, there goes
the emphasis of every
bit of adaptation
is going to make a difference
long term, every, opportunity
to compete, compete
and dominate,
is going to make a difference.
All of that goes down the
drain if 99% of the time,
there is instead
equilibrium stasis.
What we saw were the wildly
enthused attacks upon it
along the grounds of that
stasis and rapid change
for paleontologists
bears no resemblance
to what the world is like for
an evolutionary biologist.
Paleontologists can only see
the evolution of boring stuff--
morphology.
You miss the entire
world of what's going on
inside that morphology.
And the most damning
sort of complaint,
show me some
molecular mechanisms
for these
macroevolutionary changes.
What we then transitioned
to was seeing all the ways
in which the picture of the
structure of genes and DNA
is completely wrong along
the lines of there's
the intervening sequences,
the intron/exon organization
of genes.
Suddenly the opportunity
to mix and match
combinatorial abilities for
one gene, or at least one
stretch of DNA, to
specify a whole bunch
of different proteins, depending
on the function of the splicing
enzymes, and those
splicing enzymes
differing in different
parts of the body
under different circumstances.
We then saw that flabbergasting
business about 95% of DNA
not coding for proteins, not
being genes, but instead,
the instruction manuals,
the promoters, the switching
on and off, leading to
that critical notion
of transcription factors
transducing events going on
out there, out there outside
the nucleus, outside the cell,
outside the organism,
into changes in DNA,
and thus the incredibly
important role of transcription
factors, promoters.
There are a lock and
key interactions.
All that sorts of
stuff introducing
the second critical
concept-- if microevolution
is about sort of changing the
function of a protein, changes
occurring at the level
of transcription factors
or promoters, those
are about changing
the context for which
proteins are functioning
when genes are expressing.
What they are about are
introducing if/then clauses.
If this is happening outside
the nucleus, cell, universe,
whatever, then if that results
in this gene being activated,
then you will see that response.
What came along sort
of de facto with that,
the second major thing
that we thus trashed,
was DNA as the central starting
point, the dogma of life.
DNA is the only one who knows
what's going on out there.
DNA commands, RNA commands,
protein commands all of life.
And what we saw was DNA,
genes, are just a readout
and most of what it's about
is environmental regulation
of when genes activate.
Finally we began to see all
sorts of ways of futzing around
with gene expression
that has nothing
to do with the sequences
of DNA, but instead
has to do with things like
access of transcription factors
to the DNA, changing
accessibility permanently,
that whole world of
epistatic, epigenetic changes,
coming up with that
sound soundbite.
Fertilization is about genetics.
Development is about
epigenetics-- all of that
combining to show,
number one, genes
are not such a hot deal in
terms of them knowing what's up.
Number two, in
addition to mechanisms
known for
microevolutionary change,
we left just on the cusp of
seeing how all of this stuff
can set you up for some big
time macroevolutionary changes.
First example of it.
First way in which
that could occur.
So back to the modular
construction of genes.
We've got our introns,
exons, all of that.
And what we learned
the other day is here
we've got a gene coded
for with three exons.
You produce a messenger
RNA that encompasses
all of these plus the introns.
Along comes a specific splicing
enzyme, knocks out these parts,
and here is the mature protein.
So that's great.
What if you have a mutation
in your splicing factor,
in your splicing
enzyme, and as a result,
instead of clipping here,
it ignores those and clips
here instead.
What do you get?
You get two completely
novel proteins
that never existed before in
this cell, in this individual.
What you've got there
is not some sort
of little
microevolutionary change.
This is not a protein
working a little bit better
or a little bit more sluggish.
This is the invention of
entirely new proteins.
So what we see here is splicing
factors working differently.
And this is a major
change, if whatever
went on in the outside world
that causes the then of this
being made, if you've got
that mutation in the splicing
factor, you've just made
entirely new if/then.
If whatever's going on
in the outside world
happens to activate this,
you produce these two novel
proteins.
So we've suddenly
got the potential
for producing all
sorts of novelty.
They're splicing enzymes,
enzymes, proteins, thus there
are genes coding for
the splicing enzymes.
As a result, suddenly a very
different type of consequence.
Yeah, question?
How often do those [INAUDIBLE]
make it out of the [INAUDIBLE]?
Great question.
How often do they make
their way out of the--
[INAUDIBLE]
What was that?
How often do the
mis-splice [INAUDIBLE]
successfully have function?
Do they have any function?
[INAUDIBLE]
That's a critical question.
Wait about an hour
and 17 minutes
and you will get the answer
to it-- the answer being,
not very often.
Oops.
I gave it away.
The answer being not very often.
And we're going
to see why that's
real critical to
punctuated equilibrium.
So we see one realm
of major consequence.
And intrinsic in that is,
wait a second-- so if splicing
enzymes, enzymes are genes.
There's a gene for
the splicing enzyme.
And that gene has its promoters.
And that gene maybe is
in a number of exons.
And thus it needs
a splicing factor.
And we're rolling all
the way down there.
Recursive regulation.
So one splicing factor,
big consequence.
Next realm where you can
have a big consequence
is now you've got a
mutation in a promoter.
A whole world of a mutation in
a noncoding part of your DNA.
And you can immediately
run with that one.
Have a different
promoter, and it's
going to interact with a
different transcription factor.
And we go back to that business
about typically a promoter,
the same version of it, multiple
copies of that promoter,
appear upstream of various
different genes-- promoters
mediating expression of
entire network of proteins.
Change that promoter and you're
going to change the network.
Change that promoter in
only some of the places
where it occurs and
now you've created
a completely novel network,
a network consisting maybe
of half of the proteins
that you would have
made in the unmutated version.
Mutate every single
version of it,
and maybe it's an entirely
different transcription
factor that interacts
with that promoter.
And thus we've made an
entirely new if/then clause--
not just a new if/then make
a never seen before protein.
Now it's an if this
happens, then make
a network of proteins that
have never existed before,
a combination of these that
have never occurred before.
What we're beginning
to see here is
a theme of amplifying affects.
Huge, major
consequences, instead of
one little protein which,
thanks to one little base pair
changing, is 1 and
1/2 degrees more
folded this way
instead of that way
and 1.5% better at binding
this or that hormone.
That's the microevolutionary
this is setting up
for big network changes.
Novel genes, novel networks,
novel if/then clauses.
Third range-- an example of
why promoters and promoter
mutations are interesting.
Later on in the course, we
are going to hear about one
of the all time
interesting differences
that you can have in
one of your promoters
if you happen to be a vole and,
increasingly it's turning out,
equally interesting if
you happen to be a human.
This is a promoter
upstream of a gene
having to do with the
hormone vasopressin.
Do not panic or care if you
haven't heard of this yet.
But you will have in more
detail within a few weeks.
Vasopressin is this
hormone which has something
or other to do with social
affiliated behavior in males
and all sorts of
interesting stuff with that.
And naturally, it
being a hormone,
out there is a
vasopressin receptor.
And thus, there's a
vasopressin receptor gene.
And there's a promoter
upstream of that gene
which turns out to come in a
couple of different flavors.
And you look at voles, which
are a little hamster thingee
sort of things.
And there's all sorts of
different vole species.
And there's ones
in the mountains,
and there's ones in
the plains, and there's
ones from California to
the New York islands.
And there's all these
different species.
And it happens some of them
happened to be monogamous.
Some of them happen
to be polygamous.
We're off and running with
the social biology of that
and how many imprinted genes and
all that they're going to have.
But a critical difference
in monogamous vole species--
there is a different
promoter upstream
of the vasopressin
receptor gene than you
find in the polygamist ones.
And go and mess
around with them,
use gene therapy techniques
to change the promoter
to modify it, and you could
convert a polygamous male vole
into a resoundingly
monogamous one.
And I don't know if this
counts as gene therapy
like curing a disease or just
gene transfer sort of stuff,
but what you've got here
is change your promoter
and you suddenly have
a different pattern
of expression, which parts
of the brain it winds up in.
Suddenly you have made a
major shift in behavior.
You're not causing
a change in a gene.
You're causing a
change in its promoter.
You've just changed a
major if/then clause.
Another example of
it-- there is a gene
that codes for hormone
neurotransmitter that
has something to do with pain
perception called dynorphin.
It's broadly related to
things like morphine and such.
It's got a dynorphin gene
that's a little more complicated
than that.
But there's a promoter upstream.
And recent research is showing
that the number of copies
of that promoter
in different rats
predicts something about how
readily they become addicted
to various drugs.
And that winds up
being pertinent.
Back for a second.
Back to the vasopressin
gene and the vasopressin
reporter gene and it's promoter.
In the last couple of years,
a number of studies come out.
One, for example, in a
very credible journal
by a great group
showing that if you
happen to be a human male,
which version of that promoter
you have gives you a certain
significant predictive power
over how stable your social
relationships are going to be.
Get a load of that one.
And that one is coming later on.
Whoa.
Have a different type of
promoter and statistically
you are more likely to get
divorced down the line.
Back to that first
lecture freewill stuff.
There is so much more to
come along those lines.
We will look at the
vasopressin system
much more in the sex lectures.
But again, that's not
a difference in a gene.
That's a difference
in the promoter.
Next domain-- we've now seen
changes, subtle changes,
dramatic changes,
in splicing enzymes
and the genes underlying
them, changes in promoters.
Next obvious domain where you
can get a macro, macro change
is a mutation in a gene
for a transcription factor,
obviously.
Do that and you're going to have
completely different networks.
Once again, you will have
changed if/then contingencies
dramatically.
Transcription factors are very,
very important, obviously.
One measure of
this-- when you look
at the human genome
versus the chimp genome,
and we will eventually do that
in some detail and say, 98%
of our genes in common,
which is kind of accurate.
And you remember from the
other day how that's different.
It's the level of
explanation than you
sharing 50% of your genes
with your full sibling.
All of that.
Back to us sharing 90%,
98% of our DNA with chimps.
What are the differences?
And there's going to be some
really interesting differences
we're going to focus
on down the line.
But one of the patterns
that's come out
of that is a
disproportionate share
of the genetic differences
between humans and chimps
are genes that code for
transcription factors.
And that makes perfect sense.
You get a change
in some gene coding
for some structural
protein and maybe
your muscles will bend
a little bit this way
instead of that way,
or who knows what.
You get a change in the gene
coding for transcription factor
and you will have invented
all sorts of novel networks.
So a disproportionate
share of what
has gone on in evolution
differentiating us from chimps
are changes in
transcription factors.
This was a big
triumph, big support,
for a view that came
out in the '80s.
There were a pair of scientists
at Berkeley, King and Wilson,
and this iconic set
of studies they did.
They were the first
persons, people,
to come up with a
98% business there.
And using very primitive
molecular techniques
that have since been
affirmed-- and they also
came up with a prediction, a
purely theoretical one, which
is, the most interesting changes
that will occur in evolution
are in regulatory parts of
DNA rather than in the coding
parts for protein.
And everything since
then has supported
that, including
things like, you want
to turn an ancestor
of a human and a chimp
into something that
will look a whole lot
different from a
chimp, turn into us,
change stuff with
regulation, transcription
factors, promoters.
What you see with that
is this is endlessly
networks for amplifying
effects for macro changes.
And there's a new person in
the department, Bio department,
Hunter Frazier, a new
assistant professor,
who works in this
area showing just how
much evolutionary
change is being driven
by change in regulatory
parts of the DNA world,
rather than the genes itself.
Changing a little bit about how
this protein works, that's OK.
Changing if/then clauses
for entire networks,
that's hugely important.
Another interesting
factoid-- there's
now been the genomes
of, I don't know,
about 100 different species
sequenced, and ranging
from really short
genomes with I don't
know how many genes in
there, to the longest ones.
When you pile them up
and you look at them
as a function of how
long their genomes are,
the more genes you find
in a species, the greater
the percentage of
those genes are
that are transcription factors.
And this makes
wonderful sense as well.
You got one gene and you only
need one transcription factor.
You got two genes and you could
milk maximal information out
of them with three
transcription factors.
You transcribe A or B, or AB.
You've got three genes
and there's seven.
And the equation
is 2 to the nth.
This one.
Whatever.
But what you see is by four
genes, you're up to 15.
By five genes, you're
up to 30-- you're
having an exponential, a
dramatic increase in the number
of transcription factors
you need to take advantage
of all the possible combinations
of networks of gene expression.
The larger the number of
genes you find in an organism,
the greater the percentage it
is of transcription factors.
In other words, get tiny
little micro, micro changes
in DNA coding for transcription
factor splicing, enzymes,
promoters, and you're going to
have big major consequences.
So over and over here, we see
this contrast microevolution is
about the function of proteins.
Macroevolution is
about which proteins--
when networks' if/then clauses
are far more consequential.
One additional
domain of-- we're not
talking about a tiny
little micro change
in one base pair--
one additional domain,
a highly revolutionary one that
came some years ago that also
has lots of implications
for thinking
about macro stuff in evolution.
And this revolved around one of
the great irresistible musical
dramas that have ever come
out of the history of science.
Once that is-- there's got
to be a musical somewhere
in the future of this-- having
to do with a scientist named
Barbara McClintock.
Barbara McClintock--
if you are sort
of a modern molecular sort of
person, at some point or other,
you will have to have sacrificed
a goat at the altar of Barbara
McClintock.
She is so amazing and she
has such a stirring story
as to what happened with her,
one which actually is so.
Barbara McClintock was born, I
don't know, about 1900 or so,
and was a plant
geneticist and was sort of
off doing genetics of plants
and doing something or other
with maize.
Whatever those people do.
And she was
extremely successful.
She was wildly successful.
I think at age 40 or
so in the late 1930s,
she was already a
member of what's
called the National
Academy of Sciences, which
is like the most honorific
science club you can belong to
in this country.
40-year-old women
in 1940 were not
becoming members of the
National Academy of Sciences.
110-year-old white guys
with shiny foreheads
were becoming members
of the National Academy.
For her to have been
elected at that point,
she was an amazing scientist,
one of the absolute leaders
in the field.
So she's cruising along
there, being renowned.
And one day she made a
discovery that completely
destroyed her career.
So she's sitting there one day
and she studies beloved corn
maize and the patterns
of inheritance
based on colors of kernels.
Genes, molecular biology,
like nonexistent.
None of the stuff available now.
All you could do in
terms of making sense
of what is being inherited,
patterns of inheritance,
is just looking
at the phenotype,
looking at the appearance.
Peas and whether they're
wrinkly or not, people
and whether they're
wrinkly or not, corn
and what the colors are of
the various kernels there.
That was cutting edge molecular
sort of genetics at the time.
So she's working in that domain
and she's seeing a result.
She's seeing a
pattern of inheritance
which keeps popping up
in certain circumstances.
And you go through all of
the inferential math that
was available and you
crunch through everything.
And you, if you were Barbara
McClintock pursuing this,
you come up with a conclusion
that is totally nutty.
The only way to explain how
this change was occurring
was if genes were picking up
and moving around on the DNA,
if gene were jumping around,
if genes were mobile,
moving around.
And out of this, she
came up with a proposal
that there are such things
as transposable genes,
transposable genetic
elements, transposons.
All of the people who spent
decades afterward mocking her
in various ridiculing
tones of voices
soon referred to these
as jumping genes.
And the general
consensus in the field
was that Barbara McClintock
had gone out of her mind.
Yeah, genes jumping around.
Yeah, right.
I'll sell you the
Brooklyn Bridge
after that if you believe it.
That's ridiculous.
That's ridiculous.
And Barbara McClintock, having
a certain stoic self-esteem
sort of based personality of
one that was-- basically said,
you know what?
This is what I see.
You want to believe
it, believe it.
You don't want to believe
it, don't believe it.
Leave me alone, I want to
go back to my experiments.
And she essentially
disappeared from the field
and just sat out
in her cornfield
at a lab in Long Island
called Cold Spring Harbor lab,
and just chugged along on her
own for decades afterward.
She wrote papers about it
that were incomprehensible
to people, because
no one could believe
anything this ridiculous.
And she was developing
this whole story
about genes that move,
transposable genetic elements.
Everybody ignored her.
She was mocked.
She was pilloried.
She was burned at the stake.
All of that.
And then finally somewhere in
the 1980s, molecular techniques
caught up enough to show
she was absolutely right.
And these things now
are called transposons.
Transposable genetic elements.
Genes really do pick
up and move around.
And this was an amazing
landmark discovery.
The entire world went crazy
about Barbara McClintock
at the time.
She was on the cover of Post's
Wheaties boxes of cereal.
[LAUGHTER]
There were Barbara
McClintock lines
of dance clothes and exercise
videos and recipe books
and all of that.
And somewhere along the way,
they gave her her Nobel Prize.
And she was in her
late 80s at the time.
And showing exactly the
stuff she was made out of,
she said, well, that's nice.
Thanks for the Nobel Prize.
But you know what?
I didn't really need
to have gotten it.
This is what I saw.
You want to believe
it, yes or no?
You believe it now?
That's nice.
Leave me alone.
Let me go back to work.
[LAUGHTER]
And she continued to work in
her cornfields doing experiments
up until about a week before
her death in the early '90s.
This is a totally
cool, amazing figure
in the history of
science, a lonely pioneer.
As it turned out, she wasn't
that lonely of a pioneer
and people didn't think
she was quite that crazy.
And apparently a
lot of her papers
were ignored because
she could not write
and her papers were
incomprehensible.
But nonetheless,
the general picture
was, she discovered
all of this on her own,
staked her career on
this, and most people
thought she was out of her
mind and eventually vindicated.
Totally cool sort of piece
of the history of science.
Really, really
inspirational person.
And I met her once
and got to see her
with her corn and she was--
[LAUGHTER]
A remarkable-- she was like 90
at the time-- and a remarkably
nice, low-key person, where
after about 13 and a half
seconds, it was obvious
that what she mostly wanted
was for me to get
the hell out of there
so she could go back
to her corn, which
was her response
to everybody there.
But very heroic figure.
So she discovers
this entire new world
of these transposable
genetic elements.
And people have been studying
it since, these jumping genes.
The first thing that
has become clear
as the field ha matured is
she picked the right species
to study.
She never would have discovered
transposable genetic elements
if she was out there
alone in her cornfield
studying sperm
whales or something.
Separate of the funding
problems and the logistics,
she would not have found it.
She did it in the right
organisms, which were plants.
Think about it.
You are an animal.
And one of the things you can do
is, when the going gets tough,
you can get up and run away, or
you can crawl away or fly away
or whatever sort of animate
animal type things can do.
If you're a plant,
you're stuck there.
You can't run away.
And if you're going to
survive a challenge,
you're going to have
to have something
more subtle going for
you than, oh, let's run
and get out of here.
And it turns out all sorts
of realms of plant stress
responses are in just the avant
garde of molecular biology.
Plants have to
have fancier tricks
than all sorts of boring animals
because plants don't run away.
What they do instead, among
their various defenses, when
a challenge, a pathogen, a
climate change, whatever it is
comes along, one of
the things they do
is there's realms of their DNA
where they move genes around,
where they shuffle stuff around
in the hopes of stumbling
onto something novel and useful
to get them out of that mess.
Plants have induce-able
events of genes moving
transposable genetic elements.
They tend to induce
them when the plant is
under some sort of challenge,
a cellular stress response.
And the way that's
done is by activating
an enzyme called transposase.
And those of you who are
new to the business, enzymes
tend to have -ase
the end of the word--
lactase, sucrase, transposase.
And what you've
got there is, this
is a defense on the
part of the plant.
Juggle some of
its DNA prudently,
and see if you can come up
with something to help you.
Make a copy of
the gene, and then
go plunk it down somewhere
else and see if you've
stumbled into something useful.
And it was only in the
aftermath that people
started to look at the
same issue in animals
and vertebrates and mammals.
And shockingly to
everyone, except the people
who hung out with her, was the
fact that we've got them, too.
We've got transposable
genetic elements, we animals.
We've got them.
Where they were first discovered
made a lot of sense as well.
You are some scientists
and you've just
invented in your lab some
pathogen, some toxin,
some who knows what, that
has never been seen before
in the history of the planet.
You've synthesized
it and you inject it
in a whole bunch of people.
And they get totally
sick and miserable.
And then you come back two
weeks later, two months later,
and they will have made
antibodies against that thing.
Their body, their
immune systems,
will have made antibodies
against some invasive pathogen
thingee that never
existed before
in the history of the planet.
And a staggering challenge
is how does the immune system
come up with this
vast variability
for dealing with
novel pathogens,
making antibodies that
will recognize them?
And people soon discovered
one of the tricks
was splicing of genes
relevant to making
antibodies and juggling
them around-- induce-able,
transposable events--
in the hope of making
a gazillion new
types of antibodies
in a remarkable filtering
process that goes on
in the immune system,
spotting are any of them
good against this new
thing that just showed up?
That's where you had a
lot of transposable events
in the vertebrate immune system
in response to novel pathogens.
Turns out, we
weren't the only ones
doing that because there
were other things that
could be happening.
There were all sorts
of the pathogens that
could do the same exact thing.
There is one tropical
parasite, Trypanosome, which
is one you do not want to get.
And trypanosomiasis is
the inflammatory disease
you get from a
trypanosome, this parasite,
and it shows up in your
body, and your body
does this induce-able
trick and, thank god,
comes up with some
antibodies that could begin
to target it and attack it.
But trypanosomes also
worship at the altar
of Barbara McClintock.
What they do is, a
couple of weeks into it,
they take away the surface
proteins on their surface
and they juggle some
of the relevant DNA
and come up with a
novel version of it.
So just as you've got
the antibodies online,
you can't recognize the
thing with those antibodies.
You've got to start the
process all over again.
And thus trypanosomes are
always a couple steps ahead,
thus the immune
system has to have
evolved better ways of juggling,
coming up with novel stuff.
Co-evolutionary races there.
But the cornerstone
of it is inducing
movable genetic elements.
And what people have
learned since then
is it occurs outside of
just the immune system
and under interesting
circumstances.
One really amazing one, which
I was going to tell you later
but I will tell you now because
I just can't wait-- there
is one transposable
element that's
very predominant in primates.
And there is a certain cell
type and a certain time of life
when it is most mobile, when it
moves around the most-- which
is, the cells in your brain
that are going to be making
new neurons, neural
progenitor cells, at the time
that they start proliferating
and making new neurons.
There is an induce-able
event at that time
where you increase the movement
of that one genetic element.
What are you doing?
You're making some new neurons.
And, as it turns out, in
a fairly controlled realm
of your DNA, you decide to
shuffle the deck a little bit
just because you want to get
the interesting novel sort
of things that neurons can do.
This is totally amazing.
This is totally amazing because,
among other things, what
this tells you is the
cells in your body
that have the greatest thing to
do with making you who you are,
are the least constrained
by genetic determinism.
Because right when these
types of cells, neurons,
are first being
generated, they're
doing more shuffling
of genetic cards
than any other cell
type in the body.
That sure takes away
the power of genes a lot
when it comes to
the nervous system.
These transposable events make
a whole lot of variability,
some of which is wonderful.
Some of which is not,
and this is coming back
to the question that was asked
before, are these disastrous?
In most of the cases, yes.
But in a few minutes, we'll see
exactly why it is not likely
that when you randomly
shuffle a bunch of cards,
they're going to come out in
a perfect sequence of numbers
or some such thing.
It is a long shot to get
something interesting out
of it.
Nonetheless, this is a
mechanism for doing this.
What this allows you to
do by moving parts of DNA
around, making a copy of this
stretch and then moving it
and, I think-- I don't
know the field that well,
but I think, at
least in most cases,
the notion is it plunks
down randomly somewhere else
in the genome.
By moving stuff around, you can
have big macro consequences.
For example, suppose
you've got, by now,
and if/then clause
introducing this concept
already-- if/then clause,
and we can translate
this totally primitively
into worlds of promoters
and worlds of the actual gene.
So you've got an if/then clause.
Suppose you are dehydrated.
If you were dehydrated,
translating that
into actual biology, I
don't know, your hematocrit
or how wrinkly your kidneys
are getting or some such thing.
Then tell your kidneys to
start doing something or other
that kidneys do to retain
water, which I once understood
for a finale, no longer do.
But you wake them up and
they have some response.
So we've got an if/then clause.
If you were getting dehydrated,
then make your kidneys work
in a way that increases
water retention.
This is ridiculous.
There is if you are getting
dehydrated promoter.
There is no gene
that is equivalent.
There's networks, though.
There's networks,
and there's ways
in which your kidney monitors
that and other outposts
in your body.
So we have a rough
if/then clause.
Wouldn't take a whole
lot of imagination
to turn that into real biology.
Now suppose you have
some transposable events.
Suppose whatever it is,
the promoter world of that,
picks up and moves
and the if you
were dehydrated part of the
if/then clause floats around.
It gets plunked down
upstream from the genes
that say go and ovulate.
What have you just invented?
What does this allow you to do?
So now you've got an
if/then clause, a promoter
of that response to
dehydration, and it turns
on genes related to ovulation.
What does that get for you?
Any ideas?
Oh, come on.
Ovulate really frequently.
Ovulate--
Really frequently.
Really frequently.
Depends on your threshold.
If like you should be-- skip
orange juice in the morning,
does that mean you're
dehydrated enough to ovulate.
You could set it at a very
low threshold like that.
You could do that.
You could do
something else though.
What else?
[INAUDIBLE]
You're about to
die of dehydration
and that gives you
one last chance
for a round of passing
on copies of your genes,
if you could find some
guy who isn't dehydrated
to dramatic blood flow extent.
That's a possibility.
What else can you do?
Seasonal mating.
Yes, seasonal mating.
That's what it's
mostly used for.
Certainly possibilities here.
But what this
allows you-- you're
a species where six months
of the year it's dry
and six months of the year
it's wonderful wet and lush
and exactly the time you
want to be having a baby.
And you've got like a six
month gestational period.
What do you want?
You want your body to know
when it's the dry season,
and that's the signal to mate,
because you want to give birth
during the rainy season.
And then there's species where
you are pregnant for two weeks
or so.
And what you want to
have there as a rule is,
oh my god, if it's the
dry season, don't ovulate,
because I'm going to give
birth to kids who are going
to starve or some such thing.
Let's wait until I
get a signal that I'm
totally wet and hydrated.
Then ovulate.
You introduce novel
if/then clauses.
And for certain
species, this would
be how you would do
seasonal mating-- how
to know you should
obviously at a time of year
where, given your
gestation length,
it's going to set you
up for giving birth
at the time of year
when your offspring are
most likely to survive.
And thus, you will have passed
on copies of your genes.
All of that.
So that's great.
Another example.
And this one is
immediately accessible
and is a first crude
way of beginning
to approach some of this stuff
that just flowed seamlessly
and cheaply in the
forms of theories
from last week's stuff.
So you have some
if/then element in there
and a promoter
which, in some way,
can tell this individual
near me smells like me.
And we will see, by
next week, exactly how
that translates into genetics.
But this individual kind
of smells a lot like me.
And it has an if/then clause
which immediately shuts down
transcription of all sorts of
things related to fertility.
You don't mate with relatives.
Some sort of incest taboo runs
through a gazillion species
out there.
Individuals smelling like
you, if you were a hamster,
make you much less
likely to mate with them.
So a very logical
if/then clause.
All that works great.
And now you've had a
transposable genetic event.
And you plunk down the,
if it smells like me then,
into upstream of the
gene that says cooperate.
And what have we just invented?
The starts of kin selection.
And you could see all
sorts of rules like,
if you have more
promoters, you could
begin to have subtleties
of saying, if they really,
really smell a lot like me,
like if all these promoters are
going off at once, then really,
really, really cooperate.
If they smell only somewhat like
me, only somewhat cooperate.
You could begin
to fine tune that.
What have you just invented?
A way of taking
sensory information
about degree of related-ness
and turning that
into your extent of sacrificing
for one sibling or eight
cousins.
So you could begin to see how
you invent new if/then clauses.
Obviously this is ridiculous.
Obviously this bears
no relationship
to what's going on
in the real world.
This would be happening
in nose cells.
This is occurring
down in the ovaries.
There is no promoter that
responds to, oh, somebody
here is smelling like me.
But there are some that do stuff
not all that far from that.
You could begin to
imagine turning this
into real biology, how you
could program for this.
And once you've got
genes moving around,
you've plunked a promoter
down someplace else.
You've just made a
new if/then clause.
Now the possibilities is of
transposing genetic elements,
also raises the possibility
of moving around
parts of genes-- not just
parts of regulatory elements--
moving around parts of genes.
How would you do that?
How would you move
a part of a gene?
Exons.
That's that modular
construction of genes
again, where if you
get a transposase
that comes and does
its thing there,
and in making a copy of this,
moves this stretch around,
you're now moving copies
of parts of genes around.
And you can relate new genes.
For example, here we
have the basic mechanism
of action of steroid hormones.
You guys who need an
introduction to that,
we'll get it in a week or two.
Steroid hormones--
hormones like estrogen,
progesterone, testosterone,
glucocorticoids.
All of these, they
work as follows.
Steroid hormones can
enter a target cell
and they bind to their receptor.
Yes, indeed.
Lock and key.
All that happens.
Steroid hormones are
not made of amino acids.
They have a different structure.
But nonetheless, each
has a distinctive shape.
And each type of receptor
for a type of steroid hormone
has a distinctive shape driven
by its amino acid sequence
and those gene codes.
All of that.
So you've got a specific type
of steroid hormone fitting
into its specific type
of receptor-- estrogen
into an estrogen receptor,
that sort of thing.
And what it does
as a result is it
activates this receptor complex.
And on the other side
of it, is a confirmation
which recognizes a particular
promoter down on the DNA.
A, in this case, what would be
called an estrogen responsive
promoter.
So what have you got there?
You've got events going
on in the outside world.
You are reading the
right parts of some novel
and suddenly you're
secreting certain hormones
that weren't there before.
And you're changing genomic
effects shortly afterward.
This is environment
regulating genes like crazy.
What is this requiring?
One part of the receptor
recognizing the hormone,
specifically.
And one part of the
receptor recognizing
its specific
appropriate promoter.
So now along comes one of
those transposable events.
And it happens,
steroid hormones--
this would be called the
hormone binding domain.
And this would be called
the DNA binding domain.
In steroid receptor genes,
those are in different exons.
And suppose along comes
a transposable event.
And you clip this part
off and you stick it
in a different hormone
binding domain.
So you've just made a completely
different if/then clause.
If this hormone is
around, then do this.
Now suddenly instead it's,
if this hormone is around,
then do this.
New if/then clause.
Here would be one possibility.
One of the class of
steroid hormones,
glucocorticoids,
which eventually you
will come to love because you
will hear endlessly about it.
And glucocorticoids,
they're stress hormones.
Human version of hydrocortisone.
For our purposes
right now, what's
interesting about them is they
suppress the immune system.
These are steroidal
anti-inflammatories.
When you're taking
non-steroidals,
you're taking things that
work like glucocorticoids
on the immune system,
but they don't
have some of the side effects.
Glucocorticoids suppress
the immune system.
It is very well understood.
And glucocorticoids
come in and bind
to the hormone binding domain
of the glucocorticoid receptor.
And this translocates to a
glucocorticoid responsive
promoter.
That's its whole thing.
So now you have gotten
a transposable event.
And what you've done
instead is plunked down
the hormone binding domain
from the progesterone receptor.
So suddenly you've
got an if/then clause
that's novel, instead of,
if they are glucocorticoids
around, suppress immunity.
Now instead you've got,
if there's progesterone
around, suppress immunity.
What do you think
you've just invented?
Any uses for that?
If you happen to know what
progesterone is about and where
that might have been a great
invention to come up with.
Any speculation?
During pregnancy?
During pregnancy.
Progesterone, which
is progestational--
so you suppress your immune
system during pregnancy.
How come?
Why is that a
clever thing to do?
So your body doesn't
eat your baby.
[LAUGHTER]
Did you just say so your
body doesn't eat your baby?
[LAUGHTER]
Well, there you go.
I don't know what your family
is like, but I won't speculate.
[LAUGHTER]
But, yeah.
You do that so your body
won't eat your baby.
So your body doesn't do
that, so that you don't have
an immune reaction against it.
And that's a whole world of
having to decide this thing
belongs here,
instead of this thing
having invaded my
placenta-- back
to that word that was used
by gynecologists talking
about last week--
the imprinted genes.
Male derived imprinted genes
making for a more potent
invasion into the placenta.
All of that.
Yeah.
This is a great way to
now do that deal of,
you suppress immunity
during pregnancy,
you are less likely to have
some weird immune attack
on your fetus.
And that was a great invention.
That was a wonderful thing
to have come up with.
There's an interesting
consequence of that,
though, one that
pops up in medicine
often, which is--
so you are immune
suppressed because
you're pregnant
and then you give birth, and you
stop being immune suppressed.
The progesterone disappears
for the most part.
You're off into a very different
endocrine world at that point.
Your immune system comes back
to where it was before hand.
But there is a
potential problem,
which is your immune
system is so wiped out
and you're so distracted
changing diapers and having
no sleep whatsoever, and
so your immune system is
a little bit out of control.
What if it recovers from this
pregnancy immune suppression
and, instead of coming back
to where it was before,
it overshoots a little bit?
What have you gotten
at that point?
Your immune system shoots
into being more active than it
should be at that point.
What class of diseases
are you set up for now?
Autoimmune.
Autoimmune disease.
Whoa, that's as good
as the lock and key,
everybody knowing that one.
You are set up for an
autoimmune disease then.
There is a whole realm
of autoimmune diseases
that tend to have
either initial onset
or flare up in the post
parturition period for women.
And in fact, there are
some autoimmune diseases,
a very serious
form, say, of lupus,
women really should
not get pregnant,
because they are going to get
such a burst of lupus flare ups
afterward.
So this is a clever thing
during pregnancy, as usual.
You don't want to overdo it.
Our main point here
though is, by doing
some transposable event,
moving one exon around
and sticking it to
another exon that never
existed before, you've made
up a completely novel if/then
clause.
So where have we gotten so far?
We are worlds away from
the dull, gradualist world
of micromutational stuff from
the other day of one protein
working differently.
You have the capacity to invent
completely novel proteins
through splicing enzyme changes,
through transposable events.
You have the opportunity to
make completely novel networks
with mutations and
promoters, with mutations
and transcription factors.
What all of this means is, there
is going to be major changes.
And thus, after a
five minute break,
we will come back
to your question
there of, what are the odds
of these changes actually
being good for you?
So a five minute break.
Sometimes you will find a
gene will be duplicated.
There will be an extra
copy of the gene.
There will be two copies,
one after the other.
Gene duplication.
Sometimes, you can have even a
larger expansion of the number
of copies of a gene.
Or you can have duplication
of a whole stretch of genes.
And this is falling
into this new area
that people refer to, calling
it copy number variant.
And ranging from one
extra copy of one gene
to massive duplication of
whole stretches of chromosomes.
And no surprise,
you wind up getting
interestingly different
things going on at that point.
What we'll see later
on in the course is,
there is more and more evidence
that the disease schizophrenia
involves mutations in
copy number variance.
And here, this is not a
mutation in one base pair.
This is not a mutation
in one transcription.
This is extra copies
of genes sitting there.
This can have some very
interesting implications.
In some cases, the second
gene can function as a backup.
If something goes
wrong in the first one,
there's a second one
there doing its job.
And there is some suggestion
that something like that
is occurring in some subsets
of Alzheimer's disease.
Or what you can have is the
number of copies of the gene
you make has something to do
with how much of the protein
you make.
And there's recent
studies showing
that when you compare
Japanese populations
with Western European
ones, on the average,
Japanese populations have
more copies of a gene that
has multiple copies, more
copies of a gene that
makes an enzyme related
to carbohydrate digestion.
I have no idea what the
implications would be of that.
But this is not a populational
difference in a DNA sequence
or in a-- this is simply the
number of copies of the gene.
What a second copy,
what a duplication also
allows you to do in the
most metaphorical sense
is experiment with
one of the copies.
Because the other
one is there taking
care of whatever the
function is that's critical,
what you'll see is you get
faster evolution going on
with genes that you have
duplicated, where one of them
is the one that, in
a sense, is freed
to have more dramatic movement.
And what you then
see is it's more
likely to stumble
into some great use
without sacrificing the
initial use in the process.
And there's a guy
at the University
of Oregon named
Joe Thornton who's
done really interesting work
on the evolution of genes
for steroid receptors.
And what he has shown
from ancestral genes
is that's exactly
what's occurred.
A lot of what are now two
different genes for two
different types of
steroids receptors
were once duplicates
of the same gene.
And one was allowed to
float and eventually,
in at least some cases,
stumbled into something useful,
while the other one
held into place.
In passing, what
that phenomenon does
is help explain one of
the endless, frustrating,
exasperating, irritating
things that people
who attack the notion
of evolution bring up,
which is the famed sound bite
that they have of the problem
irreducible complexity.
It always runs the
same way, which
is saying that
evolution can't possibly
exist because is what
good is half of an eye?
You've got to have those
intermediate forms.
And what good is it-- you
couldn't have invented.
Evolution could not
have produced an eye
in one mutation, one
generation, and thus it
would have to be in
a series of steps.
And what good are
the series of steps?
They can't exist.
There can't be anything
such as evolution.
Off you go.
Hallelujah.
So what you get
here in these cases
is a demonstration,
instead, by having
extra copies of genes, one of
which is freed to be evolving.
You don't have to have a
rapid transition from one
to the other.
You can have this thing
moving along, stumbling along,
until it just happens to come up
with a shape of a receptor that
just happens to be able to
bind a hormone that stumbled
its own way into existence
10,000 generations earlier,
which because it was duplicated,
it didn't matter that one
copy was now of a form where
there was no receptor on earth
for it until it happened
to stumble into that.
And there is more
and more evidence
that duplicated genes
have a way of describing
these intermediate states
where you don't necessarily
have half an eye,
but instead you
have the pieces
ready in place there
for when one thing
suddenly pops up,
which completes the picture.
In fact, you can have, as
it turns out, sort of half.
Russ Fernald in the
biology department
has done really cool research
on the evolution of eyes.
And you should read
about it some time
to read basically
how eyes evolved
from a single layer of
cells on the surface
of some ancient proto something.
And you sure can
have half an eye
and a zillion
intermediate forms.
None the less, this
business of multiple copies
allowing you the freedom to have
loser evolving of single genes
of a time-- critical mechanism.
So now we've got all of our
pieces in place-- changes
in splicing enzymes and
promoters and transcription
factors and transportable
elements and number
of copies of genes,
number of copies
of whole stretches of genes.
What wind up being the
consequences of this?
Back to the question
brought up before.
So what we saw the other day is
some time futz around with one
single base pair,
one single gene,
and you've got somebody
who's going to be
dead at three months of age.
PKU, phenylketonuria.
One single gene could be
a total, utter disaster.
My god.
Instead now, thanks to these
macro evolutionary changes,
you change one single
base pair and as a result
you change-- one, two,
three-- seven different genes.
No, not seven.
But you change
more than one gene,
you have one single
base pair change,
and if it's an exon
that's used in a lot
of different
combinatorial ways, you've
now produced mutated
versions of a whole bunch
of different proteins.
One single change in the
transcription factor and you've
invented an entirely new
network of expression.
What are the odds of
stumbling into something there
that is going to suddenly be
great and wonderful in all
those different
areas of consequence?
It's really unlikely.
What have we just seen here?
This is a very stabilizing
mechanism for equilibrium.
Equilibrium, long
periods of stasis.
What we've got is,
if a single base pair
change is going to affect half
a dozen different proteins
or affect, through a
transcription factor,
entire networks, the odds are
pretty lousy that you are just
going to happen to
stumble into one that
works in all those
domains, or at least
works in enough of them that
it doesn't do you in in others.
Most of these macro
mutational changes
are going to be bad news.
Most of the time,
in other words,
there is stabilizing
selection against
macro mutational changes.
So what have we just gotten?
We've just gotten
a straight line.
We've just gotten long
periods of stasis.
So when do the changes come?
When you have some circumstance
that is extreme enough
that it doesn't matter
that if this mutation--
you have made elevendy
new types of proteins.
And elevendy minus one of
them are not great news.
And the final one
used to kill you.
If the final one now
is the trait that
is going to save
you, it is going
to carry the weight of all
the other proteins that
are changed.
If you get what is called
an evolutionary bottleneck,
if you get a circumstance of
such severe selection for such
a tiny subset of traits,
that basically the rule is
it doesn't matter-- if you have
that trait-- it doesn't matter
how much of a network
you've changed,
you're going to be one of
the ones who come through
and everybody else does not.
And the evolutionary
record is full of all sorts
of circumstances where there
have been selective bottlenecks
where 1% of a population comes
out the other end of it because
of some rare trait that they
had which carries all the macro
consequences of that.
For example, there
was clearly some sort
of bottleneck of selection that
went on with cheetahs about--
I don't know, a couple
thousand years ago or so.
People have estimated
more accurately.
Because all the cheetahs
are so genetically
similar to each other that
you can transplant tissue,
you can graft tissue
from any cheetah on earth
onto another one and there
will not be rejection.
All of the cheetah on earth
are closely related descendants
of what had to have been fairly
recently, a couple of thousand,
a tidy, remnant population
that now is highly inbred
and you had some sort
of selective bottleneck
that went on at that time.
Similarly, I can't remember
when in hominid history,
but the suggestion was at
at least a couple of points
in hominid evolution,
there have been
points of selective bottlenecks
where glaciers or comets
or knows what, where only a
small subset of individuals
with some traits that have
been, up until then, neutral
or are unlikely to be useful
because of these big macro
consequences, suddenly
only the folks who had it
came out the other end.
What are we beginning
to describe here?
Circumstances of rapid change.
Circumstances of
punctuated radical change.
There are circumstances
that begin
to make conceivable
punctuated equilibrium.
It's so intrinsic in
this huge complexity
of macroevolutionary change in
DNA because of the structure
intrinsic in it are
two critical things.
One is the vast
majority of the time,
make a change which
changes some whole network
and it's going,
to be a disaster.
The majority of the time,
there's going to be stasis.
And also intrinsic in
that is the ability
to have massive macro
changes, any of these examples
we've had here,
where, in periods
of selective bottlenecks,
you're going to get something
like that happening.
So Gould and friends
are absolutely right.
All of that.
Not necessarily.
Because again, this radical
rapid change period, that's
for paleontologists,
for biologists.
That's thousands of
generations, in some cases.
Again, what counts
as very rapid in one
scientific discipline may not
be the same for the biologist
at the other end.
Nonetheless, this winds
up being a mechanism
for long periods of spaces
and very rapid change.
So that suggests that, where
we have these mechanisms.
So how does one begin to resolve
the microevolutionary picture
of gradualist social
biology from last week
and the macro picture of
punctuated equilibrium
drama, all of that?
How do you begin to put
the pieces together?
A number of ways that
it could be done.
Let me just see here.
Yes.
A number of ways
it could be done.
One is thinking again about
micro mutational changes
or about changes in the function
of preexisting proteins.
And macro mutational changes
are about the invention
of new proteins, new networks,
new, if/then clauses,
all of that serving
different functions.
Back to the difference
in the genome
between humans and chimps.
When you look at the micro
versus the macro differences,
for example, in the domain
of the immune system,
most of the differences
between humans and chimps
genetically have to do with
microevolutionary differences.
And that comes down
to clinical pictures
that you see humans are much
more resistant to tuberculosis
than chimps are.
Chimps are much more resistant
to malaria than humans are.
Nonetheless, it's the basic nuts
and bolts of the immune system
there.
One of these guys has a
little bit better of this,
one has worse of that.
This is within a realm
of gradualist change.
The genetic differences
that explain that
are microevolutionary ones.
Where are the macro evolutionary
differences between humans
and chimp genomes?
Those are the ones that
have to do with development.
And those are the ones that
amplify differences big time.
You have one tiny little
difference and you
get an organism that's going to
look as different from a chimp
as a human does.
The other way around, some
systems, their evolution
is much more built driven by
micro changes, some much more
than macro.
Some of the most
interesting macro stuff
is going to be
developmental blueprints,
developmental trajectories.
What else?
What else in terms
of resolution?
There are plenty
of fossil histories
by now for some line that are
complete enough that it is
very clear they look like this.
And the majority
of fossil pedigrees
that are that detailed enough
support a punctuated model.
Nonetheless, there
are plenty that
are understood with as many
time points in here that
follow gradualist models.
So evidence for both.
Nonetheless mostly
punctuated evidence.
The biggest problem though
in debating all of this
is it is impossible
for the most part
to see gradualism going
on, because it's gradual,
because it's hard to spot that.
It's hard to show whether
changes are incremental
or changes are rapid.
But by now, there
are a few examples
where people have actually
been able to observe
evolutionary changes
in organisms and ones
that can count as fairly rapid.
One first example-- for reasons
I cannot begin to understand,
people in Chicago-- I don't know
if it's in the Chicago Field
Museum or the mayor's
office or something--
have all sorts of carcasses
around from rats killed
in Chicago in the 1880s.
Key to the city,
souvenirs, who knows what?
Chicago's centennial.
But those around
stored someplace.
And a few years ago,
researchers were
able to look at the
genomes of those beasts
compared to rats
that are being taken
these days off the streets
of Chicago, current ones,
and showing over the course of
a century, a lot of the genome
has evolved.
There are a lot of differences.
Over the course of a century--
I don't know, what is that?
Maybe 500, 1,000
generations or so.
There has been significant
change over that time.
Darwin's finches,
for those of you
Darwin history fans, that
started the whole thing.
All sorts of different species.
The finches found in
the Galapagos Islands
and people have
been studying them
for half a century,
three-quarters of a century.
Gene distributions are
changing-- gene distributions
for traits, like the
size of your bill
and thus what kind of
food you could break into,
in response to environmental
shifting there.
That is being documented.
That's going on.
What else?
Another one that is
really interesting
and important and
critical for lots
of us, which is the evolution
of resistance to diabetes.
This is a very
interesting phenomenon.
Diabetes comes in two forms.
Juvenile onset diabetes-- that's
the one where you need insulin.
The diabetes that's instead
becoming an epidemic
is adult onset
diabetes, which is
when you have a body
which is all built out
of lean hominid history to
store away lots of calories
and all of that, and you
throw in a westernized diet
and you get the increasing
westernized problem of obesity.
And you then wind
up getting diabetes.
For our purposes right
now, it doesn't matter
what diabetes looks like.
The main thing is,
it is driven by food
excesses in westernized diets.
So there's been a
whole literature
by now of people
studying populations
that have had rapid shifts
from traditional diets
to westernized diets.
A lot of Pacific Islanders
have been studied.
All sorts of other populations.
The group that is the
iconic one to study
is Native American
group in Arizona
called the Pima Indians.
And what's very convenient
about them is about half
of them live in the United
States and about half
in Mexico.
And there has been very
rapid changes in diet
in the American side, less so
in the Mexican one-- far more
traditional.
And one of the things
that soon emerged
once westernized sort of
typical processed food
became the predominant food
eaten by people in the Arizona
side is 90% diabetes rates by
the time you're 30 years old.
The exact same thing in
some of the Pacific Islands
that have been studied,
in the Naru and Samoa
and some of these other places.
Astronomically high
rates of diabetes.
Another population
where it's been studied
are populations of Jews
who were living in Yemen
and who-- I think in
the '60s or '70s--
moved to Israel, switching
from a very traditional diet
to a very westernized one.
Diabetes rates absolutely
through the roof.
What that's doing very
quickly was killing off
all sorts of folks very early in
their reproductive life history
periods.
Suddenly you've
got the people who
are most vulnerable to
diabetes when suddenly given
a westernized diet,
they're leaving
fewer copies of their genes.
And it's been in the
last decade or so,
some of the Pacific
island populations
that have been studied,
the diabetes rates
are beginning to go down.
In other words, there has
been this selection that
went into Western
European populations,
I don't know, a
century or so, which
is the folks who have the
most efficient metabolisms
and can store away all of
those dozens of Hershey bars
effortlessly.
They're dead.
And they died before they
left copies of their genes.
You are now selecting
for human populations
that have sloppier metabolisms.
And this is within the
course of a century.
Another example.
Here's a totally, totally
cool, irresistible one.
This is one of the
great genetics stories.
As you can see, or not,
this pure white screen
tells you that this is research
that went on in Siberia.
[LAUGHTER]
Actually, these were Siberian--
so this was a famous study done
by this Soviet
geneticists starting,
I don't know, about
50 years or so,
where you have these
Siberian silver foxes.
And that's what they look like.
And for all sorts of
reasons, who knows what,
it is highly valued
to have clothing made
out of their bodies, and thus
highly valuable wild animals,
tough to get.
And this guy decided,
well, what we need to do
is start some Siberian silver
fox domestication farming
stuff.
So he did a very logical thing.
He started selectively
breeding them for tameness.
He would have a bunch of captive
foxes that were wild born
and most of them totally
feral and crazed.
And he would see, is there
a subset, 5%, 10% of them,
that I could get relatively
closer to that were calmer
in the human's proximity?
Only let those ones breed.
Now take their offspring
and only take the 10% or so
that are most calm,
most easily tamed.
And it took about 35
generations or so to get foxes
that were as tame as dogs are.
Something else totally amazing.
So he's breeding them for only
one trait-- a behavioral trait,
which is the ability
to get close to them
if you're a human,
calmness on their part,
whatever you might
describe it as.
Breeding entirely
based on that trait.
And when you spend 35
generations breeding
a wild animal like
a fox so that it's
the ones who are
most able to function
in the role of
domesticated animals,
it's not just the
behavior that changes.
This is what the adults look
like 35 generations later.
Aw!
[LAUGHTER]
Oh, give me one.
Give me 100.
I want-- yes.
They're adorable.
Can you believe how
great they look?
What's going on here?
They were selecting
for a behavioral trait,
and they are fox puppies.
They've got a big roundy
ears and these cute
little short muzzle things.
And they wag their tails
when humans show up.
And these are not dog
descent into wolves.
This was 35 generations to
turn something on to left
into something
looking at the right.
Very interesting thing we
will come to in the ethology
lectures.
Basically, what you're
breeding for when you're
breeding a wild animal
to be tame-able,
your breeding for
the ones that behave
more childishly, the
ones who are acting more
like developing
animals who are more
dependent on other individuals.
You're breeding them
for infantile traits.
This is what a baby
fox looks like.
This is what these
domesticated foxes look like.
Totally amazing
that this happened.
Ironic ending
department-- you will
notice that the coat has changed
from the ones on the left
to these wonderful
coats that you just
want to have made into
underwear and hats and all
of that sort of thing.
And on the right, they
look like Spot and Rover
and all those guys.
It is called a piebald
coloration pattern.
Somehow also, you can't
get the domestication
without that happening.
Ironic ending--
nobody wants to wear
clothes that look like that.
They would've been killing
Dalmatians for years
if that were desirable.
In the process of
breeding them, they
became useless economically.
Nonetheless, totally
amazing demonstration.
35 generations and
you turn something
on to left into
something looking
like that on the right, who
will wag its tail like you would
lick your face and bring your
chewed up slippers back to you.
This is a very rapid change.
Final example.
This is one that is also
quite consequential,
and one possibly even
more so than diabetes,
which is if this
type of evolution
keeps occurring at the rate
that it's happening, all of us
are going to have
dramatically shortened life
expectancies-- antibiotic
resistance in various bacteria.
Evolution going on there.
What we see in all
sorts of cases is,
evolution is not just
occurring over the course
of glacial lengths of time.
It can be occurring
very rapidly.
And what we see here
also is, in some cases,
it's going to leave a
different sort of skeleton,
changing how good your kidneys
and pancreases are dealing
with westernized
food, that's not going
to make for a different fossil.
Breeding for antibiotic
resistance in bacteria
is not going to make for
a different-- actually,
can bacteria even make fossils?
Does anybody know?
Yes.
Yes.
So it's going to make bacterial
fossils that look exactly--
all of this interesting
amazing stuff going on,
and it's stuff that no
punctuated radical dogmatic
paleontology type would
ever be able to pick up.
So what are we heading to here?
We're heading to a wonderful
heart-warming resolution
of these different
schools of thought, which
is, can't we all get along?
And can't we all
have means of having
different types of
evolution happening?
So almost certainly harking
back to what mentioned before,
microevolutionary
changes-- the immune system
in chimps versus humans.
Macroevolutionary
changes development.
You don't have to choose
vanilla or chocolate.
They could be going
on at the same time.
And they could be going
on at the same time
in a very important
resolving way, which
is-- so you've got evidence
for a punctuated change
of some trait.
And single traits
don't evolve at a time.
They come in whole
packages, packages
making you wag
your tail and such.
So there is some other
punctuated thing going on.
And that's its pattern
happening there.
And then meanwhile, you've
got some other trait moving,
evolving in a punctuated manner.
I guess it doesn't go down.
And you put enough
of these together
and have enough punctuated
events happening,
and on a whole
population level, you've
just invented gradualism.
You don't have to choose.
You can have it all.
You can have it all.
So a resolution there.
Both are almost
certainly happening.
So what does this
set us up for now?
Now that we have
finished this bucket,
we are now ready on
Friday-- what is today?
Wednesday.
We are now ready on Friday to
move to the next bucket, which
is a very different world
of trying to make sense
of the genetics of behavior.
Last week's version,
you make up stories
built around
individual selection,
kin selection, group
selection, and come up
with the best story
around to show
me something more predictive.
And you win.
This week's version, showing
actual genetic changes
over the course of time.
What patterns of
evolutionary change
will those code for
with what consequences
for understanding the evolution
of behavior, competition,
reproductive
strategies, all of that?
By the end of this
week, switching over
instead to the world of
behavior geneticists, where
they try to understand
what's going on by looking
at-- so somebody gets adopted.
Do they share a trait more
with their adoptive parents
or their biological parents?
You look at identical twins
versus non-identical ones.
You look at identical
twins who were adopted
into different families right at
birth, put them back together.
A whole world of trying
to make sense that way.
And what we'll see
is the same deal
is with this-- what counts
as finishing, coming up
with an explanation--
last week's social biology
approaches-- this
version of this
is the starting point
for the next discipline.
So we'll pick up
on that on Friday.
Oh, my god.
He let us out--
For more, please visit
us at stanford.edu.
