[MUSIC PLAYING] Stanford University. So we pick up from
whatever the last day was. And we do our first
disciplinary leap as promised at the very
beginning of the course. The entire function of the
first half of the course is to leap from one bucket
to another, such that just as soon as you feel
like you are getting mildly comfortable in one,
we will spend time trashing it from the standpoint
of a different discipline. This is our first one of these. And the whole point of this jump
is to show on a certain level exactly where one discipline's
the notion of an explanation ends, another one begins. And what this one will be about
is how evolution works down on a molecular level. Where did we leave off
after finishing our overview of the evolution of behavior? We finished with a bunch
of criticisms at the end. Criticizing sort of what
some of the basic tenets were of that view. First off, that notion
of heritability. Heritability-- assuming
that all sorts of behaviors have a genetic component,
have a genetic basis, have a genetic cause. And we will see those are worlds
of differences in those words there. And what we saw was that
that could be the case. That could not be the case. That's going to be what we
focus on a great deal today. Another one of
the basic tenets-- this notion of adaptation. Everything you see is
wonderfully adaptive. The outcome is
exactly the process that evolution brings
about to optimize results. The counter view being the
world of spandrels-- a lot of the time, stuff gets
carried along as baggage. Things evolving aren't
necessarily things that have been sculpted into
being as adaptive as possible. Another critique, and one
that's also central today, is that whole emphasis
on the gradualism, on small incremental changes. And what I alluded to
at the end the other day is going to see
a viewpoint where something very, very different
is proposed to be going on. One that will make sense
only eventually when we see some pretty unexpected
things about genetics and the molecular biology of. OK, so starting off--
what we also finished with was a notion that there
are political agendas that run through every
aspect of this subject. And if that very
first lecture, back when talking about how some of
these viewpoints influence who gets a lobotomy, who
winds up exterminated, who winds up being viewed as
educatable or uneducatable, et cetera, polypolitical views
run throughout all of this you will see very
strongly in this realm. OK. So that viewpoint of
the sociobiologists, the evolutionary
psychologists the other day, one of the tenets going after
the notion of heritability. The notion that these
behaviors are heritable, or are genetically
influenced, blah, blah. How would folks in
that business do it? What they would do is
exactly what we were saying. Which is say, OK, here's
some behavioral structure. And we know how evolution works,
and evolution of behavior, and individual selection,
and kin selection, and reciprocal
altruism, and evolution of, and all the above. And then they say, Well, with
that framework, that explains the behavior pretty well. Go show me something better. Show me a better
theoretical structure that's even more
explanatory, more predictive. And until you come up
with something better, I'm going to assume
that this one is right. And this one comes with
a larger assumption of heritability of genetics
all built around inferentially. These are highly
structured models built around how genes work. They explain what we see
with these behaviors. And until you can give me a
model that does even a better job, I'm sticking
with this, and this counts as my evidence
for a genetic component to this set of behaviors. And what we'll see is
that's exactly where the molecular biologists
decide that they finally have gotten free of
people doing poetry for all the science in it. My god, that counts as science? Coming up with a
bunch of these rules there and saying until you come
up with fancier rules or a more pleasing just so story, I win? That counts as science? Complete contempt
for this approach. This is where more molecular
stance about it all takes off. And what we'll see
that that not only will have lots to say
about adaptiveness, it will also have lots
to say about gradualism. So starting with it. In order to make sense of
this, for a molecular biologist what is evolution about? When you see traits that have
evolved, what's it about? By necessity, what one is
immediately talking about is genes. Genes in this case
not as some constructs that one wants to maximize
copies of and ones that your cousins have
only whatever percentage of in common with you, but
genes instead molecules. Genes as information,
genes as strings of DNA. And I'll assume by now there's
like a basic level of shared knowledge about this after
hearing that a lot of folks came to the catchup session
last week, which I think is a good idea. But what it's all built about,
all of this notion of genes, eventually way out the
other end having something to do with behavior, is the
intermediary of proteins. Proteins are important. Proteins are important
not just to have in your diet to make you run
fast, and strong, and all. Proteins are, in lots of ways,
the structurally most important things you've got
making up cells. Proteins have endless roles. Proteins hold the shapes
of cells together. Proteins form
messengers, hormones, neurotransmitters,
all of this to come. Proteins are the enzymes
that do all sorts of the most important stuff. Proteins, et cetera,
et cetera, et cetera. Proteins are the
workhorses of what have cells doing what
they're supposed to do. So the question
of course becomes what codes for proteins? And this is where genes come in. Our basic issue here is this
flow of information-- genes specify proteins. Proteins are made up of
constituent building blocks, amino acids. There's approximately
20 different ones that are commonly occurring. And each one has to be coded
for with a different DNA sequence, a different
DNA sequence of three letters, three nucleotides. And I hope I'm not hitting
the level here where people for whom this is new this
is going way too fast and everybody else
this is way too boring. But hang on for a
while in that case. So DNA codes for amino acids. A long string of DNA coding
for a sequence of them will code for a
sequence of amino acids which get plugged together,
and you then have a protein. You've got one intervening
step, which for our purposes is like not really interesting. And we could ignore
it for the most part. Which is, there's an
intermediary step-- genes at the level of
DNA, sequences of DNA, first specify an
intermediate form called RNA. And it's from that that
you get the readout forming the proteins. Now, everything about
the function of this is built out of the
following sequence. If you know the
sequence of DNA, you will know the sequence of RNA. You will know the
amino acid sequence. You will know the protein
that thus is made. You will know the
shape of the protein. And you will then know the
function of the protein. And that is this critical
link between what DNA, genes, evolution, blah,
blah, are about, and the actual things that
pop out at the other end and do something. For the very critical
reason that everything about protein function
is built round shape. Here is a cliche that
is required by law to be said at this point. Which is, all sorts
of effector proteins fit into other molecules,
other effector proteins. Like a-- OK, everybody
say it out loud. Everybody knows this cliche. It fits in like a-- Glove. Yes. OK. Cliched education at its best. Like a lock and key
for those of you who are not tortured with
this one from early on. It's the whole notion that
a shape of a protein imparts information insofar
as it interacts with something else of a
shape which modifies it, which complements it, whatever. The whole world that we will
have of various hormones and neurotransmitters
will consist of hormones and
neurotransmitters going into receptors where there
is a critical relationship in the shape between the
messenger and the receptor. And all of this is
driven by proteins, protein shape, et cetera. All of this is driven
thus by DNA sequences. Shape is everything with this. What you get from
that is, of course, the question of where do you
get different shapes from? And those 20 amino
acids, for our purposes, for the purposes
especially people without a strong
chemistry background, all that's pertinent here is
the 20 different amino acids have different degrees
of being attracted to or repelled by water. Which, most proteins are
spending their life swimming around in water. They are pulled towards water. They avoid it. They are hydrophilic,
hydrophobic. All that means is
different amino acids gets pulled into different
positions by their relationship with water. And thus, a string
of amino acids, the shape it winds
up getting with, is determined by that
amino acid sequence. There is a whole world
of really interesting horrible neurological
diseases called prion diseases which show
that everything I just said is wrong. But for our purposes,
everything I just said is right. So this is where you get
this critical relationship. Know the DNA sequence. Know the coding. And out the other end, you
will get protein shape because of this business of
different amino acids having different
relationships with water and thus strings
of them coming up with different three
dimensional structures. And out of that will
be coming function out of the famed lock and key nature
between shapes of functions and shapes of other things. Just once again for people
fairly new at this-- nope. No diagram there. One of the most interesting--
or the blank slate. One of the most interesting
things the proteins do is when they are enzymes. Everybody knows that enzymes are
important because they put them in your laundry
detergent, and advertise about how cool it is that you
have enzymes in your detergent. But what enzymes do is
they catalyze reactions. They cause reactions to
occur which left on their own would be very, very rare events. What enzymes do is
accelerate vastly-- a gazillion times over-- the
speed with which these happen. Catalyze reactions. What do I mean by that? For our purposes, they
can take two things that aren't connected
and stick them together. Or they can take one
thing and break it apart. For our purposes,
that's what enzymes do. Virtually every enzyme
out there is a protein. So proteins fit into other
things and send on messages. Proteins are enzymes. Pull things together,
pull them apart. Proteins are structural. Again, a whole lot of the
superstructure of your cells are held together by proteins. This is the realm
of what they do. Notice here, suddenly there is
a change of shape in a protein if it's an enzyme. Because what's it doing? In some way, it's got to
be pulling apart something or putting something together. The shape, in some
cases, also can change as a function
of what this protein is doing with its job. We will see a classic
version of that are channels. Channels in which chemicals
can flow in or out of cells. Ions, for chemistry types. Channels that will open up
under some circumstances, close under others. So protein structure not only
gives shape and function, but it gives the circumstances
where the shape might change in a functionally relevant way. So out of all of this comes
of the central dogma of life. And this was proposed by Francis
Crick of Watson and Crick fame. And Francis Crick
was the one who formalized saying the
central dogma of how life and information flows
is DNA to RNA to protein. And that became defining. An entire generation of babies
were told that at birth. This is the flow of information. It has been violated
in all sorts of interesting ways, which will
dominate a lot of what comes. But this was the central dogma. One way in which
it is violated-- and again, this notion
is not DNA to RNA, but the notion of whatever
your DNA sequence is, whatever the gene is, whatever
structure of a protein it codes for-- the
flow of information is going to be from
DNA, RNA, to protein. DNA as running everything. Note the importance of that
in the very statement of this as the central dogma, the
canonical flow of information in life. It all starts with DNA. DNA is the one sitting here
deciding when information is going to flow from DNA to RNA. DNA as knowing what's happening. And a lot of what we will see
shortly is DNA knows squat. DNA is not making a whole
lot of decisions there. The one simplistic way in
which central dogma went down the tubes in the
1970s or so, and one that's tangential here,
but just as a first blow against central dogma. One of the things
that's interesting is there are things
called viruses. And what viruses do for a
living is get into organisms. Viruses, in the classical
form, being little smidgens of foreign DNA which are able
to get into the DNA of your own, hijack the processes
there, and make the cell function for its own
parasitic, vicious needs. And so you are changing
the starting step of how the central dogma of life. And thus you're going to change
RNA and protein, all of that. In the '70s, it
became apparent there was one weirdo viral
world of viruses made out of RNA, this intermediate form. All sorts of people were
extremely upset about this and tried to ostracize
the scientists who came up with this and
told them there's no way. But eventually, what
was shown in Nobel Prize winning glory was there's
a class of enzymes. Enzymes-- they pop up. A class of enzymes that could
take the RNA information and turn it back into
DNA, viral information. And then it does its thing. Huge blow to the central. Here's information running
from an RNA virus somehow being reversed back to a DNA form. And thus these are
called retro viruses. Inserting the DNA, and
off they go from there. So this was a major blow. Everybody eventually
came to terms with this. But it still is a minor
footnote in this Crickian world of everything flows from DNA. It is the Bible. It is the law giver. It is the holy grail. It is where it all starts. So stay tuned. So given that framework,
one should immediately get mighty impressed with
what if something changes in the DNA? What if one of the bits of
coding is coded incorrectly? What if we now have on
our hands a mutation? And what we'll focus on
here is classical realms of mutation, and
genetics, and how that plays out in
classical, gradualist models of evolutionary change, and
then see how all of that falls apart when you look
at what's really going on. So starting off,
what you can have-- and again, this is going
to be a review for people with a background in this. Newcomers to this-- hopefully
this won't be going too fast. But broadly when
you were talking about this world
of micromutations, for our purposes what we
will mean by a micromutation is when one letter in your
DNA sequence of information gets accidentally miscopied. Or it gets changed by radiation. Or it gets changed by
some chemical compound the environment. Some such thing where
there's a mistake and one letter in the DNA
sequence comes up wrong. As I noted before,
pairs of triplets. And there we've got
three pairs of triplets. And what we've got here
is at the DNA level, a amino acid is coded
for by three base pairs. A triplet-- three of these. Next amino acid coded for. Next one coded for. So what we've just raised is
the possibility of a mutation occurring, something
changing in one single one, and now asking what
are the consequences going to be in classical
realms of genetics and evolutionary change? Broadly, you can get
three different versions of stuff going wrong. One is where one
of these letters-- nucleotides, translating; not
essential to have that down-- where one of these
letters is accidentally changed into another
letter-- a point mutation. In some cases, point mutations
are of no consequence at all. How can that be? For this very simple reason,
going through some math here, there are four different
potential letters at each one of these sites. DNA comes in four different
letter types, letter flavors, four different types of bases. And thus, you can have
four different ones in the first
position times four, times fourr-- a total of
64 possible three-step combinations of DNA letters. A possibility of 64
of them, and you're only coding for 20 amino acids. So you use up some
of the 64 for signals saying stop or start, or
thank god it's Friday, or who knows what. But what you have, though,
is a large redundancy. You have a number of
different triplet sequences coding for the same amino acid. There's redundancy
in the genetic code. And in general, where
you get that redundancy, where you get the differences
in three triplets, a couple of different triplets that
code for the same amino acid, they'll tend to differ in
the middle one of the three letters. That's the easiest one to have
a change where it doesn't change the overall consequence of it. So you will tend
to have redundancy. Each amino acid is
coded for by a number of closely-related triplets. So first possible type of
mutation-- this point mutation where one letter is
flipped to another. Potentially, this could be
of no consequence whatsoever. If you flipped to a letter
out of the middle one, which happens to leave you
with a triplet that codes for the same amino acid. In that case, you have
a neutral mutation of zero consequence whatsoever. So that's not a very
exciting mutation. In Some cases, you can
have a single point being changed where you wind
up with a different amino acid coded for. And that's most typically, if
it's a mutation in here or here rather than the
boring middle one, you get a different amino acid. Is that the end of the world? Often not at all
or only minimally because a lot of the amino
acids have similar feelings and ambivalences about
water, similar responses and similar shapes. It won't be exactly
the same shape, but the protein will
function somewhat the same. So you could have, in this
case, a point mutation and most people would
not find the second line to be impossible to make
sense of in the context of the first one. Or you could have a
point mutation which, by changing one letter,
produces a different amino acid, and this one is
majorly different. This one has a
completely different set of attractions or being
repelled by water. Produces a protein of a very
different shape and potentially a very different message. And shown here, just changing
one letter in this case, one single point mutation,
and you dramatically change the meaning of that. And I actually did that
once in the grant proposal. Sort of the final paragraph--
we have now accomplished x, y, and z with your money
over the last five years. And no wonder it
didn't get renewed. So in that case, you see
a single point mutation of great consequence. So you can have one
of these letters, one of these nucleotide
mistaken for another-- entirely neutral, moderate
consequence, or major, disastrous consequence. Second way of
classical mutations, the second version
that it could come with is there is a deletion. One of the letters gets
lost in the process. And what you then get is a frame
shift over to the missing spot there. And the D from here
now finishes up this. And what you can
see is it suddenly becomes dramatic jibberish. And it would continue that way. A deletion mutation,
in classical genetics, is major league. It totally changes the
coding downstream from that. Third classical type--
an insertion mutation. One where you now accidentally
double the letter, and you're frame shifted
in the opposite direction. Just as screwing up of meaning. Major consequences there. So you have point
mutations, which can have major consequences,
or can have none whatsoever, and anything in between. You have point
mutations, and then you have insertion and deletion. The last two tend to
have big consequences. So all of this is built around
one single base pair change. And all of this is built
around thus one single protein changing its shape. And thus, this world of
micromutation-- single spots that are mutating--
what this tends to do, and this is an important
concept for what's to come, what it does is it changes how
well the protein does its job. It changes the efficacy
of that protein by changing the
shape a little bit, by changing it
dramatically, all of that. And we can see back
to our lock and key where if, thanks
to a mutation, this has a slightly different shade,
it will fit into the lock slightly less effectively. It may stay in there
for a shorter time before floating off and
thus send less of a message. On the other hand, if you've
got a deletion insertion that dramatically changes
the shape of this, you will change how well
this protein does its job. It won't do its job
at all, because it's going to wind up with a
completely different shape and not fit in there whatsoever. What we have here is
a world of mutations which are changing the function
of one protein at a time. That is
microevolutionary change, and that's what we're now
going to see played out. When can this make a difference? This can make huge
differences when it's in the realm where, thanks
to a change in the shape, the protein is completely
out of business. Two examples-- one where
you take out the function of the preexisting gene. First one-- there
is this amino acid. For our purposes, that's
going to derail us. For our purposes,
there's a chemical that occurs in the body
called phenylalanine, which has its uses. But you don't want
the levels of it to build up too high, because
it can become toxic, damaging to brain cells, to neurons. And fortunately,
there is an enzyme made of protein which turns
phenylalanine into something safer. That's all we need
to know about it. So you have a mutation in the
gene coding for that enzyme. Not a fancy mutation
to something. One of these categories--
a classical, single spot point mutation. And what you got there
is an enzyme that no longer does its job. And as a result,
this phenylalanine is not converted
into the safer form, builds up, and lays waste
to one's nervous system. And thus you have a disease--
PKU, phenylketonuria. Very, very common
genetic disorder. And this is one where the
outcome is a small mutation that has completely knocked
this enzyme out of business-- this enzyme which
was able to turn the phenylalanine
into something safer. This is not a subtle outcome. Have untreated PKU, and
your reproductive success by the rules of
evolution is going to be real down near zero. This destroys the nervous
system very rapidly after birth. So that's dramatic. Here's another dramatic one. And this one-- anyone
who took BIO CORE, I always bring this one in as
a big hormone crowd pleaser. But here's an
interesting thing that can go wrong with any child
you might eventually have. You've got a daughter,
and she's doing just fine. And she's growing up just
fine, and things are terrific. And around age 10, or 11, or
so, some of her classmates are beginning to reach puberty. That's on the early side
for the Western average, but it's not outrageously early. Not a big deal. By about 12, statistically about
half of the girls in her class have reached puberty. 12 is about the Westernized
average these days. She hasn't yet. Not a big deal. A year later, she still hasn't. Well, this is nothing critical,
but it's getting a little bit on the late side. A year after that, two
years after that, she has still not reached puberty. So at that point, you
take her to a physician who examines her closely
and figures out what's up. And at some point, the
physician is probably going to have pupils
dilate, or some sort of weird autonomic response,
when they figure out what's up. And then very calmly,
in a premeditated way, sit you down for a
little talk afterward, and inform you that
your daughter has not started menstruating, has
not reached puberty yet. Your daughter has not started
to do this because you don't have a daughter. You've got a son. This kid here for
these last 14 years has actually been
male, not female. You have what is called-- no,
I'm not going to tell you it. OK, it's called-- especially
since it's in the handout already-- anyone want to
guess what it's called? It's called TFM, Testicular
Feminization Syndrome. And you wind up with a
testicular feminized male. These are individuals who,
genetically, are male. At the level of chromosomes,
that XX and XY business, these are individuals
who have testes. Testes way up in their
stomach or whatever, never descended down. These are people whose
testes make testosterone. Testosterone out the wazoo. Tons of testosterone. Enough testosterone to put
like antlers on your testes, or something. That much testosterone. And nonetheless, you're
getting a female phenotype. You are getting a female
external genitalia. You are getting
female everything. Yup, question? Sorry, is that different
than androgyne insensitivity? No, that's the
fancy term for it. And you've just given away
the punchline, you creep. [LAUGHTER] So they figured out in
this disease there's an insensitivity to something. What could that be? OK, go and say it again. Yes, OK. What you've got here is one of
those simple little classical mutations. And what it does is it changed
the shape of the androgen receptor, the
testosterone receptor. And at that point it doesn't
matter how much testosterone is floating around, those target
cells are not going to listen. This is consequential. This is a major consequence. This is one of changing
gender phenotype, and there is a long and at
times absolutely appalling history of what has been
done with individuals who have Testicular
Feminization Syndrome, what counts as the medically
appropriate intervention. There's some horrifying
history there that could be straight out
of the first lecture in terms of some notions of what counts
as normal gender behavior. Another version of
this-- this one's a little bit more subtle
because in this case, it's not wiping out the
function of an enzyme. It's just making it a little bit
less effective at what it does. And this has to do
with a disease that is found in two different
populations, slight variants on it. One is up in the Dominican
Republic, in the mountains. The other is in the
mountains of New Guinea. Interesting similarity there. In both cases, some fairly
isolated, inbred populations. So that has genetics
written all over it. But in these cases, there
is a problem with enzymes that make testosterone. So this is a whole other world. Instead of the enzyme, instead
of the proteins, and thus the gene somewhere
back there, that code for the receptor
for testosterone, the receptor that responds
to this messenger, here instead it's back way
up there in the testes. A bunch of these enzymes, which
go through a bunch of steps and make testosterone,
biosynthetic enzymes there. Proteins, genes, once again. So you've got a mutation in one
of those critical, biosynthetic enzymes. And It's not a huge one. The shape is a little bit off. Its efficacy, the
effectiveness with which it makes testosterone
is down a bit-- and actually it's
down a lot-- so here's what you wind up getting. You get an individual
who before puberty has extremely low
testosterone levels, even far lower than you would see
in prepubescent males in most cases. Someone who's genetically male. Someone who never saw a
whole lot of testosterone during fetal life, way
below the threshold for the testosterone
having any effects. So the person is born
phenotypically female. Female in appearance. Female in external genitalia. And not internal-- back to those
testicular feminized males. What you find there is a
vagina which goes nowhere, because there's no ovaries
waiting somewhere above that. There is the testes. But the external
genitalia is just fine. What I think these days is
the most common medical ethics advice and what's done with that
is the physician explains what it is and says, For
all practical purposes, you have a daughter who
is perfectly healthy, who's going to have a
long, happy, healthy life, and simply cannot reproduce. That's the only consequence
that's relevant here. And there's been a
whole other world of reconstructive surgery, and
all sorts of very interesting, horrifying history. So back to this one. Because of the extremely
low testosterone levels, because at the time of
life when there's not a whole lot of testosterone
around in the fetus, in a young male, and now
it's below the threshold for causing anything. Along comes puberty, and thanks
to a whole bunch of changes in the brain, signals go out
so that testosterone levels now come roaring up into the usual,
impossible levels in the males. And what happens
here is the levels don't go up as much
as they should, because that enzyme is a
little bit on the slow side. But they go up enough
to pass threshold for beginning to have an effect. And somewhere right
around puberty, this individual changes sex. This individual
transfers, transmits, jumps ship and goes
from female to male as a result of these androgenic
effects suddenly coming in. It's not a complete
switch there, but it's somewhat
of a transition. This is bizarre. Again, this is not
something subtle. This is something
changing completely here. And again, one single mutation. And in this case, not
even a mutation wiping out the function entirely
of some protein as in PKU or Testicular
Feminization Syndrome. But now you've got
a protein that's just working differently,
slowly enough that you get this very different picture
popping out the other end. What's most interesting is you
have this intersection between molecular biology
and the bio-, endo- consequences of this
mutation, all of that. And the cultural context
of it, apparently in both of these
populations, people have kind of adapted to it. It's not a big deal. You know, puberty--
sometimes you get acne. Sometimes you get a penis. And people just deal with that. That's just part of
the whole process and cultural accommodation
to interesting biology. One final example
of where you can have a classical
type of mutation, and another version of
a very mild difference. And in this case, it is
not a very mild difference producing an overt disease. In this case, it's just
producing something that probably differs in you
from the person sitting next to you. Which is, you have a
neurochemical system, a system of chemical
messengers in your brain. If this is new stuff, hang on. It will all be explained
in a couple of weeks. But this is a class of
neurochemical signaling that has something
to do with anxiety. A chemical messenger
which decreases anxiety. And we will learn plenty
about that down the line. And there's this regular class. They're known collectively
as benzodiazepines. Do not panic if you've not
heard that word before, and certainly do not
attempt to spell it right, because it's not possible to. So benzodiazepines. There are synthetic
versions of benzodiazepines which people might
take when they're feeling anxious like
Vallium, like Librium. Vallium is the synthetic
benzodiazepine. So benzodiazepines
are protein, and they have a particular shape. And you guessed, it there are
thus benzodiazepine receptors, which could do that whole lock
and key deal going on there. And what you have
are differences, small, single point,
in this case not mutations, but simply
different versions that one letter can come in
in the DNA sequence specifying the benzodiazepine receptor. These are not mutations. This is just normal variability
is one particular spot can specify two or three
different amino acids that function roughly the same. So that you're changing somewhat
the shape of the receptor, and thus changing somewhat how
long the benzodiazepine stays in there, and how long
the signal is sent. And it's all very subtle. And what does this
begin to explain? Individual differences
in levels of anxiety. It's only one of the gazillion
ways of explaining it, but it's part of
that picture there. Here we have
individual differences. This explained a very
interesting finding. For decades, people often tried
to breed rats, different rat lines for different
behavioral traits. And it makes it
very useful models. There are alcoholism prone rats. There are rats that have
been bred for being smart, for being not as smart at
spatial maze stuff, et cetera. And for years, there'd
been a number of rat lines that have been bred that
were either high anxiety or low anxiety rats. Very useful for understanding
things like-- what are they're useful for? I don't know. They're just cool
to have around. Very useful for understand
the effects of stress, or things of that sort. So finally, modern era of
molecular biology comes in, and those high and
low anxiety strains differ in the shape of the
benzodiazepine receptor in many of these cases. Again, tiny little differences. So what we've got here
is classic old genetics at the molecular level. These tiny little changes in
one single base pair at a time-- point, deletion, insertion. A world in which it may or
may not change the shape. Where it could change it
dramatically and produce some pretty exciting,
dramatic diseases where you wind up with
a different gender than your chromosomes say. Ones where you get more
subtle differences. You change gender at
your 13th birthday. Or ones where we're
just for the first time beginning to look at the
individual differences that flow out from stuff like this. Not them and their disease,
but the individual variability. All of this is in the
realm of single base pairs being changed. What all of this
now allows us to do is translate this world
of mutational changes into what does this look
like evolutionarily? What does this look like
in terms of explaining patterns of evolution? And you will know exactly
where this goes right now. This helps explain
the classical, the gradualist picture of
little bits of change at a time. Little bits because you've got
one protein which now works a little bit
differently, and thus you get to ask a
sociobiology question. By having testosterone having
a little bit more of an effect or a little bit
less of an effect by way of molecular
changes in this receptor, is that going to increase
the number of copies of genes that individual has? Is it going to
decrease the number? How's it going to fit into
all of last week's science? And you will know exactly
how that drill will run. Oh, if thanks to one
single base pair changing, you now have a receptor
which functions in a slightly different way, which makes
this individual 1.5% more fertile than everybody else
that they're competing against, you just wait long
enough and come back, and everybody in
that population is going to have that
different version of it. We can run the logic there. We have variability--
Darwinian variability-- thanks to a mutation. We have differential fitness. We have just defined an adaptive
difference somehow or other. There there's a
smidgen of advantage, thanks to a slightly
different shape. And thus we have selection
changing distribution over time. The smidgen more
effective version will become more common
in the population. And what's also
intrinsic in that is that these are slow
little steps of change. This is gradualism. So gradualism is absolutely
commensurate with everything we got last week built around
adaptation, competition. Every little bit
makes a difference because 1% difference in
number of copies your genes. Run it enough
generations, and that's going to be a big
difference, and all of it changing in a very
gradualist, incremental way. This has popped up in
a number of domains and could be really useful,
because it allows you for one thing to trace
evolutionary history by looking at the changes of
single base pairs. And that's allowed for looking
at one really interesting gene, which we may talk about down
the line, a gene called Fox P2. Fox P2 has something
to do with language. Fox P2 was first identified
and a family, all of whom had some sort of language
communication problem. And people to this day
argue whether it was mostly about coordinating the
motoric aspects of speech or was it something about
grasping the symbolic message aspects of language,
all of that. In any case, a mutation
was found in this gene, and a whole cottage
industry has emerged since then of studying Fox P2. Because versions
of Fox P2 occur all throughout the animal
kingdom-- in birds, and rats, and non-human primates,
and all sorts of things. Fox P2 popping up
all over the place. And in all these
different places, it's got something to
do with communication. It's got something
to do with bird song. It's got something to do with
rat ultrasonic vocalizations. Rats are constantly jabbering
at each other in a range that we can't hear. And Fox P2 has something
to do within all of those. And different versions of Fox P2
in all these different species. And what becomes
most pertinent is when you look at
those differences, you will see tiny
little differences in this tree across all
these different species. One base pair difference
between rats and mice. One base pair difference
between hawks and elephants. That sort of thing varies. And then you look out at humans,
and a whole bunch of changes. A whole bunch of changes in a
very short evolutionary period. What this suggests
is no wonder this is producing some very
different stuff than these guys. A very different gene. And a very different
gene, people now have been able
to back calculate due to a series of single
base pair changes somewhere in the last quarter
million years or so. And that makes a difference. Totally cool,
unsettling experiment that was done a few
years ago, which was some people taking the
human version of Fox P2 and knocking out a mouse line,
knocking out their own Fox P2 and sticky in the human version
and seeing what happens. And it was very interesting. They immediately sing the theme
song from all the Mickey Mouse cartoons. Ha, can they prove that? OK, what you see is you've
got more complex types of ultrasonic vocalization
in these mice. That's really interesting. And there's years
of stuff to sort out what's going on with that. For our purposes, the
main thing is here you have wound up with a very
different world than chirping, and buzzing, and
barking, and all of that. And you wind up with a
very different version of this gene where you can
trace out how many amino acid changes it took. And every step of
the way, you were having some gradualist process. What also this
allows you to do is look at a footprint, an echo
of what the selection was like. Important concept here. So back to that business. There's 64 different ways
of coding for amino acids, a couple of them are just
informational, stop messages, and stuff. There's about 60 different ways
of coding for 20 amino acids. So on the average,
each amino acid could be coded for in
three different ways. So suppose you throw
in a random mutation. And of those, what you find is
of the 60 possible mutations, 40 of them will not cause
a change in the amino acid. Statistically, 2/3 of the time,
there will not be a change. So in other words,
if you scatter a whole bunch of
mutations, and you wind up seeing 2/3 are neutral in
terms of their consequence, and 1/3 third actually causes a
change in an amino acid, that's telling you it's happening
at the random expected rate of mutations popping up that are
either consequential-- changing an amino acid-- or
inconsequential-- just coding for a different version
of the same amino acid. Now suppose you find
a gene that differs. And you look at the ways
in which it differs. And 99% of the base
pair differences over the course
of this 5 million base pair-along gene,
99% of the differences make for a different amino
acid than beforehand. In other words, at much
higher than expected rate if this was a random process. What is this an echo of? Of very strong selection. Of very strongly advantageous
traits driven by these changes. Term used-- this would
be a mark of their having been positive
selection for this trait. In other words, the changes
that it has gone through over the gazillion
years has not been just by random mutational
rates of neutral. And remember, every amino
acid is coded for three ways. If 99% of them
are consequential, there has been some major, hard
ass selection going on there. Alternatively, if
you find a long gene with a whole bunch of mutations
and 99% of them are neutral, make no change at all,
what does that tell you? This protein's function
you do not want to mess with in the slightest. Even a minor change in the
function of it, and you don't pass on copies
of your genes. This would be stabilizing
selection, negative selection, strong selection to make sure
that this gene and its function downline as the protein
does not change. When you look at the number of
changes, the burst of mutations over the last quarter million
years or so that differentiated Fox P2 in humans from
these other species, it's almost entirely evidences
of positive selection. This did not just
happen by chance. Every step of coming up
with these new versions, these new amino acids
in the sequence there, clearly were ones that were
positively selected for. A lot of selection brought
about this huge difference. OK. So that begins to give
the sense here of how these little changes can occur. At this point, we
have to go through one of the all time confusing
things in genetics out there, which is something two
factoids and two soundbites that seemingly totally
contradict with each other. You share, on the
average, 50% of your DNA with a full sibling. You share 98% of your
DNA with chimpanzees. What's up with that? That seems a little
bit unexpected. And those are two soundbites
that everybody knows. Everybody knows it goes
through like basic Mendel. 50%, 100% with an identical
twin, 50% with a full sibling. You know that song
and dance by now. And meanwhile, one of
the great soundbites of our evolutionary history, and
the mark of evolution, and what in hell are you
creationists thinking, is the fact that, oh, humans
share 98% of their DNA with chimps. This doesn't make any sense. One minute here to be spent on
just clarifying that one that is not contradictory at all. Genes specify by
way of proteins-- and now this is taking
a bunch of leaps down there-- traits, aspects. Gene specify, to be
totally simplifying here, genes specify for
antlers, for dorsal fins, for petals, and pistils
and stamens, for kidneys, for-- it's totally simplifying. So right off the bat, you will
have some genetic similarities between two different
species in that both of them will have genes that
code for dorsal fins. You're thinking about two
different species of whales. So they share genes
coding for dorsal fins. Whales have dorsal fins. Neither we nor chimpanzees
have genes for dorsal fins. Meanwhile, we have genes
coding for a pelvis that has a certain shape
which either in chimps predisposes towards being
able to walk bipedal for certain strengths
of the length of time. Us as well. You don't find these
genes in apple trees. They don't have pelvises
that are shaped like those, so they don't have. So when you look at the
human and the chimp genome, 98% of the genes code for
similar kind of things. We share with chimps
an absence of genes for antlers, and trunks,
and tusks, and wings, or serve who knows what. And we share all
sorts of other genes in common having to do with
our shared immune systems, et cetera, et cetera. So 98% of the genes code
for similar types of things. So that's where we get the
98% similarity with the chimps from. For each one of
those genes, it could come in a couple of
different flavors, a bunch of different flavors. And thus asking not to do
both you and your full sibling have a gene for
opposable thumbs, do you and your sibling
have the same type of gene for opposable thumbs? So suddenly that's
a different world of variants on
each type of gene. So when talking about the
amount of DNA shared in common, the genes shared in common
with other species, what you're talking about are
the types of genes coding for the types of traits. When we're talking about,
from last week's notion, 50%, 25%, 12.5%, one
brother and eight cousins, what you're talking about
are different versions of particular genes. Important clarification. So final thing here before the
break, which is once again, notice with these models,
these point mutations, where you can get slight
differences in function. And thanks to a 1% difference
in fitness and number of copies of genes, you get
these gradualist changes. What's intrinsic
in that, and where we get the political
theme coming through is, thus there's
competition everywhere. In terms of the
evolution of behavior, the evolution of species, every
little bit of genetic advantage will play out in
some competitive way in some little
bit of an increase in reproductive success. OK. Whoa, there's a lot of
Apples there lit up. Well, that wasn't very subtle. Let's take a break. Whoever did that. OK, a five minute break. Are you slightly
more fit by the rules of your population's natural
selection, sexual selection, whatever? Even if that gives
you a tiny advantage thanks to this tiny
change in this tiny gene, enough generations
go by, and that trait is going to become
more prevalent. Final point there intrinsic in
this, is if every little bit of difference matters in
terms of fitness and gene distribution within
the realm of behavior, every little bit of
competition matters. A very, very intertwined
political, philosophical stance in gradualism as it
applies to evolution. So that's been sitting
there around forever. And in the 1980s, suddenly a
very different model emerged. And this came from
Stephen Jay Gould, who we heard about the other day. Stephen Jay Gould,
and the person, the poor schnook who
was always lost in this, another evolutionary biologist
named Niles Eldridge who somehow did not quite have
the press that Stephen Jay Gould did, so he is lost to
history except for people who know what he's up to. And he's an amazing scientist. But Gould and Eldridge came up
with a very different model. And I alluded to it the other
day and drew it right there. And their notion was that
gradualism is nonsense. There are not gradualistic
incremental changes. Evolution is not being driven
by small gradualist changes. Instead, what their
model was is that there's long periods of nothing
happening, of stasis. Long periods of
nothing happening. If there's changes in DNA
sequences thanks to mutations, they're not consequential. Or if they're
consequential enough to change the fitness
of one organism 1%, that's not going to
make a difference. Most of the time, no
change is occurring. And when it does occur,
it is in incredibly fast, explosive periods
of change followed by a new period of stasis. Evolutionary change comes in
step functions rather than smooth gradualism. Long periods of stasis
followed by dramatic jumps of evolutionary change
in short periods of time. Thus, they called
this the notion of punctuated equilibrium. Long periods of
equilibrium and stasis punctuated by periods
of very rapid change. And as I mentioned the other
day, Gould was a Marxist and felt that Marxist's
sort of stance was running through all of the
ways to think about genetics. And I don't now what's
up with Niles Eldredge, but that was the
case with Gould. And when you look
at this model, this is like classically
fitting with stasis, and revolutionary change,
and dialectical materialism, and stuff like that. The last sentence, I have
no idea what I just said. But apparently
that's got something to do with that stuff. And once again, we see
in a very different way, a political theme running
through a different worlds view of what evolution is
about-- punctuated equilibrium. OK, so where did the idea
of punctuated equilibrium come to these guys? Mainly because Gould
was not a biologist. He was certainly not an
evolutionary biologist. What he was a paleontologist. He studied fossils. He studied the history,
the evolutionary history of fossils. And apparently, like
totally separate of his large
theoretical models, he was like the world's
expert on the evolution of some Caribbean snail shell
over the last 10 billion years or something. He's one of those
paleontologists who traces lineages of evolutionary
change over the course of time with fossils, fossil
records, as the readout. So he's a paleontologist
slash geologist in some ways. And when you do that, you notice
something, which is you've got gaps in the record. You've got your
famed missing links. You have gaps in your
evolutionary record there of what fossils look like. And you're measuring some
trait or other in these snails, or trilobites, or whatever
you're looking at. And at this time period,
the trait looks like this. At this time period,
it looks like this. And this looks like a perfectly
good gradualist model. And what Gould would
notice is as the field got more and more information,
more and more intervening steps on a lot of these
fossil histories, they would start to
look more like this. And every now and then,
you would see something like this in between. And from that, that begin
to suggest to him this model of punctuated equilibrium. Most of the time, as assessed
by the fossil record, nothing dramatic is happening--
long periods of stasis. And what allowed this to occur
is that for some fossils, you have incredibly detailed
evolutionary history, where you can begin to fill in
lines, and they wind up looking punctuated in this way. So out of him comes
this whole theory that it's all about punctuated
equilibrium rather than gradualism. Right off the bat, what are
the consequences of that? Little genetic
changes don't matter. Competition driven by the notion
of little changes mattering aren't actually occurring. In model [? saying ?]
most of the time, all of the notions of if you figure
out the right kid to kidnap when the big guy
is coming at you, and you'll leave more
copies, and figuring out exactly who to be
infanticidal to, all that, it's not going to
make a difference in terms of gene distribution. Evolution is not
being driven by that. And out of it came this
very strong indictment of the sociobiological
view of what you've got there is a world where it's
all about competition, where it's all about hierarchy, where
it's all about domination, where it's all about that. Hey, isn't that interesting
that that's exactly the sort of world
that these folks live in who are benefiting from
this, who started this theory? Very different notion here. Competition, selective
advantages, all of that, most of the time,
nothing's happening. So not surprisingly, all
of the evolutionary types from last week did
not like this one bit. And this was an
attacked left and right in some extremely valid ways. First one, first form of attack
is a very simple problem there, which is that you have two
different disciplines happening here. You get a
paleontologist, and you get a evolutionary
biologist, and they're functioning in completely
different universes. OK, stomach problems. And they're functioning in
completely different universes there. What counts as fast
for a paleontologist-- these are tens of millions
of years going on. Whoa, incredibly fast
evolutionary change going on there. That's like 100,000 years. That's like, are you kidding me? Said the biologists. The ones who study one
generation at a time. That is asinine. That is ridiculous. This is them
imposing models where this has absolutely nothing to
do with how evolution actually works. These geologists get
completely thrown off, and these paleontologists
led by Gould, simply orders of magnitude
different scale of time. Yeah, maybe in some rough
approximation of what they look at. But they're not
studying evolution, because they're not biologists. Next critique-- the next
one made lots of sense also. Which was, you're not just
an evolutionary biologist, but you're one who thinks about
the evolution of the brain, or the evolution
of skin melanism, or the evolution of eye
color, or the evolution of how many chambers in your
heart you're going to have, or the evolution of
any of these things that will leave no
record whatsoever in the paleontological record. Because all
paleontology is about is shapes of stuff-- fossils. Fossils do not tell
you what kind of brain was going on inside that fern. Fossils do not tell you
anything about internal organs. Fossils do not tell you
anything about behavior. So at this point, all of
the evolutionary folks of the school from last
week attack and say, Yeah, what do they expect? They're studying the most
boring possible things-- the morphology of organisms. Ooh, just because
the fact that humans, over the last like million
years or so, have not evolved getting rid of
the large trunk and roots that they have
during springtime, and now they don't have them. Oh, that morphological
change didn't occur, so obviously
there's been stasis. Give me a break. What is interesting
about evolution and evolutionary
change, paleontologists can't pick up, because
all they can study are forms, morphology. So that was a big
attack on these folks. So you've got the
Gouldian folks, the punctuated
equilibrium people, saying when you look
at the fossil record, it's not gradualism. And we've got some
really complete ones. And to this day, the
majority of fossil pedigrees where there are
very, very complete records, show patterns of
punctuated equilibrium. And back come the rejoinders,
this is ridiculous, the time span they talk about. That makes no sense. In this period, humans evolved,
doubled their brain size in the length of time that
they call a very rapid evolutionary change. Their time span is
completely crazy, and they can't study the
evolution of anything that's interesting because
they study fossils. But in lots of ways,
the best rebuttal, the one that most
got at these folks advocating punctuated
equilibrium, would be the gradualists saying,
Show me a molecular mechanism. Show me some way in which you
can get rapid change and then long stasis. Turn that into modern
molecular biology. Which is, occurring
two minutes after the microevolutionary people
were trashing the folks from last week saying, You need
to look for the actual genes. It's not enough just
to make up stories. And once these folks had
assimilated what evolution looks like on the genetic
level, mutational level, micromutational changes,
they loved genetics. They loved the
molecular end of it, because they could now turn
around to the Gouldians and say, Show me the genes, and
show me the mutations that will account for stuff like this. Because you can't
account for it. Because we all know classical
genetics and mutation, you don't get that. You get gradualism. So this was a period of enormous
hostility between the two camps. And the gradualists called the
punctuated equilibrium people evolutionary jerks. Ha ha. And the punctuated
equilibrium people called the gradualists creeps. So ultimately, they all
got along wonderfully because they were so witty. But what you had was
enormously hostile camps. And really quite
hostile because all sorts of implications
spreading beyond like how fast the
shape of this seashell was going to be evolving. And when they first
came on in the '80s, all of this controversy, the
punctuated equilibrium people didn't have a word
to say with the show me the molecular mechanisms. Show me mechanisms for mutation
that will produce rapid change. And everything that
has occurred since then in the world of
molecular genetics that has been most striking has
supported punctuated models-- ways in which the
micromutational, microevolutionary
stuff of an hour ago is not what's going on
an awful lot of the time. Starters-- so simple
classical model. What we've got here
is a stretch of DNA. And this box
symbolizes a sequence of DNA coding for one gene. And right next to
it, once it finishes, one of those stop codon,
stop triplet signals, right after that
comes the stretch of DNA coding for the next
gene, and the next gene. And this is what DNA is about. It's the sequence genes there. And what you would
obviously then get is this arrow having this
intervening step of that RNA stuff, but eventually producing
an amino acid that produces a protein of this shape. And this is the protein
coded for by this gene. This, this, and so on, and
that's exactly how it works. That's the structure of DNA. Then, though, people began
to find that that's not the structure of DNA. And what you began
to get instead was something vastly
more interesting. Which is that,
for starters, when you look at coding
for one single gene, it's not necessarily coded
for in one continuous stretch of DNA. In other words, it's
broken into little pieces. And you will have
a stretch of DNA coding for the first
third of the protein, and then a bunch of DNA that's
got nothing to do with it. Stay tuned. Then coding for the next third,
coding for the next third, that the gene was broken up
into separate coding domains. And the term that was
given for these was these were called exons. And the in-between boring
stuff were called introns. And this was a major finding
which made no sense whatsoever. Because how are you going to
get from this to then having a protein which has its
normal sequence and shape where this part was coded
for by this exon, Exon One of this gene, and this from
Exon Two, this from Exon Three. That's a completely
different world of stuff. How are you going to do that? Because you're
going to meet an RNA that's going to
encompass all of this, and that's going to code for
something completely different because you've got these
introns in between there. And people then
guessed something had to exist which was
soon discovered-- enzymes called splicing enzymes. And what they did
was exactly what you need to do to solve this. Which is at the RNA level,
the splicing enzymes would come along, and they would
snip out the part corresponding to here. And another would
snip out there. And another one as
an enzyme catalyzing would stick this
two pieces together. And thus you have this. This utterly bizarre
world in which genes, the vast
majority of them, are not coded for in a
continuous stretch of DNA but instead are broken up
into these separate exons. And then you need these
splicing enzymes to clip out the boring in-between
parts, the introns, stick them all
together, and you've got your functional gene. Weird. OK, but that's how
they work though. I know shortly after
these were discovered that one of the giants in
this business, guy named David Baltimore who got
the Nobel Prize for some of the work on that
reverse process of RNA viruses turning
back to DNA, he was the first to really appreciate
that what you've got here is a potential for a
lot of information. Because of, and I think
he was the first person to introduce this word into
thinking about it, because of the modular
construction of genes. Because genes come in
these separate exons. What does that begin
to allow you to do? Very important stuff. OK, so we have the
same structure here. And we have a gene coded
for in a modular way in three separate exons. And thanks to splicing enzymes,
protein catalysts clipping this out, you wind up with this. What Baltimore was the first or
one of the first to appreciate was that you could wind up
with something different there as well. You could, for example, create
a very different protein-- one consisting only
of A and B. Or one consisting only of A and C.
Or one consisting of B and C, or A alone. And suddenly, you have this
combinatorial possibility of cranking out a number of
different ways of putting together-- seven different
ways since you can't transcribe this gene so that there's
no transcription-- seven different ways of combining
these different exons. Seven different
types of proteins you could generate
from the same gene. This was not accepted with
a whole lot of pleasure by the old guard. Because intrinsic in the know
the DNA sequence specifies amino acid, protein
shape, protein function, intrinsic in that is one
gene specifies one protein. One gene only specifies
a single protein. One protein is only specified,
coded for, by one gene. And suddenly, this
modular business allows you with one gene to
generate seven different kinds of proteins. For starters, how could that
possibly work that way just on a nuts and bolts level? All you need are
splicing enzymes that work a little
bit differently in different parts of the body. One that will splice
this off and is attached to an enzyme that
will degrade this, while the splicing enzyme
here-- and what have you just produced? You'll get this one. Coupling of splicing enzymes
with degradative enzymes, and suddenly you've
got a means to have tissue-specific
expression of genes. The same gene will
produce different types of proteins in different
parts of the body because of splicing enzymes
working differently. Then, just to confuse
things even more, people began to note that there
would be some splicing enzymes and genes where they would
splice at a different point. And you would now have a
gene with A, and A prime, and other splicing enzymes
that would cut at other points. One single sequence of
DNA generating all sorts of different types of proteins
in different parts of the body, at different times of life,
under different circumstances, in different individuals
in different ways. Suddenly, there's a lot more
information floating around in there. So that was a huge, huge
breakthrough in the field, understanding this modular
basis of gene construction. And for our purposes
right now, what the most interesting consequence
of that is is it's no longer one gene, one protein. One gene instead can
generate all sorts of different types of
proteins, different settings, different circumstances. The next thing that was
intrinsic in this model that's now been trashed of one
continuous gene, one continuous gene-- what we just
figured out that instead you can have the introns,
exons, all of that. The next thing that went down
the tubes was looking at, Well, how much of DNA is
actually devoted to coding for amino acids? And the answer was
obvious, like 99.9% each. One of these would just have
to have a stop codon, a stop signal at the end. And otherwise, this was just a
continuous flow of information once you have factored
in these interim things. OK, so they're
part of this gene, but immediately
starts the next one. The next major
discovery was one gene would very rarely start
immediately after the next one. There would be long
stretches of DNA in between that didn't code for a
protein-- non-coding DNA. That's mighty puzzling. What's that? Just junk or stuff? And around that time,
the phrase junk DNA was actually floating around. People trying to
make sense of this. And when people sat
and started actually like doing the numbers,
out came a number that knocked people on their
rears it was so flabbergasting. 95% of DNA is non-coding. 95% does not code for a
gene specifying a protein. In other words, in between
here on the average would be a stretch of DNA
19 times the length of that, or whatever the
math winds up being. And suddenly calling that stuff
junk DNA starting to see me a little bit tenuous,
because 95% your DNA just can't be packing
material for the whole thing. It's got to be doing something. And during that period,
became sort of the insight into this that all the
intervening, non-coding stuff was-- what was that? That was the
instruction booklet. That was the instruction
booklet on when to activate these genes. That was the on and off switches
for turning genes on or off. Upstream in the
non-coding domain just above a particular
gene sequence would be the information for
when that gene is activated. Activated when it makes RNA
into protein, all of that. And upstream of that are
the on and off switches. Implication right there off the
bat, which is Crick was wrong. DNA sequences are not
the starting point of the central dogma of life. And DNA is the rule-giver
and all of that. DNA is being regulated. Genes are being regulated
in some other way. And where 95% of
DNA is being devoted to regulation of the genes. DNA has no idea what it's doing. DNA is a readout that's
under the control of all sorts of other factors. And out of this emerged the
really, really important concepts of regulatory
sequences upstream from genes. So here we have a long string of
DNA coding for this gene which happens to come in two exons. And it is like the
space between the galaxy how long the non-coding is going
to go on until the next gene is back there. So what's going
on in the stretch just upstream from this gene? Things that were
soon being called stuff like promoter sequences
or repressor sequences. Things, stretches of DNA,
that coded for switches rather than coding for protein. That coded for things
coming into the neighborhood of the DNA and binding to some
of these promoter or repressor sequences, and then turning
on, or in some cases off, the transcription of that
gene, the process of the gene generating proteins. You would have
promoters sitting there. And this is overly literal. It would be just
a sequence of DNA, which thanks to that
sequence would have a certain subtle microshape. And along would
come something which happened to be able to fit
perfectly into that spot. And if, and only if, this
molecule-- usually a protein-- bound to this
promoter, suddenly that would trigger a whole
bunch of enzymes to come in, which would start
the process of transcribing this gene. This would be the switch,
and this is the thing that just turned the switch on. And these things that turn
these switches on, or off in some cases, were soon
called transcription factors. Totally critical concept
in there-- the fact that vast stretches of DNA
don't code for anything. Instead, they have the
instruction booklets. Here's how you turn
this gene on or off. Send in this
molecular messenger. Send in this type of
transcription factor. And if it shows
up, binds to here, you now activate
the transcription of this gene, the process
of turning that gene, making proteins derived from it. This is where the
information was. And this is not DNA
knowing what it's doing. This is outside
regulators coming in. So immediately,
that has made life a whole lot more complicated. Next complications-- you
could have different genes scattered all over
the place that would have the same
promoter upstream of it. What would that mean? In comes a transcription
factor, and it doesn't activate the
transcription of one gene producing one protein. It activates the transcription
of a whole bunch of them. In other words, now
suddenly we have messengers that could trigger activation of
genetic networks, entire arrays of proteins being produced all
with a functional similarity driven by the fact
that all of them have the same promoter upstream. So suddenly, you
have the possibility of the same promoter
being upstream regulating more than one gene. That is the general rule. Flip side of it, any
given gene, for example, could have a bunch of
different promoters responding to different types of signals. So now, suddenly,
you have this gene which can be transcribed
under this circumstance, or under this circumstance. And both are ways of turning
on activation of that gene. And in this circumstance,
the same promoter is found in Genes A, B, and
C somewhere at the other end of the chromosome. And in this case,
this promoter is found on Genes D, E, and F down
there-- different networks. So the same sort of
transcription factor logic-- once you can have different
promoters upstream of a gene, and once you can have the
same promoter upstream for multiple genes, you
suddenly have the ability with different
transcription factors to activate entire networks
of gene expression. OK. So what this has
allowed you to do is completely trash this notion
of DNA knows what it's doing. DNA is just the readout. And who knows what's going on? Whatever is controlling
the transcription factors. Whatever is causing
them to do their thing. And this could be a
world of influences. And to be absolutely
accurate, this requires introducing
the word environment. This is environment
having something to do with genetic effects. This is going to be a
way in which environment is interacting with genetic
elements, environment determining which of
these are doing what. What would that look like? Sometimes environment
could be the environment in the rest of this cell. So you've got your DNA
there, and your structures, and all of that,
and the promoter. And we could do that by now. And something is occurring
inside the cell which activates some transcription factor. And then you go change a
genetic event going on in there. The cell is running
out of energy. There's various ways
to construct sensors. In other words,
evolution has come up with a bunch of different ways
in which cells can respond to signals of low
energy, and that will activate some transcription
factor which will go and bind to a bunch of promoters
which produce proteins involved in taking up more energy from
outside the cell, transporting in more, using energy
more efficiently. So what we have here is an
environmental regulation of genetic effects. Environment-- the rest of
the environment of the cell. The DNA doesn't know
what it's doing. The gene doesn't
know what it's doing. Events going on
elsewhere in the cell is what's regulating what's up. Some of the time,
the environment can be even more far flung. And in this case, it's
now events going on outside just this one cell. In this case now, you've
got the cell with it's DNA. And now, instead, you
have a chemical messenger coming from somewhere else. And binds to its receptor
like a lock and key. And as a result of
this binding, something happens here, which
does something here, which does something
here, which eventually activates some transcription
factor, which goes and does its thing. Now we have gene expression
in the cell being regulated by the environment
somewhere else in the body, somewhere else there. What would be a classic
example of that? This is what a whole
lot hormones do. Hormones go floating around. And they affect cells
everywhere throughout the body. By definition, a hormone is a
bloodborne chemical messenger. So you could secrete
some hormone out of the top of your ear,
and it will affect things in your little toe. Very far flung. Hormones will bind to their
receptors, lock and key. Most hormones are
protein in nature, and trigger what's called
a second messenger cascade. Jargon, don't worry about it. Just get it conceptually. Activate some
transcription factor, deactivate some other
transcription factor. And suddenly, events going
on 14 counties over there are regulating what proteins
are being made in this cell. What would be an
example of that? Testosterone, for example. Testosterone secreted
from the testes, traveling far and wide and
eventually binding to androgen receptors on muscle. And what happens there is
through a pathway like this, turning on the activation of
genes, coding for proteins, all sorts of structural
proteins that will make that muscle cell bigger. Your muscles are getting
bigger thanks to testosterone. Look at this. Events occurring a gazillion
cells away in the testes, a messenger here, determining
what gene expression, what gene activation
is happening. Sometimes, though,
the environment could be completely
outside the organism. Like that. Sometimes you can have,
for example, a messenger from the outside world. What sort of messenger? A scary sight. A bit of sensory
information or whatever. Olfactory. Olfactory-- suppose
some odorant comes in. A pheromone-- you're female rat
who has recently given birth, and the pheromones
from your babies come floating in and
bind to receptors here. Very similar principle, again. And that causes them to activate
something, activate something, and some cell down there. And eventually
there is a cell here that controls some
muscles, and it makes your eyes
dilate because you love the smell of your baby. And you're just-- I don't know
if rats have their eyes dilate. But humans will in many
other circumstances. Aha, how do you do that? You just changed some structural
proteins that did this or that. Or suddenly this
female is making some hormone like oxytocin as
a result of smelling her baby. What have we got here? We got something going on in
the outside world regulating what's going on with the genes. Genes as the central
dogma of life, as the information
giver-- nonsense. Events going on in
the rest of the cell, the rest of the organism,
the rest of the universe, are determining
when genes activate. So what we see now is a
much more interesting world of regulation of
gene expression. First, the modular
ability for one gene to generate all sorts of
different proteins, which brings up an issue after
a while is, does that count as one gene? And people argue over that. And because of this 95%
regulatory sequence business, the most interesting
stuff going on with DNA is not what the protein is
like, not what the protein does, not how well the
protein does it, but when it does it,
in what contexts. And what we've just
introduced are if then clauses into this whole world. If you get a signal that there
is low glucose in the cell, then you begin to make proteins
related to glucose uptake. If you have the smell
of your child come in, then you activate
this [? path. ?] It's not changing what
the protein is like. It's changing context. And I think what we will see
is context is vastly more interesting than whether this
protein is a little bit more like this, a little
bit more like that. If it is being expressed
instead at a different time, in a different place,
in a different context, that's much more interesting. So what does that
set us up for here? Now beginning to see the
organization of this. By the way-- 95%,
this whole stuff here. I don't know what
percentage is accounted for by identified promoters,
and repressors, and stuff. But it's a tiny percentage. What that means is there's
regulatory stuff going on that no one has a clue about. The main thing, though,
here is modulatory structure to genes-- introns, exons--
and this whole world of the environment
regulating when genes are turned on and off. A whole world where
you could generate completely different proteins. Not a protein that's a
little bit more this way, a little bit more that way, in
completely different contexts. So all we need to
do now is begin to stick this into the
molecular biology of mutations and evolutionary change. Where does this begin? Oh, no, before we
do that, that's not what we're going to do. We're going to look at one
more level of regulation here. OK, so you've got your DNA. And we already know
this whole business. What's telling it what to do. You can have transcription
factors coming in, all of that, these
interesting implications. DNA-- let's see. For our purposes, protected
in sort of layers of protein that are just sort of
structurally stabilizing. This is not really what
they look like or quite what they're made of, but
they're called chromatin. There's this stuff that
stabilizes the DNA. Because these are
wispy little things. And one of the things that,
of course, they need to do is they're in wrapped
around the DNA stabilizing. You've got some transcription
factor coming in from somewhere else in the cell. It's got to be able to
get down to the DNA. And thus, you have a whole
world of chomatin opening up to allow transcription
factors to get through. And thus, you have a whole world
of what's telling the chromatin to open up where and when? Suddenly, a whole
world of regulation, of whether the
transcription factors even have access to the DNA. So you can have tons of
a transcription factor, and all set to transcribe
something off of this. And thanks to conformational
changes, folding or unfolding of chromatin, you're regulating
whether the transcription factor can even get through. And thus, there's a
whole world of stuff that changes chromatin
modeling and remodeling. Additional step here, one
that's really interesting, is you can do things--
circumstances [? arise, ?] the environment can do
things-- where you change the structure of chromatin
around a particular gene in a way that makes it
easier to transcribe, or harder to transcribe. And you can essentially
make that change permanent. You could permanently
do something in some particular
stretch of chromatin so it will never open up again
to allow the transcription factor in. And what you have
just done-- jargon-- is you have silenced that gene. You've silenced it permanently. And people know a lot of the
mechanisms for how this occurs. For those who care
about such things, the process is
called methylation. This is a little bit different. That's occurring
with the DNA itself. But this is silencing of
genes by structural access of transcription factors to it. When does that occur? There's all sorts of
circumstances early in life where you will change the
permanent accessibility of some gene and
transcription factors. You will cause long-term,
lifelong changes. As but one example,
and one that we will look at a number of
times down the pike there, in rats, the mothering
style of the mother rats, will cause chromatin
changes-- permanent ones-- in some of the genes
related to stress hormones. So that certain types of
mothering-- how often you lick the baby, and other
rat mother type stuff-- will regulate how readily
some genes will be turned on for the rest of your life. This is early experience. This is molecular mechanisms
for events early in life lasting forever. A lot of these turn out to
be a little bit reversible. But for our purposes,
lasting forever. This is a whole new
field called epigenetics. Genetics is all
about DNA sequences. Epigenetics is all
about regulation of access to DNA sequences,
things of that sort. So suddenly this
epigenetic world is entirely capable of
overriding anything going on at the transcription factor end. Just to give you a sense
of this-- researcher. This is a guy at the National
Institute of Health-- a guy named Steve
Sumi who studies primate social behavior. And what he has
shown is in monkeys, in one part of their
brain, you change the style of mothering that that monkey
is subject to as a baby, and you will change the
conformational access state of 4,000 different genes. Enormously influential there. Enormous arrays of ways of
regulating where it's not genetics, it's epigenetics. And this has given rise to a
great phrase-- fertilization is all about genetics. Development is all
about epigenetics. And what epigenetics
is about are ways in which the environment
not only can regulate what's going on with this
gene right now, but can cause lifelong
differences in the ability to access genes. So this is an enormous array
of levels of regulation. Splicing enzymes
determining how your exons get mixed and matched,
generating all sorts of different proteins. Transcription factors
representing the things that turn the switches on and
off, and the array of switches is far more interesting and
plentiful than the gene itself. Transcription factors
reflecting what's going on in the outside world,
like in the rest of the cell to the other side of the planet. And finally, this
whole additional level of regulation where some of
the regulatory consequences here can be lifelong. Enormous array of
levels of regulation. And an enormous number
of ways in which just the DNA sequence
of the gene itself is not very interesting. That determines the
shape of the protein. All this other
stuff is where is it expressed, when is
it expressed, in what contexts, what sort of
if then contingencies, whether it is ever expressed
after a certain childhood event. All of that much much
more interesting. So what we need to
do now is transition to thinking about
evolution, mutations, on the level of all the
stuff we just heard about. And all I will leave you with
and picking up on Wednesday, is think about what if you get
a mutation in a splicing enzyme? What if you get a mutation
in a transcription factor? What if you get a mutation
not in the letters coding for a gene, but
coding for a promoter? What happens in all those cases? And suddenly you
begin to see a world in which you can get stuff
that's not purely gradual. For more, please visit
us at stanford.edu.
