4. Molecular Genetics I

By: Stanford

[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.

4. Molecular Genetics I

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. I

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