4. Molecular Genetics I

Transcription for the video titled "4. Molecular Genetics I".

1970-01-24T19:57:29.000Z

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Introduction

Intro (00:00)

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.


Genetic Mutations And Microevolution

Heritability (00:21)

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 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.


Seeing spandrels (01:03)

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 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 a sense only eventually when we see some pretty unexpected things about genetics and the molecular biology.


Political assumptions movable (02:21)

Okay, 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, political views run throughout all of this, you will see very strongly in this realm. Okay, so that viewpoint of the sociobiologist and evolutionary psychologist the other day, one of the tenets going after the notion of heritability. The notion that these behaviors are heritable or are genetically influenced by blood. How would folks in that business do it? What they would do is exactly what we were seeing, which is say, okay, 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 large 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, I don't know, poetry for all the science, and it might God, that counts as science coming up with a bunch of these things. And a bunch of these rules there and say, until you come up with fancier rules or 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 is that that not only will have lots to say about adaptiveness, it will also have lots to say about gradualism. Okay, 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? Well, one is immediately talking about her 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. And so, I think that the question is, what is the question that genes as information genes as strings of DNA?


Genes (05:23)

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 catch-up session last week, which I think is a good idea. But what is all built about, all of this notion of genes eventually way out the other and having something to do with behavior is the intermediary of proteins. Not just to have in your diet and 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 rules. Proteins hold the shapes of cells together. Proteins form messengers, hormones, neurotransmitters, all of this to come. The harm of proteins are the enzymes that do all sorts of the most important stuff. Proteins, 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 a 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. Okay. So DNA codes for amino acids. A long string of DNA coding for a sequence of them will call 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 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 into the other end and do something. For the very critical reason that everything about protein function is built around 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, okay everybody say it out loud. Everybody know this cliche? It fits in like a, yes, okay, okay cliche education at its best. 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 in parts information in so far as it interacts with something else of a shape which modifies it, which complements it whatever the whole world that we will have in 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, etc. 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 of 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 that 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 become, coming function, out of the famed lock and key nature between shapes of functions and shapes of other things. Okay, 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 that proteins do is when they are enzymes, enzymes, everybody knows that enzymes are important because they put them in your lungs. 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 or enzymes pull things together, pull them apart. Proteins are structural, again a whole lot of the super structure 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 this 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 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's 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 to 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 to DNA as known as DNA.


Virus and The Central Dogma (14:12)

And a lot of what we will see shortly is DNA no squat. DNA is not making a whole lot of decisions there. But one simplistic way in which central dogma went down the tubes in the 1970s or so, 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 smidgen of foreign DNA, which you're 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're changing the starting step of how the central dogma of life, and thus you're going to change RNA protein, all of that. In the 1970s it became apparent there was one weirdo viral world of viruses made out of RNA. In 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. 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.


Classical Mutations (15:40)

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 retroviruses, and certain the DNA and off they go from there. So this was a major blow. Everybody eventually came terms with this, but it still is a minor footnote in this crickying 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 will focus on here is classical realms of mutation in 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 the background in this, newcomers to this, hopefully this won't be going too fast, but broadly when you were talking about this, we were talking about this world of micro mutations. For our purposes what we will mean by a micro mutation is when one letter in your DNA sequence of information gets accidentally miscopied or gets changed by radiation or gets changed by some chemical compound in the environment, and there is some such thing where there is a mistake and one letter in the DNA sequence comes up wrong. As I noted before, pairs of triplets, there we have three pairs of triplets, and what we have got here is 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 have just raised is the possibility of a mutation occurring.


Single point mutations (18:00)

Something changing in one single one, and now asking what are the consequences going to be in classical realms of genetics and evolutionary change. Okay, 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. So, you can 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 ambivalencies 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 what produces a protein with a very different shape and potentially a very different message.


Point Mutations; Single amino acid (21:30)

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 a grant proposal, sort of the final paragraph. We have now accomplished X, Y, and Z with your money over the last five years. And the wonder 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 nucleotides, mistaken for another entirely neutral, moderate consequence or major disastrous consequence. Second way of classical mutations, the second version that 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 gibberish. And it would continue that way. A deletion mutation in classical genetics is majorly get totally changes the coding downstream from there. Third classical type and insertion mutation, one where you now accidentally double the letter and you frame shift it 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 in 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 changing.


Microevolution (23:12)

And all of this is built around us, one single protein changing its shape. And thus this world of micro mutations single spots there mutating what this tends to do. And this is an important concept for what's to come. It does 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 shape. 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 pre-existing 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.


Phenylalanine (25:11)

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. Just something in 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 is 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.


Turner Syndrome (26:22)

Here's another dramatic one. And this one, anyone who took Bio-Chore always bring this one. It is a big hormone crowd pleaser. But here's an interesting thing that can go wrong with any child you might eventually have. Okay. You've got a daughter. And she's doing just fine. And she's growing up just fine. And things are terrific. And you know, around age 10 or 11 or so. Some of her classmates are beginning to reach puberty. You know, 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. It's not rich puberty yet. Your daughter has not started doing this because you don't have a daughter. You 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 what.


Testicular Feminization Syndrome (27:57)

Okay, it's called, especially since it's in the handout already. Anyone want to guess what it's called? It's called a 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 descend 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 antlers in the sensitivity? No, that's the fancy term for it. And you've just given away the punchline you creep. Okay. So, they figured out in this disease there's an insensitivity to something. What could that be? Okay, go and say it again. Yes, okay. What you've got here is one of those simple little classical mutations. And what it does is it changes 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 and the mountains. The other is in the mountains of New Guinea. Interesting similarity there. In both cases, some fairly isolated inbred populations. So that sort of has genetics written all over it. But in these cases, there's a problem with enzymes that make testosterone. So this is a whole other world instead of the proteins and the genes that were back there that code for the receptor for testosterone, the receptor that responds to this messenger. Here, instead it's back way up there on 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 you know, it's not a huge one. The shape is a little bit off. It's 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, like before puberty, has extremely low testosterone levels. Even far lower than you would see in pre-pubescent 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 disticular feminized males. What you find there is there's a vagina which goes nowhere because there's no ovaries waiting somewhere above that. There's the testes. But the external genitalia is just fine. What I think these days is the most common sort of medical ethics advice on what's done with that is the physician says, 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. Okay, 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 an a fetus in a young male, and now it's below threshold for causing anything, a long 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, jumpship 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.


Evolutionary Biology And Darwinian Variability

Benadozepine Receptor (34:01)

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. Puberty, sometimes you get acne, sometimes you get a penis. And people just kind of 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 Valium. Like Librium. Valium is a synthetic benzodiazepine. So benzodiazepines are protein. And they have a particular shape. And you guessed that 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. It 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 benzodiazepines 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 and levels of anxiety. It's only one of a gazillion ways of explaining it. But it's part of that picture there. Here we have individual differences. This explained a very interesting finding. In the decades, people often try 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, spatial, may stuff, etc. And years there have 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 useful for? I don't know. They're just cool to have around. Very useful for understanding the effects of stress or things of that. So finally, modern error 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. Okay. So what we've got here is classical 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 precision. And produce some pretty exciting dramatic diseases where you wind up with a different gender. Then your chromosomes say once where you get more subtle differences, you change gender at your 13th birthday.


Translation to Evolution (38:02)

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 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 social biology 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. Is that going to increase the number of copies of genes that individual has? Is going to decrease the number? How is it going to fit into all of last week's science? And you will know exactly how that drill will run.


Darwinian Variability (39:14)

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.


Gradualism: Differential fitness; single base pair differences (39:43)

We have differential fitness. We have just defined an adaptive difference somehow or other. There's a smidgen of advantage, thanks to the 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 a 1% difference in number of copies of your genes run at 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 in 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 birdsong. 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.


red queen effect; Fox P2 in humans and birds; mammary gland (41:52)

And Fox P2 has something to do with in 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 sticking in the human version and seeing what happens. And it was very interesting. The immediately seeing the theme song from all the Mickey Mouse Cartines. Can they prove that? Okay. What you see is you 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 wound up with a very different world and 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's also this allows you to do is look at a footprint and echo of what the selection was like. Okay. 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, two thirds at 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 two thirds are neutral in terms of their consequence, and one third actually causes a change in the amino acid, that's telling you what's happening at the random expected rate of mutations popping up that are either consequential, changing an amino acid, or in consequential, 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 long gene, 99% of the differences make for a different amino acid than beforehand. In other words, at a much higher than expected rate, if this was a random process, what is this an echo of a very strong selection, a very strongly advantageous trait 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 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.


Selection for neutral and/or positive mutations. 98% similarity between humans and chimps. (46:08)

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 it 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 this function down line 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. Okay, so that begins to give a 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 too factoid and too 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 who goes through like basic Mendel, 50% 100% with an identical gene, with 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 in what in hell are you creationist thinking is the fact that, oh, humans share 98% of their DNA with chimps, which 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. Genes specify to be totally simplifying here. Genes specify for antlers, for dorsal fins, for petals and pistols and stamen, for kidneys, for 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 weed or chimpanzees have genes for dorsal fins. Meanwhile, we have genes coding for a pelvis that is a certain shape, which either in chimps predisposes towards being able to walk by petal for certain lengths 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 then wings or 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 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 variance on each type of gene.


Concepts And Elements Of Evolution

Elements of evolution: Change in behavior at the edge of one gene. (50:21)

So when talking about the amount of DNA shared in common, the genes shared in common with another 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 and a half percent, one brother or eight cousins, what you're talking about are different versions of particular genes. Important clarification. Okay, 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 gradual 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.


Gradualistic vs. Punctuated equilibrium (51:27)

Okay, whoa, there's a lot of apples there, lit up. Well, that wasn't very subtle, let's take a break. Whoever did that. Okay, five minute break. Are you slightly more fit by the rules of your population's natural selection, sexual selection, whatever, even if it 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 sort of political philosophical stance in gradualism as it applies to evolution. Okay, so that's been sitting there around forever. And in the 1980s, suddenly a very different model emerged. And this came from Stephen J. Gould, who we heard about the other day, Stephen J. Gould, and the person, the poor Chinook, who has always lost in this, another evolutionary biologist named Niles Eldridge, who was a very different model. And Niles Eldridge, who somehow did not quite have the press that Stephen J. Gould did, so he has lost the 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. And 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. 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 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 call 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 sort of stance was running through all of the ways to think about genetics. And I don't know what's up with Niles Eldridge, but that was the case with Gould. And when you look at this model, this is like classically fitting with like 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 world's view of what evolution is about punctuated equilibrium. Okay, 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 was a paleontologist.


Stephen Gould and the Marxist Scientist (55:07)

He studied fossils. He studied 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/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 the fossils look like. And you're measuring some trade or other and these snails or trillabytes or whatever you're looking at. And at this time period, the trade looks like this. And at this time period, it looks like this. 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 began 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. A 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 it in the back of the head, you mean at you and you'll leave more copies and figuring out exactly who to be infanticidal to, 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 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.


Punk Ecologist (57:53)

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 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 completely different universes. Okay, stomach problems and they're functioning 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 a hundred thousand 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 got completely thrown off and these paleontologists led by Gould simply orders of magnitude different scale of time. Yeah, maybe in some rough approximation 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. 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 sort of 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 Goudian 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 gradualist 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, micro-mutational changes, they loved genetics. They loved the molecular end of it because they could now turn around to the Goulians 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 gradualist called the punctuated equilibrium people, evolutionary jerks. Ha ha. And the punctuated equilibrium people called the gradualist 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 like seashell was going to be evolving. And when it 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 micro-mutational micro-evolutionary stuff of an hour ago is not what's going on an awful lot of the time. Okay, 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 next, right next to it.


Gene (01:04:11)

Once it finishes, one of those stop codon, stop triplet signals, right after that comes the stretch of DNA coding for the next gene in the next gene. And this is what DNA is about. It's the sequence of genes there. And what you would obviously then get is this arrow having this intervening step of that RNA stuff, but eventually producing 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 this 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 sort of world of stuff. How are you going to do that? Because once you're going to make an RNA that's good to encompass all of this, and that's going to code for something completely different, because you 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, these 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, which stick these two pieces together, and thus you had 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. Okay, but that's how they work though. And shortly after these were discovered, that one of the giants in this business, a guy named David Baltimore, who got the Nobel Prize for some of the work on that reverse process of RNA viruses turning back into DNA, he was the first to really appreciate that what you 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. Okay, so we have the same structure here, and we have a gene coded for it in a modular way, and 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. So, 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.


Splitting The Atoms (01:09:05)

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 does, 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.


Gene Transcription And Its Environmental Influence

DNA Bar Codes (01:10:10)

Then, just to confuse things even more, people began to note that there would be some splicing enzymes in 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.


Modular genes (01:10:36)

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, where we just figured out those instead, even though the intronics, all of that, the next thing that went down the tubes was looking at how much of DNA is actually devoted to coding for amino acids. And the answer was obvious, like 99.99%, each one of these would just have to have a stop codon, a stop signal with the end, and otherwise this was just a continuous flow of information once you have factored in, these intron things are okay, 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, like, 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 acting, they were just doing it. People sat and started actually 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 are being, and suddenly calling that stuff junk DNA started seeming a little bit tenuous, because 95% of your DNA just can't be packing material for the whole thing, it's got to be doing something. And during that period, it came sort of the insight into this, that all that 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 quick, 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 a 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 in to 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 micro-shape, and along would come something which happens to be a sequence of DNA.


Gene wonderland (01:15:23)

Which happens 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 the switches on, or often 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.


Promoters (01:16:24)

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 a 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 from multiple genes, you suddenly have the ability with different transcription factors to activate entire networks of gene expression. Okay, 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.


Environment Determines Which Transcription Factors Binds to Which Promoters. (01:19:01)

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 the cell. So you've got your DNA there, and your structures and all of that, and your promoter. 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 on 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 that's DNA, and now, in this case, you've got the cell. And now, instead, you have a chemical messenger coming from somewhere else, and binds to its receptor like a lock-in-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 of hormones do. Hormones go floating around, and they affect cells everywhere throughout the body. By definition, a hormone is a blood-borne 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-in-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 trends, 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, secrete 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 site, a bit of sensory information, or whatever. Olfactory. Olfactory. Suppose some odorant comes in, a pheromone. You're a female rat who has recently given birth, and the pheromones from your babies come floating in and bind to receptors here. It's very similar principle again. And that causes them to activate something, activate something, and some cell down there. Eventually, there's 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, rats have their eyes dilate, but humans will, in many of those circumstances. Aha, how do you do that? You just change 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 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.


The Rule in Which Genes Are Actively Transcribed Into Rna. (01:24:33)

First, the modular ability for one gene to generate all sorts of different proteins, which brings up an issue after a while, 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 the protein is in the brain, 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. Anyway, 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, Montillatory 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 can 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? Let me just... 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. Okay, 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, and 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 enwrapped 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.


Epigenetics And Transcription Factors

Conformational changes (01:27:39)

And thus you have a whole world of chromatin 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 around 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.


Silencing of genes (01:29:11)

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 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 rat will cause chromatin changes, permanent ones, and 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.


Silencing of genes (01:32:23)

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, and 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.


Epigenetics v. genetics (01:30:13)

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 of the transcription factor. Just to give you a sense of this, research here at the SIGCHI National Institutes 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 is given rise to a great phrase, fertilization is all about genetics. Development is all about epigenetics.


Transcription factors (01:31:30)

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 in match, 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.


Splicing enzymes (01:32:11)

And finally, this whole additional level of regulation where some of the regulatory consequences here can be lifelong. Enormous array of levels of regulation.


Gene Silencing

Silencing of genes (01:29:11)

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 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 rat will cause chromatin changes, permanent ones, and 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.

Silencing of genes (01:32:23)

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, and 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.


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