[MUSIC PLAYING] Stanford University. So we pick up fromwhatever the last day was. And we do our firstdisciplinary leap as promised at the verybeginning of the course. The entire function of thefirst half of the course is to leap from one bucketto another, such that just as soon as you feellike you are getting mildly comfortable in one,we will spend time trashing it from the standpointof a different discipline. This is our first one of these. And the whole point of this jumpis to show on a certain level exactly where one discipline’sthe notion of an explanation ends, another one begins. And what this one will be aboutis how evolution works down on a molecular level.Where did we leave offafter finishing our overview of the evolution of behavior? We finished with a bunchof criticisms at the end. Criticizing sort of whatsome of the basic tenets were of that view. First off, that notionof heritability. Heritability– assumingthat all sorts of behaviors have a genetic component,have a genetic basis, have a genetic cause. And we will see those are worldsof differences in those words there. And what we saw was thatthat could be the case. That could not be the case. That’s going to be what wefocus on a great deal today. Another one ofthe basic tenets– this notion of adaptation. Everything you see iswonderfully adaptive. The outcome isexactly the process that evolution bringsabout to optimize results. The counter view being theworld of spandrels– a lot of the time, stuff getscarried along as baggage. Things evolving aren’tnecessarily things that have been sculpted intobeing as adaptive as possible.Another critique, and onethat’s also central today, is that whole emphasison the gradualism, on small incremental changes. And what I alluded toat the end the other day is going to seea viewpoint where something very, very differentis proposed to be going on. One that will make senseonly eventually when we see some pretty unexpectedthings about genetics and the molecular biology of. OK, so starting off–what we also finished with was a notion that thereare political agendas that run through everyaspect of this subject. And if that veryfirst lecture, back when talking about how some ofthese viewpoints influence who gets a lobotomy, whowinds up exterminated, who winds up being viewed aseducatable or uneducatable, et cetera, polypolitical viewsrun throughout all of this you will see verystrongly in this realm.OK. So that viewpoint ofthe sociobiologists, the evolutionarypsychologists the other day, one of the tenets going afterthe notion of heritability. The notion that thesebehaviors are heritable, or are geneticallyinfluenced, blah, blah. How would folks inthat business do it? What they would do isexactly what we were saying. Which is say, OK, here’ssome behavioral structure. And we know how evolution works,and evolution of behavior, and individual selection,and kin selection, and reciprocalaltruism, and evolution of, and all the above. And then they say, Well, withthat framework, that explains the behavior pretty well. Go show me something better. Show me a bettertheoretical structure that’s even moreexplanatory, more predictive. And until you come upwith something better, I’m going to assumethat this one is right. And this one comes witha larger assumption of heritability of geneticsall built around inferentially. These are highlystructured models built around how genes work. They explain what we seewith these behaviors. And until you can give me amodel that does even a better job, I’m stickingwith this, and this counts as my evidencefor a genetic component to this set of behaviors.And what we’ll see isthat’s exactly where the molecular biologistsdecide that they finally have gotten free ofpeople doing poetry for all the science in it. My god, that counts as science? Coming up with abunch of these rules there and saying until you comeup with fancier rules or a more pleasing just so story, I win? That counts as science? Complete contemptfor this approach. This is where more molecularstance about it all takes off. And what we’ll seethat that not only will have lots to sayabout adaptiveness, it will also have lotsto say about gradualism. So starting with it. In order to make sense ofthis, for a molecular biologist what is evolution about? When you see traits that haveevolved, what’s it about? By necessity, what one isimmediately talking about is genes. Genes in this casenot as some constructs that one wants to maximizecopies of and ones that your cousins haveonly whatever percentage of in common with you, butgenes instead molecules. Genes as information,genes as strings of DNA.And I’ll assume by now there’slike a basic level of shared knowledge about this afterhearing that a lot of folks came to the catchup sessionlast week, which I think is a good idea. But what it’s all built about,all of this notion of genes, eventually way out theother end having something to do with behavior, is theintermediary of proteins. Proteins are important. Proteins are importantnot just to have in your diet to make you runfast, and strong, and all. Proteins are, in lots of ways,the structurally most important things you’ve gotmaking up cells. Proteins have endless roles. Proteins hold the shapesof cells together. Proteins formmessengers, hormones, neurotransmitters,all of this to come. Proteins are the enzymesthat do all sorts of the most important stuff.Proteins, et cetera,et cetera, et cetera. Proteins are theworkhorses of what have cells doing whatthey’re supposed to do. So the questionof course becomes what codes for proteins? And this is where genes come in. Our basic issue here is thisflow of information– genes specify proteins. Proteins are made up ofconstituent building blocks, amino acids. There’s approximately20 different ones that are commonly occurring. And each one has to be codedfor with a different DNA sequence, a differentDNA sequence of three letters, three nucleotides. And I hope I’m not hittingthe level here where people for whom this is new thisis going way too fast and everybody elsethis is way too boring.But hang on for awhile in that case. So DNA codes for amino acids. A long string of DNA codingfor a sequence of them will code for asequence of amino acids which get plugged together,and you then have a protein. You’ve got one interveningstep, which for our purposes is like not really interesting. And we could ignoreit for the most part. Which is, there’s anintermediary step– genes at the level ofDNA, sequences of DNA, first specify anintermediate form called RNA. And it’s from that thatyou get the readout forming the proteins. Now, everything aboutthe function of this is built out of thefollowing sequence. If you know thesequence of DNA, you will know the sequence of RNA. You will know theamino acid sequence. You will know the proteinthat thus is made. You will know theshape of the protein. And you will then know thefunction of the protein. And that is this criticallink between what DNA, genes, evolution, blah,blah, are about, and the actual things thatpop out at the other end and do something.For the very criticalreason that everything about protein functionis built round shape. Here is a cliche thatis required by law to be said at this point. Which is, all sortsof effector proteins fit into other molecules,other effector proteins. Like a– OK, everybodysay it out loud. Everybody knows this cliche. It fits in like a– Glove. Yes. OK. Cliched education at its best. Like a lock and keyfor those of you who are not tortured withthis one from early on. It’s the whole notion thata shape of a protein imparts information insofaras it interacts with something else of ashape which modifies it, which complements it, whatever.The whole world that we willhave of various hormones and neurotransmitterswill consist of hormones andneurotransmitters going into receptors where thereis a critical relationship in the shape between themessenger and the receptor. And all of this isdriven by proteins, protein shape, et cetera. All of this is driventhus by DNA sequences. Shape is everything with this. What you get fromthat is, of course, the question of where do youget different shapes from? And those 20 aminoacids, for our purposes, for the purposesespecially people without a strongchemistry background, all that’s pertinent here isthe 20 different amino acids have different degreesof being attracted to or repelled by water. Which, most proteins arespending their life swimming around in water. They are pulled towards water. They avoid it. They are hydrophilic,hydrophobic. All that means isdifferent amino acids gets pulled into differentpositions by their relationship with water. And thus, a stringof amino acids, the shape it windsup getting with, is determined by thatamino acid sequence.There is a whole worldof really interesting horrible neurologicaldiseases called prion diseases which showthat everything I just said is wrong. But for our purposes,everything I just said is right. So this is where you getthis critical relationship. Know the DNA sequence. Know the coding. And out the other end, youwill get protein shape because of this business ofdifferent amino acids having differentrelationships with water and thus stringsof them coming up with different threedimensional structures.And out of that willbe coming function out of the famed lock and key naturebetween shapes of functions and shapes of other things. Just once again for peoplefairly new at this– nope. No diagram there. One of the most interesting–or the blank slate. One of the most interestingthings the proteins do is when they are enzymes. Everybody knows that enzymes areimportant because they put them in your laundrydetergent, and advertise about how cool it is that youhave enzymes in your detergent. But what enzymes do isthey catalyze reactions. They cause reactions tooccur which left on their own would be very, very rare events.What enzymes do isaccelerate vastly– a gazillion times over– thespeed with which these happen. Catalyze reactions. What do I mean by that? For our purposes, theycan take two things that aren’t connectedand stick them together. Or they can take onething and break it apart. For our purposes,that’s what enzymes do. Virtually every enzymeout there is a protein. So proteins fit into otherthings and send on messages. Proteins are enzymes. Pull things together,pull them apart. Proteins are structural. Again, a whole lot of thesuperstructure of your cells are held together by proteins. This is the realmof what they do. Notice here, suddenly there isa change of shape in a protein if it’s an enzyme. Because what’s it doing? In some way, it’s got tobe pulling apart something or putting something together.The shape, in somecases, also can change as a functionof what this protein is doing with its job. We will see a classicversion of that are channels. Channels in which chemicalscan flow in or out of cells. Ions, for chemistry types. Channels that will open upunder some circumstances, close under others. So protein structure not onlygives shape and function, but it gives the circumstanceswhere the shape might change in a functionally relevant way. So out of all of this comesof the central dogma of life. And this was proposed by FrancisCrick of Watson and Crick fame.And Francis Crickwas the one who formalized saying thecentral dogma of how life and information flowsis DNA to RNA to protein. And that became defining. An entire generation of babieswere told that at birth. This is the flow of information. It has been violatedin all sorts of interesting ways, which willdominate a lot of what comes. But this was the central dogma. One way in whichit is violated– and again, this notionis not DNA to RNA, but the notion of whateveryour DNA sequence is, whatever the gene is, whateverstructure of a protein it codes for– theflow of information is going to be fromDNA, RNA, to protein. DNA as running everything. Note the importance of thatin the very statement of this as the central dogma, thecanonical flow of information in life. It all starts with DNA. DNA is the one sitting heredeciding when information is going to flow from DNA to RNA.DNA as knowing what’s happening. And a lot of what we will seeshortly is DNA knows squat. DNA is not making a wholelot of decisions there. The one simplistic way inwhich central dogma went down the tubes in the1970s or so, and one that’s tangential here,but just as a first blow against central dogma. One of the thingsthat’s interesting is there are thingscalled viruses. And what viruses do for aliving is get into organisms.Viruses, in the classicalform, being little smidgens of foreign DNA which are ableto get into the DNA of your own, hijack the processesthere, and make the cell function for its ownparasitic, vicious needs. And so you are changingthe starting step of how the central dogma of life. And thus you’re going to changeRNA and protein, all of that. In the ’70s, itbecame apparent there was one weirdo viralworld of viruses made out of RNA, this intermediate form. All sorts of people wereextremely upset about this and tried to ostracizethe scientists who came up with this andtold them there’s no way. But eventually, whatwas shown in Nobel Prize winning glory was there’sa class of enzymes.Enzymes– they pop up. A class of enzymes that couldtake the RNA information and turn it back intoDNA, viral information. And then it does its thing. Huge blow to the central. Here’s information runningfrom an RNA virus somehow being reversed back to a DNA form. And thus these arecalled retro viruses. Inserting the DNA, andoff they go from there. So this was a major blow.Everybody eventuallycame to terms with this. But it still is a minorfootnote 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 withwhat if something changes in the DNA? What if one of the bits ofcoding is coded incorrectly? What if we now have onour hands a mutation? And what we’ll focus onhere is classical realms of mutation, andgenetics, and how that plays out inclassical, gradualist models of evolutionary change, andthen see how all of that falls apart when you lookat what’s really going on.So starting off,what you can have– and again, this is goingto be a review for people with a background in this. Newcomers to this– hopefullythis won’t be going too fast. But broadly whenyou were talking about this worldof micromutations, for our purposes what wewill mean by a micromutation is when one letter in yourDNA sequence of information gets accidentally miscopied. Or it gets changed by radiation. Or it gets changed bysome chemical compound the environment. Some such thing wherethere’s a mistake and one letter in the DNAsequence comes up wrong.As I noted before,pairs of triplets. And there we’ve gotthree pairs of triplets. And what we’ve got hereis at the DNA level, a amino acid is codedfor by three base pairs. A triplet– three of these. Next amino acid coded for. Next one coded for. So what we’ve just raised isthe possibility of a mutation occurring, somethingchanging in one single one, and now asking whatare the consequences going to be in classicalrealms of genetics and evolutionary change? Broadly, you can getthree different versions of stuff going wrong. One is where oneof these letters– nucleotides, translating; notessential to have that down– where one of theseletters is accidentally changed into anotherletter– a point mutation. In some cases, point mutationsare of no consequence at all. How can that be? For this very simple reason,going through some math here, there are four differentpotential letters at each one of these sites. DNA comes in four differentletter types, letter flavors, four different types of bases.And thus, you can havefour different ones in the firstposition times four, times fourr– a total of64 possible three-step combinations of DNA letters. A possibility of 64of them, and you’re only coding for 20 amino acids. So you use up someof the 64 for signals saying stop or start, orthank god it’s Friday, or who knows what. But what you have, though,is a large redundancy. You have a number ofdifferent triplet sequences coding for the same amino acid. There’s redundancyin the genetic code. And in general, whereyou get that redundancy, where you get the differencesin three triplets, a couple of different triplets thatcode for the same amino acid, they’ll tend to differ inthe middle one of the three letters. That’s the easiest one to havea change where it doesn’t change the overall consequence of it. So you will tendto have redundancy. Each amino acid iscoded for by a number of closely-related triplets. So first possible type ofmutation– this point mutation where one letter isflipped to another.Potentially, this could beof no consequence whatsoever. If you flipped to a letterout of the middle one, which happens to leave youwith a triplet that codes for the same amino acid. In that case, you havea neutral mutation of zero consequence whatsoever. So that’s not a veryexciting mutation. In Some cases, you canhave a single point being changed where you windup with a different amino acid coded for. And that’s most typically, ifit’s a mutation in here or here rather than theboring middle one, you get a different amino acid. Is that the end of the world? Often not at allor only minimally because a lot of the aminoacids have similar feelings and ambivalences aboutwater, similar responses and similar shapes. It won’t be exactlythe same shape, but the protein willfunction somewhat the same.So you could have, in thiscase, a point mutation and most people wouldnot find the second line to be impossible to makesense of in the context of the first one. Or you could have apoint mutation which, by changing one letter,produces a different amino acid, and this one ismajorly different. This one has acompletely different set of attractions or beingrepelled by water. Produces a protein of a verydifferent shape and potentially a very different message. And shown here, just changingone letter in this case, one single point mutation,and you dramatically change the meaning of that. And I actually did thatonce in the grant proposal. Sort of the final paragraph–we have now accomplished x, y, and z with your moneyover the last five years.And no wonder itdidn’t get renewed. So in that case, you seea single point mutation of great consequence. So you can have oneof these letters, one of these nucleotidemistaken for another– entirely neutral, moderateconsequence, or major, disastrous consequence. Second way ofclassical mutations, the second versionthat it could come with is there is a deletion. One of the letters getslost in the process. And what you then get is a frameshift over to the missing spot there. And the D from herenow finishes up this. And what you cansee is it suddenly becomes dramatic jibberish.And it would continue that way. A deletion mutation,in classical genetics, is major league. It totally changes thecoding downstream from that. Third classical type–an insertion mutation. One where you now accidentallydouble the letter, and you’re frame shiftedin the opposite direction. Just as screwing up of meaning. Major consequences there. So you have pointmutations, which can have major consequences,or can have none whatsoever, and anything in between. You have pointmutations, and then you have insertion and deletion. The last two tend tohave big consequences. So all of this is built aroundone single base pair change. And all of this is builtaround thus one single protein changing its shape. And thus, this world ofmicromutation– single spots that are mutating–what this tends to do, and this is an importantconcept for what’s to come, what it does is it changes howwell the protein does its job. It changes the efficacyof that protein by changing theshape a little bit, by changing itdramatically, all of that.And we can see backto our lock and key where if, thanksto a mutation, this has a slightly different shade,it will fit into the lock slightly less effectively. It may stay in therefor a shorter time before floating off andthus send less of a message. On the other hand, if you’vegot a deletion insertion that dramatically changesthe shape of this, you will change how wellthis protein does its job. It won’t do its jobat all, because it’s going to wind up with acompletely different shape and not fit in there whatsoever. What we have here isa world of mutations which are changing the functionof one protein at a time. That ismicroevolutionary change, and that’s what we’re nowgoing to see played out.When can this make a difference? This can make hugedifferences when it’s in the realm where, thanksto a change in the shape, the protein is completelyout of business. Two examples– one whereyou take out the function of the preexisting gene. First one– thereis this amino acid. For our purposes, that’sgoing to derail us. For our purposes,there’s a chemical that occurs in the bodycalled phenylalanine, which has its uses. But you don’t wantthe levels of it to build up too high, becauseit can become toxic, damaging to brain cells, to neurons. And fortunately,there is an enzyme made of protein which turnsphenylalanine into something safer. That’s all we needto know about it. So you have a mutation in thegene coding for that enzyme. Not a fancy mutationto something. One of these categories–a classical, single spot point mutation. And what you got thereis an enzyme that no longer does its job. And as a result,this phenylalanine is not convertedinto the safer form, builds up, and lays wasteto one’s nervous system.And thus you have a disease–PKU, phenylketonuria. Very, very commongenetic disorder. And this is one where theoutcome is a small mutation that has completely knockedthis enzyme out of business– this enzyme whichwas able to turn the phenylalanineinto something safer. This is not a subtle outcome. Have untreated PKU, andyour reproductive success by the rules ofevolution is going to be real down near zero. This destroys the nervoussystem very rapidly after birth. So that’s dramatic. Here’s another dramatic one. And this one– anyonewho took BIO CORE, I always bring this one in asa big hormone crowd pleaser. But here’s aninteresting thing that can go wrong with any childyou might eventually have. You’ve got a daughter,and she’s doing just fine. And she’s growing up justfine, and things are terrific.And around age 10, or 11, orso, some of her classmates are beginning to reach puberty. That’s on the early sidefor the Western average, but it’s not outrageously early. Not a big deal. By about 12, statistically abouthalf of the girls in her class have reached puberty. 12 is about the Westernizedaverage 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, twoyears after that, she has still not reached puberty. So at that point, youtake her to a physician who examines her closelyand figures out what’s up. And at some point, thephysician is probably going to have pupilsdilate, 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 alittle talk afterward, and inform you thatyour daughter has not started menstruating, hasnot reached puberty yet. Your daughter has not startedto do this because you don’t have a daughter.You’ve got a son. This kid here forthese last 14 years has actually beenmale, not female. You have what is called– no,I’m not going to tell you it. OK, it’s called– especiallysince it’s in the handout already– anyone want toguess what it’s called? It’s called TFM, TesticularFeminization Syndrome. And you wind up with atesticular feminized male. These are individuals who,genetically, are male. At the level of chromosomes,that XX and XY business, these are individualswho have testes. Testes way up in theirstomach or whatever, never descended down. These are people whosetestes make testosterone. Testosterone out the wazoo. Tons of testosterone. Enough testosterone to putlike antlers on your testes, or something. That much testosterone. And nonetheless, you’regetting a female phenotype. You are getting a femaleexternal genitalia. You are gettingfemale everything. Yup, question? Sorry, is that differentthan androgyne insensitivity? No, that’s thefancy term for it.And you’ve just given awaythe punchline, you creep. [LAUGHTER] So they figured out inthis 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 ofthose simple little classical mutations. And what it does is it changedthe shape of the androgen receptor, thetestosterone receptor. And at that point it doesn’tmatter how much testosterone is floating around, those targetcells are not going to listen. This is consequential. This is a major consequence. This is one of changinggender phenotype, and there is a long and attimes absolutely appalling history of what has beendone with individuals who have TesticularFeminization Syndrome, what counts as the medicallyappropriate intervention.There’s some horrifyinghistory there that could be straight outof the first lecture in terms of some notions of what countsas normal gender behavior. Another version ofthis– this one’s a little bit more subtlebecause in this case, it’s not wiping out thefunction of an enzyme. It’s just making it a little bitless effective at what it does.And this has to dowith a disease that is found in two differentpopulations, slight variants on it. One is up in the DominicanRepublic, in the mountains. The other is in themountains of New Guinea. Interesting similarity there. In both cases, some fairlyisolated, inbred populations. So that has geneticswritten all over it. But in these cases, thereis a problem with enzymes that make testosterone. So this is a whole other world. Instead of the enzyme, insteadof the proteins, and thus the gene somewhereback there, that code for the receptorfor testosterone, the receptor that respondsto this messenger, here instead it’s back wayup there in the testes.A bunch of these enzymes, whichgo through a bunch of steps and make testosterone,biosynthetic enzymes there. Proteins, genes, once again. So you’ve got a mutation in oneof those critical, biosynthetic enzymes. And It’s not a huge one. The shape is a little bit off. Its efficacy, theeffectiveness with which it makes testosteroneis down a bit– and actually it’sdown a lot– so here’s what you wind up getting. You get an individualwho before puberty has extremely lowtestosterone levels, even far lower than you would seein prepubescent males in most cases. Someone who’s genetically male. Someone who never saw awhole lot of testosterone during fetal life, waybelow the threshold for the testosteronehaving any effects. So the person is bornphenotypically female. Female in appearance. Female in external genitalia. And not internal– back to thosetesticular feminized males. What you find there is avagina which goes nowhere, because there’s no ovarieswaiting somewhere above that.There is the testes. But the externalgenitalia is just fine. What I think these days isthe most common medical ethics advice and what’s done with thatis the physician explains what it is and says, Forall practical purposes, you have a daughter whois perfectly healthy, who’s going to have along, happy, healthy life, and simply cannot reproduce. That’s the only consequencethat’s relevant here. And there’s been awhole other world of reconstructive surgery, andall sorts of very interesting, horrifying history. So back to this one. Because of the extremelylow testosterone levels, because at the time oflife when there’s not a whole lot of testosteronearound in the fetus, in a young male, and nowit’s below the threshold for causing anything.Along comes puberty, and thanksto a whole bunch of changes in the brain, signals go outso that testosterone levels now come roaring up into the usual,impossible levels in the males. And what happenshere is the levels don’t go up as muchas they should, because that enzyme is alittle bit on the slow side. But they go up enoughto pass threshold for beginning to have an effect. And somewhere rightaround puberty, this individual changes sex. This individualtransfers, transmits, jumps ship and goesfrom female to male as a result of these androgeniceffects suddenly coming in. It’s not a completeswitch there, but it’s somewhatof a transition. This is bizarre. Again, this is notsomething subtle. This is somethingchanging completely here. And again, one single mutation. And in this case, noteven a mutation wiping out the function entirelyof some protein as in PKU or TesticularFeminization Syndrome. But now you’ve gota protein that’s just working differently,slowly enough that you get this very different picturepopping out the other end.What’s most interesting is youhave this intersection between molecular biologyand the bio-, endo- consequences of thismutation, all of that. And the cultural contextof it, apparently in both of thesepopulations, 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 ofthe whole process and cultural accommodationto interesting biology. One final exampleof where you can have a classicaltype of mutation, and another version ofa very mild difference. And in this case, it isnot a very mild difference producing an overt disease. In this case, it’s justproducing something that probably differs in youfrom the person sitting next to you. Which is, you have aneurochemical system, a system of chemicalmessengers in your brain. If this is new stuff, hang on. It will all be explainedin a couple of weeks. But this is a class ofneurochemical signaling that has somethingto do with anxiety.A chemical messengerwhich decreases anxiety. And we will learn plentyabout that down the line. And there’s this regular class. They’re known collectivelyas benzodiazepines. Do not panic if you’ve notheard that word before, and certainly do notattempt to spell it right, because it’s not possible to. So benzodiazepines. There are syntheticversions of benzodiazepines which people mighttake when they’re feeling anxious likeVallium, like Librium. Vallium is the syntheticbenzodiazepine. So benzodiazepinesare protein, and they have a particular shape. And you guessed, it there arethus benzodiazepine receptors, which could do that whole lockand key deal going on there. And what you haveare differences, small, single point,in this case not mutations, but simplydifferent versions that one letter can come inin the DNA sequence specifying the benzodiazepine receptor.These are not mutations. This is just normal variabilityis one particular spot can specify two or threedifferent amino acids that function roughly the same. So that you’re changing somewhatthe shape of the receptor, and thus changing somewhat howlong the benzodiazepine stays in there, and how longthe signal is sent. And it’s all very subtle. And what does thisbegin to explain? Individual differencesin levels of anxiety. It’s only one of the gazillionways of explaining it, but it’s part ofthat picture there. Here we haveindividual differences. This explained a veryinteresting finding. For decades, people often triedto breed rats, different rat lines for differentbehavioral traits.And it makes itvery useful models. There are alcoholism prone rats. There are rats that havebeen bred for being smart, for being not as smart atspatial maze stuff, et cetera. And for years, there’dbeen a number of rat lines that have been bred thatwere either high anxiety or low anxiety rats. Very useful for understandingthings like– what are they’re useful for? I don’t know. They’re just coolto have around. Very useful for understandthe effects of stress, or things of that sort. So finally, modern era ofmolecular biology comes in, and those high andlow anxiety strains differ in the shape of thebenzodiazepine receptor in many of these cases. Again, tiny little differences. So what we’ve got hereis classic old genetics at the molecular level. These tiny little changes inone single base pair at a time– point, deletion, insertion.A world in which it may ormay not change the shape. Where it could change itdramatically and produce some pretty exciting,dramatic diseases where you wind up witha different gender than your chromosomes say. Ones where you get moresubtle differences. You change gender atyour 13th birthday. Or ones where we’rejust for the first time beginning to look at theindividual differences that flow out from stuff like this. Not them and their disease,but the individual variability. All of this is in therealm of single base pairs being changed. What all of thisnow allows us to do is translate this worldof mutational changes into what does this looklike evolutionarily? What does this look likein terms of explaining patterns of evolution? And you will know exactlywhere this goes right now.This helps explainthe classical, the gradualist picture oflittle bits of change at a time. Little bits because you’ve gotone protein which now works a little bitdifferently, and thus you get to ask asociobiology question. By having testosterone havinga little bit more of an effect or a little bitless of an effect by way of molecularchanges in this receptor, is that going to increasethe number of copies of genes that individual has? Is it going todecrease the number? How’s it going to fit intoall of last week’s science? And you will know exactlyhow that drill will run. Oh, if thanks to onesingle base pair changing, you now have a receptorwhich functions in a slightly different way, which makesthis individual 1.5% more fertile than everybody elsethat they’re competing against, you just wait longenough and come back, and everybody inthat population is going to have thatdifferent 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 adaptivedifference somehow or other. There there’s asmidgen of advantage, thanks to a slightlydifferent shape. And thus we have selectionchanging distribution over time. The smidgen moreeffective version will become more commonin the population. And what’s alsointrinsic in that is that these are slowlittle steps of change. This is gradualism. So gradualism is absolutelycommensurate with everything we got last week built aroundadaptation, competition.Every little bitmakes a difference because 1% difference innumber of copies your genes. Run it enoughgenerations, and that’s going to be a bigdifference, and all of it changing in a verygradualist, incremental way. This has popped up ina number of domains and could be really useful,because it allows you for one thing to traceevolutionary history by looking at the changes ofsingle base pairs. And that’s allowed for lookingat one really interesting gene, which we may talk about downthe line, a gene called Fox P2. Fox P2 has somethingto do with language.Fox P2 was first identifiedand a family, all of whom had some sort of languagecommunication problem. And people to this dayargue whether it was mostly about coordinating themotoric aspects of speech or was it something aboutgrasping the symbolic message aspects of language,all of that. In any case, a mutationwas found in this gene, and a whole cottageindustry has emerged since then of studying Fox P2.Because versionsof Fox P2 occur all throughout the animalkingdom– in birds, and rats, and non-human primates,and all sorts of things. Fox P2 popping upall over the place. And in all thesedifferent places, it’s got something todo with communication. It’s got somethingto do with bird song. It’s got something to do withrat ultrasonic vocalizations. Rats are constantly jabberingat each other in a range that we can’t hear. And Fox P2 has somethingto do within all of those. And different versions of Fox P2in all these different species. And what becomesmost pertinent is when you look atthose differences, you will see tinylittle differences in this tree across allthese different species. One base pair differencebetween rats and mice. One base pair differencebetween 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 avery short evolutionary period.What this suggestsis no wonder this is producing some verydifferent stuff than these guys. A very different gene. And a very differentgene, people now have been ableto back calculate due to a series of singlebase pair changes somewhere in the last quartermillion years or so. And that makes a difference. Totally cool,unsettling experiment that was done a fewyears ago, which was some people taking thehuman version of Fox P2 and knocking out a mouse line,knocking out their own Fox P2 and sticky in the human versionand seeing what happens. And it was very interesting.They immediately sing the themesong from all the Mickey Mouse cartoons. Ha, can they prove that? OK, what you see is you’vegot more complex types of ultrasonic vocalizationin these mice. That’s really interesting. And there’s yearsof stuff to sort out what’s going on with that. For our purposes, themain thing is here you have wound up with a verydifferent world than chirping, and buzzing, andbarking, and all of that. And you wind up with avery different version of this gene where you cantrace out how many amino acid changes it took. And every step ofthe way, you were having some gradualist process. What also thisallows you to do is look at a footprint, an echoof what the selection was like. Important concept here. So back to that business. There’s 64 different waysof coding for amino acids, a couple of them are justinformational, stop messages, and stuff. There’s about 60 different waysof coding for 20 amino acids. So on the average,each amino acid could be coded for inthree different ways.So suppose you throwin a random mutation. And of those, what you find isof the 60 possible mutations, 40 of them will not causea 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 ofmutations, and you wind up seeing 2/3 are neutral interms of their consequence, and 1/3 third actually causes achange in an amino acid, that’s telling you it’s happeningat the random expected rate of mutations popping up that areeither consequential– changing an amino acid– orinconsequential– just coding for a different versionof the same amino acid.Now suppose you finda gene that differs. And you look at the waysin which it differs. And 99% of the basepair differences over the courseof this 5 million base pair-along gene,99% of the differences make for a different aminoacid than beforehand. In other words, at muchhigher than expected rate if this was a random process. What is this an echo of? Of very strong selection. Of very strongly advantageoustraits driven by these changes. Term used– this wouldbe a mark of their having been positiveselection for this trait. In other words, the changesthat it has gone through over the gazillionyears has not been just by random mutationalrates of neutral. And remember, every aminoacid is coded for three ways. If 99% of themare consequential, there has been some major, hardass selection going on there.Alternatively, ifyou find a long gene with a whole bunch of mutationsand 99% of them are neutral, make no change at all,what does that tell you? This protein’s functionyou do not want to mess with in the slightest. Even a minor change in thefunction of it, and you don’t pass on copiesof your genes. This would be stabilizingselection, negative selection, strong selection to make surethat this gene and its function downline as the proteindoes not change. When you look at the number ofchanges, the burst of mutations over the last quarter millionyears or so that differentiated Fox P2 in humans fromthese other species, it’s almost entirely evidencesof positive selection. This did not justhappen by chance. Every step of coming upwith these new versions, these new amino acidsin the sequence there, clearly were ones that werepositively selected for.A lot of selection broughtabout this huge difference. OK. So that begins to givethe sense here of how these little changes can occur. At this point, wehave to go through one of the all time confusingthings in genetics out there, which is something twofactoids and two soundbites that seemingly totallycontradict with each other. You share, on theaverage, 50% of your DNA with a full sibling. You share 98% of yourDNA with chimpanzees. What’s up with that? That seems a littlebit unexpected. And those are two soundbitesthat everybody knows.Everybody knows it goesthrough like basic Mendel. 50%, 100% with an identicaltwin, 50% with a full sibling. You know that songand dance by now. And meanwhile, one ofthe great soundbites of our evolutionary history, andthe mark of evolution, and what in hell are youcreationists thinking, is the fact that, oh, humansshare 98% of their DNA with chimps. This doesn’t make any sense. One minute here to be spent onjust clarifying that one that is not contradictory at all. Genes specify byway of proteins– and now this is takinga bunch of leaps down there– traits, aspects. Gene specify, to betotally simplifying here, genes specify forantlers, for dorsal fins, for petals, and pistilsand stamens, for kidneys, for– it’s totally simplifying.So right off the bat, you willhave some genetic similarities between two differentspecies in that both of them will have genes thatcode for dorsal fins. You’re thinking about twodifferent species of whales. So they share genescoding for dorsal fins. Whales have dorsal fins. Neither we nor chimpanzeeshave genes for dorsal fins. Meanwhile, we have genescoding for a pelvis that has a certain shapewhich either in chimps predisposes towards beingable to walk bipedal for certain strengthsof the length of time. Us as well. You don’t find thesegenes in apple trees.They don’t have pelvisesthat are shaped like those, so they don’t have. So when you look at thehuman and the chimp genome, 98% of the genes code forsimilar kind of things. We share with chimpsan absence of genes for antlers, and trunks,and tusks, and wings, or serve who knows what. And we share allsorts of other genes in common having to do withour shared immune systems, et cetera, et cetera. So 98% of the genes codefor similar types of things. So that’s where we get the98% similarity with the chimps from. For each one ofthose genes, it could come in a couple ofdifferent flavors, a bunch of different flavors. And thus asking not to doboth you and your full sibling have a gene foropposable thumbs, do you and your siblinghave the same type of gene for opposable thumbs? So suddenly that’sa different world of variants oneach type of gene.So when talking about theamount of DNA shared in common, the genes shared in commonwith other species, what you’re talking about arethe types of genes coding for the types of traits. When we’re talking about,from last week’s notion, 50%, 25%, 12.5%, onebrother and eight cousins, what you’re talking aboutare different versions of particular genes. Important clarification. So final thing here before thebreak, which is once again, notice with these models,these point mutations, where you can get slightdifferences in function.And thanks to a 1% differencein fitness and number of copies of genes, you getthese gradualist changes. What’s intrinsicin that, and where we get the politicaltheme coming through is, thus there’scompetition everywhere. In terms of theevolution of behavior, the evolution of species, everylittle bit of genetic advantage will play out insome competitive way in some littlebit of an increase in reproductive success. OK. Whoa, there’s a lot ofApples there lit up. Well, that wasn’t very subtle. Let’s take a break. Whoever did that. OK, a five minute break. Are you slightlymore fit by the rules of your population’s naturalselection, sexual selection, whatever? Even if that givesyou a tiny advantage thanks to this tinychange in this tiny gene, enough generationsgo by, and that trait is going to becomemore prevalent.Final point there intrinsic inthis, is if every little bit of difference matters interms of fitness and gene distribution withinthe realm of behavior, every little bit ofcompetition matters. A very, very intertwinedpolitical, philosophical stance in gradualism as itapplies to evolution. So that’s been sittingthere around forever. And in the 1980s, suddenly avery different model emerged. And this came fromStephen Jay Gould, who we heard about the other day. Stephen Jay Gould,and the person, the poor schnook whowas always lost in this, another evolutionary biologistnamed Niles Eldridge who somehow did not quite havethe press that Stephen Jay Gould did, so he is lost tohistory except for people who know what he’s up to. And he’s an amazing scientist. But Gould and Eldridge came upwith a very different model. And I alluded to it the otherday and drew it right there. And their notion was thatgradualism is nonsense. There are not gradualisticincremental changes. Evolution is not being drivenby small gradualist changes. Instead, what theirmodel was is that there’s long periods of nothinghappening, of stasis.Long periods ofnothing happening. If there’s changes in DNAsequences thanks to mutations, they’re not consequential. Or if they’reconsequential enough to change the fitnessof one organism 1%, that’s not going tomake a difference. Most of the time, nochange is occurring. And when it does occur,it is in incredibly fast, explosive periodsof change followed by a new period of stasis. Evolutionary change comes instep functions rather than smooth gradualism. Long periods of stasisfollowed by dramatic jumps of evolutionary changein short periods of time. Thus, they calledthis the notion of punctuated equilibrium. Long periods ofequilibrium and stasis punctuated by periodsof very rapid change. And as I mentioned the otherday, Gould was a Marxist and felt that Marxist’ssort of stance was running through all of theways to think about genetics. And I don’t now what’sup with Niles Eldredge, but that was thecase with Gould.And when you lookat this model, this is like classicallyfitting with stasis, and revolutionary change,and dialectical materialism, and stuff like that. The last sentence, I haveno idea what I just said. But apparentlythat’s got something to do with that stuff. And once again, we seein a very different way, a political theme runningthrough a different worlds view of what evolution isabout– punctuated equilibrium. OK, so where did the ideaof punctuated equilibrium come to these guys? Mainly because Gouldwas not a biologist. He was certainly not anevolutionary biologist. What he was a paleontologist. He studied fossils. He studied the history,the evolutionary history of fossils. And apparently, liketotally separate of his largetheoretical models, he was like the world’sexpert on the evolution of some Caribbean snail shellover the last 10 billion years or something. He’s one of thosepaleontologists who traces lineages of evolutionarychange over the course of time with fossils, fossilrecords, as the readout. So he’s a paleontologistslash geologist in some ways.And when you do that, you noticesomething, which is you’ve got gaps in the record. You’ve got yourfamed missing links. You have gaps in yourevolutionary record there of what fossils look like. And you’re measuring sometrait or other in these snails, or trilobites, or whateveryou’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 perfectlygood gradualist model. And what Gould wouldnotice is as the field got more and more information,more and more intervening steps on a lot of thesefossil histories, they would start tolook more like this. And every now and then,you would see something like this in between.And from that, that beginto suggest to him this model of punctuated equilibrium. Most of the time, as assessedby the fossil record, nothing dramatic is happening–long periods of stasis. And what allowed this to occuris that for some fossils, you have incredibly detailedevolutionary history, where you can begin to fill inlines, and they wind up looking punctuated in this way. So out of him comesthis whole theory that it’s all about punctuatedequilibrium rather than gradualism. Right off the bat, what arethe consequences of that? Little geneticchanges don’t matter. Competition driven by the notionof little changes mattering aren’t actually occurring. In model [? saying ?]most of the time, all of the notions of if you figureout the right kid to kidnap when the big guyis coming at you, and you’ll leave morecopies, and figuring out exactly who to beinfanticidal to, all that, it’s not going tomake a difference in terms of gene distribution.Evolution is notbeing driven by that. And out of it came thisvery strong indictment of the sociobiologicalview of what you’ve got there is a world where it’sall about competition, where it’s all about hierarchy, whereit’s all about domination, where it’s all about that. Hey, isn’t that interestingthat that’s exactly the sort of worldthat these folks live in who are benefiting fromthis, who started this theory? Very different notion here. Competition, selectiveadvantages, all of that, most of the time,nothing’s happening. So not surprisingly, allof the evolutionary types from last week didnot like this one bit.And this was anattacked left and right in some extremely valid ways. First one, first form of attackis a very simple problem there, which is that you have twodifferent disciplines happening here. You get apaleontologist, and you get a evolutionarybiologist, and they’re functioning in completelydifferent universes. OK, stomach problems. And they’re functioning incompletely different universes there. What counts as fastfor a paleontologist– these are tens of millionsof years going on.Whoa, incredibly fastevolutionary change going on there. That’s like 100,000 years. That’s like, are you kidding me? Said the biologists. The ones who study onegeneration at a time. That is asinine. That is ridiculous. This is themimposing models where this has absolutely nothing todo with how evolution actually works. These geologists getcompletely thrown off, and these paleontologistsled by Gould, simply orders of magnitudedifferent scale of time. Yeah, maybe in some roughapproximation of what they look at. But they’re notstudying evolution, because they’re not biologists. Next critique– the nextone made lots of sense also. Which was, you’re not justan evolutionary biologist, but you’re one who thinks aboutthe evolution of the brain, or the evolutionof skin melanism, or the evolution of eyecolor, or the evolution of how many chambers in yourheart you’re going to have, or the evolution ofany of these things that will leave norecord whatsoever in the paleontological record.Because allpaleontology is about is shapes of stuff– fossils. Fossils do not tellyou what kind of brain was going on inside that fern. Fossils do not tell youanything about internal organs. Fossils do not tell youanything about behavior. So at this point, all ofthe evolutionary folks of the school from lastweek attack and say, Yeah, what do they expect? They’re studying the mostboring possible things– the morphology of organisms. Ooh, just becausethe fact that humans, over the last like millionyears or so, have not evolved getting rid ofthe large trunk and roots that they haveduring springtime, and now they don’t have them. Oh, that morphologicalchange didn’t occur, so obviouslythere’s been stasis. Give me a break. What is interestingabout evolution and evolutionarychange, paleontologists can’t pick up, becauseall they can study are forms, morphology.So that was a bigattack on these folks. So you’ve got theGouldian folks, the punctuatedequilibrium people, saying when you lookat the fossil record, it’s not gradualism. And we’ve got somereally complete ones. And to this day, themajority of fossil pedigrees where there arevery, very complete records, show patterns ofpunctuated 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 thatthey call a very rapid evolutionary change.Their time span iscompletely crazy, and they can’t study theevolution of anything that’s interesting becausethey study fossils. But in lots of ways,the best rebuttal, the one that mostgot at these folks advocating punctuatedequilibrium, would be the gradualists saying,Show me a molecular mechanism. Show me some way in which youcan get rapid change and then long stasis. Turn that into modernmolecular biology. Which is, occurringtwo minutes after the microevolutionary peoplewere trashing the folks from last week saying, You needto look for the actual genes. It’s not enough justto make up stories.And once these folks hadassimilated what evolution looks like on the geneticlevel, mutational level, micromutational changes,they loved genetics. They loved themolecular end of it, because they could now turnaround to the Gouldians and say, Show me the genes, andshow me the mutations that will account for stuff like this. Because you can’taccount for it. Because we all know classicalgenetics and mutation, you don’t get that. You get gradualism. So this was a period of enormoushostility between the two camps.And the gradualists called thepunctuated equilibrium people evolutionary jerks. Ha ha. And the punctuatedequilibrium people called the gradualists creeps. So ultimately, they allgot along wonderfully because they were so witty. But what you had wasenormously hostile camps. And really quitehostile because all sorts of implicationsspreading beyond like how fast theshape of this seashell was going to be evolving. And when they firstcame on in the ’80s, all of this controversy, thepunctuated equilibrium people didn’t have a wordto say with the show me the molecular mechanisms. Show me mechanisms for mutationthat will produce rapid change. And everything thathas occurred since then in the world ofmolecular genetics that has been most striking hassupported punctuated models– ways in which themicromutational, microevolutionarystuff of an hour ago is not what’s going onan awful lot of the time. Starters– so simpleclassical model. What we’ve got hereis a stretch of DNA. And this boxsymbolizes a sequence of DNA coding for one gene. And right next toit, once it finishes, one of those stop codon,stop triplet signals, right after thatcomes the stretch of DNA coding for the nextgene, and the next gene.And this is what DNA is about. It’s the sequence genes there. And what you wouldobviously then get is this arrow having thisintervening step of that RNA stuff, but eventually producingan amino acid that produces a protein of this shape. And this is the proteincoded for by this gene. This, this, and so on, andthat’s exactly how it works. That’s the structure of DNA. Then, though, people beganto find that that’s not the structure of DNA. And what you beganto get instead was something vastlymore interesting. Which is that,for starters, when you look at codingfor one single gene, it’s not necessarily codedfor in one continuous stretch of DNA.In other words, it’sbroken into little pieces. And you will havea stretch of DNA coding for the firstthird of the protein, and then a bunch of DNA that’sgot nothing to do with it. Stay tuned. Then coding for the next third,coding for the next third, that the gene was broken upinto separate coding domains. And the term that wasgiven for these was these were called exons. And the in-between boringstuff were called introns. And this was a major findingwhich made no sense whatsoever. Because how are you going toget from this to then having a protein which has itsnormal sequence and shape where this part was codedfor by this exon, Exon One of this gene, and this fromExon Two, this from Exon Three.That’s a completelydifferent world of stuff. How are you going to do that? Because you’regoing to meet an RNA that’s going toencompass all of this, and that’s going to code forsomething completely different because you’ve got theseintrons in between there. And people thenguessed something had to exist which wassoon discovered– enzymes called splicing enzymes. And what they didwas exactly what you need to do to solve this. Which is at the RNA level,the splicing enzymes would come along, and they wouldsnip out the part corresponding to here. And another wouldsnip out there. And another one asan enzyme catalyzing would stick thistwo pieces together. And thus you have this. This utterly bizarreworld in which genes, the vastmajority of them, are not coded for in acontinuous stretch of DNA but instead are broken upinto these separate exons.And then you need thesesplicing enzymes to clip out the boring in-betweenparts, the introns, stick them alltogether, and you’ve got your functional gene. Weird. OK, but that’s howthey work though. I know shortly afterthese were discovered that one of the giants inthis business, guy named David Baltimore who gotthe Nobel Prize for some of the work on thatreverse process of RNA viruses turningback to DNA, he was the first to really appreciatethat what you’ve got here is a potential for alot of information. Because of, and I thinkhe was the first person to introduce this word intothinking about it, because of the modularconstruction of genes.Because genes come inthese separate exons. What does that beginto allow you to do? Very important stuff. OK, so we have thesame structure here. And we have a gene codedfor 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 orone of the first to appreciate was that you could wind upwith something different there as well. You could, for example, createa very different protein– one consisting onlyof 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 thiscombinatorial possibility of cranking out a number ofdifferent ways of putting together– seven differentways since you can’t transcribe this gene so that there’sno transcription– seven different ways of combiningthese different exons. Seven differenttypes of proteins you could generatefrom the same gene. This was not accepted witha whole lot of pleasure by the old guard. Because intrinsic in the knowthe DNA sequence specifies amino acid, proteinshape, protein function, intrinsic in that is onegene specifies one protein.One gene only specifiesa single protein. One protein is only specified,coded for, by one gene. And suddenly, thismodular business allows you with one gene togenerate seven different kinds of proteins. For starters, how could thatpossibly work that way just on a nuts and bolts level? All you need aresplicing enzymes that work a littlebit differently in different parts of the body. One that will splicethis off and is attached to an enzyme thatwill degrade this, while the splicing enzymehere– and what have you just produced? You’ll get this one.Coupling of splicing enzymeswith degradative enzymes, and suddenly you’vegot a means to have tissue-specificexpression of genes. The same gene willproduce different types of proteins in differentparts of the body because of splicing enzymesworking differently. Then, just to confusethings even more, people began to note that therewould be some splicing enzymes and genes where they wouldsplice at a different point. And you would now have agene with A, and A prime, and other splicing enzymesthat would cut at other points. One single sequence ofDNA generating all sorts of different types of proteinsin different parts of the body, at different times of life,under different circumstances, in different individualsin different ways. Suddenly, there’s a lot moreinformation floating around in there. So that was a huge, hugebreakthrough in the field, understanding this modularbasis of gene construction.And for our purposesright now, what the most interesting consequenceof that is is it’s no longer one gene, one protein. One gene instead cangenerate all sorts of different types ofproteins, different settings, different circumstances. The next thing that wasintrinsic in this model that’s now been trashed of onecontinuous gene, one continuous gene– what we justfigured out that instead you can have the introns,exons, all of that. The next thing that went downthe tubes was looking at, Well, how much of DNA isactually devoted to coding for amino acids? And the answer wasobvious, like 99.9% each. One of these would just haveto have a stop codon, a stop signal at the end. And otherwise, this was just acontinuous flow of information once you have factoredin these interim things. OK, so they’repart of this gene, but immediatelystarts the next one. The next majordiscovery was one gene would very rarely startimmediately after the next one. There would be longstretches of DNA in between that didn’t code for aprotein– 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 tomake sense of this. And when people satand started actually like doing the numbers,out came a number that knocked people on theirrears it was so flabbergasting. 95% of DNA is non-coding. 95% does not code for agene specifying a protein. In other words, in betweenhere on the average would be a stretch of DNA19 times the length of that, or whatever themath winds up being. And suddenly calling that stuffjunk DNA starting to see me a little bit tenuous,because 95% your DNA just can’t be packingmaterial for the whole thing. It’s got to be doing something. And during that period,became sort of the insight into this that all theintervening, non-coding stuff was– what was that? That was theinstruction booklet.That was the instructionbooklet on when to activate these genes. That was the on and off switchesfor turning genes on or off. Upstream in thenon-coding domain just above a particulargene sequence would be the information forwhen that gene is activated. Activated when it makes RNAinto protein, all of that. And upstream of that arethe on and off switches. Implication right there off thebat, which is Crick was wrong. DNA sequences are notthe starting point of the central dogma of life. And DNA is the rule-giverand all of that. DNA is being regulated. Genes are being regulatedin some other way. And where 95% ofDNA is being devoted to regulation of the genes. DNA has no idea what it’s doing. DNA is a readout that’sunder the control of all sorts of other factors. And out of this emerged thereally, really important concepts of regulatorysequences upstream from genes. So here we have a long string ofDNA coding for this gene which happens to come in two exons. And it is like thespace between the galaxy how long the non-coding is goingto go on until the next gene is back there.So what’s goingon in the stretch just upstream from this gene? Things that weresoon being called stuff like promoter sequencesor repressor sequences. Things, stretches of DNA,that coded for switches rather than coding for protein. That coded for thingscoming into the neighborhood of the DNA and binding to someof these promoter or repressor sequences, and then turningon, or in some cases off, the transcription of thatgene, the process of the gene generating proteins. You would havepromoters sitting there. And this is overly literal. It would be justa sequence of DNA, which thanks to thatsequence would have a certain subtle microshape. And along wouldcome something which happened to be able to fitperfectly into that spot. And if, and only if, thismolecule– usually a protein– bound to thispromoter, suddenly that would trigger a wholebunch of enzymes to come in, which would startthe 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 turnthese switches on, or off in some cases, were sooncalled transcription factors. Totally critical conceptin there– the fact that vast stretches of DNAdon’t code for anything. Instead, they have theinstruction booklets. Here’s how you turnthis gene on or off. Send in thismolecular messenger. Send in this type oftranscription factor. And if it showsup, binds to here, you now activatethe transcription of this gene, the processof turning that gene, making proteins derived from it. This is where theinformation was. And this is not DNAknowing what it’s doing. This is outsideregulators coming in. So immediately,that has made life a whole lot more complicated. Next complications– youcould have different genes scattered all overthe place that would have the samepromoter upstream of it. What would that mean? In comes a transcriptionfactor, and it doesn’t activate thetranscription of one gene producing one protein. It activates the transcriptionof a whole bunch of them. In other words, nowsuddenly we have messengers that could trigger activation ofgenetic networks, entire arrays of proteins being produced allwith a functional similarity driven by the factthat all of them have the same promoter upstream.So suddenly, youhave the possibility of the same promoterbeing upstream regulating more than one gene. That is the general rule. Flip side of it, anygiven gene, for example, could have a bunch ofdifferent promoters responding to different types of signals. So now, suddenly,you have this gene which can be transcribedunder this circumstance, or under this circumstance. And both are ways of turningon activation of that gene. And in this circumstance,the same promoter is found in Genes A, B, andC somewhere at the other end of the chromosome.And in this case,this promoter is found on Genes D, E, and F downthere– different networks. So the same sort oftranscription factor logic– once you can have differentpromoters upstream of a gene, and once you can have thesame promoter upstream for multiple genes, yousuddenly have the ability with differenttranscription factors to activate entire networksof gene expression. OK. So what this hasallowed you to do is completely trash this notionof DNA knows what it’s doing. DNA is just the readout. And who knows what’s going on? Whatever is controllingthe transcription factors. Whatever is causingthem to do their thing. And this could be aworld of influences. And to be absolutelyaccurate, this requires introducingthe word environment. This is environmenthaving something to do with genetic effects. This is going to be away in which environment is interacting with geneticelements, environment determining which ofthese are doing what. What would that look like? Sometimes environmentcould be the environment in the rest of this cell.So you’ve got your DNAthere, and your structures, and all of that,and the promoter. And we could do that by now. And something is occurringinside the cell which activates some transcription factor. And then you go change agenetic event going on in there. The cell is runningout of energy. There’s various waysto construct sensors. In other words,evolution has come up with a bunch of different waysin which cells can respond to signals of lowenergy, and that will activate some transcriptionfactor which will go and bind to a bunch of promoterswhich produce proteins involved in taking up more energy fromoutside the cell, transporting in more, using energymore efficiently. So what we have here is anenvironmental regulation of genetic effects.Environment– the rest ofthe environment of the cell. The DNA doesn’t knowwhat it’s doing. The gene doesn’tknow what it’s doing. Events going onelsewhere 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’snow events going on outside just this one cell. In this case now, you’vegot the cell with it’s DNA. And now, instead, youhave a chemical messenger coming from somewhere else. And binds to its receptorlike a lock and key. And as a result ofthis binding, something happens here, whichdoes something here, which does somethinghere, which eventually activates some transcriptionfactor, which goes and does its thing.Now we have gene expressionin the cell being regulated by the environmentsomewhere else in the body, somewhere else there. What would be a classicexample of that? This is what a wholelot hormones do. Hormones go floating around. And they affect cellseverywhere throughout the body. By definition, a hormone is abloodborne chemical messenger. So you could secretesome hormone out of the top of your ear,and it will affect things in your little toe. Very far flung. Hormones will bind to theirreceptors, lock and key. Most hormones areprotein in nature, and trigger what’s calleda second messenger cascade. Jargon, don’t worry about it. Just get it conceptually. Activate sometranscription factor, deactivate some othertranscription factor.And suddenly, events goingon 14 counties over there are regulating what proteinsare being made in this cell. What would be anexample of that? Testosterone, for example. Testosterone secretedfrom the testes, traveling far and wide andeventually binding to androgen receptors on muscle. And what happens there isthrough a pathway like this, turning on the activation ofgenes, coding for proteins, all sorts of structuralproteins that will make that muscle cell bigger. Your muscles are gettingbigger thanks to testosterone.Look at this. Events occurring a gazillioncells away in the testes, a messenger here, determiningwhat gene expression, what gene activationis happening. Sometimes, though,the environment could be completelyoutside the organism. Like that. Sometimes you can have,for example, a messenger from the outside world. What sort of messenger? A scary sight. A bit of sensoryinformation or whatever. Olfactory. Olfactory– supposesome odorant comes in. A pheromone– you’re female ratwho has recently given birth, and the pheromonesfrom your babies come floating in andbind to receptors here. Very similar principle, again. And that causes them to activatesomething, activate something, and some cell down there. And eventuallythere is a cell here that controls somemuscles, and it makes your eyesdilate because you love the smell of your baby.And you’re just– I don’t knowif rats have their eyes dilate. But humans will in manyother circumstances. Aha, how do you do that? You just changed some structuralproteins that did this or that. Or suddenly thisfemale is making some hormone like oxytocin asa result of smelling her baby. What have we got here? We got something going on inthe outside world regulating what’s going on with the genes. Genes as the centraldogma of life, as the informationgiver– nonsense. Events going on inthe rest of the cell, the rest of the organism,the rest of the universe, are determiningwhen genes activate. So what we see now is amuch more interesting world of regulation ofgene expression. First, the modularability for one gene to generate all sorts ofdifferent proteins, which brings up an issue aftera while is, does that count as one gene? And people argue over that. And because of this 95%regulatory sequence business, the most interestingstuff going on with DNA is not what the protein islike, not what the protein does, not how well theprotein does it, but when it does it,in what contexts.And what we’ve justintroduced are if then clauses into this whole world. If you get a signal that thereis low glucose in the cell, then you begin to make proteinsrelated to glucose uptake. If you have the smellof your child come in, then you activatethis [? path. ?] It’s not changing whatthe protein is like.It’s changing context. And I think what we will seeis context is vastly more interesting than whether thisprotein is a little bit more like this, a littlebit more like that. If it is being expressedinstead at a different time, in a different place,in a different context, that’s much more interesting. So what does thatset us up for here? Now beginning to see theorganization of this. By the way– 95%,this whole stuff here. I don’t know whatpercentage is accounted for by identified promoters,and repressors, and stuff. But it’s a tiny percentage. What that means is there’sregulatory stuff going on that no one has a clue about. The main thing, though,here is modulatory structure to genes– introns, exons–and this whole world of the environmentregulating when genes are turned on and off.A whole world whereyou could generate completely different proteins. Not a protein that’s alittle bit more this way, a little bit more that way, incompletely different contexts. So all we need todo now is begin to stick this into themolecular biology of mutations and evolutionary change. Where does this begin? Oh, no, before wedo that, that’s not what we’re going to do.We’re going to look at onemore level of regulation here. OK, so you’ve got your DNA. And we already knowthis whole business. What’s telling it what to do. You can have transcriptionfactors coming in, all of that, theseinteresting implications. DNA– let’s see. For our purposes, protectedin sort of layers of protein that are just sort ofstructurally stabilizing. This is not really whatthey look like or quite what they’re made of, butthey’re called chromatin. There’s this stuff thatstabilizes the DNA. Because these arewispy little things. And one of the things that,of course, they need to do is they’re in wrappedaround the DNA stabilizing. You’ve got some transcriptionfactor coming in from somewhere else in the cell. It’s got to be able toget down to the DNA. And thus, you have a wholeworld of chomatin opening up to allow transcriptionfactors to get through.And thus, you have a whole worldof what’s telling the chromatin to open up where and when? Suddenly, a wholeworld of regulation, of whether thetranscription factors even have access to the DNA. So you can have tons ofa transcription factor, and all set to transcribesomething off of this. And thanks to conformationalchanges, folding or unfolding of chromatin, you’re regulatingwhether the transcription factor can even get through. And thus, there’s awhole world of stuff that changes chromatinmodeling and remodeling.Additional step here, onethat’s really interesting, is you can do things–circumstances [? arise, ?] the environment can dothings– where you change the structure of chromatinaround a particular gene in a way that makes iteasier to transcribe, or harder to transcribe. And you can essentiallymake that change permanent. You could permanentlydo something in some particularstretch of chromatin so it will never open up againto allow the transcription factor in. And what you havejust done– jargon– is you have silenced that gene. You’ve silenced it permanently. And people know a lot of themechanisms for how this occurs. For those who careabout such things, the process iscalled methylation. This is a little bit different. That’s occurringwith the DNA itself. But this is silencing ofgenes by structural access of transcription factors to it.When does that occur? There’s all sorts ofcircumstances early in life where you will change thepermanent accessibility of some gene andtranscription factors. You will cause long-term,lifelong changes. As but one example,and one that we will look at a number oftimes down the pike there, in rats, the motheringstyle of the mother rats, will cause chromatinchanges– permanent ones– in some of the genesrelated to stress hormones. So that certain types ofmothering– how often you lick the baby, and otherrat mother type stuff– will regulate how readilysome genes will be turned on for the rest of your life. This is early experience. This is molecular mechanismsfor events early in life lasting forever.A lot of these turn out tobe a little bit reversible. But for our purposes,lasting forever. This is a whole newfield called epigenetics. Genetics is allabout DNA sequences. Epigenetics is allabout regulation of access to DNA sequences,things of that sort. So suddenly thisepigenetic world is entirely capable ofoverriding anything going on at the transcription factor end. Just to give you a senseof this– researcher. This is a guy at the NationalInstitute of Health– a guy named SteveSumi who studies primate social behavior.And what he hasshown is in monkeys, in one part of theirbrain, you change the style of mothering that that monkeyis subject to as a baby, and you will change theconformational access state of 4,000 different genes. Enormously influential there. Enormous arrays of ways ofregulating where it’s not genetics, it’s epigenetics. And this has given rise to agreat phrase– fertilization is all about genetics. Development is allabout epigenetics. And what epigeneticsis about are ways in which the environmentnot only can regulate what’s going on with thisgene right now, but can cause lifelongdifferences in the ability to access genes. So this is an enormous arrayof levels of regulation. Splicing enzymesdetermining how your exons get mixed and matched,generating all sorts of different proteins. Transcription factorsrepresenting the things that turn the switches on andoff, and the array of switches is far more interesting andplentiful than the gene itself. Transcription factorsreflecting what’s going on in the outside world,like in the rest of the cell to the other side of the planet.And finally, thiswhole additional level of regulation where some ofthe regulatory consequences here can be lifelong. Enormous array oflevels of regulation. And an enormous numberof ways in which just the DNA sequenceof the gene itself is not very interesting. That determines theshape of the protein. All this otherstuff is where is it expressed, when isit expressed, in what contexts, what sort ofif then contingencies, whether it is ever expressedafter a certain childhood event.All of that much muchmore interesting. So what we need todo now is transition to thinking aboutevolution, mutations, on the level of all thestuff we just heard about. And all I will leave you withand picking up on Wednesday, is think about what if you geta mutation in a splicing enzyme? What if you get a mutationin a transcription factor? What if you get a mutationnot in the letters coding for a gene, butcoding for a promoter? What happens in all those cases? And suddenly youbegin to see a world in which you can get stuffthat’s not purely gradual.For more, please visitus at stanford.edu.

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