4. Molecular Genetics I

[Music] 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 were getting mildly comfortable in one we will spend time trashing it from the standpoint of a different discipline this is our first one of these and the whole point of this jump is to show on a certain level exactly where One

discipline's 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 tenants were of that view first off that notion of heritability heritability assuming that all sorts of behaviors have a genetic component have a genetic basis have a genetic cause and we will see those are worlds of differences in those words there

and what we saw was that that could be the case that could not be the case that's going to be what we focus on a great deal today another one of the basic tenants 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 viw being the world of spandrels a lot of the time stuff gets carried along as baggage things evolving aren't necessarily things that have been sculpted into being as adaptive as possible another critique and one that's also Central today

is that whole emphasis on the gradualism on small incremental changes and what I alluded to at the end the other day is going to see a Viewpoint where something very very different is proposed to be going on one that will make sense only eventually when we see some pretty unexpected things about genetics and the molecular biology of 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 labotomy who winds up exterminated who winds up being viewed as educable or uneducable Etc poitical views run throughout all of this you will see very strongly in this realm okay so that Viewpoint of The sociobiologist evolutionary psychologist the other day one of the ten it's going after the notion of heritability the notion that these behaviors are heritable are genetically influen blah blah 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 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 in it my God that counts as as science coming up with a bunch of these rules there and saying until you come up with fancier rules or a more pleasing just so story I win

that counts as science complete contempt for this approach this is where more molecular stance about it all takes off and what we'll see that that not only will have lots to say about adaptiveness it will also have lots to say about gradualism 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 what one is immediately talking about are genes genes in this case not as some constructs that one wants to maximize copies of and

ones that your cousins have only whatever percentage of in common with you but genes instead molecules genes as information genes as strings of DNA and I'll assume by now there's like a basic level of shared knowledge about this after hearing that a lot of folks came to the catchup session last week which I think is a good idea but what is all built about all of this notion of genes eventually way out the other end having something to do behavior is the intermediary of proteins proteins are important proteins are important not just to have 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 roles proteins hold the shapes of cells SS together proteins form Messengers hormones neurotransmitters all of this to come hor proteins are the enzymes that do all sorts of the most important stuff proteins etc etc etc 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 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 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 cod for a sequence of amino acids which get plugged together and you then have a protein you 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 in 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 set at this

point which is all sorts of effect eor proteins fit into other molecules other refector 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 like a lock and key for those of you who are not tortured with this one from early on it's the whole notion that a shape of a protein imparts information in so far as it interacts with something else of a shape which modifies it which complements it with whatever the whole world that we will have of

various hormones and neurotransmitters will consist of hormones and neurotransmitters going into receptors where there's 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 especially people without 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 to Amo acids gets pulled into different positions by their relationship with water and thus a string of amino acids the shape it winds up getting with is determined by that amino acid sequence there's a whole world of really interesting horrible neurological diseases called preon 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 uh three-dimensional structures and out of that will become coming function out of the fame lock and key nature between shapes of functions and shapes of other things okay just once again for people fairly new at this um nope no diagram there uh one of the most

most interesting or the blank slate um 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 laundry detergent and advertise about how cool it is that you have enzymes in your detergent but what enzymes do is they catalyze rela reactions they cause reactions to occur which left on their own would be very very rare events what enzymes do is accelerate vastly a gazillion times over the speed with which these happen catalyze reactions what do I mean by that for

our purposes they can take two things that aren't connected and stick them together or they can take one thing and break it apart for our purposes that's what enzymes do virtually every enzyme out there is a protein so proteins fit into other things and send on messages proteins are enzymes pull things together pull them apart proteins are structural again a whole lot of the the super structure of your cells are held together by proteins this is the realm of what they do notice here suddenly there's a change of shape in a protein if it's an

enzyme because what's it doing in some way it's got to like 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 his 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

okay 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 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 RNA to protein DNA as running Everything Note the importance of that and 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 knowing what's happening 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 and one that's tangential here but just as a first blow against central dogma one of the things that's interesting is there are things called viruses and what viruses do for a living is get into organisms viruses in the classical form being little smidgens of foreign DNA which are able to get into the DNA of your own hijack the processes there

and make the cell function for its own parasitic vicious needs and so your changing the starting step of how the central dogma of life and thus you're going to CH change RNA protein all of that in the 70s it became apparent there was one weirdo viral world of viruses made out of RNA this intermediate form all sorts of people were extremely upset about this and tried to ostracize the scientists who came up with this and told them there's no way but eventually what was shown in Nobel Prize wining Glory was there's a class of enzymes

enzymes they pop up a class of enzymes that could take the RNA information and turn it back into DNA viral information and then it does its thing huge blow to these Central that here's information running from an RNA virus somehow being reversed back to a DNA form and thus these are called retroviruses insert in the DNA and off they go from there so this was a major blow everybody eventually came to terms with this but it still is a minor footnote in this ccan world of everything flows from DNA it is the Bible it is

the lawgiver it is the Holy Grail it is where it all starts so stay tuned okay 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 a background in this newcomers to this hopefully this won't be going too fast but broadly when you were talking about this world of microm mutations for our purposes what we will mean by a micr 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 some such thing where there's a mistake and one letter in the DNA sequence comes up wrong

as I noted before pairs of triplets is there we've got three pairs of triplets and what we've got here is at the DNA level a amino acid is coded for by three base pairs a triplet three of these next amino acid coded for next one coded for so what we've just raised is the possibility of a m mutation occurring something changing in one single one and now asking what are the consequences going to be in classical Realms of genetics and evolutionary change 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 Time 4 * 4 a total of 64 possible three

step combinations of DNA letters a possibility of 64 of them and you're only coding for 20 amino acids so you use up some of the 64 for Signal 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 Gen gentic 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 three a number of closely related tripling 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 same amino

acid in that case you have a neutral mutation of zero consequence whatsoever so that's not a very exciting mutation in some cases you can have a single point being changed where you wind up with a different amino acid coded for and that's most typically if it's a mutation in here or here rather than the boring middle one you get a different amino acid is that the end of the world often not at all or only minimally because a lot of the amino acids have similar feelings and ambivalences about water similar responses and similar shapes it

won't be exactly the same same shape but the protein will function somewhat the same so you can 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 can 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 of a very different shape and potentially a very different message and

shown here just changing one letter in this case one single point mutation and you dramatically change the meaning of that and I actually did that once in a grant proposal sort of the final paragraph we have now accomplished X Y and Z with your money over the last 5 years and no wonder it didn't get renewed so in that case you see a single point mutation of Great consequence so you can have one of these letters one of these 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 Major League it totally changes the coding Downstream from that third classical type an insertion mutation one where you now accidentally double the letter and you 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 and anything in between you have point mutations and then you have insertion and deletion the last two tend to have big consequences so all of this is built around one single base pair changing and all of this is built around thus one single protein changing its shape and thus this world of micr mutation single spots they're 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 um where if thanks to a mutation this has a slightly different shape it will fit into the lock slightly less effectively 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 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 a 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 phenyalanine which has its uses but you don't want the levels of it to build up too high because it can become toxic damaging to brain cells to neurons and fortunately there is an enzyme made of protein which turns phenyalanine 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 fan mutation just something one of these categories a classical single spot point mutation and what you got there is an enzyme that no longer does its job and as a result this phenyalanine is not converted into the safer form builds up and lays waste to one's nervous system and thus you have a disease PKU phenol ketura very very common genetic disorder and this is one where the outcome is a small mutation that has completely knocked this enzyme out of business this enzyme which was able

to turn the fenel alanine into something safer this is not a subtle outcome have untreated PKU and your reproductive success by the rules of evolution is going to be real down near zero this destroys the nervous system very rapidly after birth so that's dramatic here's another dramatic one and this one anyone who took biocore I always bring this one and 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 12 you know 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 is 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 okay it's called especially since it's in a 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 at XX and XY business these are individuals who have testes testes way up in their stomach or whatever never descended down these

are people whose testes make testosterone testosterone out the Wazoo tons of testosterone enough testosterone to put like antlers on your testes or something that much testosterone and nonetheless you're getting a female phenotype you are getting a female external genitalia you are getting female everything yep question s is that different andity no that's the fancy term for it and you've just given away the punch line you creep okay so they figured out in this disease there's an 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's 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 variance on it one is up in the Dominican Republic and the mountains the other is in the mountains of New Guinea interesting similarity there and both cases some fairly isolated

inbred population so that's 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 enzyme instead of the proteins and thus the gene somewhere back there that code for the receptor for testosterone the receptor that responds to this messenger here instead it's back way up there in the testes a bunch of these enzymes which go through a bunch of steps and make testosterone biosynthetic enzymes they're 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 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 prepubescent males in most cases someone who's genetically male someone who never saw a whole lot of testosterone during fetal life way below the threshold for the testosterone having any effects so the person is

born phenotypically female female in appearance female in external genitalia and not internal back to those testicular feminized males what you find there is 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 and 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 is 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 a time of life when there's not a whole lot of testosterone around in a fetus in a young male and now it's below threshold for causing anything Along Comes puberty and thanks to a whole bunch of changes in the brain signals go out so that testosterone levels now come roaring up into the usual impossible

levels in the males and what happens here is the levels don't go up as much as they should because that enzyme is a little bit on the slow side but they go up enough to pass threshold for beginning to have an effect and somewhere right around puberty this individual changes sex this individual trans transfers transmits jump ship and goes from female to male as a result of these androgenic effects suddenly coming in it's not a complete switch there but it's somewhat of a transition this is bizarre again this is not something subtle this is something

changing completely here and again one single mutation and in this case not even a mutation wiping out the function entirely of some protein as in PKU or testicular feminization syndrome but now you got a protein that's just working differently slowly enough that you get this very different picture popping out the other end what's most interesting is you have this intersection between molecular biology and the bio Endo consequences of this mutation all of that and the cultural context of it apparently in both of these populations people have kind of adapted to it it's not a big

deal you know puberty sometimes you get acne sometimes you get a penis and like 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 is 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 benzodiazapines 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 benzo diazines there are synthetic versions of bod diazines which people might

take when they're feeling anxious like Valium like Librium valum is a synthetic benzodiazapine so benzodiazapines are protein and they have a particular shape and you guessed it there are thus benzodiazapine 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 mut ations but simply different versions that one letter can come in in the DNA sequence specifying the benzo aspine receptor these are not mutations this is just normal variability in this 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 benzo dipine 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 for decades people often try to breed rats different rat lines for different behavioral traits and it makes it

you know very useful models there are alcoholism prone rat s there are rats that have been bred for being smart for being not as smart at spatial maze Stuff Etc and for years there had 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 um 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 those high and

low anxiety strains differ in the shape of the benzo aspine 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 pretty exciting dramatic diseases where you wind up with a different gender and you're chromosomes say ones where you get more subtle differences you change gender at your 13th birthday

or ones where we're just for the first time beginning to look at the individual differences that flow out from stuff like this not them and their disease but the individual variability all of this is in the realm of single base pairs being changed what all of this now allows us to do is translate this world of mut ational 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 in this is that going to increase the number of copies of genes that individual has is going to decrease the number it has it how's it going to fit into all of last week's science and you will know exactly how that drill will run

oh if thanks to one single base pair changing you now have a receptor which functions in a slightly different way which makes this individual 1 and a half% 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 IM mutation we have differential Fitness we've 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 for of fox P2 occur all throughout the Animal Kingdom in birds and rats and nonhuman primates and all sorts of things Fox P2 popping up all over the place and in all these different places it's got something to do with communication it's got something to do with bird song it's got something to do with rat ultrasonic vocalizations rats are constantly jabbering at each other in

a Range that we can't hear and fox P2 has something to do with an all of those and 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 Bas pair difference between rats and mice one Bas pair difference between Hawks and elephants that sort of thing very 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 they immediately sing the theme song from all the Mickey Mouse cartoons ah 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 have wound up with a very different world than chirping and buzzing and barking and all of that and you wind up with a very different version of this Gene where you can trace out how

many amino acid changes it took and every step of the way you are having some gradualist process what's also this allows you to do is look at a footprint an 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 an amino acid statistically 2/3 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 2/3 are neutral in terms of their consequence and 1/3 actually causes a change in an amino acid that's telling you it's happening at the random expected rate of mutations popping up that are either consequential changing an amino acid or inconsequential just coding for a different

version of the same amino acid now suppose you find a gene that differs and you look at the ways in which it differs and 99% of the base pair differences over the course of this 5 million base pair 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 of very strong selection a very strongly advantageous trait driven by these changes term used this would be a mark of there 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 mut ational rates of neutral and remember every amino acid is coded for three ways if 99% of them are consequential there has been some major hard ass selection going on there alternatively if you find a long Gene with a whole bunch of mutations and 99% of them are neutral make no change at all what does that tell you this protein's function you do not want to mess with 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 its function downline as the protein does not change when you look at the number of changes the burst of mutations over the last quarter million years or so that differentiated Fox P2 in humans from these other species it's almost entirely evidences of positive selection this did not just happen by chance every step of coming up with these new versions these new amino acids in

the sequence there clearly were ones that were positively selected for a lot of selection brought about this huge difference 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 two factoid and two sound bites 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 sound bites that everybody knows everybody knows who goes through like basic mle 50% 100% with an identical Gene with identical twin 50% with the full sibling you know that song and dance by now and meanwhile one of the great sound bites of our evolutionary history and the mark of evolution and what in hell are you creationist thinking is the fact that oh humans share 98% of their DNA with chimps this doesn't make any sense one minute here to be spent on just clarifying that one that is not contradictory at all

genes specify by way of proteins and now this is taking a bunch of leaps down there traits aspects genes specify to be totally simplifying here genes specify for antlers for Dorsal fins for petals and pistols and stamin for kidneys for it's totally simplifying so right off the bat you will have some genetic similarities between two different species in that both of them will have genes that code for Dorsal fins you're thinking about two different species of whales so they share genes cating for Dorsal fins whales have Dorsal fins neither we nor chimpanzees have genes for

Dorsal fins meanwhile we have genes coding for a pelvis that is a certain shape which either in chimps pre disposes towards being able to walk by pedal for certain strengths 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 and 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 etc etc 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 so when talking about the amount of DNA shared in com 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 a half% 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 gradous 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 okay whoa there's a lot of apples there lit up um 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 natural selection sexual selection whatever even if that gives you a tiny Advantage thanks to this tiny change in this tiny Gene enough Generations go by and that trait is going to become more prevalent final point there intrinsic in this is if every little bit of difference matters in terms of fitness and Gene distribution within the realm of behavior every little bit of competition matters a very very intertwined sort of political philosophical stance in gradualism as it applies to Evolution okay so that's been sitting there around for forever and

in the 1980s suddenly a very different model emerged and this came from Steven J Gould who we heard about the other day Steph J gold and the person the poor schnook who was always lost in this another evolutionary biologist named Niles Eldridge who somehow did not quite have the press that Steven J Gould did so he is lost to history except for people who know what he's up to and he's an amazing scientist but Gould and Eldridge came up with a very different model and I alluded to it the other day and Drew it right

there and their notion was that gradualism is nonsense there are not gradualistic incremental changes evolution is not being driven by small gradualist changes instead what their model was is that there's long periods of nothing happening of stasis long periods of nothing happening if there's change in DNA sequences thanks to mutations they're not consequential or if they're consequential enough to change the fitness of one organism 1% that's not going to make a difference most 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 long periods of stasis followed by dramatic jumps of evolutionary change in short periods of time thus they called this the notion of punctuated equilibrium long periods of equilibrium and stasis punctuated by periods of very rapid change and as I mentioned the other day Gould was a Marxist and felt that Marxist sort of stance was running through all of the ways to think about genetics and n a what's up with Niles Eldridge but that was the case with ghoul 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 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 he studies studied fossils he studied the history The evolutionary history of fossils and apparently like totally separate of his large theoretical models he was like the world's expert on the evolution of some Caribbean snail shell over the last 10 billion years or something he's one of those paleontologists who traces lineages of evolutionary change over the course of time with fossils fossil records as the readout so he's a paleontologist geologist in some ways and when you do that you notice something which is you 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 trait or other and these snails or trilobites or whatever you're looking at and at this time period the trait looks like this and at this time period it looks like this and this looks like a perfectly good gradualist model and what G 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 asessed 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 the lines and they wind up looking punctuated in this way so out of him comes this whole theory that it's all about pun uated 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 more copies and figuring out exactly who to be infanticidal to all that it's not going to make a difference in terms of Gene distribution evolution is not being driven by that and out of it came this very strong indictment of the sociobiological view of what you 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 were benefiting from this who started this Theory very different notion here competition selective advantages all of that most of the time nothing's happening so not surprisingly all of the evolutionary types from last week did not like this one bit and this was attacked left and right in some extremely valid ways first one first form of attack is a

very simple problem there which is uh that you have two different disciplines Happening Here you get a paleontologist and you get a evolutionary biologist and they're function in 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 Dr that's like a 100,000 years that's like are you kidding me said the biologists the ones who study one generation at a time that is asinine that is ridiculous this is them imposing

models where this has absolutely nothing to do with how Evolution actually works these geologists got completely thrown off and these paleontologists led by Gould simply orders of magnet to different scale of time yeah maybe in some rough approximation of what they look at but they're not studying Evolution because they're not biologists next critique the next one made lots of sense also which was you're not just an evolutionary biologist but you're one who thinks about the evolution of the brain or the evolution of skin melanism or the evolution of eye color or the evolution of how

many chambers in your heart you're going to have or the evolution of any of these things that will leave no record whatsoever in the paleontological record because all paleontology is about is shapes of stuff fossils fossils do not tell you what kind of brain was going on inside that Fern fossils do not tell you anything about internal organs fossils do not tell you anything about Behavior so at this point all of the evolutionary folks of the school from last week attack and say yeah what do they expect they're studying the most boring possible things the

morphology of organisms ooh just because the fact that humans over the last like million years or so have not evolved sort of getting rid of the large trunk and roots that they have during like 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 guian 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 time span they talk about that makes no sense in this period humans evolved double 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 molecu 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 2 minutes after the micro micro evolutionary 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 is looks like on the genetic level mutational level micr

mutational changes they loved genetics they loved the molecular end of it because they could now turn around to the Gans and say show me the genes and show me the mutations that will account for stuff like this because you can't account for it because we all know classical genetics and mutation you don't get that you get gradualism so this was a period of enormous hostility between the two camps and the gradualists called the punctuated equilibrium people evolutionary jerks haha and the punctuated equilibrium people called the gradualist creeps uh 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 microm mutational microevolutionary stuff of an hour ago is not what's going on an awful lot 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 once it finishes one of those stop codon stop triplet signals right after that comes the stretch of DNA coding for the next Gene and the next Gene and this is what DNA is about it's the sequence of genes there and what

you would obviously then get is this Arrow having this intervening step of that RNA stuff but eventually producing an amino acid that produces a protein of this shape and this is the protein coded for by this Gene this this and so on and that's exactly how it works that's the structure of DNA then though people began to find that that's not the structure of DNA and what you began to get instead was something vastly more interesting which is that for starters when you look at coding for one single Gene it's not necessarily coded for in

one continuous stretch of DNA in other words it's broken into little pieces and you will have a stretch of DNA coding for the first third of the protein and then a bunch of DNA that's got nothing to do with it stay tuned then coding for the next third coding for the next third that the gene was broken up into separate coding domains and the term that was given for 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 Exxon Exxon one of this Gene and this from xon 2 this from xon 3 that's a completely different sort of world of stuff how are you going to do that because once you you're going to make an RNA that's going 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 the splicing enzymes would come along and they would snip out the part corresponding to here and another would snip out there and another one as an enzyme catalyzing 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 it shortly after these were discovered that one of the Giants in this business guy named David Baltimore who got the Nobel Prize for some of the work on that reverse process of RNA viruses turning back 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 and 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 in a modular way and three separate exons and thanks to splicing enzymes protein catalysts flipping 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 or and suddenly you have this combinatorial possibility of cranking out a number of different ways of putting together seven different ways since you can't transcribe this Gene so that there's no transcription seven different ways of combining these different exons seven different types of proteins you could generate from the same Gene this was not accepted with a whole lot of pleasure by

the old guard because intrinsic in the know the DNA sequence specifies amino acid protein shape protein function intrinsic in that is one gene specifies one protein one gene only specifies a single protein one protein is only specified coded for by one Gene and suddenly this modular business allows you with one Gene to generate seven different kinds of proteins for starters how could that possibly work that way just on a nuts and bolts level all you need are splicing enzymes that work a little bit differently in different parts of the body one that will splice this

off and is attached to an enzyme that will degrade this while the splicing enzyme here and what have you just produced you'll get this one coupling of splicing enzymes with degradative enzymes and suddenly you've got a means to have tissue specific expression of genes the sh the same gene will produce different types of proteins in different parts of the body because of splicing enzymes working differently then just to confuse things even more people began to note that there would be some splicing enzymes and genes where they would splice at a different point and you would

now have a gene with a and a prime and other splicing enzymes that would cut at other points one single sequence of DNA generating all sorts of different types of proteins in different parts of the body at different times of Life under different circumstances in different individuals in different ways suddenly there's a lot more information floating around in there so that was a huge huge breakthrough in the field understanding this modular basis of Gene construction and for our purposes right now what the most interesting consequence of that is is it's no longer one gene one

protein one gene instead can generate all sorts of different types of proteins different settings different circumstances the next thing that was intrinsic in this model that's now been trashed of one continuous gene or continuous Gene what we just figured out is instead you can have the intron exons all of that the next thing that went down on the tubes was looking at well how much of DNA is actually devoted to coding for amino acids and the answer was obvious like 99.99% each one of these would just have to have a stop codeon a stop signal

at the end and otherwise this was just a continuous flow of information once you have factored in these intron things 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 noncoding 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 actually like doing the numbers out came a number that knocked people on their rears it was so flabbergasting 95% of DNA is noncoding 95% does not code for a gene specifying a protein in other words in between here on the average would be a stretch of DNA 19 times the length of that or whatever the math winds up being and suddenly calling that stuff junk DNA started seeing seeming a little bit tenuous cuz 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 came sort of the insight into this that all 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 andof switches implication right there off the bat which is Crick was wrong

DNA sequences are not the starting point 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 this 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 happen 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 turn the switch on and these things that turn the switches on or off in some cases were soon called transcription factors totally critical Concept in there the fact that vast stretches of DNA don't code for anything instead they have the instruction booklets here's how you turn this gene on or off send in this molecular messenger send in this type of transcription factor and if it shows up binds to here you now activate the transcription of this Gene the process of turning that Gene making proteins derived from it this is where

the information was and this is not DNA knowing what it's doing this is outside Regulators coming in so immediately that has made life a whole lot more complicated next complications you could have different genes scattered all over the place that would have the same promoter Upstream of it what would that mean Inc 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 and 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 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 de 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 and who knows what's going on whatever is controlling the transcription factors whatever is causing them to do their thing and this could be a world of influences and to be absolutely accurate this requires introducing the word environment this is environment having something to do with genetic effects this is going to be a way in which environment is interacting with genetic elements environment determining which of these are doing what what would that look like sometimes environment could be the environment in the rest of the cell so you got your DNA

there and your stretches and all of that and your promoter and we could do that by now and something is occurring inside the cell which activates some transcription factor and then you go change a genetic event going on in there the cell is is running out of energy there's various ways to construct sensors in other words Evolution has come up with a bunch of different ways in which cells can respond to signals of low energy and that will activate some transcription factor which will go and bind to a bunch of promoters which produce proteins involved

in taking up more energy from outside the cell transporting in more using energy more efficiently so what we have here is an environmental regulation of genetic effects environment the rest of the environment of the cell the DNA doesn't know what it's doing the gene doesn't know what it's doing events going on elsewhere in the cell is what's regulating what's up some of the time the environment can be even more farf flown and in this case it's now events going on outside just this one cell in this case now you've got got the cell with its

DNA and now instead you have a chemical messenger coming from somewhere else and binds to its receptor like a lock and key and as a result of this binding something happens here which does something here which say 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 bloodborn chemical messenger so you could secrete some hormone out of the top of your ear and will affect things in your little toe very far flung hormones will bind to their receptor is lock and key most hormones are protein in nature and Trigger what's called a second messenger Cascade jargon don't worry about it just get it conceptually activate some transcription Factor deactivate some other trans and suddenly events going on 14 counties over there are regulating what proteins are being made in this cell what would be an

example of that testosterone for example testosterone secreted from the testes traveling far and wide and eventually binding to Androgen receptors on muscle and what happens there is through a pathway like this turning on the activation of genes coding for proteins all sorts of structural proteins that will make that muscle cell bigger your muscles are getting bigger thanks to testosterone look at this events occurring a gazillion cells away in the testes a messenger here determining What gene expression What gene activation is happening sometimes though the environment could be completely outside the organism like that sometimes you

can have for example a messenger from the outside world what sort of messenger a scary site a bit of sensory information or whatever old factory old factory suppose some odorant comes in a pheromone you're a female who has recently given birth and the pheromones from your babies come floating in and bind to receptors here very similar principle again and that causes them to activate something activate something and some cell down there and eventually there'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 if 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 give her nonsense events going on in the rest of the cell the rest of the organism

the rest of the Universe are determining when genes activate so what we see now is a much more interesting world of regulation of gene expression first the modular ability for one gene to generate all sorts of different proteins which brings up an issue after a while is does that count as one Gene and people argue over that and because of this 95% regulatory sequence business the most interesting stuff go going on with DNA is not what the protein is like not what the protein does not how well the protein does it but when it does

it in what context 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 P 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 ordin iation of this by the way 95% this whole stuff here I don't know what percentage is accounted for by identified promoters and repressors and stuff but it's a tiny percentage what that means is there's regulatory stuff going on that no one has a clue about the main thing though here is modulatory structure to genes Inon exons and this whole world of the environment regulating

when genes are turned on and off a whole world where you could generate completely different proteins not a protein that's a little bit more this way a little bit more that way in completely different contexts so all we need to do now is begin to stick this into the molecular biology of mutations and evolutionary change where does this begin 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 got got your DNA and we already know

this whole business what's telling it what to do you can have transcription factors coming in all of that these interesting implications DNA let's see for our purposes protected in sort of layers of protein that are just sort of structurally stabilizing this is not really what they look like or quite what they're made of but they're called chromatin there's this stuff that stabilizes the DNA because these are wispy little things and one of the things that of course they need to do is they're enwrapped around the DNA stabilizing you got some transcription Factor coming in from

somewhere else in the cell it's got to be able to get down to the DNA and thus you have a whole world of 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 confirmational 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 in modeling and remodeling additional step here one that's really interesting is you can do things circumstances AR the environment can do things where you change the the uh structure of Chromatin around a particular Gene in a way that makes it easier to transcribe or harder to transcribe and you can essentially make that change permanent you could permanently do something in some particular stretch of Chromatin so it will never open up again to allow the transcription factor in and what

you have just done jargon is you have silenced that Gene you've silenced it permanently and people know a lot of the mechanisms for how this occurs for those who care about such things the process is called methylation this is a little bit different that's occurring at the DNA itself but this is silencing of genes by structural access of transcription factors to it when does that occur there's all sorts of circumstances early in life where you will change the permanent accessibility of some Gene and transcription factors you will cause long-term lifelong changes as but one example

and one that we will look at a number of times down the pike there in rats the mothering style of the mother rat will cause chromatin changes permanent ones in some of the genes related to stress hormones so that certain types of mothering how often you lick the baby and other rat mother type stuff will regulate how readily some genes will be turned on for the rest of your life this is early experience this is molecular mechanisms for events early in life lasting forever a lot of these turn out to be a little bit reversible

but for our purposes lasting Forever This is a whole new field called epigenetic genetics is all about DNA sequences epigenetics is all about regulation of access to DNA sequences things of that sort so suddenly this epigenetic world is entirely capable of overriding anything going on at the transcription Factor end just to give you a sense of this researcher this is a guy National Institutes of Health a guy named Steve Sumi who studies primate social behavior here 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 confirmational access state of 4,000 different genes enormously influ 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 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 ex get mixed and matched generating all sorts of different proteins transcription factors representing the things that turn the switches on and off and the array of switches is far more interesting and plentiful than the gene itself transcription factors reflecting what's going on in the outside world like in the rest of the cell to the other side of the planet and finally this whole additional level of Regulation where some of the regulatory consequences here can be lifelong enormous array of levels of Regulation and an enormous number of ways in which just

the DNA sequence of the gene itself is not very interesting that determines the shape of the protein but all this other stuff is where is it expressed when is it expressed in what contexts what sort of if then contingencies whether it is ever expressed after a certain childhood event all of that much much more interesting so what we need to do now is transition to thinking about Evolution mutations on the level of all the stuff we just heard about and all I will leave you with and picking up on Wednesday is think about what if

you get a mutation in a splicing enzyme what if you get a mutation in a transcription Factor what if you get a mutation not in the letters coding for a gene but coding for a promoter what happens in all those cases and suddenly you begin to see a world in which you can get stuff that's not purely gradually for more please visit us at stanford.edu