Linkage and Recombination, Genetic maps | MIT 7.01SC Fundamentals of Biology

Linkage and Recombination, Genetic maps | MIT 7.01SC Fundamentals of Biology

good morning good morning so last time we ran into a problem we had Mendel my hero Mendel this MIT like mathematical physical monk had developed this gorgeous theory of particles of inheritance he didn't use the word gene yet gene doesn't get invented for much longer for every trait you had two such particles you gave one to your offspring each of the parents gave one to their offspring and that's how each offspring gets two of them those that choice of which of the two alleles to transmit to your offspring is a random draw and that explains beautifully for example the 3 to 1 segregation pattern that Mendel saw gorgeous we put that model which was an ex post facto model model made after the data were available to attest you guys insisted we had to test it before you would publish it and it holds up pretty well making pretty surprising predictions that you would otherwise not have ever expected like amongst that three-to-one the threes are not all the same some of those round peas were homozygous for the big R allele and in a selfing they'll never produce wrinkled peas but 2/3 of those round peas or heterozygous and when you sell them you get 1/4 wrinkled Peas so the wacky prediction that 1/3 of the rounds will give rise to no wrinkles and 2/3 of the rounds will give rise to 1/4 wrinkles is a surprising prediction and therefore something that bears you know stating as a scientific prediction and so all those kind of predictions can kind of merge then we turned to the question of two factors and I'm practicing using our words here right homozygous heterozygous alleles etc we now turn to two traits two phenotypes we have two phenotypes segregating we had round and wrinkled and we had green and yellow and Mendel determines rather brilliantly that they segregated were transmitted independently of each other there was no correlation between which alleles you got it round and which alleles you got it wrinkled that was pretty cool let's just go over that because there's a real tension to be resolved because we have Mendel's second law versus the chromosome theory so Mendel's second law let's just go back to it in the f0 generation we had our round green peas genotype big R big R big G big G we had our wrinkled yellow peas genotype a little R little R little G little G we cross them together we get f1 double heterozygotes big R little R big G little G we then perform a back cross or a test cross to the doubly homozygous parent with the two recessive phenotypes we're practicing our words here and what do we get well we get certain options as we said the gametes that emerge from this parent on the Left could be of the following types the gametes from the parents on the right are all those alleles are those recessive alleles no you'll forget this over time but just to make me comfortable they're actually the alleles associated with the recessive phenotype that we're talking about because you know but we'll forget I assure you because all my colleagues in the biology department of forgotten that they could also control multiple other phenotypes some of which could be dominant but that's okay I forgive you in advance that you'll call them recessive alleles anyway you get this and then these should occur at equal frequency of one two one two one two one all right now we had the chromosome theory the chromosome theory the observation of the choreography of chromosomes during meiosis chromosomes in meiosis look like this we have chromosomes lining up in pairs now I'm not drawing it terribly well but the pairs could be the two members of each pair can be of are of the same size but this pair could be bigger and this pair could be smaller it looks like they're really finding each other these chromosomes are visibly different in shape and so maybe I'll make this guy a little longer just to indicate that that it actually knows now an explanation we said for how Mendel's second law of independent assortment of two different phenotypes could occur is that for example round it could be that the gene for roundness is located on chromosome number one these are two copies of chromosome 1 that have been duplicated each of which has the big R allele next to it two copies of chromosome one that have been duplicated each of them having the little R allele over here on chromosome number two let's say lies the gene for green or yellow and in this picture here the big G's are on the two copies of this chromosome number two that are here the little G's are on the two copy of chromosome number two that are here when the cell undergoes meiosis one we get to the situation where we have big G big G little G little G we've got big R big R little R little R could it have been the case that the big G was on the right and the little G was on the left yeah of course it's totally independent which way I happen to draw up this way but with probability 50% it's the other way that's why they're independent of each other and then when it undergoes meiosis two that looks just like mitosis we end up with our four gametes here so I'm sorry our four gametes with big G big G little G little little G big R big R little R little R and that accounts for the big G big G big big R big G little R little G gametes and then when they went the other way the organism would make a set of gametes that have the other combination of big R's with little G's okay so that's that's perfectly fine and because it the second chromosome is independently ordered compared to the first chromosome when they line up at the midline they don't really care which way they are that will account for ones ones ones one it's so straightforward but what happens what happens if instead both big are both the roundness gene and the green this gene live on the same chromosome will have little R little R there will have big G big G here little G little G and then when they split we'll end up with now chromosome 2 has nothing that we care about on it it has a lot of genes in fact there could be chromosome 3 4 or 5 I'm just not drawing them but we're only really going to focus on chromosome number one here and you'll notice that here on chromosome 1 the big G's or the little G's are coupled physically coupled to each other the bigs with the bigs and smalls with smalls so now the kind of gametes that can emerge from this the kind of gametes only be big R big G type or big G type or there'll be little R little G type we can't get the reverse combination we can't get bigs and littles so this because these are independent of each other will get us one two one two one two one these are the big little and then these other combinations like that this will get us only if we look at the big R big G little R oops big G little R little G big R little G little R big G will get us one two one two zero two zero let's give a name to this type the big arse and the little geez let's call that a recombinant type okay I'm just going to use that word for the moment there were combatant types the bigs and the littles and littles and the bigs we're not going to see any of them this is a very strong difference between Mendel's second law on the chromosome theory if the chromosome theory is right and these these chromosomes are physical entities that have integrity they can't both be right so that's a great thing in science when you have two different models and they can't both be right because you learn things then you can test them now Mendel Mendel tested this without actually knowing the chromosome theory and he always got one two one two one two one for the seven traits he looked at was he just lucky that they happen to lie on the seven different chromosomes or is there some problem with this chromosome theory or what took a law took a while numbers everybody forgot about Mendel from 1865 till the year 1900 in the year 1900 people begin to rediscover Mendel cytology has come along in January of the year 1900 people start rediscovering plant breeders start rediscovering Mendel okay so oops sorry thank you see you ready thank you I can tell by the look on your face that something must be wrong there good plant breeders start rediscovering Mendel and in January of 1903 different groups say you know we found these laws and they're just like Mendel's laws which now everybody starts paying attention to but plant breeding and people's tried to do mice and people tried to do rats what turned out to be the winner the place to really study genetics was the fruit fly Thomas Hunt Morgan at Columbia University decided after he was really frustrated wasting years breeding ice and rats that just took too long around 1900 I don't know 1906 or something like that began to start breeding fruit flies fruit flies a little teeny little flies that you know when you open a banana they you'll find free or fruits or other kinds of things you'll see them and studying Drosophila gave us the answer to this question of what the problem is how can it be that either it's independent or totally dependent so we're going to talk about Drosophila melanogaster the fruit fly and the discovery of recombination so now Morgan I'm going to now start using fruit fly notation to give you some practice with fruit fly notation fruit flies we're not going to use big G's and little G's they like to refer to the normal allele and the mutant allele the normal allele is plus the mutant allele gets some kind of a name and so he had a female fly that was normal and normal at two different low side two different genes I haven't told you what the genes are and the male fly had a black colored body black across its whole body and its wings were shriveled and therefore called vestigial so the phenotype here is black and vestigial black body vestigial wings and this wasn't the normal appearance of a fly so he took these females by these males that he crossed them together and he got an F one and the F one was black over vestigial plus over plus and what was their phenotype were they normal appearance which is a white which is kind of a sandy colored body and normal way or were they this all black body and vestigial wings turns out they were normal from that what do we infer about these two traits black body and vestigial wings they're recessive traits so the here the phenotype was normal whoops normal appearance so then he crosses them back doing a test cross let's say he'll take males here and females here but it actually works either way and what he does is just like we did there he could get gametes that were that were black vestigial he could get gametes that were black plus plus vestigial or black or plus plus those are the four possibilities that come out so when he does it let's keep score I'm going to write them now plus plus black vestigial and from the other parent you got this black plus black vestigial plus vestigial black vestigial those are the four possibilities and if this was just like Mendel's traits it would be one two one two one two one these were the parental types that went in plus plus went in and black vestigial went in those were the combinations of traits here these were new combinations what we observed let's see if Mendel's right it'll be once once once one if the chromosome theory is right it will be one two one two zero two zero and who is right no one the answer was 965 to 944 to 206 to 185 neither model is right neither models right the new combinations the recombinant combinations the non-parental combinations we can call these recombinant combinations these recombinant they recombined in some way they're a new combination or they were the non-parental types we use both of those words frequently we're neither equal nor were they completely absent they occurred but at a lower frequency what was the frequency but we could just add it up the frequency of recombinant types of new types that were different than the parents is 17% what's going on now maybe this is some magic number like you know the three-to-one ratio and you should look at that 17% and say ah this is some constants of the universe that when you put in traits you get 17% of recombinant types but it takes a little judgment to say I don't think so and he actually tried other traits and sometimes he got ones ones ones one but very often he got some funny number 6% 28% 1% there was some funny business going on what's going on recombination that's what's going on is there is recombination occurring what do we mean by recombination recombination is very important stuff by the way at some point I will tell you that understanding recombination was actually the origin of the human genome project and it traces back to a good MIT story but that will be for a little later in the semester so what do we thinks happen here what we think is happening is I'm now going to draw a close-up of that chromosome and here's another chromosome the other pair and what we think here might be happening is that you might have plus and black black and Plus this sorry black right whatever black black plus plus this would be Plus this will be Plus this is the normal chromosome this is plus so this chromosome here carries the pluses this guy here carries those alleles black and vestigial right well what happens the idea was was that somehow these chromosomes exchange material here and the chromosome that was plus plus plus plus now somehow acquires that bit in this chromosome somehow gets that bit and we end up instead with a picture like this where some of this came from here and those two low sigh black and vestigial were separated from each other such that the black allele moves over to that chromosome is that clear that's the notion why did they think this was true well it turns out that in fruit flies you can actually look at eggs under the microscope and you can look at the chromosomes and if you take if you take the cells and you take a cover slip and you squash it down with your finger you can actually see chromosomes lying right over each other making little crosses like I drew there up there called chiasmata which means crosses and so people said see in the microscope you can see they're lying on top of each other are you impressed by that piece of evidence no you took the cover slip you squished it down with your finger so they're lying on top of each other big deal I'm not going to be impressed and calling it chiasmata doesn't make me any more impressed right although it's always good to call things Greek names because people think they're more sophisticated if you call them Greek names but this was the notion people had and the frequency seventeen percent would indicate how you know how often these these crossovers occur but if I were like in this situation we talked about Mendel I wrote this up and I said see it's 17 percent sometimes 6 percent sometimes 28 percent sometimes I want to look in the microscope they lie on top of each other therefore its recombination there were actually other ideas floating around too maybe it has something to do with developmental biology maybe at you know it was a puzzle when you have a really deep puzzle the most important thing in science is to find a young person because young people come without prejudice they kind of say let me just look at all this stand back I don't come with any prejudice so at MIT what is the solution when you have a problem like this a Europe you want a Europe so even in 1911 that was the solution at Columbia Thomas Hunt Morgan got a UROP I'm serious he was called Alfred Sturtevant Alfred Sturtevant was a sophomore at Columbia everybody else was busy finding this recombination data how often this we combined with this this with this this with this stirred event it's a sophomore says god this stuff seniors the professor Morgan could I have all the data and try to look at it Sturdevant took at home and actually pulled an all-nighter blew off his homework it actually says so in his autobiography he says I blew off my homework and pulled an all-nighter essentially in those words he says to the detriment of my undergraduate homework is the way he puts it but in any case sturdevant's all-nighter genetic maps and sturdevant's all-nighter what Sturdevant did was the following he said how are we gonna prove the chromosome theory I like this idea that recombination is about distance on the chromosomes right I like the concept that maybe 17% is how often these things recombine why would things only recombine 1% of the time what would that mean they got to be pretty close together so that a crossover between them happens not so often and what if things were far apart well it could be more likely so he likes the idea that recombination frequency means distance but how are you going to prove that it could mean a zillion other things it could mean biochemical pathways developmental biology how are you going to prove that recombination frequency means distance you got to make predictions right the only way to do it would be to make predictions so Sturtevant takes the data and starts making predictions I think says Sturdivant these things are alleles living at genes with locations on the chromosome black vestigial how often to black and residual vestigial recombine with each other what is the frequency of recombinant non-parental types 17% so Sturdivant goes through the data and he says what about other crosses people did in the lab well it turns out people did crosses with another mutant that produces a funny I caller called cinnabar cm so cinnabar it turns out that the recombination frequency the recombination frequency between cinnabar to vestigial was 8% vestigial cinnabar 8% recombination if this chromosome business is right where should I put cinnabar sorry where do you want it somewhere in between you'd like me to put that there oh okay wait a second on the other side okay which is it how many vote for the left how many go for the right how many conscientious abstainers are there okay do we know now there are two possibilities it could be 8% this way or it could be 8% that way how are we going to know yes black what if we knew the answer between cinnabar and black that would constrain the problem can you give me two predictions for what the answer might be either 9% if it was or 25 so now we have a prediction we don't know where cinnabar is but the answer could be that black to vestigial should either be about 9% right that's what that would be here or about 25% the answer about 9% that's what Sturdivant found that's a prediction and kind of cool and you can imagine you know taking the data home and you know it's probably 9 o'clock and you now realize wow freaky it's 9% so then he looked at he looked at the mutation lobe low but was another mutation the Lobeck mutation showed 5% recombination from vestigial where should we put it left or right well let's make some predictions suppose it's over here will it be very close to cinnabar will be closer to black then but what it was over here well it'd be further so let's put lobe in and suppose we know that lobe is 5% then what's the prediction for black – lobe 22% answer according to the notebooks 21% pretty close you'd like it to be exactly 22 but life doesn't always turn out that way 21 is pretty close to 22 what other predictions could we make if this is cinnabar here could you give me a prediction for cinnabar to Loeb 13% yep that works curved wing recombination distance from lobed 3% so now you have some predictions you have this prediction here you predict 8% answer about 8% over here you predict 16% answer about 16% bingo Sturdevant says if these genes we call them low SCI often I'll use the word locus synonymous with gene locus means a place and geneticists think about genes as a place on a chromosome if these low SCI the plural of locus if these low SCI were really arrayed along a linear structure then it would have to be the case that they would have certain attitude relationships between them and the chance that they would have these additive relationships if they weren't part of a line is pretty implausible that's a real prediction a very remarkable prediction and it holds up with the data stirred event pulls the all-nighter by the time the Sun comes up at Columbia University this is Morningside Heights he's got the whole thing worked out yes this chromosome theory must be right it fits beautifully all of these data pretty cool you are all authorized to blow off your homework anytime you make a discovery like that okay that's a course rule any homework homework will be forgiven for discoveries of that magnitude all right tell your TAS so now what does it really tell us it tells us that if genes are very close together the recombination frequency our recombination frequency or RF might be very little they could be as low as almost zero which means you never see a recombinant because they're right next to each other or it could be that they're further apart might be 1% it might be 10% could keep growing it might be 30% suppose it's way way way way way far away what's the largest it ever gets to be well if they're on different chromosomes suppose they were totally independent segregation different chromosomes what would they be now it's 50% because there remember 1 2 1 2 1 2 1 says that the recombinant said well change station let's come to that hundred they're on different chromosomes 1 2 1 2 1 2 1 means that it's 50% half of them are recombinant types it turns out on the same chromosome as you get farther and farther and farther you might say there's going to be a hundred percent chance of a crossover and you might say the recombination frequency could keep growing past 50% it turns out it doesn't the reason is that multiple crossovers can happen so mathematical interjection here if here's my gene and here's my gene there could be one crossover there could be two crossovers there could be three crossovers and so in fact it turns out as you get very far away you have to start paying attention to the probabilities of double crossovers and triple crossovers and so it turns out that it's a Poisson process of the number of crossovers that occurs give or take and you see a recombination if there's an odd number and for that reason it never gets above 50% so as the distance gets further and further and further goes from 0 to 50 which is the same number you get for separate chromosomes otherwise you might think that if there was just one crossover it gets to 100% probability of recombination but it never does because there are doubles and you can actually observe if you make a cross that has three different genes segregating in it you can actually see the double crossover type so you can see very nicely that if you make a cross involving black cinnabar and vestigial over plus plus plus you can see that cinnabar is right in the middle because this recombination happens at a pretty good frequency this recombination happens at a good frequency giving you plus cinnabar vestigial or black plus plus sometimes you will get that recombination you'll get out gametes that are black plus vestigial but at a much lower frequency because they take two crossovers what will be the probability of seeing a black cinnabar vestigial well we said that this one was about 9% this one was about 8% what's the product of a 9% chance in an 8% chance it's about a 1% chance a little less than 1% chance that's how frequently you see black plus vestigial you can even predict the probability of a double crossover event by multiplying the two events that have to happen so your bottom line rules here is that because of these double crossovers where combination frequency can go from zero to about 50% this is independent assortment and it either occurs if you're on different chromosomes or if you're very far away on the same chromosome they behave as if they're independent of each other any questions about any of yes why didn't Mendel ever see recombination turns out that with seven chromosomes in there big issue in length he never actually ran into two low side that were close enough to notice it that's why flies actually only have three major chromosomes there's a fourth but it's a puny little thing and because they were much more intensively collecting mutations in morgan's fly room they began having a lot of them and they had to bump into recombination pretty early Morgan simply a Mendel simply didn't have enough that were close enough think about what would have happened if just by chance somebody were selling the strain of peas in the market which had a mutation in a locust that had 10% recombination distance and it's screwed up Mendel's law of independent assortment of Tolosa Mendel might not have published the paper sometimes in science it's actually valuable to first get the oversimplification out like his second law and then deal with the complexity that sits on top of the oversimplification it's kind of lucky that Mendel didn't have enough of them to be bothered in the first paper but it's and so in fact all of the all of Mendel's seven Louis I have now been mapped most have been cloned molecularly and so we actually know where they are etc it's a really good question that's sort of why he didn't

34 thoughts on “Linkage and Recombination, Genetic maps | MIT 7.01SC Fundamentals of Biology

  1. So thank you Mr Lander for your teaching rarely witnessed verified by comments below. Most teachers / lecturers from when education became institutionalised career ambitions are to get out of the class room one way or another. Teaching properly is very demanding in presentation, tiring physically and assessing whether students are picking up on the lesson and when to break, loop, review, change tack and review. There are other very good teachers on line Bob W for cancer and Lewis F for bio…. and I enjoy and partially get the gist of their content. If all teachers were like these guys kids would whole heartedly embrace education……

  2. Teachers are born and edu programmes fail to make anyone other than a facilitator who pass through concepts, use slides and hand out literature which is NOT teaching. Note the use of the black board makes students follow the letters as they are written and better absorb the essence than a quick slide and covering waffle. Born teachers have a chemistry of character, clearness of expression and a passion for their knowledge to be imparted to students who will pick up the ball and take it to the next marker.

  3. You know, we lose so much fire the more we study and the more we make science so clinical and analytics. Thank you for uploading this! Doing my masters degree and spending so much time doing tasks and analysing data really takes away from the notion that science is so exciting and interesting! Really would love to meet him one day

  4. in less than 40 minutes I understood what we had in a week and i couldn't understand it! seriously Thank you Mr.Lander and for the crew who made these courses available online.

  5. Meiosis was discovered before the discovery of Morgan's recombination. In meiosis chiasmata formation is already discussed. Then, how Morgan was shocked to know about recombination or that chromosomes cross each other and form chiasmata ? Can someone explain ?

  6. At 4:50 he says "Are those recessive alleles?" and then he explains that they are alleles assosciated with the recessive phenotype . They could also control multiple other phenotypes,some of which could be dominant. So, is he talking about epistasis effects??? Can someone explain this statement ??

  7. Thanks for helping us out.
    Wish everyone had the same passion for the subject.
    Thousands across the globe are indebted to you…!!

  8. Pretty good lesson, thanks in the name of me and all of us who didn't had the opportunity to attend in MIT

  9. I'm from Central part of Ukraine, this is a great lecture, easy flowing teaching strategy. Classical type of integration making complexity down to simplicity.

  10. I really liked this speech, and how the teacher presented it. Though there are some points I couldn't get what he said 😀

  11. So if Mendels theory that all alleles assorted independently was correct, test crossing the heterozygote with the homozygous recessive would mean a 1:1:1:1 genotypic ratio of progeny. If the chromosome theory that alleles for body colour and wing shape are found on the same chromosome was correct, the genotypes observed in the progeny would be only those conserved through the F0 and F1 generations, without the recombinant types (i.e. b+ and vg+). As recombinant progeny were observed but in lower ratios, the conclusion was drawn that the genes are indeed linked, although there is some form of crossing over occurring between homologous chromosomes during meiosis.

  12. So if Mendels theory that all alleles assorted independently was correct, test crossing the heterozygote with the homozygous recessive would mean a 1:1:1:1 genotypic ratio of progeny. If the chromosome theory that alleles for body colour and wing shape are found on the same chromosome was correct, the genotypes observed in the progeny would be only those conserved through the F0 and F1 generations, without the recombinant types (i.e. b+ and vg+). As recombinant progeny were observed but in lower ratios, the conclusion was drawn that the genes are indeed linked, although there is some form of crossing over occurring between homologous chromosomes during meiosis.

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