1 00:00:01 --> 00:00:03 I want to go back a second to the end of last time because in the 2 00:00:03 --> 00:00:06 closing moments there, we, or at least I, got a little bit 3 00:00:06 --> 00:00:09 lost, and where the plusses and 4 00:00:09 --> 00:00:12 minuses were at a certain table. 5 00:00:12 --> 00:00:18 And, I want to go back and make sure we've got that straight. 6 00:00:18 --> 00:00:22 We were talking about a situation where we were trying to use genetics, 7 00:00:22 --> 00:00:27 and the phenotypes that might be observed in mutants to try to 8 00:00:27 --> 00:00:32 understand the biochemical pathway because we're beginning to try to 9 00:00:32 --> 00:00:36 unite the geneticist's point of view who looks only at mutants, 10 00:00:36 --> 00:00:40 and the biochemist's point of view who looks at pathways and proteins. 11 00:00:40 --> 00:00:44 And, I had hypothesized that there was some biochemists who had thought 12 00:00:44 --> 00:00:49 up a possible pathway for the synthesis of arginine that involved 13 00:00:49 --> 00:00:53 some precursor, alpha, beta, gamma, 14 00:00:53 --> 00:00:57 where alpha is turned into beta; beta is turned into gamma; and gamma 15 00:00:57 --> 00:01:02 is used to turn into arginine. And, hypothetically, 16 00:01:02 --> 00:01:06 there would be some enzymes: enzyme A that converts alpha, 17 00:01:06 --> 00:01:10 enzyme B that converts beta, and enzyme C that converts gamma. 18 00:01:10 --> 00:01:14 And, we were just thinking about, what would the phenotypes look like 19 00:01:14 --> 00:01:18 of different arginine auxotrophs that had blocks at different stages 20 00:01:18 --> 00:01:22 in the pathway. If I had an arginine auxotroph that 21 00:01:22 --> 00:01:26 had a block here because let's say a mutation in a gene affecting this 22 00:01:26 --> 00:01:30 enzyme, or at a block here at a mutation affecting, say, 23 00:01:30 --> 00:01:34 the gene that encodes enzyme C, how would I be able to tell very 24 00:01:34 --> 00:01:38 simply that they were in different genes? Last time, 25 00:01:38 --> 00:01:42 we found that we could tell they were in different genes by doing a 26 00:01:42 --> 00:01:46 cross between a mutant that had the first mutation, 27 00:01:46 --> 00:01:50 and a mutant that had the second mutation, and looking at the double 28 00:01:50 --> 00:01:54 heterozygote, right? And, if in the double heterozygote 29 00:01:54 --> 00:01:58 you had a wild type or a normal phenotype, then they had to be in 30 00:01:58 --> 00:02:03 different genes, OK? Remember that? 31 00:02:03 --> 00:02:06 That was called a test of complementation. 32 00:02:06 --> 00:02:09 That was how we were able to sort out which mutations were in the same 33 00:02:09 --> 00:02:12 gene, and which mutations were in different genes. 34 00:02:12 --> 00:02:15 Now we can go a step further. When we've established that they're 35 00:02:15 --> 00:02:18 in different genes, we can try to begin to think, 36 00:02:18 --> 00:02:21 how do these genes relate to a biochemical pathway? 37 00:02:21 --> 00:02:24 I wanted to begin to introduce, because it'll be relevant for today, 38 00:02:24 --> 00:02:27 this notion: so, suppose I had a mutation that affected enzyme A so 39 00:02:27 --> 00:02:31 that this enzymatic step couldn't be carried out. 40 00:02:31 --> 00:02:35 Such a mutant, when I just try to grow it on 41 00:02:35 --> 00:02:40 minimal medium won't be able to grow. If I give it the substrate alpha, 42 00:02:40 --> 00:02:45 it doesn't do it any good because it hasn't got the enzyme to convert 43 00:02:45 --> 00:02:50 alpha. So, given alpha, it won't grow. But if I give it 44 00:02:50 --> 00:02:55 beta, what will happen? It can grow because I've bypassed 45 00:02:55 --> 00:03:00 the defect. What about if I give it gamma? Arginine? 46 00:03:00 --> 00:03:18 Now, if instead the mutation were affecting enzymatic step here, 47 00:03:18 --> 00:03:36 then if I give it on minimal or medium 48 00:03:36 --> 00:03:40 but it can grow on gamma. What about this last line? 49 00:03:40 --> 00:03:44 If I have a mutation and the last enzymatic step, 50 00:03:44 --> 00:03:49 minimal medium can't grow with alpha, can't grow with beta, 51 00:03:49 --> 00:03:53 can't even grow with gamma. But, it can grow with arginine 52 00:03:53 --> 00:03:57 because I've bypassed that step. So, I get a different phenotype, 53 00:03:57 --> 00:04:02 the inability to grow even on gamma, 54 00:04:02 --> 00:04:08 but I can grow on arginine. Now, here, if I put together those 55 00:04:08 --> 00:04:13 mutants and make a double mutant, a double homozygote, let's say, 56 00:04:13 --> 00:04:19 that's defective in both A and B, which will it look like? Will it be 57 00:04:19 --> 00:04:24 able to grow on minimal medium? Will it be able to grow on alpha? 58 00:04:24 --> 00:04:30 Will it be able to grow on beta? 59 00:04:30 --> 00:04:36 Will it be able to grow on gamma and arginine? What about if I have a 60 00:04:36 --> 00:04:43 double mutant in B and C, minus, minus, minus, minus, 61 00:04:43 --> 00:04:49 plus? So this looks the same as that. This looks the same as that. 62 00:04:49 --> 00:04:56 And so, by looking at different mutant combinations, 63 00:04:56 --> 00:05:02 I can see that the phenotype of B here is what occurs in the double 64 00:05:02 --> 00:05:08 mutant. So, this phenotype is epistatic to this phenotype. 65 00:05:08 --> 00:05:13 Epistatic means stands upon, OK? So, phenotypes, just like 66 00:05:13 --> 00:05:19 phenotypes can be recessive or dominant, you can also speak about 67 00:05:19 --> 00:05:24 them being epistatic. And epistatic means when you have 68 00:05:24 --> 00:05:30 both of two mutations together at the epistatic 69 00:05:30 --> 00:05:33 then one of them is epistatic to the other, perhaps. 70 00:05:33 --> 00:05:36 It will, in fact, be the one that is present. 71 00:05:36 --> 00:05:39 So, this is not so easy to do in many cases because if I take 72 00:05:39 --> 00:05:43 different kinds of mutation affecting wing development, 73 00:05:43 --> 00:05:46 and I put them together in the same fly, I may just get a very messed up 74 00:05:46 --> 00:05:49 wing, and it's very hard to tell that the double mutant has a 75 00:05:49 --> 00:05:53 phenotype that looks like either of the two single mutants. 76 00:05:53 --> 00:05:56 But sometimes, if they fall very nicely in a pathway where this 77 00:05:56 --> 00:06:00 affects the first step, this affects the second step 78 00:06:00 --> 00:06:04 this affects the third step, this affects the fourth step, 79 00:06:04 --> 00:06:08 then the double mutant will look like one of those, 80 00:06:08 --> 00:06:12 OK? And, that way you can somehow order things in a biochemical 81 00:06:12 --> 00:06:16 pathway. Now, notice, this is all indirect, 82 00:06:16 --> 00:06:20 right? This is what geneticists did in the middle of the 20th century to 83 00:06:20 --> 00:06:24 try to figure out how to connect up mutants to biochemistry. 84 00:06:24 --> 00:06:28 Actually, that's not true. It's what geneticists still do 85 00:06:28 --> 00:06:31 today because you might think that Well, we don't need to do this 86 00:06:31 --> 00:06:34 anymore, but in fact geneticists constantly are looking at mutants 87 00:06:34 --> 00:06:38 and making connections trying to say, what does this double combination 88 00:06:38 --> 00:06:41 look like? What does that double combination look like, 89 00:06:41 --> 00:06:44 and how does that tell us about the developmental pathway, 90 00:06:44 --> 00:06:48 which cell signals which cell? This turns out to be one of the 91 00:06:48 --> 00:06:51 most powerful ways to figure out what mutations do by saying the 92 00:06:51 --> 00:06:54 combination of two mutations looks like the same as one of them, 93 00:06:54 --> 00:06:58 allowing you to order the mutations in a pathway. 94 00:06:58 --> 00:07:02 And, there's no general way to grind up a cell and order things in a 95 00:07:02 --> 00:07:06 pathway. Genetics is a very powerful tool for doing that. 96 00:07:06 --> 00:07:10 Now, there are some ways to grind up cells and order things, 97 00:07:10 --> 00:07:15 but you need both of these techniques to believe stuff. 98 00:07:15 --> 00:07:19 Anyway, I wanted to go over that, because it is an important concept, 99 00:07:19 --> 00:07:23 the concept of epistasis, the concept of relating mutations to 100 00:07:23 --> 00:07:27 steps and pathways, but what I mostly want to do today 101 00:07:27 --> 00:07:33 is go on now to talk about genetics not in organisms like yeast or fruit 102 00:07:33 --> 00:07:39 flies or even peas, but genetics in humans. 103 00:07:39 --> 00:07:46 So, what's different about genetics in humans than genetics in yeast? 104 00:07:46 --> 00:07:53 You can't choose who mates with whom. Well, you can. 105 00:07:53 --> 00:08:00 I mean, in the days of arranged marriages maybe you couldn't, 106 00:08:00 --> 00:08:04 but you can choose who mates with whom, but only for yourself, 107 00:08:04 --> 00:08:08 right? What you can't do is arrange other crosses in the human 108 00:08:08 --> 00:08:12 population as an experimentalist. Now, your own choice of mating, 109 00:08:12 --> 00:08:16 unfortunately or fortunately perhaps produces too few progeny to be 110 00:08:16 --> 00:08:20 statistically significant. As a parent of three, I think about 111 00:08:20 --> 00:08:24 what it would take to raise a statistically significant number of 112 00:08:24 --> 00:08:28 offspring to draw any conclusions, and I don't think I could do that. 113 00:08:28 --> 00:08:32 So, you're absolutely right. We can't arrange the matings that 114 00:08:32 --> 00:08:36 we want in the human population. So, that's the big difference. 115 00:08:36 --> 00:08:40 So, can we do genetics anyway? How do we do genetics even though 116 00:08:40 --> 00:08:45 we can't arrange the matings the way we'd like to? Sorry? 117 00:08:45 --> 00:08:49 Well, family trees. We have to take the matings as we find them in 118 00:08:49 --> 00:08:54 the human population. You can talk to somebody who might 119 00:08:54 --> 00:08:59 have an interesting phenotype, I don't know, attached earlobes, 120 00:08:59 --> 00:09:02 or very early heart disease, or some unusual color of eyes, 121 00:09:02 --> 00:09:05 and begin to collect a family history on that person. 122 00:09:05 --> 00:09:08 It's a little bit of a dodgy thing because you might just be relying on 123 00:09:08 --> 00:09:12 that person's recollection. So, if you were really industrious 124 00:09:12 --> 00:09:15 about this, you'd go check out each of their family members and test for 125 00:09:15 --> 00:09:18 yourself whether they have the phenotype. People who do serious 126 00:09:18 --> 00:09:21 human genetic studies often go and do that. They have to go confirm, 127 00:09:21 --> 00:09:25 either by getting hospital records or interviewing the other members of 128 00:09:25 --> 00:09:28 the family, etc. So, this is not as easy as plating 129 00:09:28 --> 00:09:39 out lots of yeasts on a Petri plate. 130 00:09:39 --> 00:09:58 And then you get pedigrees. And the pedigrees look like this. 131 00:09:58 --> 00:10:18 Here's a pedigree. Tell me what you make of it. 132 00:10:18 --> 00:10:26 Now, symbols: squares are males, circles are females by convention, 133 00:10:26 --> 00:10:32 a colored in symbol means the phenotype that we're 134 00:10:32 --> 00:10:36 interested in studying at the moment. So, in any given problem, 135 00:10:36 --> 00:10:41 somebody will tell you, well, we're studying some interesting 136 00:10:41 --> 00:10:46 phenotype. You often have an index case or a proband, 137 00:10:46 --> 00:10:50 meaning the person who comes to clinical attention, 138 00:10:50 --> 00:10:55 and then you chase back in the pedigree and try to reconstruct. 139 00:10:55 --> 00:11:00 So, suppose I saw a pedigree like this. 140 00:11:00 --> 00:11:22 What conclusions could I draw? Sorry? Recessive, sex link trait; 141 00:11:22 --> 00:11:35 why sex link trait? So, let's see if we can get your 142 00:11:35 --> 00:11:40 model up here. You think that this represents 143 00:11:40 --> 00:11:46 sex-linked inheritance. So, what would the genotype be of 144 00:11:46 --> 00:11:51 this male here? Mutant: I'll use M to denote a 145 00:11:51 --> 00:11:56 mutant carried on the X chromosome, and a Y on the opposite chromosome. 146 00:11:56 --> 00:12:02 What's the genotype of the female here? 147 00:12:02 --> 00:12:06 So, it's plus over plus where I'll use plus to denote the gene carried 148 00:12:06 --> 00:12:10 on the normal X chromosome. OK, and then what do you think 149 00:12:10 --> 00:12:14 happened over here? So, mutant over plus, 150 00:12:14 --> 00:12:18 you mate to this male who is plus over plus. Why is that male plus 151 00:12:18 --> 00:12:22 over plus? Oh, right, good point. 152 00:12:22 --> 00:12:26 It's not plus over plus. It's plus over Y. Why is that male 153 00:12:26 --> 00:12:30 plus over Y as opposed to mutant over Y? 154 00:12:30 --> 00:12:35 He'd have the mutant phenotype. So, he doesn't have the mutant 155 00:12:35 --> 00:12:40 phenotype so he can infer he's plus over Y. OK, and then what happens 156 00:12:40 --> 00:12:46 here? Mutant over Y; this is plus over Y. How did this person get 157 00:12:46 --> 00:12:51 plus over Y? They just the plus for mom, and the daughters, 158 00:12:51 --> 00:12:57 Y from dad, and a plus from mom. That's cool. Now, what about the 159 00:12:57 --> 00:13:02 daughters there? They're plus over plus, 160 00:13:02 --> 00:13:06 or M over plus? Is one, one, and one the other? Well, 161 00:13:06 --> 00:13:11 in textbooks it's always plus over plus and M over plus, 162 00:13:11 --> 00:13:16 but in real life? We don't know, right? So, this could be plus over 163 00:13:16 --> 00:13:20 plus, or M over plus, we don't know, OK? Now, 164 00:13:20 --> 00:13:25 what about on this side of the pedigree here? 165 00:13:25 --> 00:13:30 What's the genotype here? Plus over Y, OK. 166 00:13:30 --> 00:13:36 Why not mutant over Y? Because if they got the mutant, 167 00:13:36 --> 00:13:42 it would have to come from the, OK, so here, plus over plus, and then 168 00:13:42 --> 00:13:48 here, everybody is normal because there's no mutant allele segregated. 169 00:13:48 --> 00:13:54 Yes? Yeah, couldn't there just be recessive? I mean, 170 00:13:54 --> 00:14:00 it's a nice story about the sex link 171 00:14:00 --> 00:14:07 but couldn't it be recessive? So, walk me through it being 172 00:14:07 --> 00:14:15 recessive. M over plus, plus over plus. Wait, wait, 173 00:14:15 --> 00:14:22 wait, hang on. Could this be M over plus, and that person be affected? 174 00:14:22 --> 00:14:30 It's got to be M over M, right so mutants over mutants 175 00:14:30 --> 00:14:37 but that's possible. Yeah, OK. So, what would this 176 00:14:37 --> 00:14:44 person be? Plus over plus, let's say, come over here. Now, 177 00:14:44 --> 00:14:51 what would this person be? M plus. It has to be M plus because, OK, 178 00:14:51 --> 00:14:58 and what about this person here? M plus, now what about the 179 00:14:58 --> 00:15:05 offspring? So, one of them is M over M, 180 00:15:05 --> 00:15:11 plus over plus, and two M pluses. Does it always work out like that? 181 00:15:11 --> 00:15:17 [LAUGHTER] No, it doesn't always work out like that at all. 182 00:15:17 --> 00:15:23 So, I'm just going to write plus over plus here just to say, 183 00:15:23 --> 00:15:29 tough, right? In real life, it doesn't always come out like that. 184 00:15:29 --> 00:15:35 What about over here? It would have to be plus over plus. 185 00:15:35 --> 00:15:39 Why not? It doesn't because it could be M over plus and have no 186 00:15:39 --> 00:15:44 effect at offspring by chance, right? But, you were going to say 187 00:15:44 --> 00:15:48 it's plus over plus because in the textbooks it's always plus over plus 188 00:15:48 --> 00:15:53 in pictures like this, right? And then, it all turns out 189 00:15:53 --> 00:15:57 to be pluses and mutants, and pluses and mutants, and all that, 190 00:15:57 --> 00:16:02 right? Well, which picture's right? 191 00:16:02 --> 00:16:08 Sorry? You don't know. So, that's not good. There's supposed 192 00:16:08 --> 00:16:14 to be answers to these things. Could either be true? Which is 193 00:16:14 --> 00:16:19 more likely? The one on the left? Why? More statistically probable, 194 00:16:19 --> 00:16:25 how come? Because it is. It may not quite suffice as a fully 195 00:16:25 --> 00:16:31 complete scientific answer though. 196 00:16:31 --> 00:16:48 Yes? Yep. Well, but I have somebody who is affected 197 00:16:48 --> 00:17:05 here. So, given that I've gotten affected person in the family -- 198 00:17:05 --> 00:17:08 yeah, so it is actually, you're right, statistically somewhat 199 00:17:08 --> 00:17:12 less likely that you would have two independent M's entering the same 200 00:17:12 --> 00:17:16 pedigree particularly if M is relatively rare. 201 00:17:16 --> 00:17:20 If M is quite common, however, suppose M were something 202 00:17:20 --> 00:17:24 was a 20% frequency in the population, then it actually might 203 00:17:24 --> 00:17:28 be quite reasonable that this could happen. So, what would you really 204 00:17:28 --> 00:17:33 want to do to test this? Sorry? Well, if you found any females here 205 00:17:33 --> 00:17:39 maybe you'd be able to conclude that it was autosomal recessive because 206 00:17:39 --> 00:17:46 females never show a sex-linked trait. Is that true? 207 00:17:46 --> 00:17:53 No, that's not true. Why not? You're right. So, you just have to 208 00:17:53 --> 00:18:00 be homozygous for it on the X. So, having a single 209 00:18:00 --> 00:18:09 female won't, I mean, she's not going to take that as 210 00:18:09 --> 00:18:18 evidence. Get an affected female and demonstrate that all of her male 211 00:18:18 --> 00:18:28 offspring show the trait. Cross her with, wait, wait. 212 00:18:28 --> 00:18:31 This is a human pedigree guys [LAUGHTER]. Whew! There are issues 213 00:18:31 --> 00:18:35 involved here, right? You could introduce her to a 214 00:18:35 --> 00:18:39 normal guy, [LAUGHTER] but whether you can cross her to a normal guy is 215 00:18:39 --> 00:18:43 not actually allowed. So, you see, these are exactly the 216 00:18:43 --> 00:18:46 issues in making sense out of pedigrees like this. 217 00:18:46 --> 00:18:50 So, what you have to do is you have to collect a lot of data, 218 00:18:50 --> 00:18:54 and the kinds of characteristics that you look for in a pedigree, 219 00:18:54 --> 00:18:58 but they are statistical characteristics, and 220 00:18:58 --> 00:19:02 notwithstanding -- So, this could be colorblindness or 221 00:19:02 --> 00:19:06 something, but notwithstanding the pictures in the textbook of 222 00:19:06 --> 00:19:10 colorblindness and all that, you really do have to take a look at 223 00:19:10 --> 00:19:14 a number of properties. What are some properties? 224 00:19:14 --> 00:19:19 One you've already referred to which is there's a predominance in 225 00:19:19 --> 00:19:23 males if it's X-linked. Why is there a predominance in 226 00:19:23 --> 00:19:27 males? Well, there's a predominance in males because if I 227 00:19:27 --> 00:19:32 have an X over Y and I've got a mutation paired on 228 00:19:32 --> 00:19:36 this X chromosome, males only have to get it on one. 229 00:19:36 --> 00:19:40 Females have to get it on both, and therefore it's statistically more 230 00:19:40 --> 00:19:44 likely that males will get it. So, for example, the frequency of 231 00:19:44 --> 00:19:48 colorblindness amongst males is what? Yeah, it's 8-10%, 232 00:19:48 --> 00:19:52 something like that. I think it's about 8% or so. 233 00:19:52 --> 00:19:56 And, amongst females, well, if it's 8% to get one, 234 00:19:56 --> 00:20:00 what's the chance you're going to get two? 235 00:20:00 --> 00:20:08 It's 8% times 8% is a little less than 1% right? 236 00:20:08 --> 00:20:17 It's 0.64%, OK, in females. So, we'll just go 8% 237 00:20:17 --> 00:20:25 squared. So in males, 8% in females, less than one percent. 238 00:20:25 --> 00:20:33 So, there is a predominance in males 239 00:20:33 --> 00:20:39 of these sex-linked traits. Other things: affected males do not 240 00:20:39 --> 00:20:46 transmit the trait to the kids, in particular do not transmit it to 241 00:20:46 --> 00:20:53 their sons, right, because they are always sending the 242 00:20:53 --> 00:21:00 Y chromosomes to their songs. Carrier females 243 00:21:00 --> 00:21:10 transmit to half of their sons, and affected females transmit to all 244 00:21:10 --> 00:21:20 of their sons. And, the trait appears to skip 245 00:21:20 --> 00:21:30 generations, although I don't like this terminology. 246 00:21:30 --> 00:21:35 It skips generations. These are the kinds of properties 247 00:21:35 --> 00:21:40 that you have. So, hemophilia, 248 00:21:40 --> 00:21:45 a good example of this, if I have a child with hemophilia, 249 00:21:45 --> 00:21:50 male with hemophilia, would you be surprised if his uncle had 250 00:21:50 --> 00:21:55 hemophilia? Which uncle would it be, maternal or paternal? 251 00:21:55 --> 00:22:00 The maternal uncle would have hemophilia most likely. 252 00:22:00 --> 00:22:04 It's always possible it could be paternal. This is the problem with 253 00:22:04 --> 00:22:08 human genetics is you've got to get enough families so the pattern 254 00:22:08 --> 00:22:12 becomes overwhelmingly clear, OK, because otherwise, as you can 255 00:22:12 --> 00:22:16 see with small numbers, it's tough to be absolutely certain. 256 00:22:16 --> 00:22:20 So, these are properties of X linked traits. 257 00:22:20 --> 00:22:24 How about baldness? Is baldness, that's a sex-linked 258 00:22:24 --> 00:22:28 trait? How come? You don't see a lot of bald females. 259 00:22:28 --> 00:22:32 Does that prove it's sex linked? Sorry? Guys are stressed more. 260 00:22:32 --> 00:22:37 [LAUGHTER] Is there evidence that it has anything to do with stress? 261 00:22:37 --> 00:22:41 Actually, it has to do with excess testosterone it turns out, 262 00:22:41 --> 00:22:46 that high levels of testosterone are correlated with male pattern 263 00:22:46 --> 00:22:51 baldness, but does the fact that males become bald indicate that this 264 00:22:51 --> 00:22:56 is a sex linked trait? No. Just because it's predominant 265 00:22:56 --> 00:23:01 in male, we have to check these other properties. 266 00:23:01 --> 00:23:05 Is it the case that bald fathers tend to have bald sons? 267 00:23:05 --> 00:23:09 Any evidence on this point? Common-sensical evidence from 268 00:23:09 --> 00:23:14 observation? It's pretty clear. It's very clearly not a sex-linked 269 00:23:14 --> 00:23:18 trait. It's a sex-limited trait, because in order to show this you 270 00:23:18 --> 00:23:23 need to be male because the high levels of testosterone are not found 271 00:23:23 --> 00:23:27 in females even if they have the genotype that might predispose them 272 00:23:27 --> 00:23:33 to become bald if they were male. So, it actually is not a sex-linked 273 00:23:33 --> 00:23:40 trait at all, and it's very clear that male pattern baldness does run 274 00:23:40 --> 00:23:48 in families more vertically. So, you've got to be careful about 275 00:23:48 --> 00:23:55 the difference between sex linked and sex limited, 276 00:23:55 --> 00:24:02 and sex linked you can really pick out from transmission and families. 277 00:24:02 --> 00:24:10 OK, here's another one. New pedigree. 278 00:24:10 --> 00:24:43 She married twice here. OK, what do we got? 279 00:24:43 --> 00:24:53 Yep? She married again. She married twice. She didn't have 280 00:24:53 --> 00:25:01 any offspring the second time. But that happens, 281 00:25:01 --> 00:25:06 and you have to be able to draw it in the pedigree. 282 00:25:06 --> 00:25:12 She's entitled, all right. OK, so she got married again, 283 00:25:12 --> 00:25:17 no offspring from this marriage. That's her legal symbol. You guys 284 00:25:17 --> 00:25:22 think that's funny. It's real, you know? 285 00:25:22 --> 00:25:28 OK, that doesn't mean she's married to two people at the same time. 286 00:25:28 --> 00:25:33 This is not a temporal picture. So, what do we got here? Yep? 287 00:25:33 --> 00:25:38 Sorry, of this person? Well, I'm drawing them as an empty 288 00:25:38 --> 00:25:44 symbol here, indicating that we do not think they have the trait. 289 00:25:44 --> 00:25:50 They're not carriers. How do you propose to find that out? 290 00:25:50 --> 00:25:56 Look at the children. Well, the children are affected. They 291 00:25:56 --> 00:26:02 could be carriers. The data are what they are. 292 00:26:02 --> 00:26:09 You've got to interpret it. Does this person have to be a 293 00:26:09 --> 00:26:16 carrier? What kind of trait do you think this is? 294 00:26:16 --> 00:26:23 Dominant? Does this look like autosomal dominant to you? 295 00:26:23 --> 00:26:30 Yep? Oh, not all the kids have the trait 296 00:26:30 --> 00:26:34 in the first generation, and if this was dominant, 297 00:26:34 --> 00:26:38 they'd all have it? What's a possible genotype for this person? 298 00:26:38 --> 00:26:42 Mutant over plus. And, these kids could be mutant over plus. 299 00:26:42 --> 00:26:46 This could be plus over plus, and this could be plus over plus, 300 00:26:46 --> 00:26:50 mutant over plus, plus over plus, mutant over plus, 301 00:26:50 --> 00:26:54 and plus over plus would be one possibility. On average, 302 00:26:54 --> 00:26:58 what fraction of the kids should get the trait? About half 303 00:26:58 --> 00:27:06 the kids, right? So, let's see what characteristics 304 00:27:06 --> 00:27:18 we have here. We see the trait in every generation. 305 00:27:18 --> 00:27:30 On average, half the kids get the trait. 306 00:27:30 --> 00:27:42 Half of the offspring of an affected individual are affected. 307 00:27:42 --> 00:27:54 What else? Males and females? Roughly equal in males and females? 308 00:27:54 --> 00:28:02 Sorry? One, two, three, 309 00:28:02 --> 00:28:08 four, five to two. So, it's a 5:2 ratio? 310 00:28:08 --> 00:28:13 Oh, in the offspring it's a 2:1 ratio. So, this is like Mendel. 311 00:28:13 --> 00:28:19 You see this number and you say, OK, 2:1. Isn't that trying to tell 312 00:28:19 --> 00:28:24 me something? Not with six offspring. That's the problem is 313 00:28:24 --> 00:28:30 with six offspring, 2:1 might be trying to tell you 1:1. 314 00:28:30 --> 00:28:34 And it is. If I had a dominantly inherited trait where there's a 315 00:28:34 --> 00:28:39 50/50 chance of each offspring getting the disease and it was 316 00:28:39 --> 00:28:44 autosomal, not sex linked, there would be very good odds of 317 00:28:44 --> 00:28:48 getting two males and one female because it happens: flip coins and 318 00:28:48 --> 00:28:53 it happens. So, you have to take that into account, 319 00:28:53 --> 00:28:58 and here you see what else we have. Roughly equal numbers of males and 320 00:28:58 --> 00:29:03 females, they transmit equally, and unaffecteds never transmit. 321 00:29:03 --> 00:29:07 This would be the classic autosomal dominant trait. 322 00:29:07 --> 00:29:11 Right, here this mutant would go mutant over plus, 323 00:29:11 --> 00:29:15 mutant over plus, plus over plus, mutant over plus, plus over plus, 324 00:29:15 --> 00:29:19 plus over plus, and you'd see here that three out of 325 00:29:19 --> 00:29:23 the five here, and one, two, three out of the six 326 00:29:23 --> 00:29:27 there: that's a little more than half but it's small numbers 327 00:29:27 --> 00:29:33 here, right? This is a classic autosomal dominant 328 00:29:33 --> 00:29:39 as in the textbooks. Yes? Turns out not to make too 329 00:29:39 --> 00:29:46 much of a difference. It turns out that there's lots of 330 00:29:46 --> 00:29:53 genome that's on either. And so, it is true that males are 331 00:29:53 --> 00:30:00 more susceptible to certain genetic diseases. 332 00:30:00 --> 00:30:04 So, it'll be some excess, but it won't matter for this. 333 00:30:04 --> 00:30:09 Now, in real life it doesn't always work so beautifully. 334 00:30:09 --> 00:30:13 We'll take an example: colon cancer. There are particular autosomal 335 00:30:13 --> 00:30:18 dominant mutations here that cause a high risk of colon cancer. 336 00:30:18 --> 00:30:23 People who have mutations in a certain gene, MLH-1, 337 00:30:23 --> 00:30:27 have about a 70% risk of getting colon cancer in their life. 338 00:30:27 --> 00:30:33 But notice, it's not 100%. You might have incomplete penetrance. 339 00:30:33 --> 00:30:41 Incompletely penetrance means not everybody who gets the genotype gets 340 00:30:41 --> 00:30:48 the phenotype. Not all people with the M over plus 341 00:30:48 --> 00:30:56 genotype show the phenotype. Once you do that, it messes up our 342 00:30:56 --> 00:31:03 picture colossally, because, tell me, 343 00:31:03 --> 00:31:09 how do we know that this person over here is not actually M over plus. 344 00:31:09 --> 00:31:15 Maybe they're cryptic. They haven't shown the phenotype. 345 00:31:15 --> 00:31:21 And maybe, it'll appear in the next generation. That'll screw up 346 00:31:21 --> 00:31:27 everything. It screws up our rule about not transmitting through 347 00:31:27 --> 00:31:32 unaffected, it screws up the rule about not being shown in 348 00:31:32 --> 00:31:36 every generation, and it will even screw up our 50/50 349 00:31:36 --> 00:31:41 ratio because if half the offspring get M over plus, 350 00:31:41 --> 00:31:46 but only 70% of that half show the phenotype, then only 35% of the 351 00:31:46 --> 00:31:50 offspring will show the phenotype. Unfortunately, this is real life. 352 00:31:50 --> 00:31:55 When human geneticists really look at traits, many mutations, 353 00:31:55 --> 00:32:00 most except the most severe are incompletely penetrant. 354 00:32:00 --> 00:32:04 And so you have to really begin to gather a lot of data to demonstrate 355 00:32:04 --> 00:32:08 that you're dealing with an autosomal dominant trait that's 356 00:32:08 --> 00:32:12 incompletely penetrant. And then there are other issues. 357 00:32:12 --> 00:32:16 There's a gene on chromosome number 17 called BRCA-1, 358 00:32:16 --> 00:32:20 mutations in which predisposed to a very high risk of breast cancer but 359 00:32:20 --> 00:32:24 only in women. Males carry the mutation and do not 360 00:32:24 --> 00:32:28 have breast cancer. There are other mutations that do 361 00:32:28 --> 00:32:32 cause breast cancer in males. Males have breast tissue, 362 00:32:32 --> 00:32:36 and can have breast cancer, but the one on chromosome 17 does 363 00:32:36 --> 00:32:40 not. And so, there you would only see this transmitted through females. 364 00:32:40 --> 00:32:45 It would skip into males without showing a phenotype, 365 00:32:45 --> 00:32:49 etc. So, in real life, life's a bit more complicated. 366 00:32:49 --> 00:32:53 All right, so autosomal dominance. Now, let's take one more pedigree. 367 00:32:53 --> 00:32:58 Sorry? Sex limited, but not sex linked. 368 00:32:58 --> 00:33:03 So, on chromosome 17, which is a bona fide autosome, 369 00:33:03 --> 00:33:08 but it's sex limited in that phenotype can only show itself in an 370 00:33:08 --> 00:33:13 individual who happens to be female. Yes? Sorry? How come autosomal 371 00:33:13 --> 00:33:19 recessive? So, if that left guy up there is 372 00:33:19 --> 00:33:24 actually a heterozygote, and up there that individual, 373 00:33:24 --> 00:33:30 so if we had a homozygote, homozygote, heterozygote, 374 00:33:30 --> 00:33:33 homozygote, ooh, you can interpret that pedigree if 375 00:33:33 --> 00:33:37 you want to as an autosomal recessive, provided that M is pretty 376 00:33:37 --> 00:33:40 frequent in the population. That's right. Human geneticists, 377 00:33:40 --> 00:33:44 in fact, to really prove that they've got the right model, 378 00:33:44 --> 00:33:48 collect a lot of pedigrees and run a computer model. 379 00:33:48 --> 00:33:51 The computer model first tries out autosomal recessive, 380 00:33:51 --> 00:33:55 tries out autosomal dominant, tries out dominant with incomplete 381 00:33:55 --> 00:33:59 penetrance, and for every possible model figures out the statistical 382 00:33:59 --> 00:34:03 probability that you would see such data under that model. 383 00:34:03 --> 00:34:05 And when the data become overwhelming and you say, 384 00:34:05 --> 00:34:08 yeah, with one pedigree, any pedigree I draw on the board, 385 00:34:08 --> 00:34:11 it could actually fit almost any for the models. It doesn't say this in 386 00:34:11 --> 00:34:14 the textbooks, but it's true. I get enough 387 00:34:14 --> 00:34:17 pedigrees, and eventually I say the odds are 105 times more likely that 388 00:34:17 --> 00:34:20 this collection of pedigrees would arise from autosomal dominance, 389 00:34:20 --> 00:34:22 inheritance with incomplete penetrance of about 80%. 390 00:34:22 --> 00:34:25 Then, from autosomal recessive inheritance, then I get to write a 391 00:34:25 --> 00:34:28 paper about it. That's really what human 392 00:34:28 --> 00:34:32 geneticists do is they have to collect enough, 393 00:34:32 --> 00:34:36 now, any other organism, you'd just set up a cross, 394 00:34:36 --> 00:34:41 but you can't. And, as long as we have nontrivial models, 395 00:34:41 --> 00:34:46 we really have to collect a lot of data. Let's take the next pedigree, 396 00:34:46 --> 00:34:50 great, that you're thinking like a human geneticist. 397 00:34:50 --> 00:34:55 It's very good. Here's the next pedigree. Actually, 398 00:34:55 --> 00:35:00 I'm going to reverse it. There we go. 399 00:35:00 --> 00:35:03 What's that? Who knows? You can't tell. Good, I've got you 400 00:35:03 --> 00:35:07 up to training to the point where, but in textbooks, this would be 401 00:35:07 --> 00:35:11 autosomal recessive. Or it could be anything. 402 00:35:11 --> 00:35:15 You know that, right? But the textbooks would show you this 403 00:35:15 --> 00:35:18 picture as an autosomal recessive. But of course, what else could it 404 00:35:18 --> 00:35:22 be? It could be an autosomal dominant with incomplete penetrance. 405 00:35:22 --> 00:35:26 It could be sex linked. It could be a lot of things. 406 00:35:26 --> 00:35:30 It could also be, I haven't told you the phenotype. 407 00:35:30 --> 00:35:34 What if the phenotype here was getting hit by a truck? 408 00:35:34 --> 00:35:38 [LAUGHTER] Would you tend to observe this? Yep, 409 00:35:38 --> 00:35:42 so getting hit by a truck, for example, if someone gets hit by 410 00:35:42 --> 00:35:46 a truck, it's unlikely either their parents were hit by a truck, 411 00:35:46 --> 00:35:50 or going back several generations that their grandparents were hit by 412 00:35:50 --> 00:35:54 a truck. So, how do you tell being hit by a truck from, 413 00:35:54 --> 00:35:58 I mean, that is to say, how do you know that something's 414 00:35:58 --> 00:36:01 genetic at all? When it's relatively rare and it 415 00:36:01 --> 00:36:04 pops up in a pedigree, how do you know it's genetic? 416 00:36:04 --> 00:36:07 Because of the DNA. But, I mean, it takes a lot of work to find the 417 00:36:07 --> 00:36:10 gene and all that as we'll come to the course. You might want a little 418 00:36:10 --> 00:36:13 bit of assurance before you go write the grant to the NIH and say I'm 419 00:36:13 --> 00:36:16 going to find the gene for this because you write it and say I'm 420 00:36:16 --> 00:36:19 going to find the gene for getting hit by a truck, 421 00:36:19 --> 00:36:22 and they're going to write back and say show me that it's worth spending 422 00:36:22 --> 00:36:25 money to find that gene. Show me that it's true. So, 423 00:36:25 --> 00:36:28 what kind of things would we look for? If we wanted to show something 424 00:36:28 --> 00:36:32 was autosomal recessive in a population, what would we do? 425 00:36:32 --> 00:36:40 More data. So, we collect a lot of families, 426 00:36:40 --> 00:36:48 and what would we see? As we collected more and more families, 427 00:36:48 --> 00:36:56 we begin to see what things? Sometimes we might see families like 428 00:36:56 --> 00:37:04 this, or we might see families like this. [LAUGHTER] 429 00:37:04 --> 00:37:08 If both parents were mutants, all the children would be mutant, 430 00:37:08 --> 00:37:13 right? We'd color them in mutant. Is that true? Well, first off, it 431 00:37:13 --> 00:37:18 depends. Some of the things we want to study are extremely severe 432 00:37:18 --> 00:37:23 medical genetical phenotypes, and they're not going to live to 433 00:37:23 --> 00:37:28 have children. So, that's an issue that you have 434 00:37:28 --> 00:37:33 to deal with. But, it is true that if it was 435 00:37:33 --> 00:37:37 autosomal recessive, a mating between two homozygotes for 436 00:37:37 --> 00:37:42 that gene would transmit. [LAUGHTER] What if they were all in 437 00:37:42 --> 00:37:46 the same car? Which is a very important part, 438 00:37:46 --> 00:37:51 because we joke about the car, but diet, things like that, are 439 00:37:51 --> 00:37:55 familial correlated environmental factors. There are environmental 440 00:37:55 --> 00:38:00 factors that correlate within a family. 441 00:38:00 --> 00:38:04 And so, it's not trivial to make this point. So, 442 00:38:04 --> 00:38:09 all right, we'll be able to demonstrate what's the real proof of 443 00:38:09 --> 00:38:14 Mendelian inheritance here? Because they could all be in the 444 00:38:14 --> 00:38:19 same car, or they all eat the same kind of food or something like that, 445 00:38:19 --> 00:38:24 which predisposes them a certain way. So, we're going to want some better 446 00:38:24 --> 00:38:29 proofs of these things. How about Mendelian ratios? 447 00:38:29 --> 00:38:34 Mendelian ratios anyone? No, because it could be incomplete 448 00:38:34 --> 00:38:38 autosomal dominance. I don't want to mess you up. 449 00:38:38 --> 00:38:42 On the exams, you guys can think cleanly about simple things. 450 00:38:42 --> 00:38:46 But, this could be dominant with incomplete penetrance, 451 00:38:46 --> 00:38:50 though the TA's are going to hate me because I'm telling you that, 452 00:38:50 --> 00:38:54 anyway, what about Mendelian ratios? How about something that's a pretty 453 00:38:54 --> 00:38:58 good prediction? What fraction of the offspring will 454 00:38:58 --> 00:39:02 be affected? We get a lot of families, 455 00:39:02 --> 00:39:07 line them all up. What fraction of the offspring? 456 00:39:07 --> 00:39:12 A quarter. Now, that's a hard and fast prediction. 457 00:39:12 --> 00:39:17 One quarter of the offspring are effective. When I have a mating 458 00:39:17 --> 00:39:22 between two homozygotes, so what am I going to do? 459 00:39:22 --> 00:39:28 I'm going to go out. I'm going to collect a lot of families. 460 00:39:28 --> 00:39:31 Maybe I'll collect 100 families because it'll be a particular 461 00:39:31 --> 00:39:35 disease, diastrophic dysplasia or something like that, 462 00:39:35 --> 00:39:39 xeroderma pygmentosa, ataxia teleangiectasia, 463 00:39:39 --> 00:39:43 and I will go to the disease foundation, and I will get all the 464 00:39:43 --> 00:39:46 pedigrees for all the families, and I'll see how many times it was 465 00:39:46 --> 00:39:50 one affected, two affected, three affected, etc. And on average, 466 00:39:50 --> 00:39:54 the proportion affecteds will be a quarter, except it's not true. 467 00:39:54 --> 00:39:58 If I actually do that, I find that the ratio of affecteds is typically 468 00:39:58 --> 00:40:03 more like a third. It isn't a quarter. 469 00:40:03 --> 00:40:09 Now, this should disturb you greatly because you know full well 470 00:40:09 --> 00:40:16 that M over plus by M over plus should give you a quarter affecteds. 471 00:40:16 --> 00:40:23 But when you actually look at human families, it's not. 472 00:40:23 --> 00:40:30 Why? In other words, when we count up all the matings 473 00:40:30 --> 00:40:33 between heterozygotes, we'll collect all the matings that 474 00:40:33 --> 00:40:37 produce one affected child. We'll collect all the matings that 475 00:40:37 --> 00:40:41 produce two affected children. We'll collect all the matings that 476 00:40:41 --> 00:40:45 produce three affected children. But, we will fail to collect those 477 00:40:45 --> 00:40:48 matings between homozygotes that produce zero affected children. 478 00:40:48 --> 00:40:52 And so, we will systematically overestimate the proportion. 479 00:40:52 --> 00:40:56 Of course, what we really have to do is go out and get all of those 480 00:40:56 --> 00:41:00 couples who were both carriers, but because they had a small number 481 00:41:00 --> 00:41:04 of children didn't happen to have an affected child. 482 00:41:04 --> 00:41:08 That's not very easy to do especially when you don't know the 483 00:41:08 --> 00:41:12 gene in advance. So, when human geneticists try to 484 00:41:12 --> 00:41:16 go out and measure the one-quarter Mendelian ratio, 485 00:41:16 --> 00:41:21 you can't. But what you can do is the following, 486 00:41:21 --> 00:41:25 conditional on the first trial being affected, now what will be the 487 00:41:25 --> 00:41:30 proportion of subsequent children who are affected? 488 00:41:30 --> 00:41:33 A quarter. If I make it conditional, conditioning on having a first child 489 00:41:33 --> 00:41:37 who's affected, number one child who's affected, 490 00:41:37 --> 00:41:40 then I know I've got a mating between heterozygotes. 491 00:41:40 --> 00:41:44 Subsequent offspring now do not have that bias. 492 00:41:44 --> 00:41:47 And so, as a matter of fact, you think this pretty cool thought, 493 00:41:47 --> 00:41:51 right? You've got a condition on one. It turns out there's a very 494 00:41:51 --> 00:41:54 famous paper about cystic fibrosis where somebody forgot this point and 495 00:41:54 --> 00:41:58 made a huge big deal in the literature about the fact that a 496 00:41:58 --> 00:42:02 third of the kids on average had cystic fibrosis in these 497 00:42:02 --> 00:42:06 families, and proposed all sorts of models about how cystic fibrosis 498 00:42:06 --> 00:42:11 might be advantageous and would lead to fertility increases and all that. 499 00:42:11 --> 00:42:16 In fact, it was just a failure to correct for this little statistical 500 00:42:16 --> 00:42:20 bias. OK, this is what human geneticists do is they've got to 501 00:42:20 --> 00:42:25 deal with the popular, now, there's one other trick that 502 00:42:25 --> 00:42:30 you can use to know that something is autosomal recessive. 503 00:42:30 --> 00:42:37 That trick is this. To site this trick, 504 00:42:37 --> 00:42:45 I have to go back to a person called Archibald Garrett. 505 00:42:45 --> 00:42:53 Archibald Garrett was a physician in London around 1900. 506 00:42:53 --> 00:43:01 Garrett studied children with the trait alkoptonuria. 507 00:43:01 --> 00:43:06 Alkoptonuria was what alkopton means black. Uria means urine. 508 00:43:06 --> 00:43:11 They had black urine. This was evident because their urine turned 509 00:43:11 --> 00:43:16 black on treatment with alkaline. How would you treat urine with 510 00:43:16 --> 00:43:22 alkaline. How would people know this? Sorry? Outhouses with lime, 511 00:43:22 --> 00:43:27 yeah, and who's going to look at the children's urine, or something 512 00:43:27 --> 00:43:32 like that? But you're on the right track. 513 00:43:32 --> 00:43:38 How about diapers? You wash diapers, cloth diapers, 514 00:43:38 --> 00:43:43 in alkaline. They turn black. This was evident from black diapers. 515 00:43:43 --> 00:43:49 The kids' urine would turn black. So, he observed this, and you know 516 00:43:49 --> 00:43:54 what Garrett noticed is when he studied, children alkoptonuria, 517 00:43:54 --> 00:44:00 he found that a very large fraction of affected 518 00:44:00 --> 00:44:10 offspring were in fact produced from matings of first cousins. 519 00:44:10 --> 00:44:20 Consanguineous matings: now you laugh, but in fact consanguinity has 520 00:44:20 --> 00:44:30 been something that has been favored in many societies, 521 00:44:30 --> 00:44:35 and in Britain, particularly amongst the upper class 522 00:44:35 --> 00:44:40 in Britain in 1900, marriage or first cousins was quite 523 00:44:40 --> 00:44:45 common, but not as common as he observed. He found that eight out 524 00:44:45 --> 00:44:50 of 17 alkoptonuria patients were the products of first cousin marriages. 525 00:44:50 --> 00:44:55 That's way off the charts because it's nearly a half, 526 00:44:55 --> 00:45:00 when in fact the typical rate in Britain might have been about 5%. 527 00:45:00 --> 00:45:03 So, on the basis of that in the early 1900's, Garrett was able to 528 00:45:03 --> 00:45:07 show only a few years after the rediscovery of Mendel's work that 529 00:45:07 --> 00:45:11 this property of recessive traits, enrichment in the offspring of 530 00:45:11 --> 00:45:15 consanguineous marriages, was a clear demonstration of 531 00:45:15 --> 00:45:18 Mendelian inheritance. Not only did he do that, 532 00:45:18 --> 00:45:22 but Garrett knew because of the work of some biochemists, 533 00:45:22 --> 00:45:26 and this is way cool, that the problem with the urine was 534 00:45:26 --> 00:45:30 that these patients put out in their urine a lot of what's called 535 00:45:30 --> 00:45:42 homogentisic acid, HGA, which basically is a phenolic 536 00:45:42 --> 00:45:54 ring. What Garrett did was he, and that stuff turns black on 537 00:45:54 --> 00:46:02 exposure to air. What might produce from the things 538 00:46:02 --> 00:46:07 you've learned already some kind of ring like that? 539 00:46:07 --> 00:46:12 What building blocks do you know have rings like that of things 540 00:46:12 --> 00:46:17 you've studied already? Phenylalanine, tyrosine both have 541 00:46:17 --> 00:46:22 rings. Suppose somebody had problems breaking down homogentisic 542 00:46:22 --> 00:46:27 acid. Suppose there was some pathway where proteins were 543 00:46:27 --> 00:46:32 broken down into amino acids including phenylalanine 544 00:46:32 --> 00:46:37 and tyrosine. And, they were broken down into 545 00:46:37 --> 00:46:42 homogentisic acid. And they were broken down into I 546 00:46:42 --> 00:46:47 don't know what. And, suppose like we had up there, 547 00:46:47 --> 00:46:52 patients had a mutation in that enzyme. What would happen if I fed 548 00:46:52 --> 00:46:57 patients a lot of protein? In their urine, you would recover 549 00:46:57 --> 00:47:01 lots of homogentisic acid. Suppose I fed them a lot of tyrosine. 550 00:47:01 --> 00:47:05 I'd get a lot of homogentisic acid because the body couldn't break it 551 00:47:05 --> 00:47:09 down. Suppose I fed them a lot of phenylalanine. 552 00:47:09 --> 00:47:13 They would excrete a lot of homogentisic acid. 553 00:47:13 --> 00:47:16 Suppose I fed them homogentisic acid. I would get quantitative 554 00:47:16 --> 00:47:20 amounts of homogentisic acid. Garrett did this. These are the 555 00:47:20 --> 00:47:24 days before institutional review boards, you know, 556 00:47:24 --> 00:47:28 informed consent. It turns out it's harmless feeding them proteins and 557 00:47:28 --> 00:47:33 things like that. But in fact, Garrett, 558 00:47:33 --> 00:47:39 in 1911, worked out that this trait had to be recessive because of its 559 00:47:39 --> 00:47:46 population genetics, and inferred a biochemical pathway 560 00:47:46 --> 00:47:53 by feeding different things along the way and was able to connect a 561 00:47:53 --> 00:48:00 mutation in a gene to a problem with a specific biochemical pathway. 562 00:48:00 --> 00:48:05 Sorry, 1908: this was his Croonian Lecture in 1908. 563 00:48:05 --> 00:48:10 Eight years after the rediscovery of Mendel, he's able to connect 564 00:48:10 --> 00:48:15 genetic defect, showing it's genetic by transmission, 565 00:48:15 --> 00:48:20 to biochemical defect showing that he has a pathway that he can feed 566 00:48:20 --> 00:48:25 things into. And, it all blocks up at the inability to 567 00:48:25 --> 00:48:30 metabolize homogentisic acid. He has connected gene to enzyme by 568 00:48:30 --> 00:48:35 1908. What do you think the reaction to 569 00:48:35 --> 00:48:39 this was? Polite bewilderment, and it sunk like a stone. Nobody 570 00:48:39 --> 00:48:43 was prepared to hear this. This is very much like Mendel in my 571 00:48:43 --> 00:48:47 opinion. Now, he was a distinguished professor. 572 00:48:47 --> 00:48:52 It was the Croonian Lecture. He got lots of accolades and all that, 573 00:48:52 --> 00:48:56 and people said, what a lovely lecture that was, 574 00:48:56 --> 00:49:00 and proceeded to completely forget this connection between genes and 575 00:49:00 --> 00:49:05 enzymes, genes and proteins. It was not until 40 years later or 576 00:49:05 --> 00:49:09 so that Beadle and Tatum, working with a fungus, actually 577 00:49:09 --> 00:49:13 rosper not yeast, demonstrated that all these mutants 578 00:49:13 --> 00:49:17 interfered with the ability to digest or to make particular amino 579 00:49:17 --> 00:49:21 acids, and wrote this up as the one gene, one enzyme hypothesis of how 580 00:49:21 --> 00:49:25 genes encode enzymes, and won the Nobel Prize for this 581 00:49:25 --> 00:49:30 work, but in fact in their Nobel address, 582 00:49:30 --> 00:49:34 Beetle and Tatum noted, actually, you know, Garrett kind of 583 00:49:34 --> 00:49:39 knew all this. But, people weren't ready, 584 00:49:39 --> 00:49:43 yet, to digest it. Genetics had just come along, 585 00:49:43 --> 00:49:48 Biochemistry had just really been invented in the last ten years, 586 00:49:48 --> 00:49:52 and the idea of uniting genetics and biochemistry was just something 587 00:49:52 --> 49:57 people weren't prepared for yet. More next time.