1 00:00:15 --> 00:00:19 OK. We are wrapping up our segment on genetics today, 2 00:00:19 --> 00:00:24 Genetics 4. We're going to talk about human disease genetics, 3 00:00:24 --> 00:00:29 modes of inheritance for human diseased genes. 4 00:00:29 --> 00:00:34 And then we'll transition next time into molecular biology, 5 00:00:34 --> 00:00:38 which is the next blank square here. And then recombinant DNA cell 6 00:00:38 --> 00:00:43 biology and beyond. I wanted to start today by clearing 7 00:00:43 --> 00:00:48 up a couple of things. Firstly, the term F1, 8 00:00:48 --> 00:00:52 in the last lecture I gave you a list of terms, 9 00:00:52 --> 00:00:56 and I used this definition of the first filial generation, 10 00:00:56 --> 00:01:01 the F1 generation as the product of crosses between two homozygous 11 00:01:01 --> 00:01:05 individuals, homozygous for different alleles such that the 12 00:01:05 --> 00:01:09 offspring were always heterozygous, big A, little A at that particular 13 00:01:09 --> 00:01:14 gene. Well, it turns out that some people 14 00:01:14 --> 00:01:18 use the term F1 to refer to the offspring of any cross. 15 00:01:18 --> 00:01:22 So you have the parents and you have the F1s regardless of the 16 00:01:22 --> 00:01:26 genotype of the parents. So that's a looser definition of 17 00:01:26 --> 00:01:30 the term F1. And it's been used in Section and so on, 18 00:01:30 --> 00:01:33 so I didn't want to confuse you. The strict definition is the one I 19 00:01:33 --> 00:01:37 told you, but don't get hung up on that. We're always going to give 20 00:01:37 --> 00:01:40 you the relevant genotypes so you'll be able to figure out what the 21 00:01:40 --> 00:01:44 genotypes of the offspring are. Also, near the end of the last 22 00:01:44 --> 00:01:47 lecture, I talked about crosses involving linked genes. 23 00:01:47 --> 00:01:51 If you remember the Y and D gene controlling color and density, 24 00:01:51 --> 00:01:54 I think, of peas. And I told you that they were linked, 25 00:01:54 --> 00:01:58 and we carried out a test cross. And we then worked out what the 26 00:01:58 --> 00:02:02 percentages of the different phenotypes and genotypes would be. 27 00:02:02 --> 00:02:05 Well, in that example, I assumed that the Y allele and the 28 00:02:05 --> 00:02:09 D allele were together on the same chromosome. But importantly if 29 00:02:09 --> 00:02:12 you're just given the genotype as it's written here, 30 00:02:12 --> 00:02:16 you actually cannot know that. The big Y might be on the opposite 31 00:02:16 --> 00:02:20 chromosome from the big D. So to avoid confusion about that 32 00:02:20 --> 00:02:23 sort of thing, in future examples and in problems, 33 00:02:23 --> 00:02:27 problems, that is test questions, we'll always show you the 34 00:02:27 --> 00:02:31 chromosomes so you'll know that the genes are together on the same 35 00:02:31 --> 00:02:35 chromosome or on opposite. Yeah. And in the absence of this, 36 00:02:35 --> 00:02:40 if the question is to tell us what the alleles must look like and they 37 00:02:40 --> 00:02:45 give you the phenotype, you have to conclude the genotype. 38 00:02:45 --> 00:02:50 If the question is tell us what the alleles must look like then we're 39 00:02:50 --> 00:02:55 not going to give you the answer, but in other situations where 40 00:02:55 --> 00:03:00 there's ambiguity about what the alignment might be, we'll 41 00:03:00 --> 00:03:04 tell you what that is. OK? We also had a question from a 42 00:03:04 --> 00:03:08 student, actually an emailed question, those are also welcome, 43 00:03:08 --> 00:03:11 email question from a student. It was good question because in our 44 00:03:11 --> 00:03:15 discussion of dominance and recessiveness, 45 00:03:15 --> 00:03:19 we really haven't dealt with the molecular nature of that. 46 00:03:19 --> 00:03:22 And that was this individual's interest. Why is an allele dominant 47 00:03:22 --> 00:03:26 over another one? Why is a trait dominant over 48 00:03:26 --> 00:03:29 another one? And I gave an example to him, 49 00:03:29 --> 00:03:33 which I will give to you, which I think covers most of the examples 50 00:03:33 --> 00:03:37 that we've been discussing in class. And it also is an opportunity for 51 00:03:37 --> 00:03:41 me to reinforce the notions related to chromosomes, 52 00:03:41 --> 00:03:44 genes, DNA and proteins, because apparently there are some of 53 00:03:44 --> 00:03:48 you who are still a little fuzzy on those relationships. 54 00:03:48 --> 00:03:52 So let's imagine a gene which is present on a chromosome. 55 00:03:52 --> 00:03:56 Chromosome shown here. Gene shown here. And it's the S gene that 56 00:03:56 --> 00:04:00 we've talked about before that controls smooth versus 57 00:04:00 --> 00:04:04 wrinkled pea texture. So here's the S gene. 58 00:04:04 --> 00:04:08 It's made up of DNA. And based on the sequence of that DNA within the 59 00:04:08 --> 00:04:12 gene, therein lies the information to produce a protein. 60 00:04:12 --> 00:04:16 And we're going to call this protein, in our example, 61 00:04:16 --> 00:04:20 this is a hypothetical example, the starch synthase protein. It's 62 00:04:20 --> 00:04:24 an enzyme that controls a reaction, that catalyzes a reaction from some 63 00:04:24 --> 00:04:28 sugar substrate into some starch. And if you make enough of that 64 00:04:28 --> 00:04:32 starch product then you have a smooth shape. 65 00:04:32 --> 00:04:36 OK? This enzyme controls shape because it produces this product 66 00:04:36 --> 00:04:41 which is involved in the shape of a pea. OK? So this is the normal 67 00:04:41 --> 00:04:46 situation. The big S allele produces a functional starch 68 00:04:46 --> 00:04:51 synthase enzyme which produces enough product to give the pea its 69 00:04:51 --> 00:04:55 smooth shape. In this example, the little S allele, which is the 70 00:04:55 --> 00:05:00 recessive one, has a mutation within the coding 71 00:05:00 --> 00:05:04 sequence of the gene. We won't talk about the nature of 72 00:05:04 --> 00:05:07 that mutation just yet, what it is, why it causes what it 73 00:05:07 --> 00:05:10 does because you're going to get that in the next segment. 74 00:05:10 --> 00:05:13 Just suffice to say that it's a mutation, an alteration of the DNA 75 00:05:13 --> 00:05:15 such that the protein that's produced from this allele is 76 00:05:15 --> 00:05:18 nonfunctional. You might be able to see I've 77 00:05:18 --> 00:05:21 inserted a little X there. It's actually quite little and 78 00:05:21 --> 00:05:24 invisible on your handout, but you might want to just circle it 79 00:05:24 --> 00:05:27 if you look carefully. There's a little X there which is 80 00:05:27 --> 00:05:30 the result of this mutation. And that X causes the protein to be 81 00:05:30 --> 00:05:34 nonfunctional. The enzyme now does not catalyze 82 00:05:34 --> 00:05:38 the production of this starch product, so no starch product is 83 00:05:38 --> 00:05:42 produced. If you don't make the starch product you don't have a 84 00:05:42 --> 00:05:46 smooth shape, you have a wrinkled shape. OK? If the genotype of the 85 00:05:46 --> 00:05:50 pea is little S, little S then none of this enzyme is 86 00:05:50 --> 00:05:54 produced such that none of the starch product is produced such that 87 00:05:54 --> 00:05:58 the pea is wrinkled. OK? Now what happens if you're big 88 00:05:58 --> 00:06:02 S, little S, the heterozygote? Well, for many biochemical reactions, 89 00:06:02 --> 00:06:07 having just one copy of the gene that encodes the functional enzyme 90 00:06:07 --> 00:06:12 is enough. For many biochemical reactions that's true. 91 00:06:12 --> 00:06:16 And so in a situation where big S is dominant over little S, 92 00:06:16 --> 00:06:21 we assume that having one copy of big S makes enough of the starch 93 00:06:21 --> 00:06:26 synthase protein to make enough of that starch product to give the pea 94 00:06:26 --> 00:06:31 its smooth shape. OK? So that's a simple example of why 95 00:06:31 --> 00:06:35 big S is dominant over little S, why you only see the phenotype 96 00:06:35 --> 00:06:40 associated with the little S allele, the wrinkled phenotype when you have 97 00:06:40 --> 00:06:44 two copies of the little S allele. OK? So I hope that helps clarify 98 00:06:44 --> 00:06:48 the situation for you and actually is useful as we talk about human 99 00:06:48 --> 00:06:53 disease genes as well. So this is a slide from your book 100 00:06:53 --> 00:06:57 which allows us to transition from concepts of inheritance 101 00:06:57 --> 00:07:02 to real-life stuff. Genes that regulate how your body 102 00:07:02 --> 00:07:06 functions normally or in response to various environmental stresses. 103 00:07:06 --> 00:07:10 We're now in an era where we can relatively easily figure out whether 104 00:07:10 --> 00:07:15 a disease has a genetic component by looking at families that might have 105 00:07:15 --> 00:07:19 that disease, and based on that information and using mapping 106 00:07:19 --> 00:07:23 techniques like I described to you last time, we can isolate where that 107 00:07:23 --> 00:07:28 gene might lie on all of your chromosomes. 108 00:07:28 --> 00:07:32 And then using molecular techniques, which we'll talk about in future 109 00:07:32 --> 00:07:36 lectures, we can actually isolate that gene, determine its sequence, 110 00:07:36 --> 00:07:40 and based on that produce lots of various valuable things like better 111 00:07:40 --> 00:07:44 ways to diagnose the disease, better ways to understand how the 112 00:07:44 --> 00:07:48 disease process takes place such that we can then perhaps prevent the 113 00:07:48 --> 00:07:52 disease from occurring in the first place or treating it more 114 00:07:52 --> 00:07:56 effectively by replacing the gene with a new copy or producing a drug 115 00:07:56 --> 00:08:01 that can replace the gene in other ways. 116 00:08:01 --> 00:08:06 So this is what we're after. So we need to understand diseased 117 00:08:06 --> 00:08:12 genes and how they behave in such affected families. 118 00:08:12 --> 00:08:17 So there are a number of diseases which have a genetic component. 119 00:08:17 --> 00:08:23 And these diseases have various modes of inheritance. 120 00:08:23 --> 00:08:36 Some of them are autosomal dominant. 121 00:08:36 --> 00:08:42 The diseased gene is dominant over the wild type gene, 122 00:08:42 --> 00:08:48 and I'll give you examples of that. And the term autosomal means that 123 00:08:48 --> 00:08:54 it's not sex linked. That is the disease gene is carried 124 00:08:54 --> 00:09:00 on chromosomes 1 through 22, one of the those chromosomes, 125 00:09:00 --> 00:09:06 not on the X or the Y. It doesn't matter if your father, 126 00:09:06 --> 00:09:10 whether the disease gene is coming from a male or a female, 127 00:09:10 --> 00:09:15 passed on to a daughter or a son. There's no sex linkage for these 128 00:09:15 --> 00:09:19 autosomal dominant diseases. There another class of genes, 129 00:09:19 --> 00:09:24 disease genes which follow autosomal recessive inheritance patterns. 130 00:09:24 --> 00:09:29 Here the disease gene is recessive to wild type. 131 00:09:29 --> 00:09:35 You only see the disease phenotype when you're homozygous for the 132 00:09:35 --> 00:09:41 mutant allele. And, again, autosomal because it's 133 00:09:41 --> 00:09:48 not sex linked. There are X linked diseases which 134 00:09:48 --> 00:09:54 are dominant. In this case, the disease gene is on the X 135 00:09:54 --> 00:10:01 chromosome. There are also X linked diseases that are recessive. 136 00:10:01 --> 00:10:11 There are very few, 137 00:10:11 --> 00:10:15 but for the sake of completeness, Y linked diseases. But there are so 138 00:10:15 --> 00:10:20 few that we're actually not going to talk about them at all in this class. 139 00:10:20 --> 00:10:24 And, finally, there's a class of diseases that 140 00:10:24 --> 00:10:29 we're also not going to talk about but get inherited not from the genes 141 00:10:29 --> 00:10:33 that are in the nucleus of the cell along your chromosomes but rather 142 00:10:33 --> 00:10:38 get inherited from the mitochondria. 143 00:10:38 --> 00:10:42 And since we haven't talked about mitochondria with you really at all 144 00:10:42 --> 00:10:46 we're not going to expect you to know about those diseases, 145 00:10:46 --> 00:10:50 but just have in the back of your minds that those are relatively 146 00:10:50 --> 00:10:54 important. Autosomal dominant diseases are not terribly common. 147 00:10:54 --> 00:10:58 There are about 200 known. Autosomal recessive diseases are 148 00:10:58 --> 00:11:02 actually much more common, though not very frequent in the 149 00:11:02 --> 00:11:06 population. There are about 2, 150 00:11:06 --> 00:11:12 00 of these known. And together I would estimate there are about 25 151 00:11:12 --> 00:11:18 sex linked diseases. So we've used the term autosomal 152 00:11:18 --> 00:11:24 dominant, autosomal recessive, sex linked. What does this really 153 00:11:24 --> 00:11:30 look like in terms of the genes and the alleles? 154 00:11:30 --> 00:11:43 Well, just as in the case of peas, 155 00:11:43 --> 00:11:48 a dominant disease allele will cause disease regardless of the nature of 156 00:11:48 --> 00:11:54 the other allele. It's dominant over the normal 157 00:11:54 --> 00:11:59 common version of the gene. So if we call this allele the 158 00:11:59 --> 00:12:11 disease allele of some gene -- 159 00:12:11 --> 00:12:16 -- and this allele the commonly found on in the population, 160 00:12:16 --> 00:12:22 and we refer to these often as the wild type -- 161 00:12:22 --> 00:12:31 -- in an individual who has this 162 00:12:31 --> 00:12:37 genotype for a dominant disease gene, will they develop disease? 163 00:12:37 --> 00:12:43 Yes, because the disease allele is dominant over the normal copy of the 164 00:12:43 --> 00:12:49 gene. So these individuals will develop disease. 165 00:12:49 --> 00:13:04 For recessive disease alleles you 166 00:13:04 --> 00:13:08 need to have both copies, both alleles be mutant in order to 167 00:13:08 --> 00:13:12 manifest the disease. So here's another gene, 168 00:13:12 --> 00:13:16 which we'll call the H gene, which has a disease allele. This 169 00:13:16 --> 00:13:20 individual is homozygous for the disease allele. 170 00:13:20 --> 00:13:24 Will this individual develop disease? 171 00:13:24 --> 00:13:31 There might be other people in the 172 00:13:31 --> 00:13:35 population who are heterozygous for that allele and have a wild type 173 00:13:35 --> 00:13:40 allele on the other chromosome. Will they develop disease? No. 174 00:13:40 --> 00:13:45 These individuals are called heterozygous carriers. 175 00:13:45 --> 00:13:54 They carry the disease allele, 176 00:13:54 --> 00:13:58 but because they also carry a wild type allele they don't develop the 177 00:13:58 --> 00:14:03 disease. They're normal. They're normal in the sense of their 178 00:14:03 --> 00:14:09 phenotype. They have an abnormal genotype in the sense that they have 179 00:14:09 --> 00:14:16 a disease allele, but they're normal in the sense of 180 00:14:16 --> 00:14:23 their genotype, phenotype. Now, 181 00:14:23 --> 00:14:30 for X linked genes, sorry, before I do that let me -- 182 00:14:30 --> 00:14:35 Let me review for you sex determination. 183 00:14:35 --> 00:14:40 We talked about this briefly. In order to understand the 184 00:14:40 --> 00:14:45 inheritance pattern for X linked genes you need to remember this. 185 00:14:45 --> 00:14:50 That males of course have one X chromosome and one Y chromosome. 186 00:14:50 --> 00:14:55 Females have two X chromosomes. If you think of a Punnett Square 187 00:14:55 --> 00:14:59 related to the inheritance of chromosomes males will pass along an 188 00:14:59 --> 00:15:03 X or a Y at 50% each, females will pass along one of their 189 00:15:03 --> 00:15:16 two Xs. 190 00:15:16 --> 00:15:22 Will produce an equal number of males and females from such crosses. 191 00:15:22 --> 00:15:28 But it's important to think about where the X chromosomes come from, 192 00:15:28 --> 00:15:34 specifically males and the Y chromosomes. 193 00:15:34 --> 00:15:41 Males transmit their only Y, their only Y to all of their sons. 194 00:15:41 --> 00:15:48 If you're the son then you've gotten your father's only Y. 195 00:15:48 --> 00:15:56 Males transmit their only X chromosome to all of 196 00:15:56 --> 00:16:06 their daughters. 197 00:16:06 --> 00:16:11 If you're the daughter, when you're the daughter of a male, 198 00:16:11 --> 00:16:17 you have inherited his X chromosome. OK? 199 00:16:17 --> 00:16:27 Females transmit either X to each 200 00:16:27 --> 00:16:35 daughter or son. In the case of the female X, 201 00:16:35 --> 00:16:43 you can be a male who got this X chromosome or a male who got this X 202 00:16:43 --> 00:16:51 chromosome. You can be a female who got this X chromosome or a female 203 00:16:51 --> 00:16:59 who got this X chromosome. And that's important for 204 00:16:59 --> 00:17:05 understanding the disease genetics. So let's imagine a dominant disease 205 00:17:05 --> 00:17:14 involving the X chromosome. 206 00:17:14 --> 00:17:20 A gene, we'll call it Q. Males only have one X chromosome. 207 00:17:20 --> 00:17:27 They only have one X chromosome, therefore if they carry the disease 208 00:17:27 --> 00:17:34 gene they're going to get disease. 209 00:17:34 --> 00:17:38 Females have two X chromosomes. They might carry the disease allele 210 00:17:38 --> 00:17:43 on one but a normal copy on the other. In this scenario, 211 00:17:43 --> 00:17:47 will they develop disease? Yes, because it's a dominant 212 00:17:47 --> 00:18:00 disease allele. 213 00:18:00 --> 00:18:06 For recessive X linked disease, once again, males only have one X. 214 00:18:06 --> 00:18:12 Are they going to get disease? Yes. Females have two X chromosomes. 215 00:18:12 --> 00:18:18 If they carry a disease allele on one they are likely to carry a wild 216 00:18:18 --> 00:18:24 type copy on the other. Are they going to get disease? 217 00:18:24 --> 00:18:31 No. They're going to be heterozygous carriers. 218 00:18:31 --> 00:18:38 And you'll see how this plays out 219 00:18:38 --> 00:18:46 towards the end of the lecture. 220 00:18:46 --> 00:18:51 OK. So let's look at some examples. We're going to start with recessive 221 00:18:51 --> 00:18:57 diseases first, recessive autosomal diseases first. 222 00:18:57 --> 00:19:02 And one you've already seen before, 223 00:19:02 --> 00:19:08 and that's PKU, phenylketonuria. If you recall, this is a disease which 224 00:19:08 --> 00:19:14 is associated with failure to make an enzyme that converts 225 00:19:14 --> 00:19:20 phenylalanine to tyrosine. It's an enzyme called phenylalanine 226 00:19:20 --> 00:19:26 hydroxylase. If you don't have that enzyme then you produce too much of 227 00:19:26 --> 00:19:32 this byproduct, phenylpyruvic acid which is toxic 228 00:19:32 --> 00:19:38 and leads to brain damage and retardation. 229 00:19:38 --> 00:19:40 This can be avoided, the disease can be avoided by 230 00:19:40 --> 00:19:43 limiting your amount of dietary phenylalanine. 231 00:19:43 --> 00:19:46 And that's why such patients are not supposed to have Equal, 232 00:19:46 --> 00:19:49 as we discussed before. The disease, PKU, is autosomal recessive. 233 00:19:49 --> 00:19:52 The incidence is rare, about one in 10,000 to 15,000 individuals have 234 00:19:52 --> 00:19:55 PKU. As I talked to you about last time, the mutant allele has a single 235 00:19:55 --> 00:19:58 amino acid chain change in the active site of this enzyme which 236 00:19:58 --> 00:20:01 changes an arginine residue to a tryptophan residue. 237 00:20:01 --> 00:20:05 And that makes the enzyme inactive. This is an autosomal recessive 238 00:20:05 --> 00:20:10 disease. So if you have one mutant allele and one normal copy of the 239 00:20:10 --> 00:20:15 phenylalanine hydroxylase gene, do you have the disease? No. You 240 00:20:15 --> 00:20:20 would be a carrier but you would not have the disease symptoms. 241 00:20:20 --> 00:20:25 Because again, as in the other hypothetical example, 242 00:20:25 --> 00:20:29 most of the time, if you have a single normal copy of an enzyme that 243 00:20:29 --> 00:20:34 carries out some biochemical reaction that's enough and your 244 00:20:34 --> 00:20:39 phenotype is normal. Here's another common example, 245 00:20:39 --> 00:20:43 cystic fibrosis. This is actually a more common disease. 246 00:20:43 --> 00:20:47 It affects about one in 2, 00 to 3,000 individuals. That's not 247 00:20:47 --> 00:20:51 an insignificant number. So there are a lot of people with 248 00:20:51 --> 00:20:55 cystic fibrosis in this country. Again, it's autosomal recessive. 249 00:20:55 --> 00:20:59 Patients present with the disease at birth. 250 00:20:59 --> 00:21:03 They have problems both in their intestinal system as well as in 251 00:21:03 --> 00:21:07 their lungs. It tends to be the lung symptoms that ultimately kills 252 00:21:07 --> 00:21:11 the patient due to inability to breathe properly, 253 00:21:11 --> 00:21:15 but actually more importantly persistent infections which 254 00:21:15 --> 00:21:19 ultimately are so severe that they lead to death. 255 00:21:19 --> 00:21:23 And these patients tend to die within the first two to three 256 00:21:23 --> 00:21:27 decades of life. The gene encoded by the disease, 257 00:21:27 --> 00:21:31 the gene responsible for this disease is a chloride channel. 258 00:21:31 --> 00:21:34 When it functions properly it allows chloride ions to move through, 259 00:21:34 --> 00:21:38 and this achieves a proper water balance inside the cells. 260 00:21:38 --> 00:21:41 When the disease allele is present in both copies, 261 00:21:41 --> 00:21:45 this channel is not formed properly, and therefore the water balance in 262 00:21:45 --> 00:21:49 such cells is not correct and it leads to the build up of this kind 263 00:21:49 --> 00:21:52 of mucousy sticky substance both in the lungs and in the intestines. 264 00:21:52 --> 00:21:56 These individuals, as you can see, have a very hard time breathing, and 265 00:21:56 --> 00:22:00 they have to get this mucous cleared from their lungs periodically. 266 00:22:00 --> 00:22:04 And they also often have to have respirators to allow them to breath. 267 00:22:04 --> 00:22:08 OK. So that's some examples of autosomal recessive diseases. 268 00:22:08 --> 00:22:13 Let's think about the genetics. And we'll talk about CF 269 00:22:13 --> 00:22:17 specifically. Let's imagine the disease allele of CF. 270 00:22:17 --> 00:22:22 We'll call it CFD. There are actually many different disease 271 00:22:22 --> 00:22:26 alleles for this disease, but we'll just lump them together. 272 00:22:26 --> 00:22:33 Here are two individuals with this 273 00:22:33 --> 00:22:41 genotype. Do these individuals manifest the disease? 274 00:22:41 --> 00:22:49 Yes or no? Do they manifest the disease? No, because this is an 275 00:22:49 --> 00:22:58 autosomal recessive disease and they have a wild type copy. 276 00:22:58 --> 00:23:03 But if we think about the offspring that they could produce, 277 00:23:03 --> 00:23:09 this individual will produce gametes that carry the D allele and the wild 278 00:23:09 --> 00:23:15 type allele, likewise this individual, the D allele and the 279 00:23:15 --> 00:23:21 wild type allele, such that the offspring will either 280 00:23:21 --> 00:23:27 be DD, wild type D, wild type, wild type or wild type, 281 00:23:27 --> 00:23:32 D. Right? So you'll have one wild type, 282 00:23:32 --> 00:23:37 wild type individual produced out of such a cross. And this individual 283 00:23:37 --> 00:23:42 now has no disease allele present. This individual is both 284 00:23:42 --> 00:23:47 genotypically and phenotypically normal. No more issues about cystic 285 00:23:47 --> 00:23:52 fibrosis for this person or his or her descendants. 286 00:23:52 --> 00:23:57 There will be two individuals who are heterozygous, 287 00:23:57 --> 00:24:02 and these individuals are carriers. They don't have the disease but they 288 00:24:02 --> 00:24:07 do have a mutant allele. So depending on whom they marry, 289 00:24:07 --> 00:24:12 I shouldn't generalize, depending on whom they have children with they 290 00:24:12 --> 00:24:17 may or may not have to worry about the fact that they have a mutant CF 291 00:24:17 --> 00:24:22 allele. And one, on average, out of four will have 292 00:24:22 --> 00:24:28 two disease alleles and develop CF. OK? 293 00:24:28 --> 00:24:38 So we're going to now think about 294 00:24:38 --> 00:24:42 these diseases in inheritance looking at pedigrees, 295 00:24:42 --> 00:24:46 which I think are probably familiar to most of you. 296 00:24:46 --> 00:24:50 They're described in your book as well. But I just want to make sure 297 00:24:50 --> 00:24:54 you understand what the symbols mean before we get into it. 298 00:24:54 --> 00:24:58 Females are represented as circles. Males are represented as squares. 299 00:24:58 --> 00:25:03 Seems appropriate. Lines between them represent a 300 00:25:03 --> 00:25:09 mating, they have mated. And the offspring are represented 301 00:25:09 --> 00:25:21 below. 302 00:25:21 --> 00:25:27 If the symbol is left open then the individual is normal, 303 00:25:27 --> 00:25:34 genotypically and phenotypically. If the individual has a shaded 304 00:25:34 --> 00:25:41 symbol they are affected, they show disease symptoms. 305 00:25:41 --> 00:25:48 And if the symbol is partially shaded, I usually fill in half the 306 00:25:48 --> 00:25:55 symbol, the book will sometimes put a little circle inside the circle 307 00:25:55 --> 00:26:02 then they are carriers. They're heterozygous carriers. 308 00:26:02 --> 00:26:07 OK? So let's look and think about this example up here. 309 00:26:07 --> 00:26:13 We talked about two individuals who were both heterozygous for the 310 00:26:13 --> 00:26:19 disease allele, so they were carriers. 311 00:26:19 --> 00:26:25 Their genotype was CFD, CF wild type. 312 00:26:25 --> 00:26:32 They mated. They had 313 00:26:32 --> 00:26:42 four children. 314 00:26:42 --> 00:26:46 There were four possible genotypes, rather three possible genotypes. 315 00:26:46 --> 00:26:51 And, in fact, we observe all three genotypes in this generation. 316 00:26:51 --> 00:26:55 We have one individual over here who doesn't have her symbol filled. 317 00:26:55 --> 00:27:00 We have another whose symbol is fully filled. 318 00:27:00 --> 00:27:08 And then we have two whose symbols are partially filled. 319 00:27:08 --> 00:27:16 What's the genotype of this individual? Wild type, 320 00:27:16 --> 00:27:24 wild type. This one? D, D. This one? D, wild type. 321 00:27:24 --> 00:27:32 And this one? Same thing. OK? So that's what pedigrees look like. 322 00:27:32 --> 00:27:37 Let me show you a larger pedigree and give you some of the rules that 323 00:27:37 --> 00:27:43 apply to autosomal recessive diseases. So here's a large 324 00:27:43 --> 00:27:49 pedigree involving an autosomal recessive gene, 325 00:27:49 --> 00:27:55 disease gene. Again, the two parents are heterozygous. 326 00:27:55 --> 00:28:01 They had many, many offspring all here. Roughly a quarter of them 327 00:28:01 --> 00:28:07 will carry both copies of the disease gene and develop disease. 328 00:28:07 --> 00:28:11 Among the rest there will be unaffected individuals but of two 329 00:28:11 --> 00:28:16 classes, ones that don't have the disease gene at all and ones who are 330 00:28:16 --> 00:28:20 heterozygous carriers. Two-thirds of those unaffected 331 00:28:20 --> 00:28:25 offspring are themselves carriers, two-thirds. Two-thirds of the 332 00:28:25 --> 00:28:30 unaffected offspring are themselves carriers. 333 00:28:30 --> 00:28:34 Among those half of the offspring of a carrier are themselves carriers, 334 00:28:34 --> 00:28:39 as shown here. So if this individual came to you at a genetics 335 00:28:39 --> 00:28:44 clinic and wanted to know what is my likelihood of carrying the D mutant 336 00:28:44 --> 00:28:49 allele, you'd be able to say, without knowing the genotype of his 337 00:28:49 --> 00:28:54 mother you would be able to say that it's half of a half 338 00:28:54 --> 00:28:58 or a quarter. OK? Now, every once in a while two 339 00:28:58 --> 00:29:02 affected individuals, two homozygotes have children, 340 00:29:02 --> 00:29:06 as shown here. And you can see in that scenario all of the offspring 341 00:29:06 --> 00:29:09 have disease because the only alleles that are present are the 342 00:29:09 --> 00:29:13 mutant alleles. That has to be true because these 343 00:29:13 --> 00:29:17 are both affected, and therefore all of the offspring 344 00:29:17 --> 00:29:21 will also only inherit mutant alleles and develop the disease 345 00:29:21 --> 00:29:25 themselves. OK? And importantly because the disease 346 00:29:25 --> 00:29:31 gene is coming in on chromosomes 1 to 22, one of those and not the X or 347 00:29:31 --> 00:29:37 the Y, there is no gender associations here. 348 00:29:37 --> 00:29:43 Mothers can pass the disease to their daughters and their sons. 349 00:29:43 --> 00:29:49 Fathers can pass the disease to their daughters and their sons. 350 00:29:49 --> 00:29:55 There are no gender associations with this scenario. 351 00:29:55 --> 00:29:58 OK. Disease alleles are present in different frequencies in the 352 00:29:58 --> 00:30:02 population. Some of them are extremely rare, 353 00:30:02 --> 00:30:06 but some of them are actually rather common. 354 00:30:06 --> 00:30:16 So we're talking about the allele 355 00:30:16 --> 00:30:21 frequency, the percentage of alleles among all of our chromosomes that 356 00:30:21 --> 00:30:27 are the disease type. For PKU it depends a lot on where 357 00:30:27 --> 00:30:34 you're from. For example, in Turkey it's actually 358 00:30:34 --> 00:30:42 rather common, one in 206,000 alleles of this gene 359 00:30:42 --> 00:30:51 are mutant in this population, but in Japan it's much less common. 360 00:30:51 --> 00:31:00 One in 220,000 Japanese carry this allele. 361 00:31:00 --> 00:31:04 Exactly why this is we're not entirely sure, 362 00:31:04 --> 00:31:08 although I'll give you some speculation in a little while about 363 00:31:08 --> 00:31:13 what controls the frequency of these actually rather deleterious alleles. 364 00:31:13 --> 00:31:17 CF is fairly frequent. One in 25 alleles are CF. 365 00:31:17 --> 00:31:22 One in 25. There are as maybe 200 of you in this room, 366 00:31:22 --> 00:31:26 so that's some number of mutant alleles among you. It's 367 00:31:26 --> 00:31:31 a fairly high number. You're sitting there carrying a 368 00:31:31 --> 00:31:37 mutant copy of the CF allele. This is actually relevant to 369 00:31:37 --> 00:31:42 European descendancy. I'm not entirely sure whether it 370 00:31:42 --> 00:31:48 applies to all descendencies but let's just say that it's roughly 371 00:31:48 --> 00:31:53 that number. And another disease that you might have heard of 372 00:31:53 --> 00:31:59 Tay-Sachs disease in the Ashkenazi Jewish population -- 373 00:31:59 --> 00:32:08 -- is also quite common. 374 00:32:08 --> 00:32:13 One in 25. It's so common, in fact, that in certain parts of 375 00:32:13 --> 00:32:19 the world individuals undergo genetic testing before they decide 376 00:32:19 --> 00:32:24 whom to date because they want to avoid the risk that they're going to 377 00:32:24 --> 00:32:30 date somebody else who carries such a mutation. 378 00:32:30 --> 00:32:33 This is actually a very horrible disease. I shouldn't joke about it. 379 00:32:33 --> 00:32:37 So they want to avoid ever having to face the problem of having a 380 00:32:37 --> 00:32:41 child who has Tay-Sachs disease. So they undergo, in a sense, 381 00:32:41 --> 00:32:45 pre-marriage counseling to figure out their genotype to decide whether 382 00:32:45 --> 00:32:49 or not to date. And you can also imagine with 383 00:32:49 --> 00:32:53 similar tests we could figure out whether or not individuals carry 384 00:32:53 --> 00:32:57 mutations in these genes to let them know what their risks of developing 385 00:32:57 --> 00:33:01 disease are or whether or not to maintain a pregnancy of a child who 386 00:33:01 --> 00:33:05 may or may not be affected and so on. 387 00:33:05 --> 00:33:09 So they're very serious societal implications for these kinds of 388 00:33:09 --> 00:33:14 disease alleles. Now, some of the alleles are very 389 00:33:14 --> 00:33:18 rare. Here's one example in the Japanese population of PKU. 390 00:33:18 --> 00:33:23 The likelihood that two individuals would randomly get together who had 391 00:33:23 --> 00:33:27 mutant alleles of a phenylalanine hydroxylase gene and have a child is 392 00:33:27 --> 00:33:32 exceedingly small. And so in these situations, 393 00:33:32 --> 00:33:37 where the allele frequency is extremely rare, 394 00:33:37 --> 00:33:42 when you find an affected individual it's almost always a sure sign of 395 00:33:42 --> 00:33:47 inbreeding. Consanguinity is the term used in genetics where cousins 396 00:33:47 --> 00:33:52 or other relatives marry and have children. And since they are 397 00:33:52 --> 00:33:57 related and have a higher allele frequency within their families of a 398 00:33:57 --> 00:34:02 particular allele then the likelihood that they'll have an 399 00:34:02 --> 00:34:07 offspring who has two copies of the allele is much higher. 400 00:34:07 --> 00:34:11 And so when you see a pattern such as this, it's a fairly clear 401 00:34:11 --> 00:34:16 indication that you're dealing with an autosomal recessive disease 402 00:34:16 --> 00:34:21 involving consanguineous mating. Here are two cousins who are 403 00:34:21 --> 00:34:26 producing offspring both of whom are affected. And when you see a 404 00:34:26 --> 00:34:31 pattern like this you can actually figure out, or at least figure out 405 00:34:31 --> 00:34:36 pretty well who were the carriers in this scenario, 406 00:34:36 --> 00:34:41 who were the carriers in this family. Since both, since the children have 407 00:34:41 --> 00:34:46 two mutant copies then both of their parents must be heterozygous 408 00:34:46 --> 00:34:50 carriers. OK? That goes without saying. 409 00:34:50 --> 00:34:55 They're heterozygous. Since this individual is heterozygous and the 410 00:34:55 --> 00:35:00 allele was passed on from their grandparents then his mother must 411 00:35:00 --> 00:35:05 also carry the allele inherited from one of the two grandparents. 412 00:35:05 --> 00:35:09 Likewise this woman's father must carry the mutant allele. 413 00:35:09 --> 00:35:13 And in this generation we actually don't know whether it's the male or 414 00:35:13 --> 00:35:17 the female who carries the mutation. It could be either. And it's been 415 00:35:17 --> 00:35:22 passed along to both sides of this family tree and reduced to 416 00:35:22 --> 00:35:26 homozygocity in this generation. OK? You can also begin to figure 417 00:35:26 --> 00:35:30 out what the likelihood of other members of the family tree 418 00:35:30 --> 00:35:35 is being heterozygous. So this individual here has a one in 419 00:35:35 --> 00:35:39 two chance. One of these two parents is definitely a heterozygote, 420 00:35:39 --> 00:35:43 and so the likelihood that he's a heterozygote is one in two. 421 00:35:43 --> 00:35:47 And among his children you could say they have a one in four chance. 422 00:35:47 --> 00:35:51 If he has a one in two chance then there's a one in two chance that 423 00:35:51 --> 00:35:55 he'll pass it onto them, so overall there's a one in four 424 00:35:55 --> 00:35:59 chance that they will be themselves carriers. 425 00:35:59 --> 00:36:03 And this, again, this kind of genetic testing is done 426 00:36:03 --> 00:36:07 frequently to figure out what your relative risk of developing a 427 00:36:07 --> 00:36:11 particular disease are. Now, as I said, for other disease 428 00:36:11 --> 00:36:16 alleles like CF and Tay-Sachs, the allele frequency is actually 429 00:36:16 --> 00:36:20 strikingly high. And yet if you're homozygous for 430 00:36:20 --> 00:36:24 these mutations you're dead. Not necessarily right away but not 431 00:36:24 --> 00:36:28 for very long. It clearly reduces your 432 00:36:28 --> 00:36:33 reproductive fitness. And so why would these alleles be 433 00:36:33 --> 00:36:37 present in our population at all? Why wouldn't they be removed 434 00:36:37 --> 00:36:41 through natural selection? We're not going to get into this in 435 00:36:41 --> 00:36:45 great detail, but there are theories out there and some evidence to 436 00:36:45 --> 00:36:49 support them that there might be actually an advantage in certain 437 00:36:49 --> 00:36:53 circumstances for being heterozygous wild type over mutant. 438 00:36:53 --> 00:36:57 And there are theories both related to Tay-Sachs disease, 439 00:36:57 --> 00:37:01 sickle cell disease and cystic fibrosis such that if you are 440 00:37:01 --> 00:37:05 heterozygous you actually survive better in the face of certain 441 00:37:05 --> 00:37:10 pathogenic exposure than do people who are wild type for both alleles. 442 00:37:10 --> 00:37:14 And that's the argument for why these alleles actually built up, 443 00:37:14 --> 00:37:19 at least in the past, over the evolution of our species. 444 00:37:19 --> 00:37:24 OK. Let's transition now to autosomal dominant diseases. 445 00:37:24 --> 00:37:29 This is a famous example, Huntington's disease, 446 00:37:29 --> 00:37:33 otherwise called Huntington's chorea. Relatively rare. 447 00:37:33 --> 00:37:37 About one in 10, 00 to 25,000 individuals affected. 448 00:37:37 --> 00:37:41 It exhibits an autosomal dominant pattern of inheritance, 449 00:37:41 --> 00:37:45 as you'll see in a moment. The age of onset is about 35 to 40 450 00:37:45 --> 00:37:49 years of age. These individuals actually are totally normal for the 451 00:37:49 --> 00:37:53 first three to four decades. You wouldn't know that they had a 452 00:37:53 --> 00:37:57 disease. But starting at that time they begin to develop symptoms which 453 00:37:57 --> 00:38:01 involve both effects on their personalities but more importantly 454 00:38:01 --> 00:38:05 effects on their movements. That's what you first begin to see. 455 00:38:05 --> 00:38:09 That's what chorea means. It's sort of this dance-like movement. 456 00:38:09 --> 00:38:14 And then that gets much, much more severe and stereotypical. 457 00:38:14 --> 00:38:18 And eventually, in addition to that, there's death of cells in the brain. 458 00:38:18 --> 00:38:23 And the combination of these affects leads to the death of the 459 00:38:23 --> 00:38:28 individual by about the fourth or fifth decade of life. 460 00:38:28 --> 00:38:32 This is actually a movie of an individual who has Huntington's 461 00:38:32 --> 00:38:37 disease. He's being told to hold his arms 462 00:38:37 --> 00:38:41 straight out, but because of this neurogenerative process that's 463 00:38:41 --> 00:38:46 taking place within his brain and also other parts of his nervous 464 00:38:46 --> 00:38:50 system he's unable to do so. And this is sort of the 465 00:38:50 --> 00:38:55 stereotypical presentation of Huntington's chorea. 466 00:38:55 --> 00:38:59 They have this wave-like movement and also their limbs get stuck in 467 00:38:59 --> 00:39:04 particular postures, as you can see this individual here. 468 00:39:04 --> 00:39:07 At the molecular level the problem in these individuals is that their 469 00:39:07 --> 00:39:11 brain cells are dying, particular ones, actually, 470 00:39:11 --> 00:39:14 within a particular region of the brain surrounding this ventricle 471 00:39:14 --> 00:39:18 here. And this is a normal space in a normal brain. 472 00:39:18 --> 00:39:22 And there are various sets of neurons on either side of those 473 00:39:22 --> 00:39:25 ventricles. And in HD patients those cells are progressively lost 474 00:39:25 --> 00:39:29 over time, and when those cells are lost you lose motor control and you 475 00:39:29 --> 00:39:33 also develop rather severe dementia. 476 00:39:33 --> 00:39:37 And the reason that those cells are being lost is that the mutant 477 00:39:37 --> 00:39:41 protein, the mutant form of this protein called Huntington, 478 00:39:41 --> 00:39:45 the mutant form builds up inside of those cells and aggregates and 479 00:39:45 --> 00:39:49 causes the cells to die. OK? And this is why this is an 480 00:39:49 --> 00:39:53 autosomal dominant disease. If you have the disease allele then 481 00:39:53 --> 00:39:57 you will get the aggregation of the protein and you will develop 482 00:39:57 --> 00:40:07 the disease. 483 00:40:07 --> 00:40:14 So let's take another example of a cross between an individual who is 484 00:40:14 --> 00:40:22 normal, two normal copies of HD and an individual who has a disease 485 00:40:22 --> 00:40:30 allele and a wild type allele who is heterozygous. Is this 486 00:40:30 --> 00:40:36 individual diseased? He either is already or he will be 487 00:40:36 --> 00:40:40 in the case of HD. It's an autosomal dominant disease. 488 00:40:40 --> 00:40:44 If you have the disease allele you will develop disease. 489 00:40:44 --> 00:40:48 If we look at a Punnett Square, this individual will always transmit 490 00:40:48 --> 00:40:53 the wild type allele, this individual will transmit the 491 00:40:53 --> 00:40:57 mutant allele half the time the wild type allele of the other. 492 00:40:57 --> 00:41:01 These individuals will be wild type D, wild type D, 493 00:41:01 --> 00:41:06 wild type, wild type, wild type, wild type. 494 00:41:06 --> 00:41:13 So you'll get half diseased, half normal. OK? A rather 495 00:41:13 --> 00:41:21 different picture than we saw previously. And importantly, 496 00:41:21 --> 00:41:29 as I mentioned, the presence, the mere presence of the D allele leads 497 00:41:29 --> 00:41:37 to the production of this toxic protein. 498 00:41:37 --> 00:41:43 And ultimately brain damage. And that's why it's dominant. 499 00:41:43 --> 00:41:49 OK. So let's look at a pedigree of an autosomal dominant disorder. 500 00:41:49 --> 00:41:55 Here's an affected individual, a female who marries, 501 00:41:55 --> 00:42:02 who has children with an unaffected male. 502 00:42:02 --> 00:42:06 They have four children. On average half of them will 503 00:42:06 --> 00:42:10 inherit the defective allele and therefore develop disease. 504 00:42:10 --> 00:42:14 Half of the offspring of an affected parent will be affected. 505 00:42:14 --> 00:42:19 Importantly, the unaffected offspring of an affected parent have 506 00:42:19 --> 00:42:23 unaffected offspring. If you are normal, you do not 507 00:42:23 --> 00:42:27 inherit the disease allele, you're scot-free. Your children will 508 00:42:27 --> 00:42:32 no longer have to worry about this disease. 509 00:42:32 --> 00:42:35 But in this case, in this individual, 510 00:42:35 --> 00:42:38 again roughly half, in this example two-thirds of the offspring do 511 00:42:38 --> 00:42:42 develop the disease. This is another really important 512 00:42:42 --> 00:42:45 case of genetic testing. This guy might have wanted to know 513 00:42:45 --> 00:42:49 that he was going to develop Huntington's disease in order to 514 00:42:49 --> 00:42:52 decide whether to have children in the first place. 515 00:42:52 --> 00:42:55 This individual here likewise might want to know before the disease 516 00:42:55 --> 00:42:59 actually manifested itself what would happen in order to make 517 00:42:59 --> 00:43:02 lifestyle decisions. Am I going to quit work and have a 518 00:43:02 --> 00:43:06 good time for the next ten years? Because pretty soon I'm actually 519 00:43:06 --> 00:43:10 not going to be able to. So genetic testing actually can 520 00:43:10 --> 00:43:13 make an extremely important set of decisions for individuals affected 521 00:43:13 --> 00:43:17 in this way. And there's actually a subtlety here, 522 00:43:17 --> 00:43:20 too. Sometimes people don't want to know because there's actually 523 00:43:20 --> 00:43:24 nothing to be done for them. In the case of Huntington's disease 524 00:43:24 --> 00:43:28 that's true. We don't have a cure for it. 525 00:43:28 --> 00:43:32 So Arlo Guthrie who is the son of Woody Guthrie, 526 00:43:32 --> 00:43:36 who died of Huntington's disease, apparently doesn't want to know 527 00:43:36 --> 00:43:40 because if he learns that he's going to get it he's just going to be 528 00:43:40 --> 00:43:44 depressed. If he learns that he didn't get it he might be relieved, 529 00:43:44 --> 00:43:48 but he doesn't want to take that chance so he's just leading life in 530 00:43:48 --> 00:43:52 hopes that he doesn't have the disease allele. 531 00:43:52 --> 00:43:56 Now, I actually don't know in his case whether he has children or not. 532 00:43:56 --> 00:44:00 He has children, so he actually made that decision almost for his 533 00:44:00 --> 00:44:04 children as well. So important implications for these 534 00:44:04 --> 00:44:09 kinds of genetic diseases. Now, here's an interesting pattern 535 00:44:09 --> 00:44:14 that I want to share with you. And this relates to a phenomenon 536 00:44:14 --> 00:44:30 called penetrance. 537 00:44:30 --> 00:44:34 Penetrance. Penetrance is a number which reflects the percentage of 538 00:44:34 --> 00:44:38 individuals who have the disease genotype who end up getting the 539 00:44:38 --> 00:44:43 disease. I've been telling you about examples where that's 100%. 540 00:44:43 --> 00:44:47 If you have the disease genotype you get the disease. 541 00:44:47 --> 00:44:51 But that's not always true. Sometimes you can have the disease 542 00:44:51 --> 00:44:56 genotype, but because of other factors like environmental factors, 543 00:44:56 --> 00:45:00 what you eat, what you get exposed to you actually don't 544 00:45:00 --> 00:45:05 develop the disease. Or maybe you just got lucky because 545 00:45:05 --> 00:45:09 some of these diseases are stochastic in nature. 546 00:45:09 --> 00:45:13 And you might have been one of the lucky ones. That would be an 547 00:45:13 --> 00:45:17 example of lack of penetrance. You have the disease genotype but 548 00:45:17 --> 00:45:21 you don't have the disease itself. And this can lead to the 549 00:45:21 --> 00:45:25 development of individuals in pedigrees, such as the one I'm going 550 00:45:25 --> 00:45:30 to show you, who are obligate carriers, obligate carriers. 551 00:45:30 --> 00:45:34 We call them obligate carriers because they have a child who is 552 00:45:34 --> 00:45:39 affected but they themselves were not affected. And they have a 553 00:45:39 --> 00:45:43 parent who likewise was affected. So the simplest explanation for a 554 00:45:43 --> 00:45:48 pedigree such as this is that this mother passed along the disease 555 00:45:48 --> 00:45:52 allele to her daughter but she did not manifest the disease, 556 00:45:52 --> 00:45:57 an example of lack of penetrance, but she still had the disease allele 557 00:45:57 --> 00:46:02 which she passed onto her daughter who developed disease. 558 00:46:02 --> 00:46:05 OK? And we call these individuals obligate carriers. 559 00:46:05 --> 00:46:09 Even though they don't manifest the disease they must be carriers. 560 00:46:09 --> 00:46:12 And in that sense this circle should be shaded. 561 00:46:12 --> 00:46:16 We haven't shaded it because actually there are other 562 00:46:16 --> 00:46:20 explanations for how you can get this pattern. Sometimes, 563 00:46:20 --> 00:46:23 for example, the disease is such that there are non-familial forms of 564 00:46:23 --> 00:46:27 the disease which complicate the analysis. Heart disease is a good 565 00:46:27 --> 00:46:31 example. There are familial forms of heart disease and there is 566 00:46:31 --> 00:46:34 sporadic heart disease. Maybe this woman doesn't have the 567 00:46:34 --> 00:46:38 predisposing mutation and her daughter just developed heart 568 00:46:38 --> 00:46:42 disease. That can happen. Another example is that maybe she 569 00:46:42 --> 00:46:45 picked up a new mutation. Her mother is actually clean but 570 00:46:45 --> 00:46:49 she picked up her own mutation in the development of the sperm or egg 571 00:46:49 --> 00:46:53 that gave rise to her, and then she has the disease. 572 00:46:53 --> 00:46:57 That would be rare but not unprecedented. 573 00:46:57 --> 00:47:01 And the final example, which is the most interesting, 574 00:47:01 --> 00:47:05 is so-called non-paternity or even non-maternity. 575 00:47:05 --> 00:47:09 So we're making an assumption here based on what the family has 576 00:47:09 --> 00:47:13 provided us in terms of this pedigree that this girl is the 577 00:47:13 --> 00:47:17 daughter of this mating, this woman and this man. But about 578 00:47:17 --> 00:47:21 10% of kids born in this country actually have a father who isn't 579 00:47:21 --> 00:47:25 their father. It's a shocking statistic, I know, 580 00:47:25 --> 00:47:29 but it's true. This is called non-paternity. 581 00:47:29 --> 00:47:34 So it might be the case that this woman actually doesn't have the 582 00:47:34 --> 00:47:40 mutation. It's just that her father, her mate, the father of this girl 583 00:47:40 --> 00:47:45 [LAUGHTER] is not that guy. And this is sick but true, most 584 00:47:45 --> 00:47:51 often in situations like this it's Uncle Bob or brother Steve. 585 00:47:51 --> 00:47:57 I know it's disgusting but this is often an example, 586 00:47:57 --> 00:48:03 the explanation for examples such as this. 587 00:48:03 --> 00:48:07 And another interesting example is non-maternity. 588 00:48:07 --> 00:48:12 We're assuming that this is the mother of this child but sometimes 589 00:48:12 --> 00:48:16 families don't want to admit, for example, that this girl had a 590 00:48:16 --> 00:48:21 baby. And so they give it to Aunt Sue. And now Aunt Sue's child gets 591 00:48:21 --> 00:48:25 the disease, but it's not because of Aunt Sue's genes. 592 00:48:25 --> 00:48:30 It's because of her cousin. OK? So here are some examples. 593 00:48:30 --> 00:48:33 Now, I have one more minute, and I need to riffle through the 594 00:48:33 --> 00:48:37 slides because I'm going to leave you for a few days. 595 00:48:37 --> 00:48:40 And I want to just remind you that there are X linked diseases that 596 00:48:40 --> 00:48:44 affect, that are both dominant and recessive. Most of them are 597 00:48:44 --> 00:48:48 recessive. And here's a classic example, an X linked recessive 598 00:48:48 --> 00:48:51 disease involving hemophilia in the royal families of Europe. 599 00:48:51 --> 00:48:55 Importantly, when you look at X linked disease pedigrees, 600 00:48:55 --> 00:48:58 and here's Duchenne muscular dystrophy, another familiar disease, 601 00:48:58 --> 00:49:02 again X linked recessive, there are certain rules that dictate the 602 00:49:02 --> 00:49:06 development of the disease over the generations. 603 00:49:06 --> 00:49:10 They're summarized here. And you should look in your book 604 00:49:10 --> 00:49:15 for more information. And, finally, there are rare 605 00:49:15 --> 00:49:19 examples of X linked dominant diseases, and their rules of 606 00:49:19 --> 00:49:24 inheritance are somewhat different. So you should familiarize yourself 607 00:49:24 --> 00:49:27 with X linked modes of inheritance.