1 00:00:00,990 --> 00:00:02,820 [Instructor] Hello and welcome to the second lecture 2 00:00:02,820 --> 00:00:06,063 in Module Five entitled Mendelian Inheritance. 3 00:00:06,930 --> 00:00:09,540 Just a quick review of some of the material 4 00:00:09,540 --> 00:00:10,800 we've already covered. 5 00:00:10,800 --> 00:00:14,850 One copy of each autosome, so remember what autosomes are. 6 00:00:14,850 --> 00:00:16,080 Those are the numbered chromosomes, 7 00:00:16,080 --> 00:00:18,150 so those are chromosomes one through 22. 8 00:00:18,150 --> 00:00:19,980 One copy is inherited from each parent, 9 00:00:19,980 --> 00:00:21,630 plus one X chromosome from the mother 10 00:00:21,630 --> 00:00:25,260 and one X or Y chromosome from the father, so, 11 00:00:25,260 --> 00:00:26,100 this will become important 12 00:00:26,100 --> 00:00:28,200 when we start discussing diseases 13 00:00:28,200 --> 00:00:32,673 related to genes on autosomes versus the X or Y chromosome. 14 00:00:33,720 --> 00:00:36,180 We each have two copies of each autosomal genes, 15 00:00:36,180 --> 00:00:37,710 so genes on the autosomes, 16 00:00:37,710 --> 00:00:40,110 that's what an autosomal gene means. 17 00:00:40,110 --> 00:00:43,500 Males have only one copy of each gene on the X chromosome 18 00:00:43,500 --> 00:00:45,480 while females have two copies. 19 00:00:45,480 --> 00:00:46,740 Remember, one X chromosome 20 00:00:46,740 --> 00:00:49,230 is randomly inactivated in females in each cell, 21 00:00:49,230 --> 00:00:51,210 and we'll talk about why that matters 22 00:00:51,210 --> 00:00:56,210 when it comes to those X-linked genes and their disorders 23 00:00:57,420 --> 00:00:58,383 in a few slides. 24 00:00:59,520 --> 00:01:01,890 Different alleles of a gene may encode differences 25 00:01:01,890 --> 00:01:03,510 in the function of the protein encoded, 26 00:01:03,510 --> 00:01:06,240 that's what we just spent quite a bit of time discussing 27 00:01:06,240 --> 00:01:07,650 in the previous lecture. 28 00:01:07,650 --> 00:01:09,480 So, remember what alleles are, 29 00:01:09,480 --> 00:01:11,310 those are slightly different versions 30 00:01:11,310 --> 00:01:15,150 of slight different changes in the sequence of a gene, 31 00:01:15,150 --> 00:01:18,180 which results in differences in the phenotype, 32 00:01:18,180 --> 00:01:20,733 or the trait that is observed. 33 00:01:22,260 --> 00:01:24,900 So a few important terms and definitions. 34 00:01:24,900 --> 00:01:27,990 And we'll talk through each of these throughout the lecture, 35 00:01:27,990 --> 00:01:30,150 but just to give you a heads up from the beginning, 36 00:01:30,150 --> 00:01:32,970 homozygous, this means the same allele present 37 00:01:32,970 --> 00:01:36,570 for both copies of a gene, so, you inherited, 38 00:01:36,570 --> 00:01:38,850 if you remember the analogy I was talking about 39 00:01:38,850 --> 00:01:43,850 with the playing cards and each different card 40 00:01:44,130 --> 00:01:46,410 represents a different allele. 41 00:01:46,410 --> 00:01:48,810 And let's say you're playing with two or three 42 00:01:48,810 --> 00:01:50,490 or four different decks, 43 00:01:50,490 --> 00:01:54,600 so each deck has 52 different cards in it. 44 00:01:54,600 --> 00:01:55,650 So if you're playing with four, 45 00:01:55,650 --> 00:01:57,300 you're combining four different decks together 46 00:01:57,300 --> 00:01:59,940 and you're playing with that. 47 00:01:59,940 --> 00:02:01,470 And you're basically, say, 48 00:02:01,470 --> 00:02:03,840 randomly choosing two cards from the deck. 49 00:02:03,840 --> 00:02:06,810 If the two cards that you choose are are the same, 50 00:02:06,810 --> 00:02:08,790 so let's say both cards that you choose 51 00:02:08,790 --> 00:02:12,960 are the eight of hearts, then that would be homozygous, 52 00:02:12,960 --> 00:02:15,120 so you'd have two identical alleles, 53 00:02:15,120 --> 00:02:19,170 so both alleles that you inherited, one from each parent, 54 00:02:19,170 --> 00:02:22,110 happened to be the same. 55 00:02:22,110 --> 00:02:24,510 Heterozygous means you have different alleles present 56 00:02:24,510 --> 00:02:25,680 for each copy of a gene, 57 00:02:25,680 --> 00:02:28,470 so that means from each one of your parents, 58 00:02:28,470 --> 00:02:32,223 you inherited two different alleles for a particular gene. 59 00:02:33,183 --> 00:02:35,700 Autosomal is a disorder involving a gene on an autosome, 60 00:02:35,700 --> 00:02:37,170 and X-linked would be a disorder 61 00:02:37,170 --> 00:02:39,570 involving a gene on the X chromosome. 62 00:02:39,570 --> 00:02:42,690 Dominant, with dominant and recessive, 63 00:02:42,690 --> 00:02:44,010 here's where we're starting to talk about 64 00:02:44,010 --> 00:02:45,810 allelic interactions. 65 00:02:45,810 --> 00:02:48,990 And basically how we go from the genotype 66 00:02:48,990 --> 00:02:50,610 to a specific phenotype. 67 00:02:50,610 --> 00:02:52,410 'Cause as you know, in the genotype, 68 00:02:53,834 --> 00:02:55,220 if you have two copies of a gene, 69 00:02:55,220 --> 00:02:57,510 so you have two alleles, they could be the same, 70 00:02:57,510 --> 00:02:59,160 and if they're the same, you're homozygous. 71 00:02:59,160 --> 00:03:00,000 Or they could be different, 72 00:03:00,000 --> 00:03:01,860 and if they're different you're heterozygous. 73 00:03:01,860 --> 00:03:04,050 Basically, how does that get translated 74 00:03:04,050 --> 00:03:05,610 into the phenotype, 75 00:03:05,610 --> 00:03:07,200 'cause we only have one phenotype, right, 76 00:03:07,200 --> 00:03:08,400 there's only one of us. 77 00:03:08,400 --> 00:03:10,650 But each one of us has two copies of each gene, 78 00:03:10,650 --> 00:03:12,120 so how do they interact with each other 79 00:03:12,120 --> 00:03:14,493 to give us that one single phenotype? 80 00:03:15,570 --> 00:03:17,250 Well one way that's been worked out, 81 00:03:17,250 --> 00:03:19,920 and these are genes for genes 82 00:03:19,920 --> 00:03:23,250 which have what are called Mendelian inheritance. 83 00:03:23,250 --> 00:03:26,040 These would be alleles that take on characteristics 84 00:03:26,040 --> 00:03:28,410 of either being dominant or recessive to one another 85 00:03:28,410 --> 00:03:30,120 when they're combined together. 86 00:03:30,120 --> 00:03:32,400 So, a dominant allele is an allele 87 00:03:32,400 --> 00:03:33,690 that determines phenotype 88 00:03:33,690 --> 00:03:35,670 regardless of the other allele present. 89 00:03:35,670 --> 00:03:36,690 So it determines phenotype 90 00:03:36,690 --> 00:03:39,390 when the individual is either homozygous or heterozygous, 91 00:03:39,390 --> 00:03:43,500 so if you have at least one copy of a dominant allele, 92 00:03:43,500 --> 00:03:45,750 that will determine the phenotype 93 00:03:45,750 --> 00:03:48,120 regardless of what the other allele is. 94 00:03:48,120 --> 00:03:51,900 Recessive alleles are alleles that only affect phenotype 95 00:03:51,900 --> 00:03:53,430 when both copies are the same, 96 00:03:53,430 --> 00:03:55,200 so this determines phenotype 97 00:03:55,200 --> 00:03:58,740 only when the individual is homozygous for this allele. 98 00:03:58,740 --> 00:04:02,100 Otherwise, if the individual is heterozygous, 99 00:04:02,100 --> 00:04:04,170 then the other allele is dominant, 100 00:04:04,170 --> 00:04:06,320 and that's the phenotype that you will see. 101 00:04:07,710 --> 00:04:10,500 Some Mendelian inheritance, this is a weird word, Mendelian, 102 00:04:10,500 --> 00:04:12,420 who is Gregor Mendel? 103 00:04:12,420 --> 00:04:16,920 He was an Austrian monk who lived in the 1800s 104 00:04:16,920 --> 00:04:19,110 and is considered the father of genetics, 105 00:04:19,110 --> 00:04:20,970 he worked with pea plants, 106 00:04:20,970 --> 00:04:24,360 and did a lot of different crosses between pea plants, 107 00:04:24,360 --> 00:04:28,800 and took detailed notes, and made some great strides 108 00:04:28,800 --> 00:04:33,213 in deducing from the patterns of inheritance that he saw, 109 00:04:34,632 --> 00:04:39,632 certain laws that he basically was able to define 110 00:04:41,310 --> 00:04:46,140 and have really held up pretty well, rather remarkably well, 111 00:04:46,140 --> 00:04:48,930 for, you know, 200 years later, 112 00:04:48,930 --> 00:04:52,320 in that we're still really referring back to those. 113 00:04:52,320 --> 00:04:54,840 So it's quite remarkable, this was in a time, obviously, 114 00:04:54,840 --> 00:04:58,740 before any modern technology that we use today 115 00:04:58,740 --> 00:05:02,670 for genetic analysis, so, very impressive. 116 00:05:02,670 --> 00:05:06,300 And so we use his name, Mendel, 117 00:05:06,300 --> 00:05:09,060 and the name Mendelian is derived from that. 118 00:05:09,060 --> 00:05:13,140 And this is basically inheritance of monogenic diseases, 119 00:05:13,140 --> 00:05:14,850 so these would be diseases caused by a single gene, 120 00:05:14,850 --> 00:05:19,410 these are considered more simple diseases to understand. 121 00:05:19,410 --> 00:05:22,200 because they don't involve a lot of extraneous factors 122 00:05:22,200 --> 00:05:24,690 and multiple genes and, you know, just, 123 00:05:24,690 --> 00:05:27,000 things become very complicated very quickly 124 00:05:27,000 --> 00:05:28,740 in multifactorial diseases, 125 00:05:28,740 --> 00:05:32,043 but in Mendelian inheritance, it's rather straightforward. 126 00:05:35,100 --> 00:05:38,580 Okay, and he translated the different patterns you saw 127 00:05:38,580 --> 00:05:42,240 of inheritance in pea plants into human disease 128 00:05:42,240 --> 00:05:44,430 as recessive and dominant inheritance 129 00:05:44,430 --> 00:05:46,593 of single-gene disorders. 130 00:05:47,640 --> 00:05:49,800 So classifications of single-gene diseases, 131 00:05:49,800 --> 00:05:51,870 genetic diseases categorized broadly 132 00:05:51,870 --> 00:05:53,940 by how genotype affects phenotype 133 00:05:53,940 --> 00:05:55,680 and where the gene is located. 134 00:05:55,680 --> 00:05:57,540 Okay, so two parts. 135 00:05:57,540 --> 00:06:00,420 So if we're looking first, on which type of chromosome 136 00:06:00,420 --> 00:06:03,300 is the gene causing this disease located? 137 00:06:03,300 --> 00:06:06,450 Well, is it on an autosome, if so it's called autosomal. 138 00:06:06,450 --> 00:06:09,390 If it's on the X chromosome, it's called X-linked. 139 00:06:09,390 --> 00:06:12,240 And the gene causing this disease is on the X chromosome, 140 00:06:12,240 --> 00:06:14,610 so males are more likely to be affected 141 00:06:14,610 --> 00:06:17,370 as they have only one X chromosome. 142 00:06:17,370 --> 00:06:20,760 So inheritance of a single recessive disease-causing allele 143 00:06:20,760 --> 00:06:23,100 is enough to cause the disease. 144 00:06:23,100 --> 00:06:23,933 Okay. 145 00:06:23,933 --> 00:06:25,890 So that takes care of where it's located, 146 00:06:25,890 --> 00:06:28,710 so if we're categorizing a particular disease, 147 00:06:28,710 --> 00:06:31,380 first we would say, is it autosomal or is it X-linked? 148 00:06:31,380 --> 00:06:35,257 And then we would classify it based upon the alleles. 149 00:06:35,257 --> 00:06:36,592 Okay. 150 00:06:36,592 --> 00:06:39,390 So the alleles are, again, what are alleles? 151 00:06:39,390 --> 00:06:42,333 Slight variations in a single gene, 152 00:06:43,710 --> 00:06:46,170 that result in different phenotypes. 153 00:06:46,170 --> 00:06:48,900 So how do two alleles a person has for the gene 154 00:06:48,900 --> 00:06:51,570 interact to produce the disease phenotype? 155 00:06:51,570 --> 00:06:54,030 How do they interact and produce the disease phenotype? 156 00:06:54,030 --> 00:06:56,520 So there are two categories, really, from that, 157 00:06:56,520 --> 00:06:58,860 and those would be either dominant disease. 158 00:06:58,860 --> 00:07:01,590 So you only need one disease allele to get the disease, 159 00:07:01,590 --> 00:07:03,540 other allele may be perfectly functional, 160 00:07:03,540 --> 00:07:05,190 which would be called what? 161 00:07:05,190 --> 00:07:07,200 Wild type, that's right. 162 00:07:07,200 --> 00:07:08,610 So an example of a dominant disease 163 00:07:08,610 --> 00:07:09,930 would be Huntington's disease, 164 00:07:09,930 --> 00:07:12,600 so if you inherit a single allele, 165 00:07:12,600 --> 00:07:13,980 if only one of your two alleles 166 00:07:13,980 --> 00:07:16,470 that you inherit from one of your parents 167 00:07:16,470 --> 00:07:21,470 is a mutated version of the Huntington gene, 168 00:07:21,660 --> 00:07:23,220 that causes Huntington's disease, 169 00:07:23,220 --> 00:07:25,263 you will have Huntington's disease. 170 00:07:26,310 --> 00:07:27,900 On the other hand, recessive diseases 171 00:07:27,900 --> 00:07:30,390 need both disease copies to get the disease. 172 00:07:30,390 --> 00:07:33,030 So no wild type allele is present. 173 00:07:33,030 --> 00:07:36,120 So those with only one copy do not have the disease 174 00:07:36,120 --> 00:07:38,970 but are carriers, as they can pass it on to their children. 175 00:07:38,970 --> 00:07:41,760 So this would be, an example would be cystic fibrosis. 176 00:07:41,760 --> 00:07:43,890 So if you only have one copy of the disease allele 177 00:07:43,890 --> 00:07:45,540 and the other copy is wild type 178 00:07:45,540 --> 00:07:47,610 or the normal functioning, 179 00:07:47,610 --> 00:07:50,730 you actually probably don't have any symptoms of a disorder, 180 00:07:50,730 --> 00:07:52,590 but you can pass that on. 181 00:07:52,590 --> 00:07:55,650 So recessive diseases often are thought of 182 00:07:55,650 --> 00:07:57,480 as skipping generations. 183 00:07:57,480 --> 00:08:00,060 Because you may go into the carrier phase, 184 00:08:00,060 --> 00:08:02,310 where an individual for a generation 185 00:08:02,310 --> 00:08:04,620 is carrying the allele for the disease, 186 00:08:04,620 --> 00:08:06,180 but they themselves don't have it. 187 00:08:06,180 --> 00:08:08,730 However, their children, depending upon their partner, 188 00:08:08,730 --> 00:08:10,860 their children might have disease 189 00:08:10,860 --> 00:08:13,413 or at least may be carriers for the disease. 190 00:08:14,940 --> 00:08:17,400 Let's start with autosomal dominant inheritance, 191 00:08:17,400 --> 00:08:19,140 and we will take it from there, 192 00:08:19,140 --> 00:08:22,050 so again, autosomal dominance, let's go back for one second. 193 00:08:22,050 --> 00:08:24,270 We're combining, we first have to say 194 00:08:24,270 --> 00:08:28,680 is where's the gene causing the disease located? 195 00:08:28,680 --> 00:08:30,990 Okay, if it's on an autosome, it's autosomal, 196 00:08:30,990 --> 00:08:32,580 it's on an X chromosome, it's X-linked. 197 00:08:32,580 --> 00:08:33,663 And then you say, 198 00:08:36,738 --> 00:08:37,950 how do the alleles interact with one another 199 00:08:37,950 --> 00:08:41,610 to cause the disease if it's dominant or if it's recessive? 200 00:08:41,610 --> 00:08:44,367 So, in this case, it would be autosomal dominant, 201 00:08:44,367 --> 00:08:49,367 and that tells you that the gene causing this disease 202 00:08:49,800 --> 00:08:54,540 is on an autosome, and that the alleles interact 203 00:08:54,540 --> 00:08:57,030 in a way so that the disease allele, 204 00:08:57,030 --> 00:08:58,710 the mutant disease allele, 205 00:08:58,710 --> 00:09:03,710 is dominant to the recessive wild type allele. 206 00:09:03,720 --> 00:09:06,840 Which means you only need one copy of the disease allele 207 00:09:06,840 --> 00:09:08,493 to cause the disease. 208 00:09:09,660 --> 00:09:12,090 Alright, so what I'm starting to show you here, 209 00:09:12,090 --> 00:09:14,190 this will be the first time I'm showing you this, 210 00:09:14,190 --> 00:09:16,790 and we're going to it a lot throughout this lecture, 211 00:09:17,691 --> 00:09:18,900 so I'm going to orient you first 212 00:09:18,900 --> 00:09:21,464 to what it is we're actually looking at 213 00:09:21,464 --> 00:09:23,520 on this table to the right. 214 00:09:23,520 --> 00:09:26,493 So this is actually called a punnet square. 215 00:09:27,570 --> 00:09:30,180 So let me just click through here. 216 00:09:30,180 --> 00:09:31,440 Sorry I didn't actually realize 217 00:09:31,440 --> 00:09:34,740 I had them appearing that way. 218 00:09:34,740 --> 00:09:36,120 Okay (chuckles). 219 00:09:36,120 --> 00:09:36,953 Alright. 220 00:09:36,953 --> 00:09:39,900 So a punnet square is a tool to estimate risk 221 00:09:39,900 --> 00:09:42,660 of offspring having genetic disease or being a carrier, 222 00:09:42,660 --> 00:09:46,110 so it's just a way to kind of write it out, 223 00:09:46,110 --> 00:09:49,980 so you can figure out what the probabilities are 224 00:09:49,980 --> 00:09:53,610 for two individuals, given their genotype, 225 00:09:53,610 --> 00:09:55,710 given basically their two alleles, 226 00:09:55,710 --> 00:09:57,000 what are the probabilities 227 00:09:57,000 --> 00:09:59,730 that their children will be either unaffected, 228 00:09:59,730 --> 00:10:01,890 so not have the disease, will have the disease, 229 00:10:01,890 --> 00:10:03,573 or will be a carrier for it? 230 00:10:04,830 --> 00:10:06,000 And the way we draw it, remember, 231 00:10:06,000 --> 00:10:07,620 each person has two alleles. 232 00:10:07,620 --> 00:10:10,930 And the father and the mother each contribute one allele 233 00:10:13,032 --> 00:10:13,865 for each child. 234 00:10:16,530 --> 00:10:19,380 So the mother has two alleles, father has two alleles, 235 00:10:19,380 --> 00:10:21,420 that means there are four possible combinations 236 00:10:21,420 --> 00:10:23,550 of each of those two alleles. 237 00:10:23,550 --> 00:10:24,383 Okay? 238 00:10:24,383 --> 00:10:27,750 So if you draw out in this manner, 239 00:10:27,750 --> 00:10:31,470 let's say going down vertically, 240 00:10:31,470 --> 00:10:35,010 in the columns here, rather in the rows, 241 00:10:35,010 --> 00:10:36,870 we're going to do the mother's alleles, 242 00:10:36,870 --> 00:10:39,720 and we're gonna designate those alleles, 243 00:10:39,720 --> 00:10:42,330 those alleles are gonna be designated. 244 00:10:42,330 --> 00:10:44,580 So of the standard nomenclature 245 00:10:44,580 --> 00:10:46,360 when you're doing a punnet square 246 00:10:47,670 --> 00:10:50,940 is the dominant allele is capitalized, 247 00:10:50,940 --> 00:10:53,580 and the recessive allele is lowercase. 248 00:10:53,580 --> 00:10:56,460 So that way you can kind of keep track 249 00:10:56,460 --> 00:10:58,060 of what it is you're looking at. 250 00:10:59,070 --> 00:11:01,410 Let's say we're looking at a case of a father 251 00:11:01,410 --> 00:11:04,890 who has Huntington's disease and a mother who does not. 252 00:11:04,890 --> 00:11:09,890 So the father is Huntington's, so it's a dominant disorder. 253 00:11:10,110 --> 00:11:14,400 So that means he has at least one copy, 254 00:11:14,400 --> 00:11:18,330 one of his alleles is the Huntington disease-causing allele. 255 00:11:18,330 --> 00:11:20,370 And the other may be wild type 256 00:11:20,370 --> 00:11:24,660 or it may also be the Huntington disease allele, 257 00:11:24,660 --> 00:11:28,980 but let's assume as is the case in most dominant disorders, 258 00:11:28,980 --> 00:11:31,100 that the individual who has the disorder 259 00:11:31,100 --> 00:11:32,310 is actually heterozygous, 260 00:11:32,310 --> 00:11:35,910 so they have one copy that is wild type and normal. 261 00:11:35,910 --> 00:11:37,920 And the other copy is disease. 262 00:11:37,920 --> 00:11:41,100 And the reason why that is normally the case, 263 00:11:41,100 --> 00:11:45,930 that an individual with a dominant disorder is heterozygous 264 00:11:45,930 --> 00:11:48,870 is because many times, if you are homozygous 265 00:11:48,870 --> 00:11:51,150 for a dominant disorder, it's actually lethal. 266 00:11:51,150 --> 00:11:52,650 It's lethal, because you don't even have 267 00:11:52,650 --> 00:11:56,850 a single normal copy of the protein, 268 00:11:56,850 --> 00:11:59,763 or rather of the gene around to make a normal, 269 00:12:00,690 --> 00:12:03,573 at least half normal version of the protein. 270 00:12:05,820 --> 00:12:07,140 But there certainly are cases 271 00:12:07,140 --> 00:12:08,490 where you have a dominant disorder 272 00:12:08,490 --> 00:12:11,040 and individuals can be homozygous for the dominant, 273 00:12:11,040 --> 00:12:13,724 but let's just assume in this case, 274 00:12:13,724 --> 00:12:15,960 'cause this is sort of the most likely case, 275 00:12:15,960 --> 00:12:19,620 that an individual here is heterozygous, 276 00:12:19,620 --> 00:12:24,177 so, the big H represents his disease-causing allele, 277 00:12:24,177 --> 00:12:26,827 and the little H is the wild type allele that he has. 278 00:12:28,200 --> 00:12:30,510 The mother, since she does not have Huntington's disease, 279 00:12:30,510 --> 00:12:32,940 let's say, in this particular example. 280 00:12:32,940 --> 00:12:35,430 Both of her alleles would be lowercase H. 281 00:12:35,430 --> 00:12:37,620 And let's look at every possible combination 282 00:12:37,620 --> 00:12:39,960 of those four alleles. 283 00:12:39,960 --> 00:12:41,310 Well, one combination 284 00:12:41,310 --> 00:12:45,720 would be the big H allele from the father 285 00:12:45,720 --> 00:12:48,300 with the little H allele from the mother. 286 00:12:48,300 --> 00:12:50,010 And so this would be basically like 287 00:12:50,010 --> 00:12:53,493 looking at one of the possible outcomes for a child. 288 00:12:54,630 --> 00:12:58,170 Another possible outcome would be that the big H 289 00:12:58,170 --> 00:13:02,820 with the mother's other little H or other wild type allele, 290 00:13:02,820 --> 00:13:06,450 so that would be this combination for the child. 291 00:13:06,450 --> 00:13:08,940 And then another possibility, right, 292 00:13:08,940 --> 00:13:12,240 would be combining the little H allele from the mother 293 00:13:12,240 --> 00:13:14,010 with the little H allele from the father. 294 00:13:14,010 --> 00:13:16,530 So both, so this individual, 295 00:13:16,530 --> 00:13:19,260 this child is inheriting both wild type alleles 296 00:13:19,260 --> 00:13:21,300 from their parents. 297 00:13:21,300 --> 00:13:22,980 Same with this individual, 298 00:13:22,980 --> 00:13:25,110 so they're inheriting this wild type 299 00:13:25,110 --> 00:13:27,960 and this wild type allele from their parents. 300 00:13:27,960 --> 00:13:29,220 Now what does that mean? 301 00:13:29,220 --> 00:13:33,840 So now we have our four possible genotypes 302 00:13:33,840 --> 00:13:36,780 for a child that may be born to this couple. 303 00:13:36,780 --> 00:13:39,330 And now we can determine what the phenotype would be, 304 00:13:39,330 --> 00:13:43,290 because we know that the impact of this genotype, 305 00:13:43,290 --> 00:13:46,080 since we know it is a dominant disorder, 306 00:13:46,080 --> 00:13:49,470 we would know that having a single copy 307 00:13:49,470 --> 00:13:51,780 of the disease allele 308 00:13:51,780 --> 00:13:55,530 is going to result in an individual 309 00:13:55,530 --> 00:13:57,090 having the disease phenotype. 310 00:13:57,090 --> 00:14:00,210 So both of these possible outcomes, 311 00:14:00,210 --> 00:14:03,450 which are actually the same, but we draw it out like this 312 00:14:03,450 --> 00:14:07,590 because it just kind of makes it easier. 313 00:14:07,590 --> 00:14:09,360 So you would say big H, little H, 314 00:14:09,360 --> 00:14:11,325 that's Huntington's disease, 315 00:14:11,325 --> 00:14:14,670 this possible combination of alleles 316 00:14:14,670 --> 00:14:17,250 would result in a child with Huntington disease, 317 00:14:17,250 --> 00:14:19,470 as would this one as well. 318 00:14:19,470 --> 00:14:23,010 Whereas these two outcomes would both be unaffected. 319 00:14:23,010 --> 00:14:24,330 So if we add these up, 320 00:14:24,330 --> 00:14:28,643 this would be two out of the four possible outcomes, or 50%, 321 00:14:31,358 --> 00:14:34,008 there's a 50% chance that a child will be unaffected. 322 00:14:35,640 --> 00:14:36,840 And there's a 50% chance 323 00:14:36,840 --> 00:14:38,790 that the child will have Huntington's disease 324 00:14:38,790 --> 00:14:43,350 because two out of four of the possible combinations 325 00:14:43,350 --> 00:14:46,530 of their different alleles from the Huntington gene 326 00:14:46,530 --> 00:14:51,090 would result in both alleles being wild type. 327 00:14:51,090 --> 00:14:55,140 So these two out of four, this two outta four is 50%. 328 00:14:55,140 --> 00:14:57,270 There's a 50% chance that the child will be unaffected 329 00:14:57,270 --> 00:15:00,213 and a 50% chance the child will have Huntington's disease. 330 00:15:02,460 --> 00:15:06,960 As you recall, there are no carriers of genetic disease, 331 00:15:06,960 --> 00:15:09,720 and it's typically a gain of function mutation, 332 00:15:09,720 --> 00:15:11,520 if you remember the mutations I was talking about, 333 00:15:11,520 --> 00:15:13,980 gain of function isn't necessarily a good thing. 334 00:15:13,980 --> 00:15:16,230 And in this case it is definitely not. 335 00:15:16,230 --> 00:15:19,170 So there's a mutation in the gene, 336 00:15:19,170 --> 00:15:22,080 and that results in the protein 337 00:15:22,080 --> 00:15:24,510 doing some different things than it should be doing, 338 00:15:24,510 --> 00:15:25,830 so that's called a gain of function, 339 00:15:25,830 --> 00:15:27,600 it's doing an additional function, 340 00:15:27,600 --> 00:15:29,820 but that's a bad thing, actually, in this case, 341 00:15:29,820 --> 00:15:33,693 that causes a lot of problems, for the individual. 342 00:15:35,040 --> 00:15:38,160 And so that's why having just one copy 343 00:15:38,160 --> 00:15:39,930 and not requiring both copies, 344 00:15:39,930 --> 00:15:42,810 is having just one copy that is the disease allele 345 00:15:42,810 --> 00:15:45,780 is enough to give the person the disease, 346 00:15:45,780 --> 00:15:49,080 because it's basically, that mutated version 347 00:15:49,080 --> 00:15:52,230 isn't just like the protein isn't functional anymore. 348 00:15:52,230 --> 00:15:53,400 In which case you could say, well yeah, 349 00:15:53,400 --> 00:15:55,080 they have one normal copy, 350 00:15:55,080 --> 00:15:56,970 so why isn't that enough to make up for it? 351 00:15:56,970 --> 00:15:58,170 Well yeah, they have one normal copy, 352 00:15:58,170 --> 00:16:00,670 but now they have one rogue crazy copy 353 00:16:01,830 --> 00:16:04,500 that's going around doing some weird additional functions, 354 00:16:04,500 --> 00:16:06,210 and that's causing the disease. 355 00:16:06,210 --> 00:16:08,610 So having one copy is sufficient 356 00:16:08,610 --> 00:16:11,943 to cause the disease in a dominant disorder. 357 00:16:15,060 --> 00:16:16,905 So a few other examples 358 00:16:16,905 --> 00:16:18,600 of autosomal dominant disorders 359 00:16:18,600 --> 00:16:21,423 would be Marfan syndrome and myotonic dystrophy. 360 00:16:22,440 --> 00:16:23,460 Oops. 361 00:16:23,460 --> 00:16:25,140 Let's take another quick peek 362 00:16:25,140 --> 00:16:26,970 at another way of looking at this, 363 00:16:26,970 --> 00:16:29,760 which is a little more visual. 364 00:16:29,760 --> 00:16:32,430 Would be saying, for example, 365 00:16:32,430 --> 00:16:35,133 in this case, an autosomal dominant disorder. 366 00:16:36,123 --> 00:16:39,030 And this, what they're showing here, pink would indicate 367 00:16:39,030 --> 00:16:42,360 that an individual is affected with the disorder, 368 00:16:42,360 --> 00:16:45,270 blue would be unaffected, so if you look at them, 369 00:16:45,270 --> 00:16:47,880 if you're looking at, say, the two chromosomes 370 00:16:47,880 --> 00:16:50,910 that the father has for, you know, 371 00:16:50,910 --> 00:16:52,560 there are two homologous chromosomes. 372 00:16:52,560 --> 00:16:55,860 On one of those chromosomes exists the allele 373 00:16:55,860 --> 00:16:57,060 that is the disease allele, 374 00:16:57,060 --> 00:17:01,260 and on the other chromosome, that's the wild type. 375 00:17:01,260 --> 00:17:03,420 And the mother, since she's unaffected, 376 00:17:03,420 --> 00:17:05,130 both would be wild type, 377 00:17:05,130 --> 00:17:07,410 and what are their possible children they could have? 378 00:17:07,410 --> 00:17:11,550 Well, each child could inherit this chromosome from dad, 379 00:17:11,550 --> 00:17:14,430 this chromosome from mom, this chromosome from dad, 380 00:17:14,430 --> 00:17:17,490 this chromosome from mom, or any combination of those, 381 00:17:17,490 --> 00:17:20,881 so that would be four different possible combinations. 382 00:17:20,881 --> 00:17:22,830 And if we look at this, then, again, 383 00:17:22,830 --> 00:17:25,690 you can kind of see that basically 50% 384 00:17:25,690 --> 00:17:28,650 or two outta the four possible combinations 385 00:17:28,650 --> 00:17:30,660 would result in Huntington's disease, 386 00:17:30,660 --> 00:17:32,640 and two out of the four or the other 50% 387 00:17:32,640 --> 00:17:33,900 would be unaffected. 388 00:17:33,900 --> 00:17:35,820 Remember that there really are no carriers 389 00:17:35,820 --> 00:17:38,940 for dominant disorder, because having a single copy, 390 00:17:38,940 --> 00:17:40,380 which is what would make you a carrier 391 00:17:40,380 --> 00:17:41,820 for a recessive disorder, 392 00:17:41,820 --> 00:17:44,460 having a single copy of a disease allele 393 00:17:44,460 --> 00:17:47,040 for a dominant disorder gives you the disease, 394 00:17:47,040 --> 00:17:51,270 so you're not a carrier, I mean you, you have the disease. 395 00:17:51,270 --> 00:17:55,680 Here are some of the different outcomes that you might see, 396 00:17:55,680 --> 00:17:59,220 HD I'm indicating is Huntington's disease. 397 00:17:59,220 --> 00:18:04,220 And the uppercase and lowercase case H are the alleles, 398 00:18:05,280 --> 00:18:07,050 the uppercase being the disease allele 399 00:18:07,050 --> 00:18:08,820 and the lower case being the wild type, 400 00:18:08,820 --> 00:18:09,840 and we know that in this case 401 00:18:09,840 --> 00:18:11,490 because it's a dominant disorder. 402 00:18:12,450 --> 00:18:15,750 Okay, so basically, depending upon the parents, 403 00:18:15,750 --> 00:18:20,750 whether the parents are wild type or heterozygous 404 00:18:20,880 --> 00:18:24,180 for the Huntington disease allele 405 00:18:24,180 --> 00:18:25,950 or homozygous for the hunting disease allele, 406 00:18:25,950 --> 00:18:27,780 there can be some different outcomes, 407 00:18:27,780 --> 00:18:30,210 so, I'll let you look through this on your own, 408 00:18:30,210 --> 00:18:32,370 and let me know if you have any questions on it, 409 00:18:32,370 --> 00:18:37,370 but, the net result is that with the most common type, 410 00:18:38,130 --> 00:18:41,700 which would be one Huntington disease parent 411 00:18:41,700 --> 00:18:43,800 who is heterozygous and one wild type, again, 412 00:18:43,800 --> 00:18:46,350 50% of their children will have Huntington disease. 413 00:18:48,030 --> 00:18:51,000 Autosomal recessive disorders. 414 00:18:51,000 --> 00:18:53,130 So here we're talking about the need 415 00:18:53,130 --> 00:18:55,920 to have both copies of the gene to be disease alleles 416 00:18:55,920 --> 00:18:57,720 before you actually have the disease. 417 00:18:57,720 --> 00:19:00,180 And there typically is a loss of function mutation, 418 00:19:00,180 --> 00:19:01,170 which can be made up for 419 00:19:01,170 --> 00:19:03,120 by the presence of one functional copy, 420 00:19:03,120 --> 00:19:04,860 so as long as you have one wild type, 421 00:19:04,860 --> 00:19:07,230 as long as one of your two alleles is wild type, 422 00:19:07,230 --> 00:19:08,520 you actually won't have the disorder 423 00:19:08,520 --> 00:19:11,610 because while the disease allele 424 00:19:11,610 --> 00:19:13,590 actually knocked out the function of the proteins, 425 00:19:13,590 --> 00:19:16,203 the proteins just imagine like, you know, 426 00:19:17,395 --> 00:19:19,623 it's not even produced anymore, 427 00:19:21,423 --> 00:19:24,900 so you don't have that copy of it. 428 00:19:24,900 --> 00:19:27,570 But let's say if instead, 429 00:19:27,570 --> 00:19:32,570 you have both of your alleles are the mutated version, 430 00:19:32,730 --> 00:19:35,792 then you wouldn't have a functional copy of the protein, 431 00:19:35,792 --> 00:19:37,642 and that could result in the disease. 432 00:19:38,610 --> 00:19:41,700 Carriers, so here in autosomal recessive disorders, 433 00:19:41,700 --> 00:19:43,230 this is where you can have carriers. 434 00:19:43,230 --> 00:19:44,910 So they have a single disease allele 435 00:19:44,910 --> 00:19:46,110 but do not have the disease 436 00:19:46,110 --> 00:19:48,460 because they have one wild type allele as well. 437 00:19:49,726 --> 00:19:53,460 It is often thought to skip generations, and normal, 438 00:19:53,460 --> 00:19:55,950 so here let's look at cystic fibrosis 439 00:19:55,950 --> 00:19:59,130 and we'll designate the normal allele for the CFTR gene 440 00:19:59,130 --> 00:20:01,380 as uppercase F. 441 00:20:01,380 --> 00:20:02,970 Right, so that's the wild type allele, 442 00:20:02,970 --> 00:20:05,610 and the disease allele is lowercase F. 443 00:20:05,610 --> 00:20:08,970 So remember that in our designations in punnet squares, 444 00:20:08,970 --> 00:20:12,600 uppercase is always the dominant allele 445 00:20:12,600 --> 00:20:15,150 and lowercase is the recessive. 446 00:20:15,150 --> 00:20:18,930 So for a dominant disease, 447 00:20:18,930 --> 00:20:21,690 the uppercase indicates the disease allele 448 00:20:21,690 --> 00:20:23,150 because it's dominant. 449 00:20:23,150 --> 00:20:26,580 In a recessive disease, when you're doing a punnet square, 450 00:20:26,580 --> 00:20:29,643 lowercase is the disease allele because it is recessive. 451 00:20:30,480 --> 00:20:31,500 Okay. 452 00:20:31,500 --> 00:20:33,120 Again, we're showing the mother's alleles 453 00:20:33,120 --> 00:20:34,050 on the vertical axis 454 00:20:34,050 --> 00:20:36,450 and the father's alleles on the horizontal. 455 00:20:36,450 --> 00:20:39,270 And when we look at all possible combinations, 456 00:20:39,270 --> 00:20:40,530 what we start to see, 457 00:20:40,530 --> 00:20:45,530 let's assume that we have a pairing of both carriers, 458 00:20:45,870 --> 00:20:48,240 so a mother's a carrier for cystic fibrosis 459 00:20:48,240 --> 00:20:50,010 and a father is as well. 460 00:20:50,010 --> 00:20:52,710 And they want to know, 461 00:20:52,710 --> 00:20:54,330 they want to know what's the likelihood 462 00:20:54,330 --> 00:20:57,930 that their child will have cystic fibrosis. 463 00:20:57,930 --> 00:21:00,180 Well you can certainly estimate this. 464 00:21:00,180 --> 00:21:03,270 Again, using every possible combination 465 00:21:03,270 --> 00:21:05,230 of each of the two alleles, 466 00:21:05,230 --> 00:21:07,173 one from the mother, one from the father. 467 00:21:07,173 --> 00:21:11,437 And from that, you know the four possible combinations. 468 00:21:13,770 --> 00:21:18,030 You can determine what the ratios or probability is 469 00:21:18,030 --> 00:21:20,970 for each of those outcomes. 470 00:21:20,970 --> 00:21:23,610 So first of all, we take the combination, 471 00:21:23,610 --> 00:21:26,580 let's say where, you know, an individual could inherit, 472 00:21:26,580 --> 00:21:31,500 so one of their offspring could inherit the wild type allele 473 00:21:31,500 --> 00:21:33,000 from both their mother and the father, 474 00:21:33,000 --> 00:21:34,680 this individual would be completely unaffected, 475 00:21:34,680 --> 00:21:35,850 they're not even a carrier. 476 00:21:35,850 --> 00:21:38,010 Because they didn't inherit a single disease allele 477 00:21:38,010 --> 00:21:39,003 from either parent. 478 00:21:39,990 --> 00:21:43,500 Okay, and let's say some other possibilities 479 00:21:43,500 --> 00:21:47,250 would include inheriting the wild type copy from mom 480 00:21:47,250 --> 00:21:49,470 and the disease copy from dad. 481 00:21:49,470 --> 00:21:51,120 This would be a carrier. 482 00:21:51,120 --> 00:21:53,790 Same thing here, in the end, same outcome. 483 00:21:53,790 --> 00:21:56,070 You inherit a wild type copy from dad 484 00:21:56,070 --> 00:22:00,150 and a mutant or a disease-causing copy from mom. 485 00:22:00,150 --> 00:22:01,230 This is also a carrier, 486 00:22:01,230 --> 00:22:04,230 because remember, you need both copies to be the recessive 487 00:22:04,230 --> 00:22:09,230 in order for recessive disease to present. 488 00:22:09,270 --> 00:22:12,510 And then the final type of combination 489 00:22:12,510 --> 00:22:17,510 would be inheriting disease alleles from both parents. 490 00:22:18,120 --> 00:22:19,530 And this would be the individual 491 00:22:19,530 --> 00:22:20,880 who would have cystic fibrosis, 492 00:22:20,880 --> 00:22:22,620 so if we add all of these up, 493 00:22:22,620 --> 00:22:24,450 you could have an unaffected individual 494 00:22:24,450 --> 00:22:28,770 be one out of the four combinations, so 25%. 495 00:22:28,770 --> 00:22:32,040 You could have one, two of the four combinations 496 00:22:32,040 --> 00:22:34,650 would result in a child who is a carrier, 497 00:22:34,650 --> 00:22:37,320 so that'd be 50%, two outta the four. 498 00:22:37,320 --> 00:22:41,220 Or one out of the four or 25% having cystic fibrosis 499 00:22:41,220 --> 00:22:44,943 because they inherited one disease allele from each parent. 500 00:22:48,630 --> 00:22:51,030 Okay, so just a quick peek here, 501 00:22:51,030 --> 00:22:52,710 you can look through this yourself, 502 00:22:52,710 --> 00:22:55,080 but, this is just another way of looking at 503 00:22:55,080 --> 00:22:57,330 what we just described. 504 00:22:57,330 --> 00:22:59,400 And here are some other possible outcomes 505 00:22:59,400 --> 00:23:03,090 depending upon the genotype of the parents. 506 00:23:03,090 --> 00:23:06,450 So you could look at, so if instead, 507 00:23:06,450 --> 00:23:09,420 let's say you had a couple approach you, 508 00:23:09,420 --> 00:23:14,420 and one of them knows that he or she 509 00:23:14,670 --> 00:23:17,100 is a carrier for cystic fibrosis, 510 00:23:17,100 --> 00:23:19,380 and the other is not a carrier, has been tested, 511 00:23:19,380 --> 00:23:21,840 and is determined to have the wild type genotype, 512 00:23:21,840 --> 00:23:26,840 so that means both their alleles are wild type. 513 00:23:26,850 --> 00:23:30,240 Well we would know that actually 0% of their children 514 00:23:30,240 --> 00:23:31,800 will have cystic fibrosis, 515 00:23:31,800 --> 00:23:35,070 because you need both parents to be at least carriers 516 00:23:35,070 --> 00:23:37,090 in order for a recessive disorder 517 00:23:38,809 --> 00:23:42,690 to present in that generation, in the next generation 518 00:23:42,690 --> 00:23:44,790 that those two individuals would produce. 519 00:23:44,790 --> 00:23:46,950 So again, look at all the different combinations, 520 00:23:46,950 --> 00:23:50,073 let me know if you have questions as you go through. 521 00:23:51,090 --> 00:23:53,400 But this is just giving every possible combination 522 00:23:53,400 --> 00:23:55,290 of really what the parents could be, 523 00:23:55,290 --> 00:23:58,923 so are the parents unaffected carriers, 524 00:24:02,186 --> 00:24:03,090 or are they homozygous, 525 00:24:03,090 --> 00:24:06,480 so they actually have cystic fibrosis? 526 00:24:06,480 --> 00:24:08,340 And what would be the likelihood 527 00:24:08,340 --> 00:24:12,120 of their children having that, so let's take an example of, 528 00:24:12,120 --> 00:24:14,520 it probably wouldn't be the case with cystic fibrosis 529 00:24:14,520 --> 00:24:17,730 given the issues with fertility, 530 00:24:17,730 --> 00:24:20,040 and also life expectancy, 531 00:24:20,040 --> 00:24:22,530 but let's just say there are two individuals 532 00:24:22,530 --> 00:24:24,450 who both have cystic fibrosis 533 00:24:24,450 --> 00:24:27,183 who are planning to have children with one another. 534 00:24:28,200 --> 00:24:29,700 What is the likelihood that their children 535 00:24:29,700 --> 00:24:31,200 will have cystic fibrosis? 536 00:24:31,200 --> 00:24:33,300 Well it's actually 100%. 537 00:24:33,300 --> 00:24:35,790 Because both parents, if they have cystic fibrosis, 538 00:24:35,790 --> 00:24:38,733 that means they are homozygous, right, 539 00:24:39,995 --> 00:24:41,370 both copies are the same 540 00:24:41,370 --> 00:24:42,357 and both copies are the disease copy. 541 00:24:44,377 --> 00:24:47,037 So both the mother and the father 542 00:24:47,970 --> 00:24:51,000 have two copies of the disease allele, 543 00:24:51,000 --> 00:24:54,000 that means the only combinations that can occur 544 00:24:54,000 --> 00:24:55,140 would be disease allele, 545 00:24:55,140 --> 00:24:56,610 disease allele, disease, disease, 546 00:24:56,610 --> 00:24:59,700 so that would result in, there's no chance 547 00:24:59,700 --> 00:25:00,930 that they will have a child 548 00:25:00,930 --> 00:25:02,490 who doesn't have cystic fibrosis, 549 00:25:02,490 --> 00:25:05,730 so 100% chance their offspring will have cystic fibrosis. 550 00:25:05,730 --> 00:25:07,290 So it really varies 551 00:25:07,290 --> 00:25:12,000 and depends upon the genotypes of the parents, 552 00:25:12,000 --> 00:25:13,530 whether they're both carriers, 553 00:25:13,530 --> 00:25:17,190 one is whether one or both has the disease 554 00:25:17,190 --> 00:25:19,530 will affect the probabilities 555 00:25:19,530 --> 00:25:21,580 of their children having disease with it. 556 00:25:22,560 --> 00:25:24,630 Alright, let's look at X-linked diseases. 557 00:25:24,630 --> 00:25:28,350 So these would be diseases involving a gene 558 00:25:28,350 --> 00:25:30,000 that's on the X chromosome. 559 00:25:30,000 --> 00:25:31,800 So they're generally inherited from the mother 560 00:25:31,800 --> 00:25:33,630 and expressed in sons, 561 00:25:33,630 --> 00:25:35,940 for X-linked recessive, which is the most common, 562 00:25:35,940 --> 00:25:39,630 X-linked dominant disorders are actually pretty rare. 563 00:25:39,630 --> 00:25:41,400 Most X-linked diseases are recessive, 564 00:25:41,400 --> 00:25:45,480 so females may be asymptomatic carriers, remember recessive, 565 00:25:45,480 --> 00:25:48,870 remember females have two X chromosomes, 566 00:25:48,870 --> 00:25:50,370 and males only have one. 567 00:25:50,370 --> 00:25:52,380 So in a recessive disorder, 568 00:25:52,380 --> 00:25:57,380 the males inheriting a single copy of the disease allele 569 00:25:59,370 --> 00:26:02,160 will be sufficient to result in them having a disease, 570 00:26:02,160 --> 00:26:05,790 and females, on the other hand, if they inherit, 571 00:26:05,790 --> 00:26:10,290 if one of their X chromosomes has, say, the disease allele, 572 00:26:10,290 --> 00:26:12,360 but then the other X chromosome that they have 573 00:26:12,360 --> 00:26:14,310 has the wild type allele. 574 00:26:14,310 --> 00:26:16,860 Well then they will be carriers, 575 00:26:16,860 --> 00:26:18,710 but they won't actually have disease. 576 00:26:20,610 --> 00:26:23,190 Males have only one allele for each X-linked gene, 577 00:26:23,190 --> 00:26:24,840 so there's no backup copy. 578 00:26:24,840 --> 00:26:26,100 Females have two copies, 579 00:26:26,100 --> 00:26:28,770 though one is inactivated randomly in each cell, 580 00:26:28,770 --> 00:26:30,360 remember X inactivation? 581 00:26:30,360 --> 00:26:32,820 But having one functional copy in half of the cells 582 00:26:32,820 --> 00:26:35,220 is usually enough to compensate for the loss. 583 00:26:35,220 --> 00:26:37,770 So you can think of female carriers as really mosaics, 584 00:26:37,770 --> 00:26:39,240 and you know what I mean when I say that 585 00:26:39,240 --> 00:26:41,350 because we had that whole section on it 586 00:26:42,360 --> 00:26:43,950 in the previous module, isn't it cool 587 00:26:43,950 --> 00:26:45,930 when things start to come together a little bit? 588 00:26:45,930 --> 00:26:47,670 I don't know, I think it is. 589 00:26:47,670 --> 00:26:50,460 X-Linked dominant disorders are generally lethal in males 590 00:26:50,460 --> 00:26:52,620 because they lack any functional copy of the gene, 591 00:26:52,620 --> 00:26:55,020 remember as I was saying before 592 00:26:55,020 --> 00:26:57,300 when we were talking about autosomal dominant disorders, 593 00:26:57,300 --> 00:27:00,540 that usually it's a heterozygous condition, 594 00:27:00,540 --> 00:27:05,540 so usually individuals who have the disorder 595 00:27:07,050 --> 00:27:08,640 will have one normal copy, 596 00:27:08,640 --> 00:27:09,597 like one wild type copy, 597 00:27:09,597 --> 00:27:12,060 and the other copy will be the disease copy, 598 00:27:12,060 --> 00:27:17,060 and that's because in most dominant disorders, 599 00:27:17,910 --> 00:27:22,910 having both copies be the disease copy results in lethality 600 00:27:24,630 --> 00:27:27,960 because there's no rescue copy, there's no normal copy 601 00:27:27,960 --> 00:27:31,350 to kind of come back and balance it out to any extent. 602 00:27:31,350 --> 00:27:32,550 And in males that's the case 603 00:27:32,550 --> 00:27:34,590 because they only have one copy 604 00:27:34,590 --> 00:27:37,533 of every gene on the X chromosome. 605 00:27:38,460 --> 00:27:41,220 A few examples of X-linked diseases: Rett syndrome, 606 00:27:41,220 --> 00:27:45,810 which is one of those more rare X-linked dominant disorders. 607 00:27:45,810 --> 00:27:48,120 Duchenne muscular dystrophy, which is recessive, 608 00:27:48,120 --> 00:27:50,190 and hemophilia, which is recessive. 609 00:27:50,190 --> 00:27:51,663 And these are all X-linked. 610 00:27:52,650 --> 00:27:55,683 So let's take a peek at X-linked recessive disorders. 611 00:27:57,000 --> 00:28:01,113 And here we'll look at hemophilia. 612 00:28:02,130 --> 00:28:05,640 Hemophilia A caused by mutation on the F8 gene. 613 00:28:05,640 --> 00:28:08,820 F8 gene is located on the X chromosome. 614 00:28:08,820 --> 00:28:12,810 And here we're gonna designate capital H 615 00:28:12,810 --> 00:28:17,130 as the wild type because it's recessive, remember that. 616 00:28:17,130 --> 00:28:21,063 And lowercase H as the disease allele. 617 00:28:22,050 --> 00:28:23,370 Again, 'cause it's recessive. 618 00:28:23,370 --> 00:28:25,080 Now when we do a punnet square for this, 619 00:28:25,080 --> 00:28:26,040 it's a little different, 620 00:28:26,040 --> 00:28:29,790 because, in the father's case, he only has one X chromosome, 621 00:28:29,790 --> 00:28:32,040 so he only has one allele that he can contribute. 622 00:28:32,040 --> 00:28:33,390 The mother has two alleles, 623 00:28:33,390 --> 00:28:35,460 so we would draw it like this, 624 00:28:35,460 --> 00:28:37,860 and here we're actually showing possible combinations 625 00:28:37,860 --> 00:28:40,890 in a female offspring or a daughter that they would have 626 00:28:40,890 --> 00:28:42,660 and possible combinations in male 627 00:28:42,660 --> 00:28:44,340 or their son that they would have. 628 00:28:44,340 --> 00:28:47,190 Because remember, the sons are only going to inherit 629 00:28:47,190 --> 00:28:48,390 one X chromosome, 630 00:28:48,390 --> 00:28:50,100 and then they're going to have the Y chromosome. 631 00:28:50,100 --> 00:28:52,440 But the Y chromosome does not contain the same genes 632 00:28:52,440 --> 00:28:54,540 as the X chromosome, so it's totally different. 633 00:28:54,540 --> 00:28:56,700 There were very few genes on the Y chromosome, 634 00:28:56,700 --> 00:28:58,470 and very few disorders actually associated 635 00:28:58,470 --> 00:29:01,050 with Y-linked genes, 636 00:29:01,050 --> 00:29:03,750 so we're not actually gonna bother talking about that. 637 00:29:05,610 --> 00:29:07,140 So here we're kinda showing something a little different, 638 00:29:07,140 --> 00:29:09,780 these are all the daughters, this column here, 639 00:29:09,780 --> 00:29:11,790 because they inherit two. 640 00:29:11,790 --> 00:29:15,120 They inherit both one of the two X chromosomes 641 00:29:15,120 --> 00:29:15,953 from their mother 642 00:29:15,953 --> 00:29:18,060 and the X chromosome from their father. 643 00:29:18,060 --> 00:29:21,450 Whereas the sons do not inherit an X chromosome 644 00:29:21,450 --> 00:29:22,500 from their father, 645 00:29:22,500 --> 00:29:25,680 they inherit the Y chromosome from the father, 646 00:29:25,680 --> 00:29:28,980 so they inherit either one of the two X chromosomes 647 00:29:28,980 --> 00:29:30,450 from their mother. 648 00:29:30,450 --> 00:29:32,190 And that will determine 649 00:29:32,190 --> 00:29:33,780 whether or not they have the disorder, 650 00:29:33,780 --> 00:29:38,100 so in this case, basically it's, in an X-linked D disorder, 651 00:29:38,100 --> 00:29:40,110 inheritance is is typically coming 652 00:29:40,110 --> 00:29:42,000 from the mother as as a carrier, 653 00:29:42,000 --> 00:29:47,000 because the father would know if he had the disease allele, 654 00:29:47,160 --> 00:29:49,393 because he would have the disease, 655 00:29:49,393 --> 00:29:51,600 'cause he only has one one allele. 656 00:29:51,600 --> 00:29:53,790 So if we add these up, then we would see 657 00:29:53,790 --> 00:29:57,270 that one of the two combinations for daughters 658 00:29:57,270 --> 00:30:02,270 would be inheriting both the wild type copy from the father, 659 00:30:02,850 --> 00:30:05,010 which is the only copy she'd get from the father. 660 00:30:05,010 --> 00:30:07,290 And the wild type copy from the mother, 661 00:30:07,290 --> 00:30:09,210 which would leave her unaffected. 662 00:30:09,210 --> 00:30:14,100 Or she could inherit the disease copy from the mother. 663 00:30:14,100 --> 00:30:16,440 And of course, she continues to inherit 664 00:30:16,440 --> 00:30:17,330 the wild type copy from the father, 665 00:30:17,330 --> 00:30:19,470 in which case she is a carrier. 666 00:30:19,470 --> 00:30:21,030 The sons on the other hand, 667 00:30:21,030 --> 00:30:22,860 here you can actually start to get 668 00:30:22,860 --> 00:30:27,180 the expression of the disorder, so, they will inherit 669 00:30:27,180 --> 00:30:29,700 one of the two X chromosomes from the mother, 670 00:30:29,700 --> 00:30:32,070 and of course the Y chromosome from the father. 671 00:30:32,070 --> 00:30:35,670 But again, that doesn't play a role in X-linked disorders, 672 00:30:35,670 --> 00:30:37,110 the Y chromosome does not. 673 00:30:37,110 --> 00:30:40,950 So, they would either get the wild type, 674 00:30:40,950 --> 00:30:45,950 50% of sons would inherit the wild type allele, 675 00:30:50,580 --> 00:30:52,680 this particular X chromosome from the mother. 676 00:30:52,680 --> 00:30:57,420 And 50% would inherit the disease allele, 677 00:30:57,420 --> 00:30:59,130 or the other X chromosome from the mother, 678 00:30:59,130 --> 00:31:03,300 and this individual would present with a disorder, 679 00:31:03,300 --> 00:31:06,660 so this individual would have hemophilia. 680 00:31:06,660 --> 00:31:09,090 So in total we would say 50% of daughters 681 00:31:09,090 --> 00:31:09,930 would be unaffected, 682 00:31:09,930 --> 00:31:11,580 50% of daughters will be carriers, 683 00:31:11,580 --> 00:31:13,230 but they won't actually have the disease, 684 00:31:13,230 --> 00:31:14,063 they'll be carriers, 685 00:31:14,063 --> 00:31:16,560 and so the next generation might have it. 686 00:31:16,560 --> 00:31:18,570 50% of sons will be unaffected 687 00:31:18,570 --> 00:31:21,870 and 50% of sons will have the disorder. 688 00:31:21,870 --> 00:31:23,820 So as you can see, there's differences 689 00:31:23,820 --> 00:31:26,583 depending upon the gender of the child. 690 00:31:27,720 --> 00:31:30,210 Alright, so a reminder, father only has one allele. 691 00:31:30,210 --> 00:31:32,517 Mother has two alleles, 50% of daughters will be carriers, 692 00:31:32,517 --> 00:31:36,063 and 50% of males or sons will have hemophilia. 693 00:31:37,500 --> 00:31:41,970 And here you can take a peek at some different combinations, 694 00:31:41,970 --> 00:31:44,040 again, just another way of looking at it. 695 00:31:44,040 --> 00:31:44,873 Alright. 696 00:31:44,873 --> 00:31:46,920 X-linked dominant inheritance, 697 00:31:46,920 --> 00:31:48,720 so this would be Rett syndrome, 698 00:31:48,720 --> 00:31:51,120 and here it's gonna look a little different. 699 00:31:51,120 --> 00:31:56,120 Because in most X-linked dominant disorders, 700 00:31:56,430 --> 00:32:01,430 inheritance of the disease allele in sons. 701 00:32:02,340 --> 00:32:06,240 So sons who inherit only the, 702 00:32:06,240 --> 00:32:07,740 they only get one copy, remember, 703 00:32:07,740 --> 00:32:11,160 and if the one copy they inherit is the disease copy, 704 00:32:11,160 --> 00:32:13,770 then it is most likely going to be lethal, 705 00:32:13,770 --> 00:32:16,050 'cause again, they don't have a normal copy 706 00:32:16,050 --> 00:32:18,483 to kinda rescue it, or balance it out at all. 707 00:32:20,400 --> 00:32:23,400 So it's usually lethal in males and homozygous females, 708 00:32:23,400 --> 00:32:25,650 so females who would inherit. 709 00:32:25,650 --> 00:32:28,380 But, I mean you really wouldn't have a homozygous female. 710 00:32:28,380 --> 00:32:30,240 Why do you think that is? 711 00:32:30,240 --> 00:32:31,620 You wouldn't have a homozygous female 712 00:32:31,620 --> 00:32:33,120 if it's lethal in males, 713 00:32:33,120 --> 00:32:36,600 because her father couldn't possibly have 714 00:32:36,600 --> 00:32:38,130 the disease allele to begin with, 715 00:32:38,130 --> 00:32:41,370 'cause if he did, he wouldn't survive. 716 00:32:41,370 --> 00:32:45,630 So, homozygous females are really just not going to occur. 717 00:32:45,630 --> 00:32:47,700 So one example of this would be Rett syndrome, 718 00:32:47,700 --> 00:32:49,130 where you have the normal allele 719 00:32:49,130 --> 00:32:53,280 of the MECP2 gene is designated as lowercase R, 720 00:32:53,280 --> 00:32:54,510 so the wild type is lowercase R 721 00:32:54,510 --> 00:32:56,010 because this is dominant, remember. 722 00:32:56,010 --> 00:32:59,283 Dominant disease allele is uppercase R. 723 00:33:00,420 --> 00:33:02,490 And again, we do our combinations here. 724 00:33:02,490 --> 00:33:04,440 What we would see is that in the daughters, 725 00:33:04,440 --> 00:33:08,370 we have a daughter with Rett syndrome. 726 00:33:08,370 --> 00:33:09,390 And this would be a daughter 727 00:33:09,390 --> 00:33:13,950 who inherited the mutant allele from her mother. 728 00:33:13,950 --> 00:33:15,870 And an unaffected daughter, 729 00:33:15,870 --> 00:33:18,180 so 50% of daughters would have Rett, 730 00:33:18,180 --> 00:33:20,760 50% would be unaffected. 731 00:33:20,760 --> 00:33:24,120 And in the sons, really none of the sons who survive 732 00:33:24,120 --> 00:33:25,590 would be affected. 733 00:33:25,590 --> 00:33:30,390 But there would be likely a loss of the embryos 734 00:33:30,390 --> 00:33:31,890 that are conceived, 735 00:33:31,890 --> 00:33:36,213 that inherited the disease allele from the mother. 736 00:33:37,980 --> 00:33:39,870 So again, reminder, father only has one allele, 737 00:33:39,870 --> 00:33:42,990 mother has two, 50% of daughters will have Rett, 738 00:33:42,990 --> 00:33:45,180 just like an autosomal dominant disorder. 739 00:33:45,180 --> 00:33:47,820 And males inheriting disease allele from the mother 740 00:33:47,820 --> 00:33:50,700 will not survive, because presence of no wild type alleles 741 00:33:50,700 --> 00:33:52,743 increases disease severity. 742 00:33:53,850 --> 00:33:55,230 Here you can take another peek 743 00:33:55,230 --> 00:33:56,760 at some different combinations, 744 00:33:56,760 --> 00:33:58,410 and they're actually showing, oh, 745 00:33:59,280 --> 00:34:01,650 there are the rare, rare exceptions 746 00:34:01,650 --> 00:34:03,690 of X-linked dominant disorders 747 00:34:03,690 --> 00:34:05,430 which are not lethal in males, 748 00:34:05,430 --> 00:34:06,510 and they're showing an example 749 00:34:06,510 --> 00:34:08,190 of what the inheritance patterns for that 750 00:34:08,190 --> 00:34:09,890 might look like on the right here. 751 00:34:10,800 --> 00:34:12,900 Alright, so what are some implications for nursing? 752 00:34:12,900 --> 00:34:15,090 Some red flags of Mendelian genetic disease, 753 00:34:15,090 --> 00:34:17,850 clear multiple generation family history. 754 00:34:17,850 --> 00:34:20,010 If it's dominant, it's seen in every generation, 755 00:34:20,010 --> 00:34:22,230 if it's recessive, it skips generations. 756 00:34:22,230 --> 00:34:23,370 Now let's go back for one second 757 00:34:23,370 --> 00:34:25,890 to seen in every generation with a dominant disorder. 758 00:34:25,890 --> 00:34:28,320 You can also have, if you recall from the previous lecture, 759 00:34:28,320 --> 00:34:30,690 a de novo mutation, which, 760 00:34:30,690 --> 00:34:33,960 we've been really talking about inherited mutations, 761 00:34:33,960 --> 00:34:35,310 so this was a mutation that occurred 762 00:34:35,310 --> 00:34:37,590 sometime way in the past in your ancestors 763 00:34:37,590 --> 00:34:39,170 that's been passed on generation to generation 764 00:34:39,170 --> 00:34:40,173 to generation. 765 00:34:41,040 --> 00:34:44,430 A de nova mutation is a new mutation that has occurred 766 00:34:44,430 --> 00:34:48,240 for the first time, and it occurred in the germline cell 767 00:34:48,240 --> 00:34:50,730 likely of one of your parents. 768 00:34:50,730 --> 00:34:54,360 And so in that case, there may not be a past history 769 00:34:54,360 --> 00:34:56,580 of a family history of the traditional family history 770 00:34:56,580 --> 00:34:58,770 you would expect to see in an individual 771 00:34:58,770 --> 00:35:00,450 if they have a de novo mutation, 772 00:35:00,450 --> 00:35:01,500 and this can be determined 773 00:35:01,500 --> 00:35:04,350 by genotyping both of the parents, 774 00:35:04,350 --> 00:35:05,970 and genotyping the child. 775 00:35:05,970 --> 00:35:09,993 And, you know, of course making sure that the parents, 776 00:35:12,398 --> 00:35:14,310 how do I put this, that the individuals 777 00:35:14,310 --> 00:35:16,710 who are claiming to be the parents of that person 778 00:35:16,710 --> 00:35:19,050 are truly their biological parents. 779 00:35:19,050 --> 00:35:20,670 Once that has been confirmed, 780 00:35:20,670 --> 00:35:25,670 then if the individual has a mutation 781 00:35:26,520 --> 00:35:28,440 that neither parent has, 782 00:35:28,440 --> 00:35:30,840 then you know that this was a de novo mutation, 783 00:35:30,840 --> 00:35:34,680 or one that spontaneously occurred in that generation. 784 00:35:34,680 --> 00:35:38,040 X-linked only presents in males in recessive, 785 00:35:38,040 --> 00:35:40,953 X-linked recessive, or females primarily, 786 00:35:42,090 --> 00:35:45,360 which would be a dominant X-linked disorder in the family. 787 00:35:45,360 --> 00:35:48,540 Remember, because in males, dominant X-linked disorders 788 00:35:48,540 --> 00:35:50,283 primarily are lethal. 789 00:35:51,210 --> 00:35:53,520 There's importance in gathering family history information, 790 00:35:53,520 --> 00:35:54,870 which I'm sure you all appreciate, 791 00:35:54,870 --> 00:35:57,660 genetic testing is available for most Mendelian diseases, 792 00:35:57,660 --> 00:35:59,550 because these are rather simple diseases, 793 00:35:59,550 --> 00:36:03,210 they're monogenic, and we know quite a lot about them. 794 00:36:03,210 --> 00:36:05,115 Granted there are, 795 00:36:05,115 --> 00:36:06,600 I think there are something like 6000 different diseases 796 00:36:06,600 --> 00:36:08,040 that have been classified. 797 00:36:08,040 --> 00:36:10,620 But, we do actually know quite a bit about most of them. 798 00:36:10,620 --> 00:36:12,480 There are some very rare diseases 799 00:36:12,480 --> 00:36:14,670 where there may not be a genetic test available, 800 00:36:14,670 --> 00:36:16,740 but I'd say the vast majority of them 801 00:36:16,740 --> 00:36:19,020 there are genetic tests available. 802 00:36:19,020 --> 00:36:21,000 So knowing both parents' genotypes, 803 00:36:21,000 --> 00:36:22,800 it is possible to predict the likelihood 804 00:36:22,800 --> 00:36:25,140 a couple will have a child with a Mendelian disease 805 00:36:25,140 --> 00:36:26,610 or will be a carrier. 806 00:36:26,610 --> 00:36:29,040 But again, advise referral for genetic counseling 807 00:36:29,040 --> 00:36:30,300 where possible, 808 00:36:30,300 --> 00:36:32,790 as opposed to trying to do back of the envelope 809 00:36:32,790 --> 00:36:34,170 estimations of probability, 810 00:36:34,170 --> 00:36:35,940 not that you would, but, you know, 811 00:36:35,940 --> 00:36:37,353 just to be clear about that. 812 00:36:38,430 --> 00:36:41,520 There are subtleties in these different diseases 813 00:36:41,520 --> 00:36:43,140 and patterns of inheritance. 814 00:36:43,140 --> 00:36:45,270 But just so you know in general 815 00:36:45,270 --> 00:36:48,250 how you could estimate the probability 816 00:36:49,533 --> 00:36:52,560 for these monogenic disorders, and their inheritance. 817 00:36:52,560 --> 00:36:55,170 So some other red flags of genetic disorders. 818 00:36:55,170 --> 00:36:57,780 Consanguinity, so parental relatedness, 819 00:36:57,780 --> 00:37:00,510 and why is that, why is that a red flag? 820 00:37:00,510 --> 00:37:05,130 Well, recessive alleles are actually relatively rare 821 00:37:05,130 --> 00:37:08,580 in the population and in the general population, 822 00:37:08,580 --> 00:37:11,710 and so if you have two individuals coming together 823 00:37:12,630 --> 00:37:14,550 who are completely unrelated with one another, 824 00:37:14,550 --> 00:37:19,080 the likelihood that they'll share much genetic similarity 825 00:37:19,080 --> 00:37:21,000 between one another in terms of their alleles 826 00:37:21,000 --> 00:37:22,440 is relatively low. 827 00:37:22,440 --> 00:37:23,640 But if you have two individuals 828 00:37:23,640 --> 00:37:25,260 who are related to one another, 829 00:37:25,260 --> 00:37:27,240 they have very similar genetic backgrounds, 830 00:37:27,240 --> 00:37:30,930 and the likelihood that they'll both have the same alleles 831 00:37:30,930 --> 00:37:33,960 is very, very high. 832 00:37:33,960 --> 00:37:37,980 So the recessive disorders become much more common 833 00:37:37,980 --> 00:37:39,960 in individuals who are related, 834 00:37:39,960 --> 00:37:44,960 which is why we actually have laws that prohibit marriage 835 00:37:46,380 --> 00:37:50,100 between closely related individuals, 836 00:37:50,100 --> 00:37:55,100 to prevent the expression of recessive disorders. 837 00:37:56,280 --> 00:37:59,610 Abnormal fetal ultrasound is also sometimes a red flag, 838 00:37:59,610 --> 00:38:01,290 as well as cutaneous disorders, 839 00:38:01,290 --> 00:38:05,640 hypotonia is very often associated with genetic disorder, 840 00:38:05,640 --> 00:38:09,030 as is seizure growth abnormalities, developmental delays, 841 00:38:09,030 --> 00:38:11,280 abnormal newborn screens as well. 842 00:38:11,280 --> 00:38:13,590 And along with the developmental delays, 843 00:38:13,590 --> 00:38:17,730 intellectual disability is often a red flag 844 00:38:17,730 --> 00:38:20,400 for some genetic conditions, 845 00:38:20,400 --> 00:38:25,020 especially some of the types of genetic syndromes 846 00:38:25,020 --> 00:38:28,863 that you remember reading about in Module Four. 847 00:38:29,970 --> 00:38:31,800 Many of those are actually associated 848 00:38:31,800 --> 00:38:33,390 with intellectual disability as well, 849 00:38:33,390 --> 00:38:35,883 so that's often a red flag. 850 00:38:36,930 --> 00:38:39,420 Alright, well let's give it a quick summary here. 851 00:38:39,420 --> 00:38:41,820 Recessive disorders require both alleles 852 00:38:41,820 --> 00:38:43,230 to be disease alleles 853 00:38:43,230 --> 00:38:45,780 before the disease phenotype is seen. 854 00:38:45,780 --> 00:38:47,760 Those with one disease allele are carriers 855 00:38:47,760 --> 00:38:50,430 and are generally asymptomatic, and remember, 856 00:38:50,430 --> 00:38:53,080 when we draw out those punnet squares 857 00:38:54,801 --> 00:38:57,330 that you learned about and you're gonna come to love, 858 00:38:57,330 --> 00:38:59,100 I have no doubt, 859 00:38:59,100 --> 00:39:02,400 that when we designate an allele by a single letter, 860 00:39:02,400 --> 00:39:04,170 whether it's uppercase or lowercase, 861 00:39:04,170 --> 00:39:08,040 that indicates whether or not it is recessive or dominant, 862 00:39:08,040 --> 00:39:09,720 not necessarily whether or not 863 00:39:09,720 --> 00:39:13,050 it is disease or wild type. 864 00:39:13,050 --> 00:39:17,610 So, remember that using the lowercase for the letter, 865 00:39:17,610 --> 00:39:20,070 that indicates it's recessive allele. 866 00:39:20,070 --> 00:39:22,623 And it may or may not be the disease allele, 867 00:39:23,902 --> 00:39:25,740 for a recessive disease, it would be, 868 00:39:25,740 --> 00:39:27,870 for something that's a dominant disease, it would not be, 869 00:39:27,870 --> 00:39:31,650 but, recessive alleles, remember, at lowercase. 870 00:39:31,650 --> 00:39:35,040 Dominant disorders require only one of the two alleles 871 00:39:35,040 --> 00:39:36,360 to be a disease allele 872 00:39:36,360 --> 00:39:37,950 for the disease phenotype to be present, 873 00:39:37,950 --> 00:39:40,200 and there are no carriers for dominant disorders, 874 00:39:40,200 --> 00:39:43,200 because if you have one copy, you have the disease. 875 00:39:43,200 --> 00:39:45,720 And remember, again, dominant would be denoted 876 00:39:45,720 --> 00:39:47,400 as an uppercase letter. 877 00:39:47,400 --> 00:39:50,370 Recessive X-linked disorders present primarily in males 878 00:39:50,370 --> 00:39:51,780 and are inherited from the mother, 879 00:39:51,780 --> 00:39:54,150 and remember, they're primarily seen in males, 880 00:39:54,150 --> 00:39:56,640 because males only have one X chromosome. 881 00:39:56,640 --> 00:40:00,180 And so while females are only really expressing 882 00:40:00,180 --> 00:40:03,870 one of the two X chromosomes, because of X inactivation, 883 00:40:03,870 --> 00:40:06,570 they have sort of a mixture of cells 884 00:40:06,570 --> 00:40:10,500 that are going to actually have the normal function, 885 00:40:10,500 --> 00:40:14,583 have a normal functioning copy if they're heterozygous. 886 00:40:15,480 --> 00:40:17,610 So that leaves the males, 887 00:40:17,610 --> 00:40:22,610 so any of the males who inherit a disease allele, 888 00:40:23,160 --> 00:40:26,220 from their, it would be from their mother, 889 00:40:26,220 --> 00:40:28,050 'cause it would be on the X chromosome, 890 00:40:28,050 --> 00:40:30,780 then they're going to have the disease. 891 00:40:30,780 --> 00:40:33,060 So that's often a hallmark of a condition 892 00:40:33,060 --> 00:40:36,870 that's likely to be an X-linked disorder, is if you see, 893 00:40:36,870 --> 00:40:40,470 and say, going through generations of a family tree 894 00:40:40,470 --> 00:40:42,240 and you're taking the history and you're looking at it, 895 00:40:42,240 --> 00:40:45,450 and it's only males that actually have the same disease 896 00:40:45,450 --> 00:40:47,310 generation after generation. 897 00:40:47,310 --> 00:40:50,010 And it seems to be going down the maternal line, 898 00:40:50,010 --> 00:40:51,840 so you can always be tracked back through 899 00:40:51,840 --> 00:40:54,150 the mother's side of the family. 900 00:40:54,150 --> 00:40:59,010 While the mother didn't have the condition, her sons did, 901 00:40:59,010 --> 00:41:00,600 then that would be an indication 902 00:41:00,600 --> 00:41:02,670 that this is an X-linked condition, 903 00:41:02,670 --> 00:41:04,320 and probably a recessive one. 904 00:41:04,320 --> 00:41:07,380 Dominant X-linked disorders present primarily in females, 905 00:41:07,380 --> 00:41:08,760 and are usually lethal in males 906 00:41:08,760 --> 00:41:10,290 who do not have a functional copy, 907 00:41:10,290 --> 00:41:14,310 so remember that, in females, 908 00:41:14,310 --> 00:41:17,790 so if this is a dominant X-linked condition they have, 909 00:41:17,790 --> 00:41:20,369 they inherit one disease allele 910 00:41:20,369 --> 00:41:22,170 they're going to have the disease in, 911 00:41:22,170 --> 00:41:25,110 but they still have that second copy 912 00:41:25,110 --> 00:41:28,590 that is presumably normal and normally functioning, 913 00:41:28,590 --> 00:41:32,760 and again, given that they can be heterozygous with that 914 00:41:32,760 --> 00:41:37,230 and have some cells that are expressing the normal copy, 915 00:41:37,230 --> 00:41:40,650 they can generally make up for some of the loss function. 916 00:41:40,650 --> 00:41:42,600 But that will result in the disease, 917 00:41:42,600 --> 00:41:45,870 but not lethality in the females. 918 00:41:45,870 --> 00:41:47,700 In the males, on the other hand, 919 00:41:47,700 --> 00:41:51,840 having a dominant X-linked condition is oftentimes lethal 920 00:41:51,840 --> 00:41:54,540 because they don't have a single good functioning copy 921 00:41:54,540 --> 00:41:56,840 because they only have one copy to begin with. 922 00:41:57,810 --> 00:41:59,730 So these are some red flags, if you're seeing something 923 00:41:59,730 --> 00:42:02,460 that is really only presenting in females, 924 00:42:02,460 --> 00:42:04,020 it may be an indication 925 00:42:04,020 --> 00:42:06,783 that this is a dominant X-linked disorder. 926 00:42:07,950 --> 00:42:10,020 Alright, well what's up next, well now that we've learned, 927 00:42:10,020 --> 00:42:12,450 and reviewed, for some of you, the basics. 928 00:42:12,450 --> 00:42:14,850 Now we're going to take it a step farther 929 00:42:14,850 --> 00:42:17,640 and start to look at all of the exceptions, 930 00:42:17,640 --> 00:42:20,010 and there are quite a few of them, 931 00:42:20,010 --> 00:42:22,380 and some of them are actually pretty important, 932 00:42:22,380 --> 00:42:24,690 and you may very well see some of these in your practice, 933 00:42:24,690 --> 00:42:26,670 and, the point of talking about them 934 00:42:26,670 --> 00:42:30,780 and going into a little bit of detail with each one of them, 935 00:42:30,780 --> 00:42:34,440 is that you can be aware that if you see a situation 936 00:42:34,440 --> 00:42:36,300 in which something isn't quite fitting 937 00:42:36,300 --> 00:42:39,090 what you would expect from Mendelian inheritance, 938 00:42:39,090 --> 00:42:40,650 even if it's a single-gene disorder, 939 00:42:40,650 --> 00:42:42,660 there may be really good reasons for that, 940 00:42:42,660 --> 00:42:46,650 and that could be falling into one of these categories 941 00:42:46,650 --> 00:42:50,460 of exceptions and extensions to Mendel 942 00:42:50,460 --> 00:42:52,380 and to Mendelian inheritance, 943 00:42:52,380 --> 00:42:56,163 so, that is what's up next, thanks very much.