1 00:00:00,900 --> 00:00:03,150 [Instructor] Hello and welcome to Module Four. 2 00:00:03,150 --> 00:00:05,550 This first lecture focus on aneuploidy. 3 00:00:05,550 --> 00:00:07,770 We'll talk about what it is, how it occurs, 4 00:00:07,770 --> 00:00:10,020 and some of the clinical manifestations. 5 00:00:10,020 --> 00:00:11,460 So let's jump right in. 6 00:00:11,460 --> 00:00:14,880 First, a quick review from our previous module. 7 00:00:14,880 --> 00:00:16,710 Mitosis is the process of cell division, 8 00:00:16,710 --> 00:00:18,300 which occurs in somatic cells 9 00:00:18,300 --> 00:00:20,850 to produce two diploid daughter cells. 10 00:00:20,850 --> 00:00:24,000 Recall that somatic cells are basically all the cells 11 00:00:24,000 --> 00:00:28,380 in your body with the exception of egg and sperm cell. 12 00:00:28,380 --> 00:00:31,410 Those egg and sperm cell are called gametes, 13 00:00:31,410 --> 00:00:34,110 and the cells that lead to gametes, 14 00:00:34,110 --> 00:00:37,110 so the cells which will develop into gametes, 15 00:00:37,110 --> 00:00:39,303 are called germline cells. 16 00:00:41,040 --> 00:00:43,560 In Meiosis, this is the process of cell division 17 00:00:43,560 --> 00:00:45,750 which occurs in those pre-gamete cells, 18 00:00:45,750 --> 00:00:47,160 also called germline cells, 19 00:00:47,160 --> 00:00:50,190 to produce four haploid gametes. 20 00:00:50,190 --> 00:00:53,640 Gametes, or egg and sperm, must have 23 chromosomes each, 21 00:00:53,640 --> 00:00:55,440 one copy of each, so that when they fuse 22 00:00:55,440 --> 00:00:56,850 the resulting fertilized egg 23 00:00:56,850 --> 00:00:59,883 will have the correct number of 46 total chromosomes. 24 00:01:00,720 --> 00:01:04,320 In Meiosis I, remember that there are two phases of Meiosis 25 00:01:04,320 --> 00:01:05,280 that follow one another. 26 00:01:05,280 --> 00:01:07,860 The first major stage is Meiosis I, 27 00:01:07,860 --> 00:01:10,890 and this is when homologous chromosomes separate. 28 00:01:10,890 --> 00:01:13,530 In Meiosis II, which follows Meiosis I, 29 00:01:13,530 --> 00:01:16,770 and also in which occurs in mitosis 30 00:01:16,770 --> 00:01:18,813 is sister chromatids will separate. 31 00:01:20,070 --> 00:01:22,860 Let's take a peek at a human karyotype. 32 00:01:22,860 --> 00:01:27,139 Recall that karyotypes are basically microscopic examination 33 00:01:27,139 --> 00:01:29,820 of each of the chromosomes. 34 00:01:29,820 --> 00:01:32,430 And they're oftentimes they're done to identify 35 00:01:32,430 --> 00:01:34,440 if there's an aneuploidy in an individual 36 00:01:34,440 --> 00:01:37,110 or an improper number of chromosomes. 37 00:01:37,110 --> 00:01:39,090 So they're aligned here and spread out, 38 00:01:39,090 --> 00:01:43,170 and identified by their chromosome number or identification. 39 00:01:43,170 --> 00:01:46,290 Each chromosome has two copies, one from mom, one from dad. 40 00:01:46,290 --> 00:01:48,150 So in total we have 46 chromosomes. 41 00:01:48,150 --> 00:01:50,760 Remember that the two copies of each chromosome 42 00:01:50,760 --> 00:01:52,530 are homologous chromosomes. 43 00:01:52,530 --> 00:01:55,170 Each chromosome contains a specific set of genes 44 00:01:55,170 --> 00:01:56,880 and the chromosomes are numbered 45 00:01:56,880 --> 00:01:59,130 one through 22 for autosomes. 46 00:01:59,130 --> 00:02:01,380 The remaining are sex chromosomes, 47 00:02:01,380 --> 00:02:02,850 two X chromosomes would be female, 48 00:02:02,850 --> 00:02:04,983 one X and one Y would be male. 49 00:02:08,250 --> 00:02:12,840 A quick review of Meiosis as well, and normal Meiosis. 50 00:02:12,840 --> 00:02:14,370 There again, there are two phases. 51 00:02:14,370 --> 00:02:15,750 The first phase, Meiosis I, 52 00:02:15,750 --> 00:02:18,420 is when the homologous chromosomes align 53 00:02:18,420 --> 00:02:21,390 and are separated from one another, 54 00:02:21,390 --> 00:02:25,260 creating two daughter cells each with 23 chromosomes. 55 00:02:25,260 --> 00:02:27,630 But each of those has a sister chromatid, 56 00:02:27,630 --> 00:02:30,120 if you remember that the sister chromatids 57 00:02:30,120 --> 00:02:33,630 are the identical copies of the chromosome 58 00:02:33,630 --> 00:02:36,000 which were created during DNA replication. 59 00:02:36,000 --> 00:02:39,120 And those sister chromatids are separated from one another 60 00:02:39,120 --> 00:02:40,803 during Meiosis II. 61 00:02:44,040 --> 00:02:46,260 Sperm cells determine the sex of the embryo 62 00:02:46,260 --> 00:02:47,940 and the sperm with the X chromosome 63 00:02:47,940 --> 00:02:49,710 results in a female embryo, 64 00:02:49,710 --> 00:02:51,660 while sperm with the Y chromosome 65 00:02:51,660 --> 00:02:54,450 will result in the male embryo. 66 00:02:54,450 --> 00:02:56,520 And these numbers are indicating 22, 67 00:02:56,520 --> 00:02:58,770 which would be the number of autosomes 68 00:02:58,770 --> 00:03:00,060 each of these cells has. 69 00:03:00,060 --> 00:03:02,610 And then neither has, well, in the case of females, 70 00:03:02,610 --> 00:03:05,550 there'll always be 22 autosomes plus an X chromosome 71 00:03:05,550 --> 00:03:09,240 because all females have two X chromosomes. 72 00:03:09,240 --> 00:03:12,000 In males, however, you have an X and you have a Y. 73 00:03:12,000 --> 00:03:14,220 And during Meiosis, the X and Y chromosomes 74 00:03:14,220 --> 00:03:16,650 actually will pair together as homologous chromosomes 75 00:03:16,650 --> 00:03:18,480 and will be separated from one another. 76 00:03:18,480 --> 00:03:21,971 So 50% of the sperm will have an X chromosome 77 00:03:21,971 --> 00:03:24,480 and 50% of the sperm will have a Y chromosome. 78 00:03:24,480 --> 00:03:27,340 If the sperm that fertilizes the egg has an X chromosome, 79 00:03:27,340 --> 00:03:30,150 this will become a female. 80 00:03:30,150 --> 00:03:33,093 If the sperm has a Y chromosome, this will become a male. 81 00:03:35,160 --> 00:03:38,160 So why do we need exactly 46 chromosomes? 82 00:03:38,160 --> 00:03:39,900 Well, each chromosome has many genes, 83 00:03:39,900 --> 00:03:42,780 anywhere from 2,000 genes on chromosome one, 84 00:03:42,780 --> 00:03:46,170 which as you can recall is the largest chromosome, 85 00:03:46,170 --> 00:03:48,090 to around 50 genes on the Y chromosome, 86 00:03:48,090 --> 00:03:51,030 and Y chromosome is the smallest chromosome 87 00:03:51,030 --> 00:03:52,590 that humans have. 88 00:03:52,590 --> 00:03:54,750 Cells have adapted a finely tuned balance 89 00:03:54,750 --> 00:03:56,940 of gene regulation systems based on having 90 00:03:56,940 --> 00:03:59,790 exactly two copies of the genes on autosomes. 91 00:03:59,790 --> 00:04:01,950 So changes in the number of autosomes 92 00:04:01,950 --> 00:04:03,300 affect gene expression. 93 00:04:03,300 --> 00:04:05,190 So remember that's a big deal. 94 00:04:05,190 --> 00:04:08,670 If you have too many copies or too few copies of something 95 00:04:08,670 --> 00:04:11,370 and transcription is occurring at its regular rate, 96 00:04:11,370 --> 00:04:14,700 well if you have 50% more of that gene present, 97 00:04:14,700 --> 00:04:16,440 which would mean say you have three copies 98 00:04:16,440 --> 00:04:18,090 instead of two copies, 99 00:04:18,090 --> 00:04:20,460 then you're going to have 50% more of that protein around, 100 00:04:20,460 --> 00:04:22,110 which completely throws off 101 00:04:22,110 --> 00:04:23,700 many of the functions in the cell. 102 00:04:23,700 --> 00:04:25,560 So this is a real problem. 103 00:04:25,560 --> 00:04:27,480 If say on the other hand you only have one copy 104 00:04:27,480 --> 00:04:30,030 instead of two copies in a somatic cell, 105 00:04:30,030 --> 00:04:32,280 well then that means only half of the 106 00:04:32,280 --> 00:04:34,050 normal amount of protein will be formed 107 00:04:34,050 --> 00:04:38,880 for the genes on that chromosome code for. 108 00:04:38,880 --> 00:04:40,230 So it's really, really important 109 00:04:40,230 --> 00:04:42,840 that you have the right number because 110 00:04:42,840 --> 00:04:45,540 we have adapted a system in which you need 111 00:04:45,540 --> 00:04:48,120 exactly two copies on autosomes. 112 00:04:48,120 --> 00:04:49,920 It's a little bit different on the sex chromosomes 113 00:04:49,920 --> 00:04:52,380 and we'll talk about that in a little bit. 114 00:04:52,380 --> 00:04:55,050 Having an extra autosome will result in too much expression 115 00:04:55,050 --> 00:04:57,150 of all of the genes on that chromosome 116 00:04:57,150 --> 00:04:59,520 because there are three copies being transcribed. 117 00:04:59,520 --> 00:05:02,310 Again, and having only one copy of an autosome, 118 00:05:02,310 --> 00:05:04,920 so for example, only one copy of chromosome 12 119 00:05:04,920 --> 00:05:06,630 would result in too little expression 120 00:05:06,630 --> 00:05:08,280 of all of the genes on that chromosome 121 00:05:08,280 --> 00:05:10,560 because only one copy is being transcribed. 122 00:05:10,560 --> 00:05:14,280 Either way it's bad and it's usually incompatible with life. 123 00:05:14,280 --> 00:05:16,590 There are a few exceptions to this, 124 00:05:16,590 --> 00:05:18,120 but the general rule is if you have too many 125 00:05:18,120 --> 00:05:19,740 or too few of any chromosome, 126 00:05:19,740 --> 00:05:21,633 that those cells cannot survive. 127 00:05:24,270 --> 00:05:26,220 So what can go wrong here? 128 00:05:26,220 --> 00:05:29,190 Aneuploidy is the incorrect number of chromosomes in a cell, 129 00:05:29,190 --> 00:05:30,570 either too many or too few. 130 00:05:30,570 --> 00:05:33,150 And they're further sort of categorized 131 00:05:33,150 --> 00:05:35,670 or defined clinically as trisomy. 132 00:05:35,670 --> 00:05:37,950 And that's one extra copy of a chromosome. 133 00:05:37,950 --> 00:05:39,690 So why is it called trisomy? 134 00:05:39,690 --> 00:05:43,350 Tri- being three. So three copies of a chromosome. 135 00:05:43,350 --> 00:05:45,990 You normally have two copies of each chromosome, 136 00:05:45,990 --> 00:05:48,660 so that would be an extra, one extra copy. 137 00:05:48,660 --> 00:05:49,920 So that would be trisomy. 138 00:05:49,920 --> 00:05:53,190 Tetrasomy would be two extra copies, Tetra- being four. 139 00:05:53,190 --> 00:05:55,710 So it would be a total of four copies of an autosome. 140 00:05:55,710 --> 00:05:58,830 Monosomy would be one fewer copy of a chromosome. 141 00:05:58,830 --> 00:06:00,510 So mono- being one. 142 00:06:00,510 --> 00:06:03,210 So you would only have one copy of an autosome, for example. 143 00:06:03,210 --> 00:06:05,880 Nullisomy would be zero copies of a chromosome. 144 00:06:05,880 --> 00:06:09,330 So you completely do not have 145 00:06:09,330 --> 00:06:11,580 one of the particular chromosomes. 146 00:06:11,580 --> 00:06:14,640 Aneuploidy occurs when chromosomes do not divide 147 00:06:14,640 --> 00:06:16,560 evenly in Meiosis I or II, 148 00:06:16,560 --> 00:06:18,390 which would create an egg or sperm 149 00:06:18,390 --> 00:06:20,160 with the incorrect number of chromosomes. 150 00:06:20,160 --> 00:06:21,600 So the resulting fertilized egg 151 00:06:21,600 --> 00:06:23,040 created with one of these cells 152 00:06:23,040 --> 00:06:26,820 develops into a zygote with too few or too many chromosomes. 153 00:06:26,820 --> 00:06:29,520 And as you recall, this is really problematic 154 00:06:29,520 --> 00:06:31,710 for the levels of gene expression 155 00:06:31,710 --> 00:06:33,570 for all of the genes on the chromosome 156 00:06:33,570 --> 00:06:36,330 that either has too many or too few copies. 157 00:06:36,330 --> 00:06:39,240 Aneuploidy is the leading cause of spontaneous abortions 158 00:06:39,240 --> 00:06:41,370 because the embryo simply cannot survive 159 00:06:41,370 --> 00:06:43,170 with the wrong number of chromosomes, 160 00:06:43,170 --> 00:06:46,530 with a few exceptions and we will talk about those. 161 00:06:46,530 --> 00:06:49,380 But generally the vast majority of the chromosomes, 162 00:06:49,380 --> 00:06:51,870 you cannot have the incorrect number 163 00:06:51,870 --> 00:06:55,773 and have an embryo actually survive and develop. 164 00:06:57,450 --> 00:07:00,150 That's how important it is to have gene expression 165 00:07:00,150 --> 00:07:03,300 be perfectly regulated and be exactly correct. 166 00:07:03,300 --> 00:07:07,143 Otherwise, the entire system falls apart. 167 00:07:08,340 --> 00:07:11,220 In surviving aneuploidy, the child will have a syndrome 168 00:07:11,220 --> 00:07:13,830 with usually widespread and various health conditions 169 00:07:13,830 --> 00:07:15,870 depending on the chromosome affected. 170 00:07:15,870 --> 00:07:18,240 And there really are only a few chromosomes 171 00:07:18,240 --> 00:07:22,500 that you can have aneuploidy and have any expected survival. 172 00:07:22,500 --> 00:07:25,350 So let's take a peek at what could go wrong here. 173 00:07:25,350 --> 00:07:26,580 So it could happen, remember, 174 00:07:26,580 --> 00:07:29,460 it could happen again in either Meiosis I or Meiosis II. 175 00:07:29,460 --> 00:07:31,620 So if it's happening in Meiosis I, 176 00:07:31,620 --> 00:07:33,330 what's actually happening is an event 177 00:07:33,330 --> 00:07:36,153 called nondisjunction. 178 00:07:36,153 --> 00:07:38,820 Nondisjunction means that chromosomes 179 00:07:38,820 --> 00:07:42,000 are not properly separating from one another 180 00:07:42,000 --> 00:07:44,520 during a process of cell division. 181 00:07:44,520 --> 00:07:45,960 In the case of Meiosis I, 182 00:07:45,960 --> 00:07:49,680 nondisjunction would happen between homologous chromosomes 183 00:07:49,680 --> 00:07:52,770 because it's in Meiosis I when homologous chromosomes 184 00:07:52,770 --> 00:07:54,510 are supposed to separate from each other, 185 00:07:54,510 --> 00:07:57,420 go to opposite sides to form two new cells. 186 00:07:57,420 --> 00:08:00,150 If that does not happen, and this is showing here 187 00:08:00,150 --> 00:08:01,770 that these two homologous chromosomes 188 00:08:01,770 --> 00:08:04,143 are both going to one cell, 189 00:08:05,130 --> 00:08:10,130 which results in two cells coming out of Meiosis I. 190 00:08:10,320 --> 00:08:14,100 One which has two copies of this particular chromosome 191 00:08:14,100 --> 00:08:17,253 and one which has zero copies of that chromosome. 192 00:08:18,240 --> 00:08:21,570 This is followed up by Meiosis II in these cells 193 00:08:21,570 --> 00:08:23,190 where the end result is 194 00:08:23,190 --> 00:08:25,680 if the sister chromatids then separate 195 00:08:25,680 --> 00:08:27,060 and this is denoted here, 196 00:08:27,060 --> 00:08:30,900 'n' being denoted as the correct number of chromosomes 197 00:08:30,900 --> 00:08:32,970 that should be present in the cell. 198 00:08:32,970 --> 00:08:36,990 And this is being designated as how many additional 199 00:08:36,990 --> 00:08:38,850 or how many fewer chromosomes. 200 00:08:38,850 --> 00:08:41,790 So in a gamete that has the proper number of chromosomes, 201 00:08:41,790 --> 00:08:43,740 it would just be designated as 'n.' 202 00:08:43,740 --> 00:08:48,420 In a gamete with one additional chromosome it would be 'n+1' 203 00:08:48,420 --> 00:08:50,517 With one fewer, it would be 'n-1.' 204 00:08:51,360 --> 00:08:53,073 If you were looking at the same, 205 00:08:54,600 --> 00:08:56,700 if you were looking at the same way of denoting it 206 00:08:56,700 --> 00:09:00,050 in the same way of denoting the number of chromosomes 207 00:09:00,050 --> 00:09:02,100 in a somatic cell, 208 00:09:02,100 --> 00:09:05,070 which has two copies of each chromosome, 209 00:09:05,070 --> 00:09:07,890 you would denote that as '2n,' 210 00:09:07,890 --> 00:09:10,890 or two times the number of chromosomes. 211 00:09:10,890 --> 00:09:12,954 All right, so the other possibility 212 00:09:12,954 --> 00:09:17,460 of when an aneuploidy event can occur 213 00:09:17,460 --> 00:09:18,900 would be in Meiosis II. 214 00:09:18,900 --> 00:09:21,840 So let's assume Meiosis I happens normally 215 00:09:21,840 --> 00:09:23,730 and you produce two cells, 216 00:09:23,730 --> 00:09:27,360 each has one copy of each of the chromosomes. 217 00:09:27,360 --> 00:09:28,680 Well now you have to separate 218 00:09:28,680 --> 00:09:31,320 the sister chromatids in Meiosis II. 219 00:09:31,320 --> 00:09:36,150 And during that process, nondisjunction can also occur here. 220 00:09:36,150 --> 00:09:38,790 Nondisjunction being a lack of separation 221 00:09:38,790 --> 00:09:41,880 in the case of Meiosis II of sister chromatids. 222 00:09:41,880 --> 00:09:44,730 So both sister chromatids for one chromosome 223 00:09:44,730 --> 00:09:49,230 will go to one cell, and the other cell will receive 224 00:09:49,230 --> 00:09:51,900 no copies of that particular chromosome. 225 00:09:51,900 --> 00:09:54,180 Since this is happening in Meiosis II. 226 00:09:54,180 --> 00:09:56,100 this cell that was the other product 227 00:09:56,100 --> 00:09:58,830 of the original normal Meiosis I event 228 00:09:58,830 --> 00:10:00,750 has the correct number of chromosomes 229 00:10:00,750 --> 00:10:02,640 and so it will undergo normal Meiosis. 230 00:10:02,640 --> 00:10:04,740 And if it undergoes normal Meiosis II, 231 00:10:04,740 --> 00:10:08,007 it produces two normal gametes with the designation of 'n.' 232 00:10:09,540 --> 00:10:10,950 In the case where there was 233 00:10:10,950 --> 00:10:13,625 nondisjunction in Meiosis II in this cell, 234 00:10:13,625 --> 00:10:17,820 it will result in one gamete that has 'n + 1' chromosomes, 235 00:10:17,820 --> 00:10:19,350 or one additional chromosome, 236 00:10:19,350 --> 00:10:23,253 and one gamete with 'n - 1' or one fewer chromosome. 237 00:10:24,750 --> 00:10:26,910 So let's review this all together. 238 00:10:26,910 --> 00:10:28,500 Meiosis I aneuploidy. 239 00:10:28,500 --> 00:10:31,500 In normal Meiosis I, this is when homologous chromosomes 240 00:10:31,500 --> 00:10:33,150 separate to two daughter cells, 241 00:10:33,150 --> 00:10:35,635 which then is followed by Meiosis II. 242 00:10:35,635 --> 00:10:39,750 In nondisjunction, this results when homologous chromosomes 243 00:10:39,750 --> 00:10:43,530 both go to the same daughter cell and are not separated. 244 00:10:43,530 --> 00:10:46,170 This results in two gametes with one extra chromosome 245 00:10:46,170 --> 00:10:48,690 and two gametes with one fewer chromosome. 246 00:10:48,690 --> 00:10:51,660 Most aneuploidy occurs from nondisjunction in Meiosis I 247 00:10:51,660 --> 00:10:54,660 because of crossing over, remember crossing over? 248 00:10:54,660 --> 00:10:56,670 and that's when homologous chromosomes all start to like 249 00:10:56,670 --> 00:10:58,980 swapping bits and pieces with each other. 250 00:10:58,980 --> 00:11:02,010 While during this process, they are actually 251 00:11:02,010 --> 00:11:04,650 physically being connected to one another. 252 00:11:04,650 --> 00:11:06,840 If the process doesn't occur properly 253 00:11:06,840 --> 00:11:10,560 and if crossing over does not complete normally, 254 00:11:10,560 --> 00:11:12,720 then it becomes very difficult for these chromosomes 255 00:11:12,720 --> 00:11:14,430 to physically separate from one another. 256 00:11:14,430 --> 00:11:15,983 And you can have nondisjunction. 257 00:11:17,880 --> 00:11:19,590 Meiosis II aneuploidy, 258 00:11:19,590 --> 00:11:22,860 if the aneuploidy event occurs in Meiosis II, 259 00:11:22,860 --> 00:11:25,470 if you recall Meiosis II is when sister chromatids 260 00:11:25,470 --> 00:11:28,080 separate to the two daughter cells from Meiosis I 261 00:11:28,080 --> 00:11:29,820 to create four daughter cells, 262 00:11:29,820 --> 00:11:32,820 each with one sister chromatid for each chromosome. 263 00:11:32,820 --> 00:11:35,730 Nondisjunction results when sister chromatids 264 00:11:35,730 --> 00:11:39,780 both go to the same daughter cell and are not separated. 265 00:11:39,780 --> 00:11:41,623 This results in one gamete with one extra chromosome, 266 00:11:41,623 --> 00:11:43,437 one gamete with one fewer chromosome, 267 00:11:43,437 --> 00:11:45,063 and two normal gametes. 268 00:11:47,520 --> 00:11:49,530 Let's talk a little bit about 269 00:11:49,530 --> 00:11:51,600 some of the nomenclature and statistics 270 00:11:51,600 --> 00:11:53,220 associated with aneuploidy. 271 00:11:53,220 --> 00:11:54,930 So aneuploidy is denoted using 272 00:11:54,930 --> 00:11:57,090 a common karyotype nomenclature, 273 00:11:57,090 --> 00:12:01,140 which would be the total number of chromosomes, comma, 274 00:12:01,140 --> 00:12:03,477 the sex chromosomes present, comma, 275 00:12:03,477 --> 00:12:08,477 and then here would go the any derivation from that. 276 00:12:09,540 --> 00:12:11,610 So any aneuploidy would be denoted here 277 00:12:11,610 --> 00:12:14,670 as either plus, if it's a trisomy for example. 278 00:12:14,670 --> 00:12:17,100 And then the number of the autosome 279 00:12:17,100 --> 00:12:19,950 which is the improper number, 280 00:12:19,950 --> 00:12:21,780 or minus in the case of monosomy, 281 00:12:21,780 --> 00:12:24,120 or the loss of one with the chromosomes 282 00:12:24,120 --> 00:12:26,070 and then that particular number. 283 00:12:26,070 --> 00:12:27,570 So let's take a look at an example. 284 00:12:27,570 --> 00:12:31,230 A male with Down Syndrome, which is trisomy of chromosome 21 285 00:12:31,230 --> 00:12:33,060 is denoted as 47, 286 00:12:33,060 --> 00:12:35,910 because instead of having the normal 46 chromosomes, 287 00:12:35,910 --> 00:12:40,140 he has 47 given that he has an extra chromosome 21. 288 00:12:40,140 --> 00:12:44,670 So it would be denoted first as 47, comma, XY, 289 00:12:44,670 --> 00:12:47,700 'cause he's male and has both X and Y chromosome, 290 00:12:47,700 --> 00:12:49,710 and then +21. 291 00:12:49,710 --> 00:12:53,793 And that indicates, plus is that there's an addition to 21. 292 00:12:54,870 --> 00:12:58,920 Or sometimes it can just be denoted for short as +21. 293 00:12:58,920 --> 00:13:01,590 This does not tell you the sex of the individual, 294 00:13:01,590 --> 00:13:03,480 but it could just tell you that 295 00:13:03,480 --> 00:13:06,213 this person has Down Syndrome. 296 00:13:07,560 --> 00:13:09,930 A female with monosomy of X chromosomes, 297 00:13:09,930 --> 00:13:13,290 is also called Turner Syndrome, would be denoted as 45 298 00:13:13,290 --> 00:13:16,650 because instead of having 46 chromosomes, she has 45, 299 00:13:16,650 --> 00:13:18,570 she's missing an X chromosome, 300 00:13:18,570 --> 00:13:20,670 comma X, and just X. 301 00:13:20,670 --> 00:13:23,250 And why is that? Because she only has one X chromosome. 302 00:13:23,250 --> 00:13:26,370 So that's denoting the aneuploidy right there. 303 00:13:26,370 --> 00:13:28,440 We don't need to put anything else with that 304 00:13:28,440 --> 00:13:30,990 because you're denoting, it would be expected 305 00:13:30,990 --> 00:13:34,830 in a normal individual to have either XX or XY. 306 00:13:34,830 --> 00:13:37,050 So just denoting it as X indicates 307 00:13:37,050 --> 00:13:39,483 this person has monosomy of X chromosome. 308 00:13:40,320 --> 00:13:42,257 A normal male would be denoted as 46 309 00:13:42,257 --> 00:13:44,460 'cause you have, that's the normal chromosome number, 310 00:13:44,460 --> 00:13:45,783 comma XY. 311 00:13:46,920 --> 00:13:50,670 A female with monosomy of chromosome 13 would be 45. 312 00:13:50,670 --> 00:13:52,830 Again, she's lacking one of her chromosomes. 313 00:13:52,830 --> 00:13:55,050 Comma XX, 'cause she's female. 314 00:13:55,050 --> 00:13:59,460 Comma -13, minus meaning that you're lacking a chromosome. 315 00:13:59,460 --> 00:14:01,353 Which chromosome? Chromosome 13. 316 00:14:02,490 --> 00:14:04,200 All right, a few statistics here. 317 00:14:04,200 --> 00:14:06,510 30% of all pregnancies are estimated 318 00:14:06,510 --> 00:14:08,460 to result in spontaneous abortion. 319 00:14:08,460 --> 00:14:10,380 That's of all pregnancies. 320 00:14:10,380 --> 00:14:12,540 Most are occurring before the woman knows she is pregnant. 321 00:14:12,540 --> 00:14:13,980 What's actually happening here? 322 00:14:13,980 --> 00:14:17,180 Well it's estimated that 50 to 70% 323 00:14:17,180 --> 00:14:20,460 of all spontaneous abortions are due to aneuploidy. 324 00:14:20,460 --> 00:14:22,230 If you remember, I had mentioned 325 00:14:22,230 --> 00:14:25,260 that it is not consistent with life. 326 00:14:25,260 --> 00:14:29,160 And so in the majority of aneuploidy cases, 327 00:14:29,160 --> 00:14:31,050 the embryo simply will not survive, 328 00:14:31,050 --> 00:14:33,780 and a spontaneous abortion will result. 329 00:14:33,780 --> 00:14:38,640 Of live births, about approximately one third of 1% 330 00:14:38,640 --> 00:14:40,860 are a born with an aneuploidy. 331 00:14:40,860 --> 00:14:42,990 The most common of those including 332 00:14:42,990 --> 00:14:47,040 trisomies of chromosomes 13, 18 and 21, 333 00:14:47,040 --> 00:14:50,790 having an extra X chromosome in females, 334 00:14:50,790 --> 00:14:53,520 having an extra X chromosome in males, 335 00:14:53,520 --> 00:14:55,710 having an extra Y chromosome in males, 336 00:14:55,710 --> 00:14:58,473 or lacking an X chromosome in females. 337 00:14:59,700 --> 00:15:02,190 You can take a look at this table listed below 338 00:15:02,190 --> 00:15:05,430 for some more statistics on the time and gestation 339 00:15:05,430 --> 00:15:08,673 when these spontaneous abortions may occur. 340 00:15:11,040 --> 00:15:12,960 Let's take a quick peek at a karyotype 341 00:15:12,960 --> 00:15:14,880 of someone with Down Syndrome 342 00:15:14,880 --> 00:15:17,400 compared with a normal male karyotype. 343 00:15:17,400 --> 00:15:19,380 So the Down Syndrome female, 344 00:15:19,380 --> 00:15:21,900 this is a female, and we know this why? 345 00:15:21,900 --> 00:15:25,380 Well, we can look here and see in the X chromosome category, 346 00:15:25,380 --> 00:15:27,480 she has two copies. 347 00:15:27,480 --> 00:15:29,370 And this would be where Y would be located. 348 00:15:29,370 --> 00:15:31,533 There's no chromosome, this is a female. 349 00:15:33,330 --> 00:15:36,180 How do we know this individual has Trisomy 21 350 00:15:36,180 --> 00:15:37,440 or Down Syndrome? 351 00:15:37,440 --> 00:15:39,840 We can look here at chromosome 21 352 00:15:39,840 --> 00:15:43,170 where we see one, two, three copies. 353 00:15:43,170 --> 00:15:45,450 Three copies of chromosome 21, 354 00:15:45,450 --> 00:15:48,003 that's trisomy 21 or Down Syndrome. 355 00:15:49,020 --> 00:15:52,320 Let's talk through some of the aneuploidy syndromes 356 00:15:52,320 --> 00:15:54,270 that are most common. 357 00:15:54,270 --> 00:15:59,270 Down syndrome occurring in one in 830 live births in total. 358 00:15:59,370 --> 00:16:04,350 Now, the incidence of Down Syndrome increases dramatically 359 00:16:04,350 --> 00:16:07,350 with maternal age and we'll talk some more about that later. 360 00:16:08,610 --> 00:16:13,290 The karyotype designation would be written as 47 comma, 361 00:16:13,290 --> 00:16:15,237 and then if it's a female "XX,+21," 362 00:16:16,320 --> 00:16:20,637 if it's a male "47,XY,+21." 363 00:16:21,930 --> 00:16:23,790 It's associated with intellectual disability, 364 00:16:23,790 --> 00:16:27,030 characteristic facial appearance, and hypotonia in infancy. 365 00:16:27,030 --> 00:16:30,000 All affected individuals experience cognitive delays, 366 00:16:30,000 --> 00:16:33,450 but the intellectual disability is usually mild to moderate. 367 00:16:33,450 --> 00:16:36,930 Approximately 50% are born with a heart defect 368 00:16:36,930 --> 00:16:39,540 and increased risk of other medical conditions 369 00:16:39,540 --> 00:16:42,450 developing as well as hearing and vision problems. 370 00:16:42,450 --> 00:16:44,910 Delayed development and behavioral problems 371 00:16:44,910 --> 00:16:45,870 are often reported. 372 00:16:45,870 --> 00:16:47,820 Speech and language develop later 373 00:16:47,820 --> 00:16:50,460 and more slowly than in children without Down Syndrome, 374 00:16:50,460 --> 00:16:51,930 and affected individual's speech 375 00:16:51,930 --> 00:16:54,660 may be more difficult to understand. 376 00:16:54,660 --> 00:16:57,060 Behavioral issues can include attention problems, 377 00:16:57,060 --> 00:17:00,030 obsessive compulsive behavior, and stubbornness or tantrums. 378 00:17:00,030 --> 00:17:02,460 And there's a gradual decline in cognition 379 00:17:02,460 --> 00:17:05,700 as the individual ages, usually starting around age 50. 380 00:17:05,700 --> 00:17:08,010 And approximately half of adults with Down Syndrome 381 00:17:08,010 --> 00:17:09,930 develop Alzheimer's disease 382 00:17:09,930 --> 00:17:12,360 usually developing that in their fifties or sixties, 383 00:17:12,360 --> 00:17:14,670 which is earlier than individuals 384 00:17:14,670 --> 00:17:16,353 who do not have Down Syndrome. 385 00:17:17,790 --> 00:17:20,940 So why would this be compatible with life? 386 00:17:20,940 --> 00:17:22,290 Let's go back for just one second 387 00:17:22,290 --> 00:17:24,900 and we'll take a peek at chromosome 21. 388 00:17:24,900 --> 00:17:26,700 What do we notice about chromosome 21 389 00:17:26,700 --> 00:17:29,850 compared with all of the other chromosomes? 390 00:17:29,850 --> 00:17:32,190 Well, it's pretty small. 391 00:17:32,190 --> 00:17:33,390 It's pretty small, right? 392 00:17:33,390 --> 00:17:36,930 So the number of genes contained on chromosome 21 393 00:17:36,930 --> 00:17:38,640 is relatively small. 394 00:17:38,640 --> 00:17:41,760 When there's an extra copy around, 395 00:17:41,760 --> 00:17:45,450 the cells can adapt to at least remain alive. 396 00:17:45,450 --> 00:17:47,460 However, there certainly are deficits 397 00:17:47,460 --> 00:17:50,940 in certain cell functions and the structures that form 398 00:17:50,940 --> 00:17:52,830 within those individuals. 399 00:17:52,830 --> 00:17:54,450 And it's very complicated because 400 00:17:54,450 --> 00:17:55,890 we're not looking at a single gene here, 401 00:17:55,890 --> 00:17:58,440 we're looking at a chromosome full of genes 402 00:17:58,440 --> 00:18:01,110 and we are adding an extra copy. 403 00:18:01,110 --> 00:18:05,130 So it's going to be just a combination of effects 404 00:18:05,130 --> 00:18:07,410 on many different genes which 405 00:18:07,410 --> 00:18:09,000 code for many different proteins 406 00:18:09,000 --> 00:18:12,690 and will impact various different functions 407 00:18:12,690 --> 00:18:14,493 within cell and an individual. 408 00:18:16,560 --> 00:18:18,510 So as a result with Down Syndrome, 409 00:18:18,510 --> 00:18:21,090 as well as with really any other aneuploidy syndrome, 410 00:18:21,090 --> 00:18:24,360 you have a spectrum of conditions that can result. 411 00:18:24,360 --> 00:18:25,860 So it's not just one single thing. 412 00:18:25,860 --> 00:18:29,400 It's going to be a variety of different 413 00:18:29,400 --> 00:18:33,480 aspects of normal growth, development, and function, 414 00:18:33,480 --> 00:18:34,893 which can be affected. 415 00:18:36,930 --> 00:18:41,160 Edwards Syndrome, this occurs in one in 5,000 live births 416 00:18:41,160 --> 00:18:44,097 and is a trisomy of chromosome 18. 417 00:18:44,097 --> 00:18:47,253 And so it would be designated as you see up above here. 418 00:18:48,180 --> 00:18:49,680 It's associated with abnormalities 419 00:18:49,680 --> 00:18:51,330 and many parts of the body 420 00:18:51,330 --> 00:18:55,920 often have slow growth before birth and low birth weight. 421 00:18:55,920 --> 00:18:57,390 Heart defects and abnormalities 422 00:18:57,390 --> 00:18:59,730 of other organs that develop before birth are common. 423 00:18:59,730 --> 00:19:01,650 And other features of trisomy 18 include 424 00:19:01,650 --> 00:19:05,820 a small abnormally shaped head, a small jaw and mouth, 425 00:19:05,820 --> 00:19:09,030 and clenched fists with overlapping fingers. 426 00:19:09,030 --> 00:19:10,650 Due to the presence of several 427 00:19:10,650 --> 00:19:12,330 life-threatening medical problems, 428 00:19:12,330 --> 00:19:14,130 many individuals die before birth 429 00:19:14,130 --> 00:19:15,840 or within their first month. 430 00:19:15,840 --> 00:19:18,030 Five to 10% of children with this condition 431 00:19:18,030 --> 00:19:19,950 will live past their first year, 432 00:19:19,950 --> 00:19:21,540 and these children often have 433 00:19:21,540 --> 00:19:23,610 severe intellectual disability. 434 00:19:23,610 --> 00:19:28,170 So this is a more severe condition than Down Syndrome. 435 00:19:28,170 --> 00:19:31,600 And this is a trisomy, again, in chromosome 18 436 00:19:32,700 --> 00:19:36,690 Patau Syndrome, which is a trisomy of chromosome 13 437 00:19:36,690 --> 00:19:41,430 designated here, occurs in one in 16,000 live births 438 00:19:41,430 --> 00:19:44,400 and it's associated with very severe intellectual disability 439 00:19:44,400 --> 00:19:47,790 and physical abnormalities in many parts of the body. 440 00:19:47,790 --> 00:19:50,580 Heart defects, brain or spinal cord abnormalities, 441 00:19:50,580 --> 00:19:53,280 very small or poorly developed eyes, 442 00:19:53,280 --> 00:19:55,410 extra fingers or toes, a cleft lip 443 00:19:55,410 --> 00:19:58,860 with or without a cleft palate, and hypotonia are common. 444 00:19:58,860 --> 00:19:59,700 Due to the presence 445 00:19:59,700 --> 00:20:01,650 of several life-threatening medical problems, 446 00:20:01,650 --> 00:20:04,920 many infants with Trisomy 13 die within their first days 447 00:20:04,920 --> 00:20:06,150 or weeks of life. 448 00:20:06,150 --> 00:20:08,910 And only five to 10% of children with this condition 449 00:20:08,910 --> 00:20:10,683 will live past their first year. 450 00:20:11,700 --> 00:20:14,700 Let's go back for a moment to our karyotype 451 00:20:14,700 --> 00:20:19,633 and let's take a look at chromosomes 13, and 18, and 21. 452 00:20:20,640 --> 00:20:24,120 And as you recall, so Trisomy 21 is Down Syndrome. 453 00:20:24,120 --> 00:20:26,100 Trisomy 18 is Edwards Syndrome. 454 00:20:26,100 --> 00:20:28,860 Trisomy 13 is Patau Syndrome. 455 00:20:28,860 --> 00:20:32,190 And with increasing severity you have 456 00:20:32,190 --> 00:20:35,673 Down Syndrome being the most compatible with life. 457 00:20:36,660 --> 00:20:41,130 Trisomy of the 18 chromosome, trisomy of chromosome 18, 458 00:20:41,130 --> 00:20:44,220 being more severe with Edwards Syndrome. 459 00:20:44,220 --> 00:20:46,890 And you can see, perhaps you can start to hypothesize why. 460 00:20:46,890 --> 00:20:47,733 This is a larger chromosome, 461 00:20:47,733 --> 00:20:49,200 it's going to have more genes on it, 462 00:20:49,200 --> 00:20:51,840 it's going to have potentially a bigger impact 463 00:20:51,840 --> 00:20:54,540 on the overall survivability of that individual. 464 00:20:54,540 --> 00:20:57,420 And then finally, chromosome 13, Patau syndrome, 465 00:20:57,420 --> 00:21:00,420 which is an extremely severe condition 466 00:21:00,420 --> 00:21:04,050 and most individuals do not survive past 467 00:21:04,050 --> 00:21:06,510 really the first weeks of life. 468 00:21:06,510 --> 00:21:07,920 So what we've been talking about so far 469 00:21:07,920 --> 00:21:10,740 has to do with the autosomes, 470 00:21:10,740 --> 00:21:14,580 but what about changes in our sex chromosomes? 471 00:21:14,580 --> 00:21:18,060 And if we start to think about it, are we all aneuploid? 472 00:21:18,060 --> 00:21:20,610 Because females have two copies of every chromosome 473 00:21:20,610 --> 00:21:22,830 including X, but have no Y chromosomes. 474 00:21:22,830 --> 00:21:26,460 So are females, nullisomy for the Y chromosome? 475 00:21:26,460 --> 00:21:29,490 And males have only one copy of X and one copy of Y, 476 00:21:29,490 --> 00:21:31,917 so are they monosomy for X chromosome 477 00:21:31,917 --> 00:21:34,320 and monosomy for Y chromosome? 478 00:21:34,320 --> 00:21:36,180 Well, the interesting thing here is that 479 00:21:36,180 --> 00:21:39,840 cells have adapted to use only one X chromosome. 480 00:21:39,840 --> 00:21:41,580 And then the genes on the Y chromosome, 481 00:21:41,580 --> 00:21:44,763 remember the Y is the smallest chromosome that we have, 482 00:21:45,784 --> 00:21:48,600 all the genes on the Y chromosome 483 00:21:48,600 --> 00:21:50,640 are really used for sex determination 484 00:21:50,640 --> 00:21:52,860 and are not necessary for survival. 485 00:21:52,860 --> 00:21:55,260 So by default we are all female 486 00:21:55,260 --> 00:21:58,053 unless a Y chromosome is present to make us male. 487 00:21:59,490 --> 00:22:03,000 Females inactivate one of their X chromosomes in each cell 488 00:22:03,000 --> 00:22:05,220 to balance it out, which means that no genes 489 00:22:05,220 --> 00:22:08,400 are transcribed from that inactive X chromosome. 490 00:22:08,400 --> 00:22:11,790 This is accomplished by extensive DNA methylation 491 00:22:11,790 --> 00:22:13,800 that sound familiar, I hope, 492 00:22:13,800 --> 00:22:16,560 of the copy of the X chromosome which will be inactive. 493 00:22:16,560 --> 00:22:18,750 This is called X inactivation. 494 00:22:18,750 --> 00:22:22,410 So basically in females, a cell will select 495 00:22:22,410 --> 00:22:24,210 one of the two X chromosomes 496 00:22:24,210 --> 00:22:27,540 and it will inactivate one of those two by methylating it, 497 00:22:27,540 --> 00:22:30,120 by basically attaching methyl groups 498 00:22:30,120 --> 00:22:34,260 throughout the X chromosome to completely shut it down. 499 00:22:34,260 --> 00:22:35,790 So no genes are transcribed 500 00:22:35,790 --> 00:22:38,010 off of that inactive X chromosome. 501 00:22:38,010 --> 00:22:41,100 And in that way, males and females both have 502 00:22:41,100 --> 00:22:42,990 one copy of the X chromosome, 503 00:22:42,990 --> 00:22:45,273 which is active and being transcribed. 504 00:22:46,590 --> 00:22:48,960 Having an incorrect number of sex chromosomes 505 00:22:48,960 --> 00:22:51,750 has less severe impact on health of the individual 506 00:22:51,750 --> 00:22:53,760 than aneuploidy of autosomes. 507 00:22:53,760 --> 00:22:55,860 And let's look at a few examples of those 508 00:22:55,860 --> 00:22:58,110 because those are actually more common 509 00:22:58,110 --> 00:23:01,950 than the autosomal aneuploidies. 510 00:23:01,950 --> 00:23:04,860 So trisomy X, or triple X Syndrome, 511 00:23:04,860 --> 00:23:07,500 which would occur in females. 512 00:23:07,500 --> 00:23:09,480 So in females we would have, 513 00:23:09,480 --> 00:23:12,240 with the syndrome would have 47 chromosomes 514 00:23:12,240 --> 00:23:14,970 and then they would have three X chromosomes. 515 00:23:14,970 --> 00:23:17,430 This occurs in one and 1,000 newborn girls. 516 00:23:17,430 --> 00:23:18,870 And although females with this condition 517 00:23:18,870 --> 00:23:20,040 may be taller than average, 518 00:23:20,040 --> 00:23:22,980 they typically have no unusual physical features. 519 00:23:22,980 --> 00:23:24,720 Most have normal sexual development 520 00:23:24,720 --> 00:23:26,700 and are able to conceive children. 521 00:23:26,700 --> 00:23:28,620 This is associated with an increased risk 522 00:23:28,620 --> 00:23:30,870 of learning disabilities and delayed development 523 00:23:30,870 --> 00:23:31,980 of speech and language skills, 524 00:23:31,980 --> 00:23:33,780 but it's pretty mild. 525 00:23:33,780 --> 00:23:35,580 Seizures or kidney abnormalities occur 526 00:23:35,580 --> 00:23:37,620 in about 10% of affected females. 527 00:23:37,620 --> 00:23:40,290 And due to mild symptoms, most trisomy X females 528 00:23:40,290 --> 00:23:42,033 are actually never diagnosed. 529 00:23:43,830 --> 00:23:46,496 Oh, and this is a picture of a 530 00:23:46,496 --> 00:23:51,090 beautiful baby girl with trisomy X. 531 00:23:51,090 --> 00:23:53,970 She is perfectly normal and would be 532 00:23:53,970 --> 00:23:56,100 really not viewed any differently 533 00:23:56,100 --> 00:23:58,410 from anyone else on the street that you walk past. 534 00:23:58,410 --> 00:24:01,623 You would not assume that she has a trisomy. 535 00:24:03,480 --> 00:24:07,620 Turner Syndrome, this is basically a loss 536 00:24:07,620 --> 00:24:09,570 of one of the X chromosomes. 537 00:24:09,570 --> 00:24:13,110 This is basically a monosomy of X chromosome in females. 538 00:24:13,110 --> 00:24:14,820 So it would be designated 45 539 00:24:14,820 --> 00:24:16,830 because there are 45 chromosomes. 540 00:24:16,830 --> 00:24:19,290 The individual would have 44 normal autosomes 541 00:24:19,290 --> 00:24:21,450 and then simply one X chromosome. 542 00:24:21,450 --> 00:24:23,520 So 45 chromosomes in total. 543 00:24:23,520 --> 00:24:25,740 And then would be designated as comma X 544 00:24:25,740 --> 00:24:28,170 because there's only one X chromosome. 545 00:24:28,170 --> 00:24:31,740 Occurs in one in 2,500 newborn girls. 546 00:24:31,740 --> 00:24:34,620 And the most common feature is really just a short stature. 547 00:24:34,620 --> 00:24:37,200 You can see here these are two sisters. 548 00:24:37,200 --> 00:24:40,410 The sister, the woman on the left here, 549 00:24:40,410 --> 00:24:44,880 she has Turner Syndrome and on the right she does not. 550 00:24:44,880 --> 00:24:47,070 The most common feature is short stature. 551 00:24:47,070 --> 00:24:51,000 An early loss of ovarian function is also very common 552 00:24:51,000 --> 00:24:53,310 and many affected girls do not undergo puberty 553 00:24:53,310 --> 00:24:54,930 unless they receive hormone therapy. 554 00:24:54,930 --> 00:24:56,640 And most are infertile. 555 00:24:56,640 --> 00:24:58,770 About 30% of females with Turner Syndrome 556 00:24:58,770 --> 00:25:01,140 have a webbed neck, low hairline, 557 00:25:01,140 --> 00:25:03,210 and low hairline at the back of the neck, 558 00:25:03,210 --> 00:25:05,550 puffiness or swelling of the hands and feet, 559 00:25:05,550 --> 00:25:08,103 skeletal abnormalities or kidney problems. 560 00:25:09,420 --> 00:25:12,300 About 30 to 50% are born with a heart defect 561 00:25:12,300 --> 00:25:14,340 and most girls and women with Turner Syndrome 562 00:25:14,340 --> 00:25:15,630 have normal intelligence. 563 00:25:15,630 --> 00:25:19,380 So it's not as though there's any intellectual disability 564 00:25:19,380 --> 00:25:20,493 with Turner Syndrome. 565 00:25:22,290 --> 00:25:26,670 Klinefelter syndrome, this occurs in males where, 566 00:25:26,670 --> 00:25:29,580 this occurs in males who have two X chromosomes 567 00:25:29,580 --> 00:25:30,690 as well as a Y chromosome. 568 00:25:30,690 --> 00:25:34,140 If you recall, I mentioned that having a Y chromosome 569 00:25:34,140 --> 00:25:36,063 basically makes an individual male. 570 00:25:37,050 --> 00:25:40,920 In the case of males with Klinefelter syndrome, 571 00:25:40,920 --> 00:25:42,630 they also have two X chromosomes. 572 00:25:42,630 --> 00:25:44,310 So this would be designated 47 573 00:25:44,310 --> 00:25:47,490 for a total number of chromosomes, XXY. 574 00:25:47,490 --> 00:25:51,120 This occurs in one in 500 to 1000 newborn boys. 575 00:25:51,120 --> 00:25:53,370 It results in small testes that do not produce 576 00:25:53,370 --> 00:25:55,170 as much testosterone as usual, 577 00:25:55,170 --> 00:25:57,720 which leads to delayed or incomplete puberty, 578 00:25:57,720 --> 00:26:00,600 breast enlargement, reduced facial hair and body hair, 579 00:26:00,600 --> 00:26:01,743 and infertility. 580 00:26:02,790 --> 00:26:04,350 Some also have genital differences 581 00:26:04,350 --> 00:26:07,530 including undescended testes, the opening of the urethra 582 00:26:07,530 --> 00:26:09,900 on the underside of the penis, 583 00:26:09,900 --> 00:26:12,886 or an unusually small penis. 584 00:26:12,886 --> 00:26:16,950 Older children and adults tend to be taller than their peers 585 00:26:16,950 --> 00:26:18,480 and adults have increased risk 586 00:26:18,480 --> 00:26:20,460 of developing breast cancer and lupus, 587 00:26:20,460 --> 00:26:22,770 remember this is in males. 588 00:26:22,770 --> 00:26:26,190 So their risk of developing breast cancer or lupus 589 00:26:26,190 --> 00:26:30,120 is actually about equivalent to a normal females risk 590 00:26:30,120 --> 00:26:32,730 for developing breast cancer and lupus. 591 00:26:32,730 --> 00:26:34,500 Children may have learning disabilities 592 00:26:34,500 --> 00:26:36,240 and delayed speech and language development. 593 00:26:36,240 --> 00:26:38,850 They tend to be quiet, sensitive, and unassertive. 594 00:26:38,850 --> 00:26:41,190 But personality characteristics vary greatly 595 00:26:41,190 --> 00:26:42,843 among affected individuals. 596 00:26:45,300 --> 00:26:47,250 Now, let's look at what happens if you have, 597 00:26:47,250 --> 00:26:51,180 as a male, two Y chromosomes, XYY syndrome. 598 00:26:51,180 --> 00:26:54,120 47, XYY, is what it would be designated. 599 00:26:54,120 --> 00:26:57,420 This occurs in around one in 1000 newborn boys 600 00:26:57,420 --> 00:26:58,680 and it's actually really unclear 601 00:26:58,680 --> 00:27:00,030 if that's an accurate statistic 602 00:27:00,030 --> 00:27:02,880 because many of them are never diagnosed. 603 00:27:02,880 --> 00:27:05,490 Although taller than average, this chromosomal change, 604 00:27:05,490 --> 00:27:07,980 typically causes no unusual physical features. 605 00:27:07,980 --> 00:27:10,650 This is an image of a mother with her son 606 00:27:10,650 --> 00:27:12,363 who has XYY syndrome. 607 00:27:14,430 --> 00:27:16,080 Most have normal sexual development 608 00:27:16,080 --> 00:27:17,460 and are able to father children. 609 00:27:17,460 --> 00:27:19,230 This is associated with an increased risk 610 00:27:19,230 --> 00:27:21,480 of learning disabilities and delayed development 611 00:27:21,480 --> 00:27:23,280 of speech and language skills, 612 00:27:23,280 --> 00:27:24,930 delayed development of motor skills, 613 00:27:24,930 --> 00:27:27,180 such as sitting and walking, weak muscle tone, 614 00:27:27,180 --> 00:27:29,940 hand tremors or other involuntary movements. 615 00:27:29,940 --> 00:27:33,270 And behavioral and emotional difficulties are also possible, 616 00:27:33,270 --> 00:27:34,950 though again it's a spectrum. 617 00:27:34,950 --> 00:27:37,740 So some it may be more severe than others, 618 00:27:37,740 --> 00:27:40,170 and some males, absolutely is expected 619 00:27:40,170 --> 00:27:41,640 that there are many men out there 620 00:27:41,640 --> 00:27:44,310 who will never be diagnosed with XYY syndrome 621 00:27:44,310 --> 00:27:48,483 simply because it has given them no problems. 622 00:27:49,740 --> 00:27:53,220 A small percentage of males with 47, XYY syndrome 623 00:27:53,220 --> 00:27:55,290 are diagnosed with autistic spectrum disorder. 624 00:27:55,290 --> 00:27:58,983 So there may be a link between this condition and autism. 625 00:28:01,290 --> 00:28:03,480 So now, let's talk about what are the risks 626 00:28:03,480 --> 00:28:05,250 for aneuploidy in the mother. 627 00:28:05,250 --> 00:28:08,640 So we're looking at basically aneuploidy 628 00:28:08,640 --> 00:28:10,170 which is occurring in an embryo. 629 00:28:10,170 --> 00:28:12,780 So the risks are associated with, 630 00:28:12,780 --> 00:28:15,240 the risks of this happening in an embryo, 631 00:28:15,240 --> 00:28:18,060 are related mostly to the mother. 632 00:28:18,060 --> 00:28:19,890 And as I mentioned with Down Syndrome, 633 00:28:19,890 --> 00:28:23,040 advanced maternal age is a major risk factor. 634 00:28:23,040 --> 00:28:25,170 Risk of aneuploidy increases significantly 635 00:28:25,170 --> 00:28:27,592 for mothers older than 45. 636 00:28:27,592 --> 00:28:30,450 In addition exposure to toxins and carcinogens 637 00:28:30,450 --> 00:28:32,940 prior to conception can interfere in Meiosis 638 00:28:32,940 --> 00:28:36,450 and lead to increased rates of nondisjunction. 639 00:28:36,450 --> 00:28:39,930 Previous aneuploidy birth or spontaneous abortion, 640 00:28:39,930 --> 00:28:41,943 many spontaneous abortions prior, 641 00:28:43,110 --> 00:28:44,880 is associated with a higher risk 642 00:28:44,880 --> 00:28:46,230 of subsequent aneuploidy birth. 643 00:28:46,230 --> 00:28:48,180 It doesn't mean it's a given. 644 00:28:48,180 --> 00:28:52,710 So if a woman has had, say, a child with Down Syndrome, 645 00:28:52,710 --> 00:28:54,930 it does not necessarily mean her next child 646 00:28:54,930 --> 00:28:56,070 will have Down Syndrome. 647 00:28:56,070 --> 00:28:58,620 It does increase the risk slightly. 648 00:28:58,620 --> 00:29:00,060 It increases the risk slightly. 649 00:29:00,060 --> 00:29:01,830 But actually advanced maternal age 650 00:29:01,830 --> 00:29:03,900 is going to have a much greater impact 651 00:29:03,900 --> 00:29:07,560 on the likelihood of having a child with Down Syndrome, 652 00:29:07,560 --> 00:29:11,043 than would having had a child previously with Down Syndrome. 653 00:29:12,990 --> 00:29:16,380 Let's look at the difference between women and men. 654 00:29:16,380 --> 00:29:18,210 So why does it seem like we're really 655 00:29:18,210 --> 00:29:19,830 focusing on the risks in women? 656 00:29:19,830 --> 00:29:23,100 Don't men also undergo Meiosis in order to produce sperm 657 00:29:23,100 --> 00:29:26,370 and could it not happen in the sperm instead of in the egg? 658 00:29:26,370 --> 00:29:28,980 Well, it certainly could and it does at times. 659 00:29:28,980 --> 00:29:31,290 Nondisjunction in the egg is by far 660 00:29:31,290 --> 00:29:34,620 the most common reason for aneuploidy. 661 00:29:34,620 --> 00:29:37,290 Meaning that it happens far less often in the sperm. 662 00:29:37,290 --> 00:29:38,760 And why is that the case? 663 00:29:38,760 --> 00:29:40,980 Well, egg cells in females enter Meiosis 664 00:29:40,980 --> 00:29:43,170 while still in utero. 665 00:29:43,170 --> 00:29:44,940 Then are halted in prophase I 666 00:29:44,940 --> 00:29:47,910 until puberty and ovulation when Meiosis completes. 667 00:29:47,910 --> 00:29:49,260 So what do I mean by this? 668 00:29:49,260 --> 00:29:53,520 A female embryo in utero forms the germline cells. 669 00:29:53,520 --> 00:29:56,070 Remember those are the cells that will become gametes, 670 00:29:56,070 --> 00:30:00,390 forms germline cells and basically initiates Meiosis I, 671 00:30:00,390 --> 00:30:03,630 The very beginning stage of Meiosis I does not complete, 672 00:30:03,630 --> 00:30:05,220 it just enters actually prophase, 673 00:30:05,220 --> 00:30:07,110 that very first stage of Meiosis I, 674 00:30:07,110 --> 00:30:10,890 and then it halts it and it stops it for a very long time. 675 00:30:10,890 --> 00:30:14,370 It will stop it for about the next 13 years. 676 00:30:14,370 --> 00:30:18,000 So those cells, those very same cells are just sitting there 677 00:30:18,000 --> 00:30:22,200 in the ovary waiting of the developing girl 678 00:30:22,200 --> 00:30:25,350 until she reaches puberty and until ovulation begins 679 00:30:25,350 --> 00:30:27,300 when Meiosis is kicked back into gear 680 00:30:27,300 --> 00:30:31,920 and those cells finish up Meiosis I and Meiosis II, 681 00:30:31,920 --> 00:30:33,820 and then you have the mature egg cell. 682 00:30:34,680 --> 00:30:36,570 So why is that a problem? 683 00:30:36,570 --> 00:30:38,730 Well, it's a problem because these egg cells 684 00:30:38,730 --> 00:30:42,000 build up mutations and toxin exposure over time, 685 00:30:42,000 --> 00:30:43,710 which contribute to aneuploidy. 686 00:30:43,710 --> 00:30:45,060 So over those 13 years, 687 00:30:45,060 --> 00:30:47,700 that's the very earliest stage of ovulation, 688 00:30:47,700 --> 00:30:50,880 say when a girl is 12 or 13 years old. 689 00:30:50,880 --> 00:30:52,317 But you can imagine then, 690 00:30:52,317 --> 00:30:55,380 the more advanced a woman becomes in her age, 691 00:30:55,380 --> 00:30:58,890 the more likely that her egg cells, 692 00:30:58,890 --> 00:31:02,130 which were formed when she was in utero, 693 00:31:02,130 --> 00:31:04,050 are going to develop some problems. 694 00:31:04,050 --> 00:31:07,590 And this absolutely happens just from normal exposure, 695 00:31:07,590 --> 00:31:08,970 but especially from, you know, 696 00:31:08,970 --> 00:31:11,610 if there are extra toxins or carcinogens 697 00:31:11,610 --> 00:31:14,430 around those can speed up the process. 698 00:31:14,430 --> 00:31:17,460 And she, if we're talking about a woman who's 40 years old 699 00:31:17,460 --> 00:31:19,350 and she's going to become pregnant, 700 00:31:19,350 --> 00:31:24,350 the cell that will become that egg is over 40 years old. 701 00:31:25,620 --> 00:31:27,210 That's a really old cell. 702 00:31:27,210 --> 00:31:29,400 Most of our cells in our body are turned over 703 00:31:29,400 --> 00:31:30,840 regularly and rapidly. 704 00:31:30,840 --> 00:31:32,940 Say within about a year or so, 705 00:31:32,940 --> 00:31:36,030 most of our cells have actually turned over, 706 00:31:36,030 --> 00:31:40,650 except for egg cells which are with us, 707 00:31:40,650 --> 00:31:43,680 which are with females from the very beginning. 708 00:31:43,680 --> 00:31:45,630 So as a result, these are older cells 709 00:31:45,630 --> 00:31:48,780 and older cells are likely to have more mistakes, 710 00:31:48,780 --> 00:31:51,420 are likely to have accumulated more mutations 711 00:31:51,420 --> 00:31:53,460 and damage over time. 712 00:31:53,460 --> 00:31:58,380 And as a result you have more issues that occur in Meiosis. 713 00:31:58,380 --> 00:32:00,120 On the other hand, sperm cells in men 714 00:32:00,120 --> 00:32:01,800 are continuously made fresh 715 00:32:01,800 --> 00:32:03,960 and only start Meiosis when needed. 716 00:32:03,960 --> 00:32:05,700 Meaning these cells are not as old 717 00:32:05,700 --> 00:32:08,940 and less likely to have accumulated mutations and errors. 718 00:32:08,940 --> 00:32:11,010 Sperm also compete amongst themselves 719 00:32:11,010 --> 00:32:12,570 to reach the fertilized egg. 720 00:32:12,570 --> 00:32:14,850 Damaged sperm cells are less likely to win. 721 00:32:14,850 --> 00:32:17,730 So it's a kind of selection that happens 722 00:32:17,730 --> 00:32:19,920 in the process of fertilization 723 00:32:19,920 --> 00:32:22,290 because only really the strongest sperm 724 00:32:22,290 --> 00:32:23,640 will ever make it to the egg. 725 00:32:23,640 --> 00:32:26,620 So those that have damage or 726 00:32:28,170 --> 00:32:29,910 issues that occurred during Meiosis 727 00:32:29,910 --> 00:32:33,063 will probably never make it to fertilize an egg. 728 00:32:35,310 --> 00:32:37,257 Let's take a quick peek at a 729 00:32:38,307 --> 00:32:41,010 karyotype of an individual with aneuploidy. 730 00:32:41,010 --> 00:32:42,240 I want you to take a look at this 731 00:32:42,240 --> 00:32:44,463 and take a moment please to, 732 00:32:45,720 --> 00:32:47,190 and I want you to take a peek at this. 733 00:32:47,190 --> 00:32:49,620 Put the video on pause in a moment here. 734 00:32:49,620 --> 00:32:53,640 And I want you to write down for yourself 735 00:32:53,640 --> 00:32:55,650 what you think, what you would write up 736 00:32:55,650 --> 00:32:57,930 as the karyotype designation here. 737 00:32:57,930 --> 00:33:00,630 Remember karyotype designation would be 738 00:33:00,630 --> 00:33:03,030 total number of chromosomes, comma, 739 00:33:03,030 --> 00:33:05,370 sex chromosome designation, comma, 740 00:33:05,370 --> 00:33:09,783 plus/minus, any autosomes that are in trisomy or monosomy. 741 00:33:11,040 --> 00:33:14,280 So I want you to take a look at this, put it on pause, 742 00:33:14,280 --> 00:33:18,570 and I want you to write, or I want you to think 743 00:33:18,570 --> 00:33:20,520 of what that designation would be. 744 00:33:20,520 --> 00:33:22,710 And even what these, if you can recall, 745 00:33:22,710 --> 00:33:25,590 what the syndrome would be associated with this. 746 00:33:25,590 --> 00:33:28,563 So you can put it on pause now and you can come right back. 747 00:33:32,400 --> 00:33:34,290 Okay. Have you worked it out? 748 00:33:34,290 --> 00:33:36,450 Well, it's Klinefelter syndrome, 749 00:33:36,450 --> 00:33:39,270 which would be designated 47,XXY. 750 00:33:39,270 --> 00:33:44,100 As you can see here, this individual has two X chromosomes, 751 00:33:44,100 --> 00:33:46,260 which would be normal in a female, 752 00:33:46,260 --> 00:33:48,150 except there's also a Y chromosome. 753 00:33:48,150 --> 00:33:50,790 Y chromosome means this individual is male 754 00:33:50,790 --> 00:33:53,190 'cause there's a presence of a Y chromosome. 755 00:33:53,190 --> 00:33:56,040 Two X chromosomes means this individual 756 00:33:56,040 --> 00:33:58,383 will have Klinefelter Syndrome. 757 00:33:59,970 --> 00:34:01,710 All right, let's take a summary of 758 00:34:01,710 --> 00:34:03,960 what we have covered so far. 759 00:34:03,960 --> 00:34:07,080 Aneuploidy results from a nondisjunction event in Meiosis. 760 00:34:07,080 --> 00:34:12,080 Remember nondisjunction is classified as 761 00:34:12,240 --> 00:34:15,738 chromosomes not separating from each other properly, 762 00:34:15,738 --> 00:34:18,690 in which paired chromosomes do not segregate properly 763 00:34:18,690 --> 00:34:20,460 creating daughter cells with either too many 764 00:34:20,460 --> 00:34:22,290 or too few chromosomes. 765 00:34:22,290 --> 00:34:25,440 Most autosomal aneuploidy is incompatible with life 766 00:34:25,440 --> 00:34:27,870 and results in spontaneous abortion. 767 00:34:27,870 --> 00:34:30,720 Autosomal aneuploidy is far more severe 768 00:34:30,720 --> 00:34:33,000 than sex chromosome aneuploidy. 769 00:34:33,000 --> 00:34:35,070 Advanced maternal age, carcinogens, 770 00:34:35,070 --> 00:34:37,050 and previous aneuploidy birth in the mother 771 00:34:37,050 --> 00:34:38,640 increase the risk of aneuploidy. 772 00:34:38,640 --> 00:34:42,750 But remember, that really it's about advanced maternal age 773 00:34:42,750 --> 00:34:47,750 is the most likely culprit given the aging of the egg cells. 774 00:34:49,350 --> 00:34:52,080 All right, well with that, what's next in this module? 775 00:34:52,080 --> 00:34:54,150 So we'll follow this up with discussion 776 00:34:54,150 --> 00:34:55,890 of other chromosomal abnormalities. 777 00:34:55,890 --> 00:34:58,350 And these are going to be instead of at the scale 778 00:34:58,350 --> 00:35:01,710 of an entire chromosome being present or absent, 779 00:35:01,710 --> 00:35:05,250 this would be of a disorder in a chunk of a chromosome 780 00:35:05,250 --> 00:35:08,760 and how that can result in some clinical manifestations, 781 00:35:08,760 --> 00:35:10,050 which we'll discuss. 782 00:35:10,050 --> 00:35:11,070 And then we'll follow that up 783 00:35:11,070 --> 00:35:13,680 with a discussion on mosaicism. 784 00:35:13,680 --> 00:35:15,270 All right, well please let me know 785 00:35:15,270 --> 00:35:16,920 if you have any questions on aneuploidy, 786 00:35:16,920 --> 00:35:20,313 and I look forward to speaking with you in the next lecture.