1 00:00:01,140 --> 00:00:02,250 [Instructor] Hello, and welcome 2 00:00:02,250 --> 00:00:04,530 to the second lecture in Module 4, 3 00:00:04,530 --> 00:00:06,800 called Chromosomal Abnormalities. 4 00:00:06,800 --> 00:00:08,370 In this lecture we're going to talk 5 00:00:08,370 --> 00:00:11,250 about chromosomal abnormalities. 6 00:00:11,250 --> 00:00:15,840 And by that I mean changes in chromosome structure 7 00:00:15,840 --> 00:00:19,110 that will affect gene expression 8 00:00:19,110 --> 00:00:21,090 or can affect gene expression 9 00:00:21,090 --> 00:00:23,610 for genes in the region of the chromosome 10 00:00:23,610 --> 00:00:26,070 that has an abnormality. 11 00:00:26,070 --> 00:00:28,680 This is different from aneuploidy in that aneuploidy 12 00:00:28,680 --> 00:00:33,600 is the incorrect number of the copies of chromosomes 13 00:00:33,600 --> 00:00:35,190 present in a cell. 14 00:00:35,190 --> 00:00:38,100 Either an extra copy or one fewer copies 15 00:00:38,100 --> 00:00:41,040 of an entire chromosome would be aneuploidy. 16 00:00:41,040 --> 00:00:43,380 Chromosomal abnormalities will be looking 17 00:00:43,380 --> 00:00:45,360 at a segment of a chromosome 18 00:00:45,360 --> 00:00:47,373 as opposed to an entire chromosome. 19 00:00:48,630 --> 00:00:50,520 So just one last quick review, 20 00:00:50,520 --> 00:00:53,070 you saw this in the previous lecture as well. 21 00:00:53,070 --> 00:00:56,370 Looking at a karyotype, this is a karyotype of a male 22 00:00:56,370 --> 00:00:58,800 who has one X and one Y chromosome. 23 00:00:58,800 --> 00:01:00,093 And just as a reminder, 24 00:01:01,650 --> 00:01:03,900 there are a specific set of genes, 25 00:01:03,900 --> 00:01:06,630 specific set of genes on each of these chromosomes, 26 00:01:06,630 --> 00:01:08,790 one through 22, X and Y, 27 00:01:08,790 --> 00:01:10,590 and each of these genes is located 28 00:01:10,590 --> 00:01:13,983 in a specific location along its chromosome. 29 00:01:15,900 --> 00:01:18,300 And what I mean by that is, say for example, 30 00:01:18,300 --> 00:01:20,640 a gene related to eye color, 31 00:01:20,640 --> 00:01:24,930 and let's say that gene happens to be on chromosome eight. 32 00:01:24,930 --> 00:01:26,220 Well, it's on chromosome eight, 33 00:01:26,220 --> 00:01:28,200 it will always be on chromosome eight. 34 00:01:28,200 --> 00:01:29,940 And let's say it's on chromosome eight, 35 00:01:29,940 --> 00:01:32,420 and it's always, let's say it's always located right here. 36 00:01:32,420 --> 00:01:35,070 So you can think of it as an address. 37 00:01:35,070 --> 00:01:37,200 So each gene has its specific address 38 00:01:37,200 --> 00:01:39,240 where it lives on a chromosome, 39 00:01:39,240 --> 00:01:41,970 and that gene is always in that particular location. 40 00:01:41,970 --> 00:01:43,920 And if it is not in that location, 41 00:01:43,920 --> 00:01:46,590 this can affect the gene expression. 42 00:01:46,590 --> 00:01:48,660 And as you recall from the previous lecture, 43 00:01:48,660 --> 00:01:50,670 any changes in gene expression 44 00:01:50,670 --> 00:01:53,403 can have some significant clinical implications. 45 00:01:54,990 --> 00:01:58,650 So let's dissect the anatomy of a chromosome here. 46 00:01:58,650 --> 00:02:01,320 So a chromosome, and if you recall here, 47 00:02:01,320 --> 00:02:04,830 this would be a chromosome which has been duplicated. 48 00:02:04,830 --> 00:02:08,973 So there are two sister chromatids, one and two. 49 00:02:10,200 --> 00:02:12,450 At either end of the chromosome 50 00:02:12,450 --> 00:02:14,970 is a region called a telomere. 51 00:02:14,970 --> 00:02:19,740 A telomere is just simply the end caps for chromatids. 52 00:02:19,740 --> 00:02:20,820 When we look at a chromosome, 53 00:02:20,820 --> 00:02:22,410 there's the portion of the chromosome 54 00:02:22,410 --> 00:02:25,020 where the two sister chromatids come together 55 00:02:25,020 --> 00:02:27,510 and are attached, and this is at the centromere. 56 00:02:27,510 --> 00:02:29,550 Typically, it's around the center of the chromosome, 57 00:02:29,550 --> 00:02:30,710 but in some of the shorter chromosomes, 58 00:02:30,710 --> 00:02:33,660 it can actually be very close to the top of the chromosome. 59 00:02:35,250 --> 00:02:39,180 This leaves two what are called arms for each chromatid. 60 00:02:39,180 --> 00:02:42,090 And these are gonna be on either side of the centromere. 61 00:02:42,090 --> 00:02:45,090 The short arm of the chromosome 62 00:02:45,090 --> 00:02:46,410 is always going to be designated 63 00:02:46,410 --> 00:02:49,560 as the p arm, or for petite. 64 00:02:49,560 --> 00:02:53,610 The q arm is going to be the longer arm of the chromosome. 65 00:02:53,610 --> 00:02:54,960 This is important to know 66 00:02:54,960 --> 00:02:59,010 because it will help in defining that specific address 67 00:02:59,010 --> 00:03:04,010 where a gene or a abnormality on a chromosome lies. 68 00:03:04,500 --> 00:03:06,810 And remember, as I mentioned in the previous slide, 69 00:03:06,810 --> 00:03:08,760 genes are always located on the same place 70 00:03:08,760 --> 00:03:11,190 along the chromosome called the gene's locus. 71 00:03:11,190 --> 00:03:14,730 So the locus is sort of like its specific address. 72 00:03:14,730 --> 00:03:17,340 And an example of that would be the beta globin gene 73 00:03:17,340 --> 00:03:20,463 is always located on chromosome 11 on the p arm. 74 00:03:22,950 --> 00:03:25,110 Just wanted to give you a reminder 75 00:03:25,110 --> 00:03:27,450 of the perspective of what a chromosome is. 76 00:03:27,450 --> 00:03:30,450 As you recall, if you zoom into a chromosome, 77 00:03:30,450 --> 00:03:33,420 you can actually see it's double-stranded DNA 78 00:03:33,420 --> 00:03:34,530 wrapped around histones. 79 00:03:34,530 --> 00:03:36,840 They're not showing histones in this particular picture, 80 00:03:36,840 --> 00:03:39,390 but as you recall it, they wind around histones. 81 00:03:39,390 --> 00:03:41,070 And as you zoom in further and further, 82 00:03:41,070 --> 00:03:43,530 you see the double-stranded, 83 00:03:43,530 --> 00:03:46,440 the double strands which are base paired together 84 00:03:46,440 --> 00:03:50,820 along the nucleotide bases, C, T, A and G, 85 00:03:50,820 --> 00:03:53,850 and they base pair together across the two strands. 86 00:03:53,850 --> 00:03:56,400 All right, so there are some common designations 87 00:03:56,400 --> 00:03:58,470 for locations that we'll use. 88 00:03:58,470 --> 00:04:02,490 And you don't need to necessarily memorize all of these, 89 00:04:02,490 --> 00:04:04,110 it's just more for a point of reference 90 00:04:04,110 --> 00:04:06,330 so that you can have an understanding 91 00:04:06,330 --> 00:04:09,900 when you read some of the shorthand designations 92 00:04:09,900 --> 00:04:11,880 for particular chromosomal abnormalities 93 00:04:11,880 --> 00:04:15,390 or even locations of normally functioning genes, 94 00:04:15,390 --> 00:04:17,730 you can have an understanding of what they're talking about. 95 00:04:17,730 --> 00:04:20,328 So if we look at, let's say this is, you know, 96 00:04:20,328 --> 00:04:22,920 this is a chromatid from a chromosome. 97 00:04:22,920 --> 00:04:24,990 Again, as I mentioned, you have the centromere, 98 00:04:24,990 --> 00:04:27,600 which is that center point, which is the constricted part, 99 00:04:27,600 --> 00:04:30,210 generally more towards the center of the chromosome, 100 00:04:30,210 --> 00:04:33,150 the short arm, which would be the p arm, 101 00:04:33,150 --> 00:04:35,040 the long arm, which is the q arm, 102 00:04:35,040 --> 00:04:37,440 and then within that, you have different banding patterns 103 00:04:37,440 --> 00:04:40,290 which appear when chromosomes are stained 104 00:04:40,290 --> 00:04:43,470 with a particular dye called Giemsa. 105 00:04:43,470 --> 00:04:46,320 And this is used by cytogeneticists 106 00:04:46,320 --> 00:04:49,440 who will analyze chromosomes 107 00:04:49,440 --> 00:04:53,790 and put together karyotypes to make diagnoses 108 00:04:53,790 --> 00:04:55,323 of genetic conditions. 109 00:04:57,150 --> 00:04:58,740 There are regular banding patterns 110 00:04:58,740 --> 00:05:00,750 which appear on karyotypes of chromosomes, 111 00:05:00,750 --> 00:05:01,830 which, and these are used 112 00:05:01,830 --> 00:05:05,940 to define the physical location of a region on a chromosome. 113 00:05:05,940 --> 00:05:09,150 If you remember from looking at those karyotypes, 114 00:05:09,150 --> 00:05:10,470 let's go back for a moment, 115 00:05:10,470 --> 00:05:12,600 you can see there are regions which are darker 116 00:05:12,600 --> 00:05:13,590 and regions which are lighter. 117 00:05:13,590 --> 00:05:16,200 These are the bands that we're referring to. 118 00:05:16,200 --> 00:05:19,290 And these are consistent between individuals, 119 00:05:19,290 --> 00:05:22,260 so they will always stain in this particular manner, 120 00:05:22,260 --> 00:05:24,360 which is very helpful because it allows us 121 00:05:24,360 --> 00:05:28,710 to have a way to standardize location along the chromosome. 122 00:05:28,710 --> 00:05:30,150 Alright, so if we look at this, 123 00:05:30,150 --> 00:05:33,310 the way that we're starting to designate locations 124 00:05:34,440 --> 00:05:35,850 in this particular chromosome, 125 00:05:35,850 --> 00:05:39,000 and for shorter chromosomes or longer chromosomes, 126 00:05:39,000 --> 00:05:42,870 you may have more or fewer of these particular designations, 127 00:05:42,870 --> 00:05:45,150 but this is generally the way it works. 128 00:05:45,150 --> 00:05:49,473 It will be written with the chromosome number first. 129 00:05:51,030 --> 00:05:52,130 So let's say this is chromosome 12, 130 00:05:52,130 --> 00:05:54,030 it would be written as 12. 131 00:05:54,030 --> 00:05:56,470 So let's say the region we're trying to get to 132 00:05:57,426 --> 00:06:00,450 is the p22.1 band, so let's say we're trying 133 00:06:00,450 --> 00:06:03,870 to describe this particular region here. 134 00:06:03,870 --> 00:06:07,410 So what we would describe it as is it's on the p arm, right? 135 00:06:07,410 --> 00:06:09,903 It's on the short arm relative to the centromere. 136 00:06:11,520 --> 00:06:15,420 Within that, the region between regions one and two, 137 00:06:15,420 --> 00:06:18,973 well, it's located in region two, so it would be p2. 138 00:06:20,610 --> 00:06:24,750 Within region two, it's located in sub region two, 139 00:06:24,750 --> 00:06:26,790 so it would be two two. 140 00:06:26,790 --> 00:06:29,280 And then within that, it's located on band one. 141 00:06:29,280 --> 00:06:31,650 So it would be identified as, 142 00:06:31,650 --> 00:06:34,350 since it's chromosome 12, would be 12 p, 143 00:06:34,350 --> 00:06:38,760 it's on the p arm, 2, 2.1. 144 00:06:38,760 --> 00:06:41,760 This is the band location that you're looking for. 145 00:06:41,760 --> 00:06:43,890 So if we do this again as the address, 146 00:06:43,890 --> 00:06:47,220 it would be like giving your location as the United States, 147 00:06:47,220 --> 00:06:48,900 which would be like chromosome 12. 148 00:06:48,900 --> 00:06:51,000 So now you know which of the chromosomes it's on, 149 00:06:51,000 --> 00:06:53,070 which of the countries you're in, United States. 150 00:06:53,070 --> 00:06:55,320 Then you would say Vermont, which is the p arm, 151 00:06:55,320 --> 00:06:58,590 so you know, within the United States, it's in Vermont. 152 00:06:58,590 --> 00:06:59,940 So let's say this is, you know, 153 00:06:59,940 --> 00:07:02,643 it's getting you closer and closer on the p arm. 154 00:07:03,660 --> 00:07:05,790 Within Vermont, where are you? 155 00:07:05,790 --> 00:07:07,140 You're located in Burlington. 156 00:07:07,140 --> 00:07:10,170 That's like saying you're located in region two. 157 00:07:10,170 --> 00:07:12,150 Within Burlington, where are you located? 158 00:07:12,150 --> 00:07:14,670 You're located in sub region two. 159 00:07:14,670 --> 00:07:18,030 So you know it's in this portion here somewhere. 160 00:07:18,030 --> 00:07:19,290 Okay, we're getting closer and closer, 161 00:07:19,290 --> 00:07:22,830 and now we know that okay, on sub region two, 162 00:07:22,830 --> 00:07:24,990 which is like saying you're on Main Street, 163 00:07:24,990 --> 00:07:26,970 where are you in 32 Main Street? 164 00:07:26,970 --> 00:07:28,290 Well, you're in apartment four. 165 00:07:28,290 --> 00:07:32,430 So we know now that not only are you on the p arm, 166 00:07:32,430 --> 00:07:34,770 you're in region two, you're in sub region two, 167 00:07:34,770 --> 00:07:36,810 you're in band one. 168 00:07:36,810 --> 00:07:38,630 So this would be p22.1. 169 00:07:40,140 --> 00:07:41,760 So that's like giving your address 170 00:07:41,760 --> 00:07:43,230 and getting closer and closer and closer 171 00:07:43,230 --> 00:07:44,763 into your actual location. 172 00:07:47,280 --> 00:07:50,880 Chromosomal rearrangements, these actually can occur 173 00:07:50,880 --> 00:07:54,960 as a result of damage to chromosomes and to DNA 174 00:07:54,960 --> 00:07:56,370 that make up chromosomes 175 00:07:56,370 --> 00:07:59,760 when the DNA has a double-strand break. 176 00:07:59,760 --> 00:08:03,480 And what I mean by that is that the DNA is actually severed 177 00:08:03,480 --> 00:08:07,260 between both strands with both strands of the DNA. 178 00:08:07,260 --> 00:08:12,260 That can allow for some improper structures that result. 179 00:08:13,380 --> 00:08:15,720 Similarly, improper DNA replication 180 00:08:15,720 --> 00:08:18,090 or improper attachment to other chromosomes 181 00:08:18,090 --> 00:08:20,520 can also result in these abnormalities. 182 00:08:20,520 --> 00:08:23,130 Segments of chromosomes may break off and become lost. 183 00:08:23,130 --> 00:08:24,600 This is called deletion. 184 00:08:24,600 --> 00:08:26,520 They may attach to other chromosomes. 185 00:08:26,520 --> 00:08:28,320 This is a translocation. 186 00:08:28,320 --> 00:08:30,690 They could duplicate a specific region. 187 00:08:30,690 --> 00:08:32,970 This is a duplication or flip around 188 00:08:32,970 --> 00:08:34,230 and which is an inversion, 189 00:08:34,230 --> 00:08:36,270 and we'll look at each of these separately. 190 00:08:36,270 --> 00:08:38,730 These can each result in improper gene expression 191 00:08:38,730 --> 00:08:41,823 of the genes on those segments and can lead to disease. 192 00:08:42,990 --> 00:08:44,490 Let's start with deletion. 193 00:08:44,490 --> 00:08:46,710 This is probably one of the easier ones to understand. 194 00:08:46,710 --> 00:08:50,010 So if we're looking at this as like a chromatid, right, 195 00:08:50,010 --> 00:08:52,680 one of a chromosome, 196 00:08:52,680 --> 00:08:54,450 let's say this particular region here, 197 00:08:54,450 --> 00:08:56,100 there's a double-strand break on this side 198 00:08:56,100 --> 00:08:58,500 and there's a double-strand break on this side. 199 00:08:58,500 --> 00:09:01,500 And the result is that, potentially, what can happen 200 00:09:01,500 --> 00:09:02,940 is that this entire segment 201 00:09:02,940 --> 00:09:05,430 between those two double-strand breaks gets lost 202 00:09:05,430 --> 00:09:07,140 in a process called deletion, 203 00:09:07,140 --> 00:09:10,440 and the chromosome will actually reattach itself 204 00:09:10,440 --> 00:09:12,420 without that particular segment being there, 205 00:09:12,420 --> 00:09:15,270 and it will try to continue on as as best as possible. 206 00:09:15,270 --> 00:09:18,300 But many times this is quite problematic to the cell 207 00:09:18,300 --> 00:09:20,700 because you're actually losing genetic material. 208 00:09:22,410 --> 00:09:25,470 In duplication, a portion of the chromosome is duplicated 209 00:09:25,470 --> 00:09:27,600 during an error in DNA replication. 210 00:09:27,600 --> 00:09:29,670 A portion of the chromosome is duplicated 211 00:09:29,670 --> 00:09:31,290 during an error in DNA replication, 212 00:09:31,290 --> 00:09:33,870 resulting in genes in that region being duplicated 213 00:09:33,870 --> 00:09:35,340 and likely misexpressed. 214 00:09:35,340 --> 00:09:36,930 So what do we mean by that? 215 00:09:36,930 --> 00:09:39,180 So if you have, let's say this particular segment, 216 00:09:39,180 --> 00:09:41,670 and as part of DNA replication, 217 00:09:41,670 --> 00:09:45,570 the DNA replication machinery accidentally duplicates this. 218 00:09:45,570 --> 00:09:49,050 So it goes over it, and it makes this particular region, 219 00:09:49,050 --> 00:09:50,280 but then it actually goes back over it, 220 00:09:50,280 --> 00:09:53,100 makes it again, that's a problem. 221 00:09:53,100 --> 00:09:54,840 Then you have twice as much 222 00:09:54,840 --> 00:09:56,970 of this particular region on the chromosome. 223 00:09:56,970 --> 00:10:00,120 And so you have these genes in this particular segment 224 00:10:00,120 --> 00:10:05,120 replicated, represented in higher copy number. 225 00:10:07,740 --> 00:10:10,470 And inversion can occur if there's, again, 226 00:10:10,470 --> 00:10:14,820 a double-stranded break on either side of a segment, 227 00:10:14,820 --> 00:10:17,910 and then when you could have it basically reattaching, 228 00:10:17,910 --> 00:10:20,340 but instead of it just totally reattaching back 229 00:10:20,340 --> 00:10:21,990 and forming the chromosome 230 00:10:21,990 --> 00:10:24,390 before it was the DNA breakage occurred, 231 00:10:24,390 --> 00:10:25,920 there's actually the piece of chromosome 232 00:10:25,920 --> 00:10:29,340 flips around 180 degrees and reattaches. 233 00:10:29,340 --> 00:10:32,370 But now the segment that was down here 234 00:10:32,370 --> 00:10:35,400 closer to the end of the q arm is now up here 235 00:10:35,400 --> 00:10:36,813 closer to the centromere. 236 00:10:37,860 --> 00:10:39,510 There are two different kinds of inversions. 237 00:10:39,510 --> 00:10:41,760 It's not really that important for you to know, 238 00:10:41,760 --> 00:10:43,440 but basically there can be an inversion 239 00:10:43,440 --> 00:10:46,050 just solely along the arm of a chromosome, 240 00:10:46,050 --> 00:10:47,310 which would be paracentric, 241 00:10:47,310 --> 00:10:50,220 which means not involving the centromere, 242 00:10:50,220 --> 00:10:52,080 or a pericentric inversion, 243 00:10:52,080 --> 00:10:55,920 which basically means an inversion between the p and q arms 244 00:10:55,920 --> 00:10:58,893 of a segment that involves the centromere. 245 00:11:01,230 --> 00:11:03,720 A translocation is interesting 246 00:11:03,720 --> 00:11:06,420 because here you basically have a double-strand break 247 00:11:06,420 --> 00:11:08,250 between two different chromosomes. 248 00:11:08,250 --> 00:11:10,260 So these are not homologous chromosomes, 249 00:11:10,260 --> 00:11:11,400 these are two different chromosomes, 250 00:11:11,400 --> 00:11:13,860 like chromosome nine and three, let's say, 251 00:11:13,860 --> 00:11:15,480 that both of those chromosomes 252 00:11:15,480 --> 00:11:17,610 each had a double-strand break occur. 253 00:11:17,610 --> 00:11:20,970 And now what happens is that instead of them reattaching 254 00:11:20,970 --> 00:11:23,010 back to their original chromosome, 255 00:11:23,010 --> 00:11:24,690 they actually get swapped around. 256 00:11:24,690 --> 00:11:28,350 So now a piece of, say, chromosome nine gets stuck 257 00:11:28,350 --> 00:11:31,470 under the bottom of chromosome three and vice versa. 258 00:11:31,470 --> 00:11:34,020 And this can be a problem because the different chromosome 259 00:11:34,020 --> 00:11:37,260 each kind of have their own signatures of gene regulation. 260 00:11:37,260 --> 00:11:40,800 So this can definitely kind of mess things up 261 00:11:40,800 --> 00:11:43,050 when we're talking about that delicate balance 262 00:11:43,050 --> 00:11:44,463 of gene expression. 263 00:11:47,700 --> 00:11:50,370 So let's talk about some of the nomenclature 264 00:11:50,370 --> 00:11:53,250 to designate some of these different types 265 00:11:53,250 --> 00:11:55,020 of chromosomal abnormalities. 266 00:11:55,020 --> 00:11:58,770 So for a deletion, it would be noted as D-E-L or Del, 267 00:11:58,770 --> 00:12:01,200 and duplication would be D-U-P or Dup, 268 00:12:01,200 --> 00:12:02,580 along with the chromosome number 269 00:12:02,580 --> 00:12:05,160 and location of the deletion or duplication 270 00:12:05,160 --> 00:12:08,010 by its arm, p or q, and its band number. 271 00:12:08,010 --> 00:12:11,490 So this would result in, let's look at a couple of examples. 272 00:12:11,490 --> 00:12:13,710 I think it's easiest just to look at a few examples. 273 00:12:13,710 --> 00:12:15,840 So if we're looking at something 274 00:12:15,840 --> 00:12:19,200 that's designated Del 17 q11.2, 275 00:12:19,200 --> 00:12:23,690 that would be a deletion on the q arm of chromosome 17 276 00:12:27,370 --> 00:12:29,640 at band location 11.2. 277 00:12:29,640 --> 00:12:34,640 So that would be region one, sub region one, band two 278 00:12:36,960 --> 00:12:38,850 along chromosome 17. 279 00:12:38,850 --> 00:12:43,380 Another example, Dup 11 q15 would be a duplication 280 00:12:43,380 --> 00:12:47,520 on the q arm of chromosome 11 at location 15. 281 00:12:47,520 --> 00:12:51,120 For translocations, these are noted as t for translocation, 282 00:12:51,120 --> 00:12:53,550 and then in parentheses, the two chromosomes 283 00:12:53,550 --> 00:12:56,010 in which the translocation has occurred between 284 00:12:56,010 --> 00:12:58,950 and then following that in parentheses, 285 00:12:58,950 --> 00:13:00,600 the locations for each of those. 286 00:13:00,600 --> 00:13:04,523 So an example of a translocation of chromosome 12 p22 287 00:13:05,970 --> 00:13:09,990 and chromosome 22 q21 will be denoted 288 00:13:09,990 --> 00:13:13,620 as t for translocation, parentheses 12 and 22, 289 00:13:13,620 --> 00:13:15,300 these are the two chromosomes 290 00:13:15,300 --> 00:13:18,960 which have participated in this translocation. 291 00:13:18,960 --> 00:13:22,200 Then you'd have q22, which would be the location 292 00:13:22,200 --> 00:13:25,380 of the first chromosome designated here 293 00:13:25,380 --> 00:13:28,110 that has been swapped with this location 294 00:13:28,110 --> 00:13:30,090 of the second chromosome. 295 00:13:30,090 --> 00:13:32,250 Chromosome 22 would be q21. 296 00:13:32,250 --> 00:13:35,130 So it would be t(12;22)(q22;q21) 297 00:13:42,780 --> 00:13:45,900 And I know it seems like a little bit like gibberish, 298 00:13:45,900 --> 00:13:48,960 but hopefully it's really just to raise your awareness 299 00:13:48,960 --> 00:13:50,430 of how to interpret these. 300 00:13:50,430 --> 00:13:51,690 It's not as though I'm expecting you 301 00:13:51,690 --> 00:13:53,070 to really memorize them, 302 00:13:53,070 --> 00:13:55,800 just to functionally understand when you look at one, 303 00:13:55,800 --> 00:13:57,240 when you look at a designation like this, 304 00:13:57,240 --> 00:13:59,940 you can start to understand what they're referring to. 305 00:14:01,042 --> 00:14:04,140 An inversion is noted as inv for inversion 306 00:14:04,140 --> 00:14:06,210 and in parentheses the chromosome number, 307 00:14:06,210 --> 00:14:08,490 and then following that, the, in parentheses, 308 00:14:08,490 --> 00:14:10,050 the location of the inversion. 309 00:14:10,050 --> 00:14:12,120 Example, an inversion on chromosome four 310 00:14:12,120 --> 00:14:15,753 between p12 and q21, which would be a pericentric inversion 311 00:14:17,760 --> 00:14:20,850 because it's crossing the p and q arm, 312 00:14:20,850 --> 00:14:23,610 so therefore, it must be crossing a centromere. 313 00:14:23,610 --> 00:14:26,700 This would be denoted as inv for inversion, 314 00:14:26,700 --> 00:14:29,340 parentheses 4 because it's on chromosome four, 315 00:14:29,340 --> 00:14:32,220 and then parentheses p12 q21 316 00:14:32,220 --> 00:14:36,007 because it is an inversion between p12 and q21. 317 00:14:37,950 --> 00:14:40,410 So let's look at some diagnosis. 318 00:14:40,410 --> 00:14:43,140 And this can occur through cytogenetic analysis. 319 00:14:43,140 --> 00:14:44,670 And a common approach for this 320 00:14:44,670 --> 00:14:47,610 is called fluorescence in situ hybridization, 321 00:14:47,610 --> 00:14:50,010 or shorthand is called FISH. 322 00:14:50,010 --> 00:14:52,200 And this stains specific regions of chromosomes 323 00:14:52,200 --> 00:14:54,510 with different colors for detection. 324 00:14:54,510 --> 00:14:56,370 Blue dye stains all the chromosomes. 325 00:14:56,370 --> 00:14:58,920 So all that you're seeing here that's blue, 326 00:14:58,920 --> 00:15:01,170 that's just a general dye for any chromosomes. 327 00:15:01,170 --> 00:15:05,793 The green dots in this particular FISH, 328 00:15:06,750 --> 00:15:10,410 the green dots mark the ends of chromosome 22. 329 00:15:10,410 --> 00:15:15,210 And the red dots mark the q11.2 region on chromosome 22. 330 00:15:15,210 --> 00:15:17,430 And the reason why they would be looking for this 331 00:15:17,430 --> 00:15:21,480 is a common chromosomal abnormality 332 00:15:21,480 --> 00:15:26,480 is chromosome 22, a deletion of the q11.2 band. 333 00:15:26,580 --> 00:15:28,620 And here you can actually see a patient 334 00:15:28,620 --> 00:15:29,760 where that's the case. 335 00:15:29,760 --> 00:15:33,210 So what we're looking at is this particular chromosome 336 00:15:33,210 --> 00:15:35,037 and this chromosome are both chromosome 22, 337 00:15:35,037 --> 00:15:38,280 and we know that because they each have the green dots, 338 00:15:38,280 --> 00:15:39,690 and the green dots represent 339 00:15:39,690 --> 00:15:41,910 basically anywhere on chromosome 22. 340 00:15:41,910 --> 00:15:44,070 So it represents the end of chromosome 22. 341 00:15:44,070 --> 00:15:46,380 So we know these are both chromosome 22, 342 00:15:46,380 --> 00:15:48,960 and then the red or this pinkish color 343 00:15:48,960 --> 00:15:53,960 is going to be where the q11.2 band would be. 344 00:15:56,340 --> 00:15:59,280 So you can see it just fine on this chromosome 22, 345 00:15:59,280 --> 00:16:02,460 but on this chromosome 22, there's no red dot. 346 00:16:02,460 --> 00:16:03,780 And that basically is telling us 347 00:16:03,780 --> 00:16:07,860 that this patient has a deletion of the q11.2, 348 00:16:07,860 --> 00:16:10,920 and this person would have a diagnosis 349 00:16:10,920 --> 00:16:15,513 of the 22 q11.2 deletion syndrome. 350 00:16:17,610 --> 00:16:20,730 Here's another example of a cytogenetic analysis 351 00:16:20,730 --> 00:16:25,680 and being able to diagnose another chromosomal abnormality. 352 00:16:25,680 --> 00:16:27,990 In this case, it's a translocation. 353 00:16:27,990 --> 00:16:32,340 This happens more so in diagnosis of tumors, 354 00:16:32,340 --> 00:16:36,600 so might happen specifically in certain cells in the body 355 00:16:36,600 --> 00:16:38,580 in which a cancer will develop 356 00:16:38,580 --> 00:16:41,463 as opposed to it happening from birth. 357 00:16:42,870 --> 00:16:44,873 So each chromosome in what we're looking at here, 358 00:16:44,873 --> 00:16:46,560 this is a little bit different, 359 00:16:46,560 --> 00:16:49,080 each chromosome is stained with a different color 360 00:16:49,080 --> 00:16:51,360 to make it easy to see translocation, 361 00:16:51,360 --> 00:16:53,070 so a piece of one chromosome 362 00:16:53,070 --> 00:16:55,670 being stuck on another chromosome and vice versa. 363 00:16:55,670 --> 00:17:00,270 In this case, the end of q arm of chromosome nine 364 00:17:00,270 --> 00:17:04,770 is translocated with the end of the q arm of chromosome 22. 365 00:17:04,770 --> 00:17:07,800 This resulted in a patient developing lymphoma. 366 00:17:07,800 --> 00:17:10,560 So here you can see this chromosome nine 367 00:17:10,560 --> 00:17:12,690 should be this darker red color. 368 00:17:12,690 --> 00:17:15,390 And chromosome 22 is this lighter pink color. 369 00:17:15,390 --> 00:17:17,070 And what you can see is that there's a little piece 370 00:17:17,070 --> 00:17:20,220 of pink chromosome on the end of chromosome nine 371 00:17:20,220 --> 00:17:22,560 and that the chunk of chromosome nine that's missing 372 00:17:22,560 --> 00:17:25,740 is actually now on chromosome 22 and vice versa. 373 00:17:25,740 --> 00:17:28,233 So here we have a translocation. 374 00:17:31,830 --> 00:17:35,940 All right, so let's switch gears just for a moment here. 375 00:17:35,940 --> 00:17:38,190 And I want to mention the importance 376 00:17:38,190 --> 00:17:42,000 of a particular genetic phenomenon that occurs. 377 00:17:42,000 --> 00:17:45,960 And the reason being it can actually significantly influence 378 00:17:45,960 --> 00:17:50,430 the outcome of patients, depending upon the parent 379 00:17:50,430 --> 00:17:53,850 who contributed one of these types 380 00:17:53,850 --> 00:17:56,040 of chromosomal abnormalities. 381 00:17:56,040 --> 00:17:58,890 This is called imprinting, imprinting. 382 00:17:58,890 --> 00:18:00,840 Imprinted genes are genes expressed 383 00:18:00,840 --> 00:18:03,360 only from one of the two homologous chromosomes, 384 00:18:03,360 --> 00:18:05,610 either the maternal or paternal. 385 00:18:05,610 --> 00:18:09,360 Only a few hundred of our 25,000 genes are imprinted. 386 00:18:09,360 --> 00:18:11,160 The parental copy that is silenced 387 00:18:11,160 --> 00:18:13,110 is methylated in the fertilized egg 388 00:18:13,110 --> 00:18:16,050 and remains methylated and shut off forever. 389 00:18:16,050 --> 00:18:18,570 So what do we mean by this? 390 00:18:18,570 --> 00:18:21,720 Basically what we're saying is that in certain genes, 391 00:18:21,720 --> 00:18:25,410 only, let's say the paternal copy is ever expressed, 392 00:18:25,410 --> 00:18:27,600 and the maternal copy is permanently shut off, 393 00:18:27,600 --> 00:18:30,660 and in other genes, only the maternal copy is ever expressed 394 00:18:30,660 --> 00:18:32,760 and the paternal copy is shut off. 395 00:18:32,760 --> 00:18:36,510 So only the copy of the gene 396 00:18:36,510 --> 00:18:38,400 that you got from your mom might be expressed, 397 00:18:38,400 --> 00:18:40,590 or the copy that you got from your dad might be expressed, 398 00:18:40,590 --> 00:18:44,100 and the other one would be shut off by being methylated. 399 00:18:44,100 --> 00:18:46,950 Most imprinted genes are related to growth and metabolism. 400 00:18:46,950 --> 00:18:48,300 And why would that be? 401 00:18:48,300 --> 00:18:49,133 Well, it's actually 402 00:18:49,133 --> 00:18:51,210 kind of an interesting evolutionary story. 403 00:18:51,210 --> 00:18:54,360 It's part of the battle of the sexes for maternal resources 404 00:18:54,360 --> 00:18:56,580 for the man's baby. 405 00:18:56,580 --> 00:18:58,380 So let's think about this for a minute. 406 00:18:58,380 --> 00:19:01,890 Paternal imprinted genes, genes that are only expressed 407 00:19:01,890 --> 00:19:03,870 from the copy received from the father, 408 00:19:03,870 --> 00:19:08,130 generally promote big babies, big baby. 409 00:19:08,130 --> 00:19:11,460 So why would the father wanna have a big baby? 410 00:19:11,460 --> 00:19:14,010 Well, in part it's because he wants to make sure 411 00:19:14,010 --> 00:19:17,370 his offspring have all of the resources of the mother. 412 00:19:17,370 --> 00:19:20,040 And the mother, on the other hand, wants to balance this. 413 00:19:20,040 --> 00:19:21,600 So maternal imprinted genes, 414 00:19:21,600 --> 00:19:24,570 genes only expressed from the copy received from the mother, 415 00:19:24,570 --> 00:19:27,030 generally promote normal sized babies. 416 00:19:27,030 --> 00:19:29,760 Why would she want to have a normal sized baby? 417 00:19:29,760 --> 00:19:33,450 Well, in part because it conveys less harm to the mother 418 00:19:33,450 --> 00:19:35,580 to have a normal sized baby, 419 00:19:35,580 --> 00:19:38,610 and it also allows her to provide her resources 420 00:19:38,610 --> 00:19:41,460 to her other children instead of just the one child 421 00:19:41,460 --> 00:19:43,830 from this particular father. 422 00:19:43,830 --> 00:19:47,490 So the father is really trying to promote the passing on 423 00:19:47,490 --> 00:19:50,160 of his genes ahead of others 424 00:19:50,160 --> 00:19:52,560 because, and in doing that, 425 00:19:52,560 --> 00:19:54,480 he's doing that, basically, by trying to ensure 426 00:19:54,480 --> 00:19:57,510 his baby's going to be the biggest and the strongest. 427 00:19:57,510 --> 00:19:59,913 So we have, as a result of this, 428 00:19:59,913 --> 00:20:02,880 this crazy battle of the sexes has been waged 429 00:20:02,880 --> 00:20:05,700 in species long before there were actually humans, 430 00:20:05,700 --> 00:20:09,090 that as a result of this, we have a subset of genes, 431 00:20:09,090 --> 00:20:10,890 again, not all of them, not by long shot, 432 00:20:10,890 --> 00:20:14,040 only a few hundred over 25,000 genes 433 00:20:14,040 --> 00:20:17,670 are regulated in this way, 434 00:20:17,670 --> 00:20:20,880 that only one copy, either the mother's copy 435 00:20:20,880 --> 00:20:23,250 or the father's copy, depending on the gene, 436 00:20:23,250 --> 00:20:26,070 would be expressed and the other one would be shut off. 437 00:20:26,070 --> 00:20:28,320 So why do we care about this? 438 00:20:28,320 --> 00:20:31,710 Basically, there can be differences in the outcome, 439 00:20:31,710 --> 00:20:34,980 depending upon whether the chromosomal abnormality 440 00:20:34,980 --> 00:20:37,443 was inherited from the mother or the father. 441 00:20:38,430 --> 00:20:39,930 And let's look an example of this. 442 00:20:39,930 --> 00:20:41,610 We'll take a peek at a couple 443 00:20:41,610 --> 00:20:43,830 of different chromosomal abnormalities here. 444 00:20:43,830 --> 00:20:46,140 And the first couple we'll look at 445 00:20:46,140 --> 00:20:48,660 actually involve regions of a chromosome 446 00:20:48,660 --> 00:20:50,130 which contain imprinted genes, 447 00:20:50,130 --> 00:20:53,370 and as a result, it matters whether the, as a result, 448 00:20:53,370 --> 00:20:58,370 the actual symptoms related to the disorder 449 00:20:58,980 --> 00:20:59,813 are very different 450 00:20:59,813 --> 00:21:01,350 depending upon whether they're inherited 451 00:21:01,350 --> 00:21:02,490 from the mother or the father. 452 00:21:02,490 --> 00:21:03,930 And they're so different 453 00:21:03,930 --> 00:21:06,780 that they're actually called two different names 454 00:21:06,780 --> 00:21:08,670 for the different syndromes, 455 00:21:08,670 --> 00:21:10,860 the first being Angelman syndrome. 456 00:21:10,860 --> 00:21:15,860 This is a deletion of chromosome 15 on the q arm in band 12, 457 00:21:16,710 --> 00:21:19,530 and Angelman syndrome only happens, 458 00:21:19,530 --> 00:21:21,720 Angelman syndrome only happens if this deletion 459 00:21:21,720 --> 00:21:24,660 was inherited from the mother. 460 00:21:24,660 --> 00:21:28,020 It occurs in one in 12,000 to 20,000 live births, 461 00:21:28,020 --> 00:21:30,000 and it primarily affects the nervous system 462 00:21:30,000 --> 00:21:32,700 with characteristic features of delayed development, 463 00:21:32,700 --> 00:21:34,200 intellectual disability, 464 00:21:34,200 --> 00:21:37,140 severe speech impairment and ataxia. 465 00:21:37,140 --> 00:21:40,500 Most affected children also have epilepsy and microcephaly. 466 00:21:40,500 --> 00:21:43,080 Delayed development becomes noticeable 467 00:21:43,080 --> 00:21:44,730 by the age of six to 12 months. 468 00:21:44,730 --> 00:21:46,560 And other common signs and symptoms 469 00:21:46,560 --> 00:21:48,570 usually appear in early childhood. 470 00:21:48,570 --> 00:21:50,910 Children typically have a happy excitable demeanor 471 00:21:50,910 --> 00:21:54,330 with frequent smiling laughter and hand flapping movements. 472 00:21:54,330 --> 00:21:56,040 It's also associated with hyperactivity, 473 00:21:56,040 --> 00:21:59,490 a short attention span and a fascination with water. 474 00:21:59,490 --> 00:22:02,040 Most affected children also have difficulty sleeping 475 00:22:02,040 --> 00:22:03,630 and need less sleep than usual. 476 00:22:03,630 --> 00:22:07,440 Here are a few pictures of a couple of individuals 477 00:22:07,440 --> 00:22:09,210 with Angelman syndrome. 478 00:22:09,210 --> 00:22:11,610 So remember, this is a deletion 479 00:22:11,610 --> 00:22:13,800 in a portion of chromosome 15 480 00:22:13,800 --> 00:22:16,500 if it was inherited from the mother. 481 00:22:16,500 --> 00:22:19,680 If, on the other hand, this very same deletion 482 00:22:19,680 --> 00:22:23,370 was inherited from the father, from the father, 483 00:22:23,370 --> 00:22:28,370 it will result in a child having Prader-Willi syndrome. 484 00:22:28,710 --> 00:22:32,400 This occurs in about one to 10,000 to 30,000 live births, 485 00:22:32,400 --> 00:22:33,870 and in infancy, it's characterized 486 00:22:33,870 --> 00:22:35,970 by hypotonia, feeding difficulties, 487 00:22:35,970 --> 00:22:38,130 poor growth and delayed development. 488 00:22:38,130 --> 00:22:40,200 Beginning in childhood, affected individuals 489 00:22:40,200 --> 00:22:41,910 develop an insatiable appetite 490 00:22:41,910 --> 00:22:44,820 which leads to chronic overeating and obesity. 491 00:22:44,820 --> 00:22:48,570 Some also develop type 2 diabetes as a result. 492 00:22:48,570 --> 00:22:51,060 Associated with mild to moderate intellectual impairment 493 00:22:51,060 --> 00:22:53,910 and learning disabilities, behavioral problems are common, 494 00:22:53,910 --> 00:22:55,680 including temper outbursts, stubbornness 495 00:22:55,680 --> 00:22:59,040 and compulsive behavior such as picking at the skin. 496 00:22:59,040 --> 00:23:00,510 Additional features of this condition 497 00:23:00,510 --> 00:23:03,660 include distinctive facial features such as narrow forehead, 498 00:23:03,660 --> 00:23:05,790 almond-shaped eyes and a triangular mouth, 499 00:23:05,790 --> 00:23:08,160 short stature and small hands and feet. 500 00:23:08,160 --> 00:23:09,780 Both affected males and females 501 00:23:09,780 --> 00:23:11,190 have underdeveloped genitals. 502 00:23:11,190 --> 00:23:13,050 Puberty is delayed or incomplete, 503 00:23:13,050 --> 00:23:15,690 and most affected individuals are infertile. 504 00:23:15,690 --> 00:23:17,850 So remember, there are two different syndromes 505 00:23:17,850 --> 00:23:19,650 that can come from the very same deletion. 506 00:23:19,650 --> 00:23:21,420 It just depends upon whether it was inherited 507 00:23:21,420 --> 00:23:23,070 from mom or from dad. 508 00:23:23,070 --> 00:23:25,110 So you can have Angelman syndrome 509 00:23:25,110 --> 00:23:27,510 in males and females, right, 510 00:23:27,510 --> 00:23:30,300 but it was just in Angelman syndrome 511 00:23:30,300 --> 00:23:34,530 the deletion was inherited from the mom's copy. 512 00:23:34,530 --> 00:23:37,950 And in Prader-Willi syndrome, the very same deletion 513 00:23:37,950 --> 00:23:39,300 was inherited from the father, 514 00:23:39,300 --> 00:23:42,240 but it gives very different clinical manifestations. 515 00:23:42,240 --> 00:23:44,310 And so imprinting can have a big impact 516 00:23:44,310 --> 00:23:49,310 on the clinical manifestations of a chromosomal abnormality. 517 00:23:51,750 --> 00:23:55,830 This is the 22q11.2 deletion syndrome 518 00:23:55,830 --> 00:23:59,597 that I mentioned and showed you the fluorescence 519 00:23:59,597 --> 00:24:02,340 and C2 hybridization for, with the, you know, 520 00:24:02,340 --> 00:24:04,290 the green dots and the red dots. 521 00:24:04,290 --> 00:24:06,630 This is also commonly called VCFS 522 00:24:06,630 --> 00:24:08,605 or sometimes called DiGeorge syndrome. 523 00:24:08,605 --> 00:24:09,990 There's actually a number of different names 524 00:24:09,990 --> 00:24:14,010 for the very same condition. 525 00:24:14,010 --> 00:24:17,550 It's a, again, a deletion within chromosome 22 526 00:24:17,550 --> 00:24:19,680 of the q11 portion. 527 00:24:19,680 --> 00:24:22,320 It occurs in about one in 4,000 live births, 528 00:24:22,320 --> 00:24:23,820 and the features vary widely. 529 00:24:23,820 --> 00:24:26,200 Common signs include heart abnormalities 530 00:24:27,510 --> 00:24:29,850 that are often present from birth, cleft palate 531 00:24:29,850 --> 00:24:31,260 and distinctive facial features. 532 00:24:31,260 --> 00:24:34,830 You can sort of see between these two individuals 533 00:24:34,830 --> 00:24:38,520 who have 22q11 deletion syndrome, 534 00:24:38,520 --> 00:24:40,230 you can start to see some similarities 535 00:24:40,230 --> 00:24:45,230 in slightly wider set eyes, similar nose and mouth shape 536 00:24:46,200 --> 00:24:49,263 and smaller and low-set ears. 537 00:24:50,910 --> 00:24:52,530 It often causes recurrent infections 538 00:24:52,530 --> 00:24:54,060 caused by problems with the immune system, 539 00:24:54,060 --> 00:24:57,150 and affected individuals may also have breathing problems, 540 00:24:57,150 --> 00:25:00,510 kidney abnormalities, low levels of calcium in the blood, 541 00:25:00,510 --> 00:25:03,480 thrombocytopenia, significant feeding difficulties, 542 00:25:03,480 --> 00:25:05,970 gastrointestinal problems and hearing loss. 543 00:25:05,970 --> 00:25:07,650 Children may have developmental delays 544 00:25:07,650 --> 00:25:09,600 including delayed growth and speech development 545 00:25:09,600 --> 00:25:10,770 and learning disabilities. 546 00:25:10,770 --> 00:25:13,680 And later in life, they're at increased risk 547 00:25:13,680 --> 00:25:16,350 of developing mental illness such as schizophrenia, 548 00:25:16,350 --> 00:25:19,860 depression, anxiety and bipolar disorder. 549 00:25:19,860 --> 00:25:22,980 Beckwith Wiedemann syndrome is a duplication 550 00:25:22,980 --> 00:25:26,550 in chromosome 11 on the q15 band. 551 00:25:26,550 --> 00:25:29,790 And this only comes from the paternal inheritance, 552 00:25:29,790 --> 00:25:34,590 so only if the individual inherited this from their father. 553 00:25:34,590 --> 00:25:36,630 Occurs in one in 12,000 live births, 554 00:25:36,630 --> 00:25:39,180 and it results in an overgrowth syndrome, 555 00:25:39,180 --> 00:25:42,260 with macrosomia and continued growth 556 00:25:42,260 --> 00:25:44,880 at an unusual rate during childhood. 557 00:25:44,880 --> 00:25:46,410 Growth slows by age eight, 558 00:25:46,410 --> 00:25:49,260 and adults with this condition are not unusually tall. 559 00:25:49,260 --> 00:25:51,960 May be born with an opening in the wall of the abdomen 560 00:25:51,960 --> 00:25:53,730 that allows the abdominal organs 561 00:25:53,730 --> 00:25:55,200 to protrude through the navel. 562 00:25:55,200 --> 00:25:58,020 Most infants have an abnormally large tongue, 563 00:25:58,020 --> 00:25:59,880 abnormally large abdominal organs, 564 00:25:59,880 --> 00:26:02,070 creases or pits in the skin near the ears, 565 00:26:02,070 --> 00:26:04,830 hypoglycemia and kidney abnormalities. 566 00:26:04,830 --> 00:26:07,530 Increased risk of developing several types of cancerous 567 00:26:07,530 --> 00:26:08,730 and non-cancerous tumors, 568 00:26:08,730 --> 00:26:11,790 and this is, again, related to the overgrowth condition. 569 00:26:11,790 --> 00:26:14,340 Tumors develop in about 10% of people with this condition 570 00:26:14,340 --> 00:26:16,260 and almost always appear in childhood. 571 00:26:16,260 --> 00:26:19,260 About one in five infants dies early in life. 572 00:26:19,260 --> 00:26:21,810 So why this, I think this is a good example 573 00:26:21,810 --> 00:26:24,180 of that battle of the sexes that I mentioned, 574 00:26:24,180 --> 00:26:26,100 with imprinting being related 575 00:26:26,100 --> 00:26:31,100 primarily to genes which regulate growth. 576 00:26:31,260 --> 00:26:34,980 So here, this is inherited from the father 577 00:26:34,980 --> 00:26:38,100 if there's a duplication of this particular region 578 00:26:38,100 --> 00:26:40,110 of the chromosome from the father. 579 00:26:40,110 --> 00:26:41,940 Basically, this is what would happen 580 00:26:41,940 --> 00:26:44,040 if you didn't have the female balance 581 00:26:44,040 --> 00:26:45,600 to the male contribution. 582 00:26:45,600 --> 00:26:46,717 Male contributions being, 583 00:26:46,717 --> 00:26:49,080 "I want a really, I want a big baby." 584 00:26:49,080 --> 00:26:50,670 And the female saying, "Well, we need 585 00:26:50,670 --> 00:26:53,160 to dial that back a little bit." 586 00:26:53,160 --> 00:26:55,980 Unfortunately, if there is an abnormality, 587 00:26:55,980 --> 00:26:58,923 say a duplication in the father's copy, 588 00:27:01,229 --> 00:27:02,820 then the genes that he's contributed 589 00:27:02,820 --> 00:27:04,740 will be overexpressed 590 00:27:04,740 --> 00:27:07,860 relative to the maternally contributed genes 591 00:27:07,860 --> 00:27:10,380 and will result in overgrowth conditions 592 00:27:10,380 --> 00:27:12,753 such as Beckwith-Wiedemann syndrome. 593 00:27:14,520 --> 00:27:16,710 So what about the risks of chromosomal abnormalities? 594 00:27:16,710 --> 00:27:17,820 Well, these are very similar 595 00:27:17,820 --> 00:27:20,010 to the risks associated with aneuploidy. 596 00:27:20,010 --> 00:27:22,260 Advanced maternal age is a significant risk, 597 00:27:22,260 --> 00:27:24,870 especially over the age of 45. 598 00:27:24,870 --> 00:27:26,700 And it's very similar to what we talked about 599 00:27:26,700 --> 00:27:29,310 before with aneuploidy. 600 00:27:29,310 --> 00:27:32,880 It's just an accumulation of damage 601 00:27:32,880 --> 00:27:34,350 to the cells over time 602 00:27:34,350 --> 00:27:36,390 and specifically damage to the DNA, 603 00:27:36,390 --> 00:27:39,930 which can result in increased breakage. 604 00:27:39,930 --> 00:27:41,820 Similarly, exposure to toxins 605 00:27:41,820 --> 00:27:44,820 and carcinogens prior to conception can lead to DNA breakage 606 00:27:44,820 --> 00:27:46,950 in either sperm or egg. 607 00:27:46,950 --> 00:27:49,470 Previous chromosomal abnormality, birth 608 00:27:49,470 --> 00:27:51,870 or spontaneous abortions may indicate 609 00:27:51,870 --> 00:27:54,510 a parent has chromosomal abnormality in the germline, 610 00:27:54,510 --> 00:27:57,360 so in cells which are precursors to egg and sperm. 611 00:27:57,360 --> 00:27:59,970 So, in basically all of their egg 612 00:27:59,970 --> 00:28:01,680 or sperm that they produce, 613 00:28:01,680 --> 00:28:04,803 this chromosomal abnormality may exist. 614 00:28:06,120 --> 00:28:08,070 So let's do a quick summary here. 615 00:28:08,070 --> 00:28:10,980 Chromosomes must have their genes in the right locations 616 00:28:10,980 --> 00:28:12,930 and right numbers for proper gene expression. 617 00:28:12,930 --> 00:28:14,880 I keep hammering you over the head with this, 618 00:28:14,880 --> 00:28:17,460 and I apologize, but it's actually very, very important 619 00:28:17,460 --> 00:28:19,020 that you understand this. 620 00:28:19,020 --> 00:28:21,660 It's not even that there's necessarily a specific problem 621 00:28:21,660 --> 00:28:23,430 in the sequence of the genes. 622 00:28:23,430 --> 00:28:25,680 It's just that there are too many or too few of them 623 00:28:25,680 --> 00:28:28,680 that can result in significant health problems. 624 00:28:28,680 --> 00:28:31,470 DNA damage can result in chromosomes with deletions, 625 00:28:31,470 --> 00:28:34,260 duplications, inversions or translocations, 626 00:28:34,260 --> 00:28:36,660 all of which can lead to health issues. 627 00:28:36,660 --> 00:28:39,210 Certain genes are only expressed from the maternal 628 00:28:39,210 --> 00:28:40,043 or paternal chromosomes, 629 00:28:40,043 --> 00:28:41,973 and these are called imprinted genes. 630 00:28:44,100 --> 00:28:47,190 So outcomes may vary with the same chromosomal abnormality, 631 00:28:47,190 --> 00:28:48,600 depending on whether it was inherited 632 00:28:48,600 --> 00:28:49,740 from the mother or father. 633 00:28:49,740 --> 00:28:53,820 Think of the Angelman syndrome and Prader-Willi syndrome, 634 00:28:53,820 --> 00:28:56,580 same chromosomal abnormality, different outcomes 635 00:28:56,580 --> 00:28:59,550 depending on whether it was inherited from mom or dad. 636 00:28:59,550 --> 00:29:01,650 Chromosomal abnormalities generally result 637 00:29:01,650 --> 00:29:03,240 in a wide range of symptoms, 638 00:29:03,240 --> 00:29:05,310 and the risks for chromosomal abnormalities 639 00:29:05,310 --> 00:29:07,110 are similar to risks for aneuploidy. 640 00:29:08,190 --> 00:29:10,080 All right, so what's next in this module? 641 00:29:10,080 --> 00:29:12,720 We'll finish it off with a rather brief discussion 642 00:29:12,720 --> 00:29:15,060 on the concept of mosaicism. 643 00:29:15,060 --> 00:29:17,790 So I will talk with you in the next lecture. 644 00:29:17,790 --> 00:29:20,670 I look forward to hearing your thoughts 645 00:29:20,670 --> 00:29:23,550 and any comments that you might have about this lecture 646 00:29:23,550 --> 00:29:25,350 or anything else in this module. 647 00:29:25,350 --> 00:29:26,673 I will talk with you soon.