1 00:00:00,270 --> 00:00:03,630 [Lecturer] Hello, all right, well, in this module, 2 00:00:03,630 --> 00:00:06,390 as you heard from the intro video, 3 00:00:06,390 --> 00:00:10,947 we are going to take some time to review Modules 2-5 4 00:00:12,390 --> 00:00:15,840 so that we make sure we are all clear on those concepts 5 00:00:15,840 --> 00:00:20,490 before the midterm take home exam is given out 6 00:00:20,490 --> 00:00:24,000 and also before we move on to topics 7 00:00:24,000 --> 00:00:25,170 that build on what you've learned 8 00:00:25,170 --> 00:00:28,713 in these first five modules. 9 00:00:29,820 --> 00:00:31,380 So what we really need, right? 10 00:00:31,380 --> 00:00:34,290 It's like after you've eaten a big Thanksgiving dinner, 11 00:00:34,290 --> 00:00:36,402 you just need some time to digest. 12 00:00:36,402 --> 00:00:38,460 I've given you a lot of information 13 00:00:38,460 --> 00:00:41,370 and you have learned an extraordinary amount 14 00:00:41,370 --> 00:00:45,390 and over a relatively short period of time 15 00:00:45,390 --> 00:00:50,390 and I think it is beneficial to our comprehension 16 00:00:52,290 --> 00:00:55,260 and to, again, to ensure that we have 17 00:00:55,260 --> 00:00:58,400 all of these main concepts down before we move on. 18 00:00:58,400 --> 00:01:01,830 It just take some time to digest, let things sink in, 19 00:01:01,830 --> 00:01:04,590 maybe go back over them again even if you think 20 00:01:04,590 --> 00:01:07,083 you've got it, go back over again just to make sure. 21 00:01:07,083 --> 00:01:09,510 You may see something in a different light than you did 22 00:01:09,510 --> 00:01:11,430 the first time you went over it 23 00:01:11,430 --> 00:01:13,860 now that you have more knowledge 24 00:01:13,860 --> 00:01:15,990 and more experience with this, going back and looking 25 00:01:15,990 --> 00:01:18,150 at some of that earlier material might help it to fit 26 00:01:18,150 --> 00:01:19,700 into place a little bit better. 27 00:01:20,790 --> 00:01:23,100 So what I'm going to do here in these slides 28 00:01:23,100 --> 00:01:27,990 is I've pulled some images from some figures 29 00:01:27,990 --> 00:01:30,630 from some of the past slides 30 00:01:30,630 --> 00:01:33,930 or like a greatest hits (laughs) highlight reel, 31 00:01:33,930 --> 00:01:36,390 if you will, of past lectures 32 00:01:36,390 --> 00:01:38,880 and there aren't very many words on these slides 33 00:01:38,880 --> 00:01:41,460 because I'm primarily just going to talk through them 34 00:01:41,460 --> 00:01:43,890 and I would encourage you to, you know, 35 00:01:43,890 --> 00:01:46,980 if you're interested in getting some of the details 36 00:01:46,980 --> 00:01:49,320 around these concepts again, 37 00:01:49,320 --> 00:01:52,980 go back to the PowerPoint slides 38 00:01:52,980 --> 00:01:55,980 for each of those separate lectures 39 00:01:55,980 --> 00:01:59,070 and each of those modules and revisit those 40 00:01:59,070 --> 00:02:00,870 because all the details are there. 41 00:02:00,870 --> 00:02:02,460 Whether it's just in the PowerPoint slide 42 00:02:02,460 --> 00:02:04,890 or if you go back and listen to the lectures again, 43 00:02:04,890 --> 00:02:06,480 either way, you'll get that information. 44 00:02:06,480 --> 00:02:10,350 This is just a review of, as I said, 45 00:02:10,350 --> 00:02:13,233 some of the highlights of what we've covered. 46 00:02:14,820 --> 00:02:17,310 So let's start back at Module 2 47 00:02:17,310 --> 00:02:19,950 where we all began with the cell. 48 00:02:19,950 --> 00:02:24,104 Remember our first look at the cell, basic cell anatomy, 49 00:02:24,104 --> 00:02:26,640 this image here on the left, 50 00:02:26,640 --> 00:02:30,390 and this is just to show you, reminder that, you know, 51 00:02:30,390 --> 00:02:32,490 we're made up of about 50 trillion cells, 52 00:02:32,490 --> 00:02:35,070 each one of these looks a bit different, you know, 53 00:02:35,070 --> 00:02:37,710 one from another and they may have different functions 54 00:02:37,710 --> 00:02:40,680 and exist in different areas of the body, 55 00:02:40,680 --> 00:02:43,320 but generally, they all have a plasma membrane, 56 00:02:43,320 --> 00:02:45,540 which is that outer shell, 57 00:02:45,540 --> 00:02:47,730 and then on the inside, you have cytoplasm, 58 00:02:47,730 --> 00:02:51,000 which is sort of the goo inside of the cell 59 00:02:51,000 --> 00:02:52,320 where you have proteins, 60 00:02:52,320 --> 00:02:55,470 you have all sorts of things kind of moving around 61 00:02:55,470 --> 00:02:59,280 and you have individual what are called organelles 62 00:02:59,280 --> 00:03:01,350 or these separate structures that you see here. 63 00:03:01,350 --> 00:03:02,940 It's not really important that you know 64 00:03:02,940 --> 00:03:04,980 what each of those does, just that they do have 65 00:03:04,980 --> 00:03:09,960 individual functions, and you can see in the center there 66 00:03:09,960 --> 00:03:11,190 the nucleus. 67 00:03:11,190 --> 00:03:13,170 That's important, as we talked about... 68 00:03:13,170 --> 00:03:17,953 That has its own separate membrane to protect the DNA 69 00:03:19,560 --> 00:03:23,100 from any potential damage. 70 00:03:23,100 --> 00:03:25,800 It also helps to kind of keep it in one location. 71 00:03:25,800 --> 00:03:28,260 The exception to this, of course, is during mitosis 72 00:03:28,260 --> 00:03:31,020 when in a very short period of time 73 00:03:31,020 --> 00:03:33,510 during mitosis when the DNA... 74 00:03:33,510 --> 00:03:35,010 When your chromosomes are actually separating 75 00:03:35,010 --> 00:03:35,970 from one another. 76 00:03:35,970 --> 00:03:38,550 In order to allow that to happen and form two new cells, 77 00:03:38,550 --> 00:03:41,730 the nuclear membrane has to actually dissolve 78 00:03:41,730 --> 00:03:44,400 and then it will reform two nuclear membranes 79 00:03:44,400 --> 00:03:49,290 around each set of the genomes so that way, 80 00:03:49,290 --> 00:03:51,810 each cell has one set of... 81 00:03:51,810 --> 00:03:53,673 One complete set of DNA. 82 00:03:54,900 --> 00:03:56,490 So that's the basic cell anatomy, 83 00:03:56,490 --> 00:03:58,200 and then also remember, as I said, you know, 84 00:03:58,200 --> 00:04:00,540 you have many different types of cells 85 00:04:00,540 --> 00:04:02,820 that perform specific functions 86 00:04:02,820 --> 00:04:05,130 and that's a product of cell differentiation. 87 00:04:05,130 --> 00:04:07,710 As you can see down there, there's a few examples 88 00:04:07,710 --> 00:04:10,710 of what types of cells come from the mesoderm 89 00:04:10,710 --> 00:04:14,170 and the endoderm from early stages of development 90 00:04:15,344 --> 00:04:18,930 of an embryo and that would include cells, you know, 91 00:04:18,930 --> 00:04:23,930 you have muscle cells, blood cells, kidney cells, 92 00:04:24,240 --> 00:04:26,430 thyroid cells, pancreatic cells, all sorts 93 00:04:26,430 --> 00:04:28,260 of different cells that look different 94 00:04:28,260 --> 00:04:30,240 from one another form different functions. 95 00:04:30,240 --> 00:04:32,490 However, they all actually have, as you remember, 96 00:04:32,490 --> 00:04:34,500 they all have the same genetic material, 97 00:04:34,500 --> 00:04:36,600 they all have the same genome. 98 00:04:36,600 --> 00:04:38,580 Yet they perform very different functions 99 00:04:38,580 --> 00:04:39,810 and look very different from one another, 100 00:04:39,810 --> 00:04:41,490 so how does that happen? 101 00:04:41,490 --> 00:04:45,780 Well, it ties into what we learned in a different module, 102 00:04:45,780 --> 00:04:48,000 which has to do with gene expression. 103 00:04:48,000 --> 00:04:50,820 So which genes are on, which genes are off, 104 00:04:50,820 --> 00:04:52,650 and for the ones that are on, 105 00:04:52,650 --> 00:04:54,750 to what extent they're on, remember that? 106 00:04:54,750 --> 00:04:58,320 So all that regulation from transcription factors 107 00:04:58,320 --> 00:05:01,020 and other factors that play a role 108 00:05:01,020 --> 00:05:04,410 in determining the expression of a specific subset of genes, 109 00:05:04,410 --> 00:05:06,780 how these can be different from... 110 00:05:06,780 --> 00:05:09,273 In one cell type to another cell type. 111 00:05:11,280 --> 00:05:14,400 Now, taking a peek at the structure of DNA, 112 00:05:14,400 --> 00:05:17,250 looking first on the left here, as you remember, 113 00:05:17,250 --> 00:05:20,760 the molecular structure of DNA, it's two strands, 114 00:05:20,760 --> 00:05:25,760 and you can see there's the deoxyribose sugar backbone, 115 00:05:25,920 --> 00:05:27,630 the sugar phosphate backbone, 116 00:05:27,630 --> 00:05:29,520 the sugars are connected by phosphates 117 00:05:29,520 --> 00:05:31,560 and that provides the backbone... 118 00:05:31,560 --> 00:05:33,870 That's homogenous, you know, that's the same 119 00:05:33,870 --> 00:05:37,230 all the way through each strand. 120 00:05:37,230 --> 00:05:39,003 The different part is the part that you... 121 00:05:39,003 --> 00:05:42,810 That picture here in the middle, which is the actual bases, 122 00:05:42,810 --> 00:05:46,140 so that's the A, T, G, or C. 123 00:05:46,140 --> 00:05:47,880 Remember there's complementarity. 124 00:05:47,880 --> 00:05:49,740 So A and T bind together, 125 00:05:49,740 --> 00:05:51,990 A and T have hydrogen bonds together 126 00:05:51,990 --> 00:05:53,670 across those two strands, 127 00:05:53,670 --> 00:05:58,440 and G and C bond together, they have three hydrogen bonds 128 00:05:58,440 --> 00:06:01,140 across the double strands and that's what holds 129 00:06:01,140 --> 00:06:04,920 those two strands together, is the complementarity 130 00:06:04,920 --> 00:06:07,530 and the binding, the hydrogen bonding, 131 00:06:07,530 --> 00:06:12,530 between complementary bases across the way there. 132 00:06:12,900 --> 00:06:15,030 So these are your nucleotides, 133 00:06:15,030 --> 00:06:17,070 as you can see outlined in red there, 134 00:06:17,070 --> 00:06:19,320 that would be a single nucleotide, 135 00:06:19,320 --> 00:06:20,700 which would include the base 136 00:06:20,700 --> 00:06:24,300 and the sugar phosphate backbone, all right? 137 00:06:24,300 --> 00:06:26,910 And typically, we just refer to when we actually are looking 138 00:06:26,910 --> 00:06:28,860 at sequence, we just refer to the bases, 139 00:06:28,860 --> 00:06:30,960 so we would say As, Ts, Cs, or Gs 140 00:06:30,960 --> 00:06:33,390 because the sugar phosphate backbone is going 141 00:06:33,390 --> 00:06:37,053 to really be the same throughout the entire strand of DNA, 142 00:06:38,340 --> 00:06:40,500 and as you can see here on the right, higher order structure 143 00:06:40,500 --> 00:06:43,710 when we zoom out a bit, so that's the... 144 00:06:43,710 --> 00:06:46,230 Really zoomed in really close view on the left 145 00:06:46,230 --> 00:06:48,630 the molecular structure, if we start to zoom out a bit, 146 00:06:48,630 --> 00:06:53,160 and now, we're just looking at it sort 147 00:06:53,160 --> 00:06:55,500 of from a bit farther distance, 148 00:06:55,500 --> 00:06:58,590 you can see the double strands here and remember 149 00:06:58,590 --> 00:07:03,420 that they wrap around these proteins called histones, 150 00:07:03,420 --> 00:07:06,840 which is like the spools around which thread would wrap 151 00:07:06,840 --> 00:07:10,980 and that helps to compact the DNA and keep it organized 152 00:07:10,980 --> 00:07:12,990 and protected because otherwise, you know, 153 00:07:12,990 --> 00:07:17,130 one long strand would be really susceptible to breakage 154 00:07:17,130 --> 00:07:20,070 because it's, you know, it's a really thin strand. 155 00:07:20,070 --> 00:07:22,470 So a wrap around these systems helps keep it protected, 156 00:07:22,470 --> 00:07:25,740 helps to keep it sort of compact and in one place 157 00:07:25,740 --> 00:07:28,110 and that further compacts down 158 00:07:28,110 --> 00:07:30,720 into the chromosome structure. 159 00:07:30,720 --> 00:07:32,490 This would be duplicated chromosome 160 00:07:32,490 --> 00:07:33,960 because it has the X shape. 161 00:07:33,960 --> 00:07:38,310 So two sister chromatids attached at the centromere 162 00:07:38,310 --> 00:07:42,720 with the short or p arm on the long or q arm, 163 00:07:42,720 --> 00:07:45,510 as you can see here and, again, it only compacts down 164 00:07:45,510 --> 00:07:49,980 into this shape before mitosis or meiosis. 165 00:07:49,980 --> 00:07:53,280 Normally, it's sort of a little more relaxed 166 00:07:53,280 --> 00:07:56,490 in order for those histones to get out of the way of, 167 00:07:56,490 --> 00:08:01,200 as you remember, and as we learned in another module, 168 00:08:01,200 --> 00:08:03,420 so the histones can kind of get out the way 169 00:08:03,420 --> 00:08:05,370 of the transcription factors coming 170 00:08:05,370 --> 00:08:07,770 in and activating expression of genes. 171 00:08:07,770 --> 00:08:10,500 In order for that to happen, the chromosome has to sort 172 00:08:10,500 --> 00:08:15,500 of loosen up a bit, relax, and take a more loose structure, 173 00:08:15,780 --> 00:08:17,730 which it does more like that bowl of spaghetti kind 174 00:08:17,730 --> 00:08:18,900 of structure. 175 00:08:18,900 --> 00:08:23,340 The X shape as shown here, this is a very convenient shape 176 00:08:23,340 --> 00:08:24,540 because it... 177 00:08:24,540 --> 00:08:27,870 You can easily separate one chromosome from another 178 00:08:27,870 --> 00:08:32,107 and that's why when you would say, 179 00:08:32,107 --> 00:08:34,680 "Send a sample out for karyotyping," 180 00:08:34,680 --> 00:08:38,430 they would look for cells that are undergoing mitosis 181 00:08:38,430 --> 00:08:42,990 so that way they would be able to see the chromosomes 182 00:08:42,990 --> 00:08:44,580 in their condensed form and be able to tell 183 00:08:44,580 --> 00:08:48,630 one from another so they can see does this individual have 184 00:08:48,630 --> 00:08:50,460 the correct number of chromosomes 185 00:08:50,460 --> 00:08:53,040 and are there any, you know, major chromosome abnormalities 186 00:08:53,040 --> 00:08:54,480 that could be detected? 187 00:08:54,480 --> 00:08:55,980 That's what you're seeing here, 188 00:08:55,980 --> 00:08:58,140 that's sort of the higher order structure 189 00:08:58,140 --> 00:09:00,300 and remember, you know, like if you zoom in a little bit 190 00:09:00,300 --> 00:09:03,240 into this double stranded structure, 191 00:09:03,240 --> 00:09:05,340 we would read the sequence, we would only read 192 00:09:05,340 --> 00:09:07,920 one of the strands 'cause the other strand's going 193 00:09:07,920 --> 00:09:10,410 to be just exactly complementary to that, 194 00:09:10,410 --> 00:09:11,970 so you only need to know the sequence 195 00:09:11,970 --> 00:09:15,090 of one of those strands and that would be your sequence 196 00:09:15,090 --> 00:09:19,530 of bases, so ACCGTG, whatever, 197 00:09:19,530 --> 00:09:22,380 reading all the way through, okay? 198 00:09:22,380 --> 00:09:23,760 And so that's where that comes from, 199 00:09:23,760 --> 00:09:28,760 and a gene would be located along a segment of a chromosome 200 00:09:30,060 --> 00:09:34,590 like a stretch of a chromosome might constitute a gene 201 00:09:34,590 --> 00:09:37,770 and as we'll talk about momentarily, you know, 202 00:09:37,770 --> 00:09:42,770 that would have a start and a stop codon to it for... 203 00:09:44,631 --> 00:09:49,140 And as well as a promoter region to help align the machinery 204 00:09:49,140 --> 00:09:52,380 for transcription to form mRNA, right? 205 00:09:52,380 --> 00:09:57,380 Because the gene is a unit of DNA that encodes 206 00:09:57,930 --> 00:10:00,027 the instructions for making a protein, 207 00:10:00,027 --> 00:10:01,710 and in order for that to happen, 208 00:10:01,710 --> 00:10:04,110 it has to be transcribed into mRNA. 209 00:10:04,110 --> 00:10:06,724 So it has to have all of that in place. 210 00:10:06,724 --> 00:10:09,000 It has to have a promoter, it has to have the, 211 00:10:09,000 --> 00:10:11,709 you know, the start sequence, it has to have a stop codon, 212 00:10:11,709 --> 00:10:14,610 and that whole space between the start and stop, 213 00:10:14,610 --> 00:10:16,503 that is going to be your gene, 214 00:10:17,340 --> 00:10:20,370 and you'll have many genes along the length of a chromosome 215 00:10:20,370 --> 00:10:22,470 and you'll also have spaces in between genes 216 00:10:22,470 --> 00:10:24,120 that are actually quite large 217 00:10:24,120 --> 00:10:25,860 and these are the non-coding regions. 218 00:10:25,860 --> 00:10:28,620 Remember we talked about those non-coding regions 219 00:10:28,620 --> 00:10:29,520 as being... 220 00:10:29,520 --> 00:10:33,900 Actually, a lot of our whole genome, 221 00:10:33,900 --> 00:10:36,060 98% of our genome is actually non-coding, 222 00:10:36,060 --> 00:10:39,810 which means likely spaces between genes, right? 223 00:10:39,810 --> 00:10:42,240 It would include both spaces between genes, 224 00:10:42,240 --> 00:10:46,770 as well as the regions within genes that are not going 225 00:10:46,770 --> 00:10:48,810 to code for a protein. 226 00:10:48,810 --> 00:10:52,203 So those would be the introns, those are also non-coding. 227 00:10:53,190 --> 00:10:55,470 Just a little reminder there. 228 00:10:55,470 --> 00:10:57,000 All right, so let's see what we have next. 229 00:10:57,000 --> 00:10:59,250 Well, here's the flow of information, the central dogma. 230 00:10:59,250 --> 00:11:01,500 We know it, we love it, let's review it one more time. 231 00:11:01,500 --> 00:11:04,650 So that's the, again, the flow of information, 232 00:11:04,650 --> 00:11:09,650 which we start from DNA and that gets transcribed into mRNA, 233 00:11:11,370 --> 00:11:14,790 which is single stranded and is complementary 234 00:11:14,790 --> 00:11:19,790 to the antisense strand of the DNA, 235 00:11:20,610 --> 00:11:22,470 from which it was transcribed, 236 00:11:22,470 --> 00:11:25,710 and it's complementary with the exception 237 00:11:25,710 --> 00:11:28,927 that the T is now replaced with U or uracil. 238 00:11:28,927 --> 00:11:31,200 So thymine is now replaced with uracil 239 00:11:31,200 --> 00:11:36,107 and that allows the mRNA to leave the nucleus 240 00:11:38,482 --> 00:11:42,450 and in doing that, because you can not have translation 241 00:11:42,450 --> 00:11:45,150 within the nucleus, you don't have translation 242 00:11:45,150 --> 00:11:47,490 in the nucleus, translation happens outside of the nucleus 243 00:11:47,490 --> 00:11:50,850 where you have all this machinery ready, 244 00:11:50,850 --> 00:11:54,690 the ribosome and other machinery, the tRNA as well, 245 00:11:54,690 --> 00:11:59,690 ready to kind of swoop in and decode the mRNA 246 00:11:59,910 --> 00:12:02,970 into the proper order of amino acids 247 00:12:02,970 --> 00:12:05,760 and assemble those amino acids along to make the protein, 248 00:12:05,760 --> 00:12:06,993 and that's translation. 249 00:12:07,890 --> 00:12:10,530 Right, so the first step is transcription into mRNA, 250 00:12:10,530 --> 00:12:14,640 that mRNA leaves the nucleus, and then is picked up 251 00:12:14,640 --> 00:12:18,510 by the translational machinery, the ribosome, 252 00:12:18,510 --> 00:12:23,510 and the ribosome helps in the proper tRNA binding 253 00:12:24,930 --> 00:12:29,130 to its complementary codon in the mRNA. 254 00:12:29,130 --> 00:12:32,970 This tRNA has attached to it this specific amino acid 255 00:12:32,970 --> 00:12:37,230 that is code for by this codon to which it is complementary 256 00:12:37,230 --> 00:12:40,230 and that then brings in that amino acid 257 00:12:40,230 --> 00:12:43,260 and adds it to the chain and then they move down the line, 258 00:12:43,260 --> 00:12:46,170 so then you'll move down to the next three bases, 259 00:12:46,170 --> 00:12:48,120 which is a codon remember that? 260 00:12:48,120 --> 00:12:51,780 Moves to the next three bases and brings in the next tRNA 261 00:12:51,780 --> 00:12:56,220 that was called charged or has the amino acid on it 262 00:12:56,220 --> 00:12:58,980 that is associated with that particular codon 263 00:12:58,980 --> 00:13:03,150 and then the tRNA attaches its amino acid to the chain 264 00:13:03,150 --> 00:13:06,780 of amino acids and then once it reaches the stop codon, 265 00:13:06,780 --> 00:13:11,780 there's no tRNA that actually is complementary 266 00:13:11,790 --> 00:13:15,487 to the stop codon, so then basically, the ribosome says, 267 00:13:15,487 --> 00:13:17,250 "Well, okay, I guess we're done here," 268 00:13:17,250 --> 00:13:19,470 and the machinery falls apart 269 00:13:19,470 --> 00:13:22,020 and you have your fully formed protein now, 270 00:13:22,020 --> 00:13:25,020 and the protein, remember is just a specific sequence 271 00:13:25,020 --> 00:13:26,853 of amino acids. 272 00:13:27,810 --> 00:13:30,570 All right, so then remember here's your codon table 273 00:13:30,570 --> 00:13:35,570 and this is the way that we would read and know 274 00:13:35,610 --> 00:13:39,690 which amino acid is coded for by which codon in the mRNA. 275 00:13:41,700 --> 00:13:45,543 So if for example, the mRNA were to read GUU, 276 00:13:46,860 --> 00:13:50,580 we would know that would be coded for by a valine. 277 00:13:50,580 --> 00:13:55,230 So the tRNA that's complementary to GUU would be attached 278 00:13:55,230 --> 00:13:57,840 to valine and it would deliver that valine 279 00:13:57,840 --> 00:14:00,183 to the chain of forming amino acids. 280 00:14:01,020 --> 00:14:04,860 So let's take a peek at regulation of expression. 281 00:14:04,860 --> 00:14:09,860 So that's the basic idea of how expression is happening. 282 00:14:09,960 --> 00:14:11,970 Now, how is it actually regulated? 283 00:14:11,970 --> 00:14:14,460 How's transcription regulated? 284 00:14:14,460 --> 00:14:17,640 Well, if we're looking at a depiction of a gene here, 285 00:14:17,640 --> 00:14:20,190 let's say, and then we have this stretch of... 286 00:14:20,190 --> 00:14:24,120 This is non-coding DNA, but it's really essential 287 00:14:24,120 --> 00:14:29,120 for the regulation of expression of a particular gene. 288 00:14:29,130 --> 00:14:32,839 So while it doesn't actually encode for a protein, 289 00:14:32,839 --> 00:14:36,780 its sequence is necessary and important to be specific 290 00:14:36,780 --> 00:14:40,290 to allow for transcription factors to bind there. 291 00:14:40,290 --> 00:14:42,330 Transcription factors you remember 292 00:14:42,330 --> 00:14:45,720 are these specific proteins that are in the nucleus 293 00:14:45,720 --> 00:14:50,520 that will bind to specific sites in the promoter 294 00:14:50,520 --> 00:14:54,360 to allow for the transcription to actually happen 295 00:14:54,360 --> 00:14:55,950 of a particular gene. 296 00:14:55,950 --> 00:14:57,300 So let's take a peek at that. 297 00:14:57,300 --> 00:15:00,450 Transcription factors bounce on in and they bind to... 298 00:15:00,450 --> 00:15:02,940 They locate their specific spot in the promoter, 299 00:15:02,940 --> 00:15:04,960 their sequence, they bind there 300 00:15:06,570 --> 00:15:10,530 and then that allows for scaffolding proteins to bind. 301 00:15:10,530 --> 00:15:13,230 So RNA polymerase comes in and now can bind, 302 00:15:13,230 --> 00:15:16,710 is lined up properly in order to perform its function, 303 00:15:16,710 --> 00:15:20,880 which is to help to make the complementary mRNA 304 00:15:20,880 --> 00:15:22,590 for that gene. 305 00:15:22,590 --> 00:15:24,690 Okay, so the mRNA is transcribed 306 00:15:24,690 --> 00:15:27,150 and this means that the gene is on. 307 00:15:27,150 --> 00:15:30,630 If, however, if for whatever reason 308 00:15:30,630 --> 00:15:32,970 one of these steps does not happen properly 309 00:15:32,970 --> 00:15:36,090 and it's most likely the transcription factor's not binding, 310 00:15:36,090 --> 00:15:38,820 then the gene would not be transcribed, 311 00:15:38,820 --> 00:15:40,710 the gene would be considered off. 312 00:15:40,710 --> 00:15:44,460 So what could possibly cause the transcription factors 313 00:15:44,460 --> 00:15:45,723 to not bind? 314 00:15:46,740 --> 00:15:48,540 Well, there could be any number of reasons, 315 00:15:48,540 --> 00:15:50,880 but the main reasons would include 316 00:15:50,880 --> 00:15:53,730 that the transcription factors are not present 317 00:15:53,730 --> 00:15:58,730 in the nucleus and that could be due to the regulation 318 00:15:58,950 --> 00:16:02,040 of where that transcription factor is located. 319 00:16:02,040 --> 00:16:04,350 So moving it from the cytoplasm, for example, 320 00:16:04,350 --> 00:16:07,170 into the nucleus, that could be a highly regulated event 321 00:16:07,170 --> 00:16:11,100 depending upon some external factor in the environment. 322 00:16:11,100 --> 00:16:14,310 So the cell is able to respond to something 323 00:16:14,310 --> 00:16:19,310 in its environment by basically modifying the location 324 00:16:21,180 --> 00:16:23,490 of its transcription factor, whether it's in the cytoplasm 325 00:16:23,490 --> 00:16:25,530 or if it's moved to the nucleus. 326 00:16:25,530 --> 00:16:29,550 It can also be that the transcription factor needs to bind 327 00:16:29,550 --> 00:16:32,970 to another protein in order to make it 328 00:16:32,970 --> 00:16:35,460 in the right confirmation, it's in the right shape, 329 00:16:35,460 --> 00:16:38,190 basically, so that that transcription factor can bind 330 00:16:38,190 --> 00:16:41,463 to the promoter properly and allow for transcription. 331 00:16:42,630 --> 00:16:44,160 There are many, many different ways 332 00:16:44,160 --> 00:16:46,800 in which transcription factors are regulated, 333 00:16:46,800 --> 00:16:49,650 but you can think of them as, really, the primary way 334 00:16:49,650 --> 00:16:54,240 in which cells will be responsive in terms 335 00:16:54,240 --> 00:16:57,870 of their gene expression to changes in their environment. 336 00:16:57,870 --> 00:17:02,635 So another way that transcription factors may be blocked 337 00:17:02,635 --> 00:17:06,240 from binding to their promoter 338 00:17:06,240 --> 00:17:08,550 is through epigenetic modifications. 339 00:17:08,550 --> 00:17:11,430 So remember with the two main ones that we learned 340 00:17:11,430 --> 00:17:16,430 about are histone modifications and DNA methylation. 341 00:17:17,520 --> 00:17:21,905 So histone modifications, as you can see here on the bottom, 342 00:17:21,905 --> 00:17:24,810 depending upon the particular types of modifications, 343 00:17:24,810 --> 00:17:29,810 they can result in a loosening of the histones 344 00:17:30,660 --> 00:17:35,660 around the strand of DNA and that basically leaves open 345 00:17:35,670 --> 00:17:37,740 larger stretches of DNA. 346 00:17:37,740 --> 00:17:41,250 That basically makes room for this transcription factors 347 00:17:41,250 --> 00:17:43,380 to be able to come in and the other machinery to be able 348 00:17:43,380 --> 00:17:47,080 to come in and bind and transcribe that gene 349 00:17:48,180 --> 00:17:51,150 or particular modifications to histones could cause it 350 00:17:51,150 --> 00:17:53,820 to tighten up and to just really become really tight 351 00:17:53,820 --> 00:17:56,820 and condensed, which wouldn't allow much to get in there 352 00:17:56,820 --> 00:17:57,986 by way of transcription factors 353 00:17:57,986 --> 00:18:01,410 or other machinery, transcriptional machinery. 354 00:18:01,410 --> 00:18:06,330 DNA methylation is basically adding a methyl group 355 00:18:06,330 --> 00:18:11,010 to cytosine and those cytosines, if they're in the promoter, 356 00:18:11,010 --> 00:18:14,040 it's possible that if they're specifically in a site 357 00:18:14,040 --> 00:18:16,710 in the promoter that is necessary for a transcription factor 358 00:18:16,710 --> 00:18:18,810 to recognize and bind there, 359 00:18:18,810 --> 00:18:20,340 that when that cytosine is methylated, 360 00:18:20,340 --> 00:18:23,340 the transcription factor very well might not bind 361 00:18:23,340 --> 00:18:28,170 to that promoter anymore because it's blocking it, 362 00:18:28,170 --> 00:18:29,580 the methyl group is actually blocking 363 00:18:29,580 --> 00:18:32,130 the transcription factor from recognizing its sight 364 00:18:32,130 --> 00:18:33,030 and binding there. 365 00:18:34,710 --> 00:18:39,030 Both of these kinds of modifications are regulated 366 00:18:39,030 --> 00:18:41,730 themselves through a number of different mechanisms 367 00:18:41,730 --> 00:18:45,090 and can be responsive to environmental factors, 368 00:18:45,090 --> 00:18:46,440 and we talked a little bit about... 369 00:18:46,440 --> 00:18:51,440 Actually, these types of modifications can be responsive 370 00:18:51,960 --> 00:18:56,960 to stress, to diet, to all sorts of other factors 371 00:18:58,290 --> 00:19:01,110 that are related to general health and can accumulate 372 00:19:01,110 --> 00:19:03,660 over our lifetimes in our cells, 373 00:19:03,660 --> 00:19:05,040 so we can actually accumulate 374 00:19:05,040 --> 00:19:09,570 more and more epigenetic modifications that could cause... 375 00:19:09,570 --> 00:19:12,450 Could be detrimental in the long run to our health 376 00:19:12,450 --> 00:19:14,610 and are actually thought to be related 377 00:19:14,610 --> 00:19:16,860 to the processes of aging. 378 00:19:16,860 --> 00:19:20,220 Another way that we can regulate the proteins 379 00:19:20,220 --> 00:19:24,180 that are found in our cells is not necessarily 380 00:19:24,180 --> 00:19:28,050 just through transcription, so you could transcribe an mRNA, 381 00:19:28,050 --> 00:19:31,410 but it's through that next step of splicing. 382 00:19:31,410 --> 00:19:35,010 So remember splicing is removing the introns, 383 00:19:35,010 --> 00:19:38,430 those non-coding sequences in between exons, 384 00:19:38,430 --> 00:19:39,780 which are coding. 385 00:19:39,780 --> 00:19:43,560 Introns are non-coding and so they are removed, 386 00:19:43,560 --> 00:19:45,840 but you can also have alternative splicing, 387 00:19:45,840 --> 00:19:49,110 which basically means some of the exons could be removed. 388 00:19:49,110 --> 00:19:53,130 If for example, a particular version or form of a protein 389 00:19:53,130 --> 00:19:57,150 is needed one say maybe one version over another in response 390 00:19:57,150 --> 00:19:59,700 to something in the cell's environment, 391 00:19:59,700 --> 00:20:01,470 the cell needs to adapt to that, 392 00:20:01,470 --> 00:20:03,838 it needs a particular version of a protein 393 00:20:03,838 --> 00:20:06,810 of one type more than another, 394 00:20:06,810 --> 00:20:11,810 it may induce alternative splicing such that it will create 395 00:20:12,840 --> 00:20:17,190 mRNAs that after being spliced that contain 396 00:20:17,190 --> 00:20:19,230 a specific set of axons. 397 00:20:19,230 --> 00:20:22,770 So here's an example of a specific example 398 00:20:22,770 --> 00:20:25,680 of an environmental factor. 399 00:20:25,680 --> 00:20:28,710 This is estrogen, we know it, we love it, 400 00:20:28,710 --> 00:20:30,120 some of us have it. (laughs) 401 00:20:30,120 --> 00:20:35,120 So estrogen is a molecule that is sort of floating around, 402 00:20:36,180 --> 00:20:39,420 sometimes more of it around than others 403 00:20:39,420 --> 00:20:40,950 and in some tissues more than others, 404 00:20:40,950 --> 00:20:44,400 but the estrogen molecule, there's a receptor 405 00:20:44,400 --> 00:20:46,110 that we have to estrogen, 406 00:20:46,110 --> 00:20:49,680 and when estrogen enters the cell and binds to the receptor, 407 00:20:49,680 --> 00:20:54,060 that receptor will actually act as a transcription factor, 408 00:20:54,060 --> 00:20:56,850 but only when it's bound to estrogen. 409 00:20:56,850 --> 00:21:00,450 So this is an example of a transcription factor changing 410 00:21:00,450 --> 00:21:04,620 its conformation or its shape in order to be able to bind 411 00:21:04,620 --> 00:21:07,890 to the promoter and initiate transcription 412 00:21:07,890 --> 00:21:10,380 and turn a gene on initiate transcription, 413 00:21:10,380 --> 00:21:15,094 but only when there's some kind of incentive 414 00:21:15,094 --> 00:21:16,190 for it to do that. 415 00:21:16,190 --> 00:21:18,090 In this case, the presence of estrogen, 416 00:21:18,090 --> 00:21:21,360 the molecule of estrogen binding to it causes it 417 00:21:21,360 --> 00:21:25,180 to change shape such that now, it can bind to the promoter 418 00:21:26,250 --> 00:21:29,100 and activate expression of... 419 00:21:29,100 --> 00:21:31,800 Actually, a number of different genes will have an estrogen, 420 00:21:31,800 --> 00:21:35,940 what's called an estrogen response element. 421 00:21:35,940 --> 00:21:39,630 When the estrogen receptor is in its confirmation 422 00:21:39,630 --> 00:21:43,020 such that it can bind to those promoters will activate 423 00:21:43,020 --> 00:21:48,020 expression of those genes and those specific genes 424 00:21:48,240 --> 00:21:51,516 that are activated in the case of estrogen receptor... 425 00:21:51,516 --> 00:21:56,490 Responsive genes, those tend to be those genes 426 00:21:56,490 --> 00:22:00,660 that will induce cell proliferation, cell division, 427 00:22:00,660 --> 00:22:04,020 and the reason why that's the case is that in breast tissue 428 00:22:04,020 --> 00:22:09,020 and in uterine tissue that will prepare the uterus 429 00:22:09,180 --> 00:22:14,180 and the breast tissue potentially for a potential pregnancy. 430 00:22:15,030 --> 00:22:18,030 Let's take a peek at DNA replication. 431 00:22:18,030 --> 00:22:22,200 So remember that is what's called semi-conservative method 432 00:22:22,200 --> 00:22:24,570 of replication, which means that the... 433 00:22:24,570 --> 00:22:26,550 You have your original double strand 434 00:22:26,550 --> 00:22:31,350 and it sort of forks off and each one of those strands goes 435 00:22:31,350 --> 00:22:36,350 to form one strand of a new double stranded DNA. 436 00:22:36,780 --> 00:22:39,930 So the complementary strand is formed off of that, 437 00:22:39,930 --> 00:22:43,470 two new strands are formed and just, again, a quick peek 438 00:22:43,470 --> 00:22:45,330 at what it actually looks like, say if you're looking 439 00:22:45,330 --> 00:22:48,630 at a karyotype and what we have here, this... 440 00:22:48,630 --> 00:22:50,310 Let's say this is chromosome 1. 441 00:22:50,310 --> 00:22:53,970 We're looking at here are duplicated chromosomes 442 00:22:53,970 --> 00:22:56,640 and so these are sister chromatids 443 00:22:56,640 --> 00:22:58,330 as you can see labeled here 444 00:22:59,495 --> 00:23:01,260 and these are homologous chromosomes, 445 00:23:01,260 --> 00:23:02,643 homologous to one another. 446 00:23:03,510 --> 00:23:06,720 So that indicates, if we're looking at this karyotype, 447 00:23:06,720 --> 00:23:10,410 this happened after DNA replication, 448 00:23:10,410 --> 00:23:15,090 but before mitosis has completed here, 449 00:23:15,090 --> 00:23:17,283 so you have duplicated chromosomes. 450 00:23:19,380 --> 00:23:22,080 All right, let's take a look at the cell cycle. 451 00:23:22,080 --> 00:23:26,880 So in the cell cycle, we have multiple stages. 452 00:23:26,880 --> 00:23:28,710 So starting here with G1 phase, 453 00:23:28,710 --> 00:23:31,680 this is growth and is preparing for DNA synthesis 454 00:23:31,680 --> 00:23:34,950 and then S phase, that's synthesis phase or DNA... 455 00:23:34,950 --> 00:23:37,350 Where DNA replication actually happens 456 00:23:37,350 --> 00:23:40,590 and that's in preparation for the cell to divide. 457 00:23:40,590 --> 00:23:42,651 In G2, that's what's happening 458 00:23:42,651 --> 00:23:45,990 after DNA has been replicated, you have preparation 459 00:23:45,990 --> 00:23:50,010 for mitosis, which would include, you know, basically making 460 00:23:50,010 --> 00:23:52,920 all of those proteins that are going to be needed 461 00:23:52,920 --> 00:23:57,630 during mitosis and immediately after mitosis is that... 462 00:23:57,630 --> 00:23:59,935 You remember the four stages of mitosis, 463 00:23:59,935 --> 00:24:02,700 prophase, metaphase, anaphase, and telophase 464 00:24:02,700 --> 00:24:05,890 in order to essentially that the process is basically 465 00:24:06,929 --> 00:24:10,680 to line up and evenly distribute the chromosomes 466 00:24:10,680 --> 00:24:14,970 into each one of two new forming cells, 467 00:24:14,970 --> 00:24:16,890 and then on the right-hand side, we see meiosis, 468 00:24:16,890 --> 00:24:19,740 which is what's happening in only in those cells 469 00:24:19,740 --> 00:24:23,940 that are going to form germ cells or egg or sperm cells. 470 00:24:23,940 --> 00:24:28,110 Remember, the goal of meiosis is to create a cell 471 00:24:28,110 --> 00:24:30,430 that has haploid. 472 00:24:31,508 --> 00:24:36,030 Remember, haploid means that it has only one copy 473 00:24:36,030 --> 00:24:41,030 of each chromosome in order to basically allow for it 474 00:24:42,030 --> 00:24:47,030 to fuse with its complementary derm cell 475 00:24:47,190 --> 00:24:51,000 and form an embryo that has if the diploid 476 00:24:51,000 --> 00:24:53,733 or two copies of each chromosome. 477 00:24:56,220 --> 00:24:58,980 All right, now, sometimes problems can happen, right? 478 00:24:58,980 --> 00:25:02,790 Sometimes bad things happen and this is an example, 479 00:25:02,790 --> 00:25:06,060 an aneuploidy, where during meiosis where you can... 480 00:25:06,060 --> 00:25:08,250 Where you're actually in meiosis 1 separating 481 00:25:08,250 --> 00:25:11,940 homologous chromosomes, meiosis 2 separating duplicated 482 00:25:11,940 --> 00:25:16,860 or sister chromatids, you can have non-disjunction occur. 483 00:25:16,860 --> 00:25:19,920 Non-disjunction means that they don't let go 484 00:25:19,920 --> 00:25:22,740 of one another properly and the chromosomes, 485 00:25:22,740 --> 00:25:24,390 whether they're homologous chromosomes 486 00:25:24,390 --> 00:25:29,267 or the sister chromatids, two of them go to the same cell 487 00:25:29,267 --> 00:25:33,360 and so that means one of the cells has zero copies 488 00:25:33,360 --> 00:25:36,450 of that and the other cell will have two 489 00:25:36,450 --> 00:25:40,710 or duplicate copies of that and you can see the net result 490 00:25:40,710 --> 00:25:42,330 down at the bottom of the gametes. 491 00:25:42,330 --> 00:25:47,160 You might have one too many or one too few copies 492 00:25:47,160 --> 00:25:49,520 of the chromosomes and if that... 493 00:25:51,180 --> 00:25:55,230 So here's a karyotype that we're looking at here. 494 00:25:55,230 --> 00:26:00,150 This actually, if you look at this karyotype, what stage 495 00:26:00,150 --> 00:26:04,500 of cell cycle would this karyotype have come from? 496 00:26:04,500 --> 00:26:07,680 Well, we're looking at it, what do you notice? 497 00:26:07,680 --> 00:26:09,720 Do they look like Xs? 498 00:26:09,720 --> 00:26:12,660 Nope, they look like single columns, right? 499 00:26:12,660 --> 00:26:16,200 So they look like just one line for each. 500 00:26:16,200 --> 00:26:17,580 There's a pair of each, right? 501 00:26:17,580 --> 00:26:20,340 But that makes sense because we have 502 00:26:20,340 --> 00:26:22,680 two copies of each chromosome, but what you don't see 503 00:26:22,680 --> 00:26:24,480 is that X shape where they're being held together 504 00:26:24,480 --> 00:26:25,500 at the center. 505 00:26:25,500 --> 00:26:27,170 Remember that those would be the sister chromatids 506 00:26:27,170 --> 00:26:29,880 or the duplicated, the identical chromosomes have been 507 00:26:29,880 --> 00:26:33,480 duplicated in S phase of the cell cycles. 508 00:26:33,480 --> 00:26:38,480 So we would say in this karyotype that it was from cells 509 00:26:39,840 --> 00:26:43,980 that had not yet undergone S phase. 510 00:26:43,980 --> 00:26:47,790 Probably where they got these was just immediately following 511 00:26:47,790 --> 00:26:50,520 mitosis because they're still condensed 512 00:26:50,520 --> 00:26:51,750 and they haven't relaxed yet, 513 00:26:51,750 --> 00:26:53,910 but it was probably cells that had... 514 00:26:53,910 --> 00:26:57,570 From a cell that had recently completed mitosis. 515 00:26:57,570 --> 00:26:59,790 So if we're looking at this karyotype, what do we notice? 516 00:26:59,790 --> 00:27:01,353 What would we diagnose here? 517 00:27:03,120 --> 00:27:07,777 Well, it looks like we have the normal expected pair 518 00:27:07,777 --> 00:27:12,777 of chromosomes for each of the autosomes, chromosomes 1-22, 519 00:27:13,140 --> 00:27:15,150 then we have two X chromosomes, okay, great, 520 00:27:15,150 --> 00:27:17,000 but then we also have a Y chromosome. 521 00:27:18,000 --> 00:27:21,930 That would give us the diagnosis of Klinefelter syndrome 522 00:27:21,930 --> 00:27:26,930 or 47 because there are now 47 chromosomes XXY, okay? 523 00:27:30,900 --> 00:27:31,950 All right, now, let's think 524 00:27:31,950 --> 00:27:33,990 about some of those chromosomal abnormalities. 525 00:27:33,990 --> 00:27:35,820 There's a number of them that can happen 526 00:27:35,820 --> 00:27:37,050 and you're looking here on the left, 527 00:27:37,050 --> 00:27:39,960 remember that's the ideogram of how we look 528 00:27:39,960 --> 00:27:43,770 at and designate specific areas of a chromosome. 529 00:27:43,770 --> 00:27:45,330 You may wanna go back and take a peek 530 00:27:45,330 --> 00:27:49,770 at how we designate specific chromosomal abnormalities. 531 00:27:49,770 --> 00:27:51,240 I'm not gonna talk about that here 'cause I think 532 00:27:51,240 --> 00:27:53,733 it's in pretty good detail in your lecture notes, 533 00:27:54,810 --> 00:27:56,850 but you can have a deletion where a segment 534 00:27:56,850 --> 00:27:59,760 is deleted, removed. 535 00:27:59,760 --> 00:28:03,300 You could have a duplication where that particular region 536 00:28:03,300 --> 00:28:05,430 is duplicated and added in. 537 00:28:05,430 --> 00:28:07,920 So now, you'll have double copies 538 00:28:07,920 --> 00:28:12,840 of that in that one chromosome, which is a problem, 539 00:28:12,840 --> 00:28:14,490 potentially, depending upon the genes 540 00:28:14,490 --> 00:28:16,230 that are in the location. 541 00:28:16,230 --> 00:28:17,790 You could have inversions. 542 00:28:17,790 --> 00:28:20,790 So you can have paracentric with an A 543 00:28:20,790 --> 00:28:24,630 and that's an inversion that's in within one arm 544 00:28:24,630 --> 00:28:28,212 or you can have pericentric inversion, which is an inversion 545 00:28:28,212 --> 00:28:29,970 that involves the centromere, 546 00:28:29,970 --> 00:28:34,970 so between the p and the q arms and this can actually wreak 547 00:28:36,300 --> 00:28:37,620 more havoc than you might think. 548 00:28:37,620 --> 00:28:38,940 Well, you might say, "Well, you're not losing 549 00:28:38,940 --> 00:28:41,880 or gaining any genetic material, you're just flip-flopping 550 00:28:41,880 --> 00:28:44,430 it around a little bit, so why should that matter?" 551 00:28:45,984 --> 00:28:47,610 Well, a couple things can matter. 552 00:28:47,610 --> 00:28:51,210 One is if that flip-flop, if where it's being cut 553 00:28:51,210 --> 00:28:54,960 on either side is within an important region, 554 00:28:54,960 --> 00:28:59,670 either regulatory region for regulating gene expression 555 00:28:59,670 --> 00:29:03,540 or within a gene itself, you've just disrupted that gene 556 00:29:03,540 --> 00:29:07,926 or the regulation of the gene that is associated 557 00:29:07,926 --> 00:29:10,110 with that regulatory region. 558 00:29:10,110 --> 00:29:14,640 It could also kind of screw up local regulation 559 00:29:14,640 --> 00:29:16,170 within those regions. 560 00:29:16,170 --> 00:29:20,370 So you can have regions of chromosome that have a lot 561 00:29:20,370 --> 00:29:24,840 of non-coding DNA in them and those stretches tend 562 00:29:24,840 --> 00:29:27,450 to be really compacted by histones. 563 00:29:27,450 --> 00:29:29,640 If you start flip-flopping things around, 564 00:29:29,640 --> 00:29:33,570 you might put a region that has genes in it, 565 00:29:33,570 --> 00:29:36,480 that needs to be active, in an active part of the chromosome 566 00:29:36,480 --> 00:29:40,110 into a region that is inactive 567 00:29:40,110 --> 00:29:42,310 and then those genes might not be expressed. 568 00:29:43,170 --> 00:29:47,100 So it can really cause some problems, 569 00:29:47,100 --> 00:29:51,150 and then you also have similarly a translocation, 570 00:29:51,150 --> 00:29:53,760 which would be flip-flopping bits and pieces 571 00:29:53,760 --> 00:29:56,793 between two different chromosomes. 572 00:29:58,170 --> 00:30:02,370 Here is an example of a fluorescence in C2 hybridization 573 00:30:02,370 --> 00:30:06,960 or fish and each one of the chromosomes is colored 574 00:30:06,960 --> 00:30:09,810 with a different color fluorescent marker 575 00:30:09,810 --> 00:30:14,587 and they do this in order to see some of these inversions 576 00:30:14,587 --> 00:30:17,070 and translocations and things like that. 577 00:30:17,070 --> 00:30:19,200 So you can see that that piece 578 00:30:19,200 --> 00:30:21,870 of chromosome 22 has been flip-flopped 579 00:30:21,870 --> 00:30:26,490 with the piece of chromosome 9 and that can cause 580 00:30:26,490 --> 00:30:29,940 some issues for the individual, again, 581 00:30:29,940 --> 00:30:32,070 depending upon the genes that are involved there 582 00:30:32,070 --> 00:30:35,073 and the region, specifically the regions that are affected. 583 00:30:37,440 --> 00:30:41,400 All right, and either of these chromosomal abnormalities 584 00:30:41,400 --> 00:30:46,350 or aneuploidies, they can occur in every cell in the body 585 00:30:46,350 --> 00:30:50,430 and if that happened, it was likely that the aneuploidy 586 00:30:50,430 --> 00:30:53,610 or chromosomal abnormality happened in the gamete, 587 00:30:53,610 --> 00:30:55,170 so either the egg or the sperm. 588 00:30:55,170 --> 00:30:59,530 So from moment time zero, you know, from second one 589 00:31:01,770 --> 00:31:05,580 the embryo had the fertilized egg, which then became 590 00:31:05,580 --> 00:31:08,280 the embryo, had those chromosomal abnormalities 591 00:31:08,280 --> 00:31:10,830 or aneuploidy in every single cell. 592 00:31:10,830 --> 00:31:14,310 Every single cell, completely, all of it 100%. 593 00:31:14,310 --> 00:31:15,840 You can also have situations 594 00:31:15,840 --> 00:31:19,430 in which there are certain patches of a person. 595 00:31:19,430 --> 00:31:23,550 Certain, I mean, this would include tissues, organs, 596 00:31:23,550 --> 00:31:26,190 it could be patches of skin, it could be patches of... 597 00:31:26,190 --> 00:31:29,430 It could be, you know, percentage of blood or lymph. 598 00:31:29,430 --> 00:31:34,020 Any parts of the body could be mosaic or, you know, 599 00:31:34,020 --> 00:31:37,710 some parts may be normal and some parts may have aneuploidy 600 00:31:37,710 --> 00:31:41,190 or may have a chromosomal abnormality 601 00:31:41,190 --> 00:31:43,470 and that would be due to likely... 602 00:31:43,470 --> 00:31:47,553 It could be due to really either one of two situations. 603 00:31:48,409 --> 00:31:52,110 The first situation is that the aneuploidy 604 00:31:52,110 --> 00:31:54,650 or chromosomal abnormality was... 605 00:31:56,666 --> 00:31:59,515 Happened in the embryo or in the individual 606 00:31:59,515 --> 00:32:03,525 at some stage in their life after conception 607 00:32:03,525 --> 00:32:06,690 and then it only was passed on to those cells 608 00:32:06,690 --> 00:32:09,300 that came from that initial cell that had 609 00:32:09,300 --> 00:32:12,480 that aneuploidy or chromosomal abnormality, 610 00:32:12,480 --> 00:32:14,340 so it wouldn't be everywhere. 611 00:32:14,340 --> 00:32:17,160 The other possibility is what's called a rescue 612 00:32:17,160 --> 00:32:20,690 and that would be in an individual, let's say their... 613 00:32:22,320 --> 00:32:25,860 One of the gametes did have an aneuploidy 614 00:32:25,860 --> 00:32:27,930 and formed a fertilized egg. 615 00:32:27,930 --> 00:32:32,790 So you know, we have this single cell embryo that will form, 616 00:32:32,790 --> 00:32:36,960 you know, will form an embryo that's say has an aneuploidy. 617 00:32:36,960 --> 00:32:39,900 At some early stage in development, one of the cells could 618 00:32:39,900 --> 00:32:44,040 actually spit out the extra chromosome, 619 00:32:44,040 --> 00:32:48,570 let's say it's trisomy 21, which you saw an example 620 00:32:48,570 --> 00:32:53,070 of that, a mosaic trisomy 21 in one of your assignments, 621 00:32:53,070 --> 00:32:57,360 let's say that one of the cells was able to actually remove 622 00:32:57,360 --> 00:33:00,210 the extra chromosome from itself, then all of the cells 623 00:33:00,210 --> 00:33:03,420 that that cell will develop into would have 624 00:33:03,420 --> 00:33:05,163 the normal number of chromosomes. 625 00:33:07,020 --> 00:33:08,580 All right, now, let's talk about some of these different 626 00:33:08,580 --> 00:33:10,770 kinds of mutations that can happen. 627 00:33:10,770 --> 00:33:12,840 So we're getting smaller and smaller with aneuploidy, 628 00:33:12,840 --> 00:33:15,060 which is the wrong number of chromosomes sort 629 00:33:15,060 --> 00:33:17,550 of very large scale chromosomal abnormalities, 630 00:33:17,550 --> 00:33:19,350 which is within a chromosome you can have 631 00:33:19,350 --> 00:33:21,300 some of these large scale issues. 632 00:33:21,300 --> 00:33:24,270 Now, let's look even smaller into the sequence level. 633 00:33:24,270 --> 00:33:26,220 You could have mutations that could result 634 00:33:26,220 --> 00:33:30,780 in different effects and one effect is basically no effect, 635 00:33:30,780 --> 00:33:34,680 which means while the base itself is changed in a mutation, 636 00:33:34,680 --> 00:33:37,350 it doesn't have any effect on the protein 637 00:33:37,350 --> 00:33:39,720 that it's being coded for because it still codes 638 00:33:39,720 --> 00:33:41,460 for the same protein. 639 00:33:41,460 --> 00:33:44,040 As you remember from your codon table, 640 00:33:44,040 --> 00:33:47,430 there are multiple codons that code for the same amino acid. 641 00:33:47,430 --> 00:33:50,550 So you could have a change and actually still code 642 00:33:50,550 --> 00:33:52,350 for the same amino acid. 643 00:33:52,350 --> 00:33:54,180 That doesn't have any detrimental effect 644 00:33:54,180 --> 00:33:55,410 on the individual whatsoever 645 00:33:55,410 --> 00:33:56,805 'cause it's the exact same protein that's forming 646 00:33:56,805 --> 00:33:59,103 and these are called silent, no effect. 647 00:34:00,360 --> 00:34:04,170 This sense mutations, what happens here is that you have... 648 00:34:04,170 --> 00:34:07,380 So what they're showing here is a T instead of a C 649 00:34:07,380 --> 00:34:10,230 in the mutated version down below. 650 00:34:10,230 --> 00:34:13,950 So we'll change that codon from, instead of it being 651 00:34:13,950 --> 00:34:18,950 GGC encoding for glycine, it's now AGC encodes for serine. 652 00:34:20,460 --> 00:34:22,290 So you get a different amino acid. 653 00:34:22,290 --> 00:34:24,507 So the protein is one amino acid different, 654 00:34:24,507 --> 00:34:26,460 and you might think, "Well, big deal, you know, 655 00:34:26,460 --> 00:34:27,870 it's like one amino acid." 656 00:34:27,870 --> 00:34:31,680 It might not be a problem or it might be a big problem. 657 00:34:31,680 --> 00:34:33,420 It depends upon where in the protein 658 00:34:33,420 --> 00:34:35,820 this amino acid substitution is happening 659 00:34:35,820 --> 00:34:39,420 and the type of substitution that has occurred. 660 00:34:39,420 --> 00:34:41,760 If it's changing to a completely different amino acid, 661 00:34:41,760 --> 00:34:43,890 it might totally screw up the normal function 662 00:34:43,890 --> 00:34:44,940 of this protein. 663 00:34:44,940 --> 00:34:47,340 If it's happening in a region in the protein 664 00:34:47,340 --> 00:34:50,520 that's really necessary for that protein's function, 665 00:34:50,520 --> 00:34:51,570 it could screw it up. 666 00:34:51,570 --> 00:34:56,570 Nonsense mutation is what would happen if you change a codon 667 00:34:58,020 --> 00:35:01,110 and it now is, instead of whatever it was coding 668 00:35:01,110 --> 00:35:04,500 for a normal amino acid, it's now a stop codon, 669 00:35:04,500 --> 00:35:05,333 a stop codon. 670 00:35:05,333 --> 00:35:09,870 So you see down below an A instead of a T in this one spot. 671 00:35:09,870 --> 00:35:11,670 So now, that codon, instead of it being 672 00:35:11,670 --> 00:35:15,990 AAG encoding for lysine, it's now UAG encodes for nothing, 673 00:35:15,990 --> 00:35:17,040 encodes for a stop. 674 00:35:17,040 --> 00:35:19,905 So then the protein is truncated, which basically means 675 00:35:19,905 --> 00:35:22,140 it's not going to be the full length. 676 00:35:22,140 --> 00:35:24,840 If that happens like really close to the end of the protein, 677 00:35:24,840 --> 00:35:28,680 it might not be a problem, but if it happens midway 678 00:35:28,680 --> 00:35:31,020 through or at the very beginning of the protein, 679 00:35:31,020 --> 00:35:33,030 you essentially could have no function 680 00:35:33,030 --> 00:35:34,503 for that protein whatsoever. 681 00:35:36,690 --> 00:35:39,720 Now, let's talk about inserting or deleting 682 00:35:39,720 --> 00:35:42,630 a number of bases. 683 00:35:42,630 --> 00:35:45,210 So we were talking about substituting or mutation, 684 00:35:45,210 --> 00:35:48,630 so this instead of that, but let's say you take out a chunk. 685 00:35:48,630 --> 00:35:51,240 Well, if you're taking out a chunk that's a multiple 686 00:35:51,240 --> 00:35:53,490 of three, and why do I say multiple of three? 687 00:35:53,490 --> 00:35:55,370 Because three is the number of codon... 688 00:35:55,370 --> 00:35:57,270 Is the number of bases in a codon 689 00:35:57,270 --> 00:35:58,280 If you do that, then it would be 690 00:35:58,280 --> 00:36:00,960 an in-frame insertion or deletion 691 00:36:00,960 --> 00:36:05,280 and that would basically affect just that one amino acid, 692 00:36:05,280 --> 00:36:07,770 either deleting an amino acid or adding an amino acid, 693 00:36:07,770 --> 00:36:09,300 so that's your in-frame insertion, 694 00:36:09,300 --> 00:36:11,700 same thing in-frame deletion, okay? 695 00:36:11,700 --> 00:36:13,140 Frame shift is the bigger problem 696 00:36:13,140 --> 00:36:15,620 and this is gonna be more likely if you're adding 697 00:36:15,620 --> 00:36:19,830 or deleting bases because, you know, 698 00:36:19,830 --> 00:36:23,100 that's basically anything that's not a multiple of three. 699 00:36:23,100 --> 00:36:25,920 So that gets everything off kilter 700 00:36:25,920 --> 00:36:29,010 and remember, back from that lecture I was talking about, 701 00:36:29,010 --> 00:36:32,550 looking at at words and, you know, the red... 702 00:36:32,550 --> 00:36:33,383 I forget what it was. 703 00:36:33,383 --> 00:36:35,730 The red bug bit the dog or something like that, 704 00:36:35,730 --> 00:36:38,640 and if you move that over just by one letter, 705 00:36:38,640 --> 00:36:41,526 it becomes gibberish and that's kind of what happens 706 00:36:41,526 --> 00:36:43,950 in frameshift mutations as well. 707 00:36:43,950 --> 00:36:45,660 It shifts everything over by a base 708 00:36:45,660 --> 00:36:47,140 and that screws up everything 709 00:36:48,985 --> 00:36:50,340 and the protein's completely different. 710 00:36:50,340 --> 00:36:54,660 So that could be an insertion or a deletion, all right. 711 00:36:54,660 --> 00:36:56,130 All right, let's switch gears here. 712 00:36:56,130 --> 00:36:58,039 Keep going, we're just gonna power on through. 713 00:36:58,039 --> 00:36:59,730 We're gonna switch gears and talk 714 00:36:59,730 --> 00:37:01,740 about modes of inheritance, 715 00:37:01,740 --> 00:37:05,580 and so we have a number of different common ones 716 00:37:05,580 --> 00:37:08,640 and these are autosomal dominant, autosomal recessive, 717 00:37:08,640 --> 00:37:10,710 X-linked dominant, and X-linked recessive. 718 00:37:10,710 --> 00:37:12,420 Remember, these are Mendelian inheritance, 719 00:37:12,420 --> 00:37:17,420 which means that it is a phenotype associated with one gene. 720 00:37:17,730 --> 00:37:20,100 So let's look at the case of autosomal dominant. 721 00:37:20,100 --> 00:37:21,750 Remember how we designate each of these? 722 00:37:21,750 --> 00:37:26,750 So uppercase indicates the dominant allele 723 00:37:27,540 --> 00:37:30,870 and lowercase indicates the recessive allele. 724 00:37:30,870 --> 00:37:33,420 Whether the uppercase dominant 725 00:37:33,420 --> 00:37:38,420 or the lowercase recessive alleles are disease alleles 726 00:37:38,550 --> 00:37:42,120 or wild type alleles depends upon the disease, 727 00:37:42,120 --> 00:37:45,120 whether the disease is dominant or the disease is recessive. 728 00:37:46,470 --> 00:37:48,480 Here, we're showing in the top left corner, 729 00:37:48,480 --> 00:37:49,530 autosomal dominant. 730 00:37:49,530 --> 00:37:52,260 If you have, let's say a... 731 00:37:52,260 --> 00:37:54,240 Let's say we're talking about Huntington's disease 732 00:37:54,240 --> 00:37:57,180 and the father has Huntington's disease 733 00:37:57,180 --> 00:37:58,800 and let's say he's heterozygous for it, 734 00:37:58,800 --> 00:38:02,010 which means he has one copy, that's the disease copy 735 00:38:02,010 --> 00:38:05,250 that's indicated by the big H, uppercase H, right? 736 00:38:05,250 --> 00:38:07,733 Because that's the dominant version that happens 737 00:38:07,733 --> 00:38:10,620 to be the disease version, in this case. 738 00:38:10,620 --> 00:38:13,170 Lowercase h 'cause he's heterozygous, 739 00:38:13,170 --> 00:38:16,200 and let's say the mother doesn't have Huntington's disease. 740 00:38:16,200 --> 00:38:19,950 So both of her copies, both of her alleles are wild type, 741 00:38:19,950 --> 00:38:22,770 and since this, again, wild type is recessive, 742 00:38:22,770 --> 00:38:24,930 we would show it as lowercase h. 743 00:38:24,930 --> 00:38:26,820 When we do our Punnett square and we see 744 00:38:26,820 --> 00:38:29,460 all the combinations, the possible combinations 745 00:38:29,460 --> 00:38:30,810 for their offspring. 746 00:38:30,810 --> 00:38:32,460 Since this is an autosomal condition, 747 00:38:32,460 --> 00:38:37,323 which means that the Huntington gene exists on an autosome, 748 00:38:38,940 --> 00:38:42,240 we look at all the combinations that could happen here. 749 00:38:42,240 --> 00:38:45,930 We have big H, little h, little h, little h, big H, 750 00:38:45,930 --> 00:38:46,947 little H, little H, little h, 751 00:38:46,947 --> 00:38:49,290 and we can count them up and we would say 752 00:38:49,290 --> 00:38:51,630 two out of the four possible combinations 753 00:38:51,630 --> 00:38:56,630 of these alleles would give us little h, little h, 754 00:38:56,670 --> 00:38:59,850 or both wild type alleles 755 00:38:59,850 --> 00:39:02,313 and so those would be unaffected children. 756 00:39:03,180 --> 00:39:07,500 However, we would also note that two of the four would have 757 00:39:07,500 --> 00:39:10,950 one copy of the disease or big H alleles, 758 00:39:10,950 --> 00:39:12,360 so that would be big H, little h. 759 00:39:12,360 --> 00:39:15,600 So these two out of the four would have 760 00:39:15,600 --> 00:39:16,713 Huntington's disease. 761 00:39:18,420 --> 00:39:21,210 As you know from statistics, that does not mean 762 00:39:21,210 --> 00:39:23,190 if a family... 763 00:39:23,190 --> 00:39:26,280 If let's say this couple has four children, 764 00:39:26,280 --> 00:39:28,620 it's guaranteed that two of the four are going 765 00:39:28,620 --> 00:39:31,920 to have Huntington's disease and two of the four are not. 766 00:39:31,920 --> 00:39:35,160 It's for each individual there's a 50% chance 767 00:39:35,160 --> 00:39:37,920 or two out of four, there's a 50% chance 768 00:39:37,920 --> 00:39:40,950 that each child they have would have Huntington's disease. 769 00:39:40,950 --> 00:39:42,600 No matter how many children they end up having, 770 00:39:42,600 --> 00:39:43,433 each child... 771 00:39:43,433 --> 00:39:44,850 It's like flipping a coin. 772 00:39:44,850 --> 00:39:48,180 Each time you flip the coin, it's 50% chance it'll be heads 773 00:39:48,180 --> 00:39:50,760 or tails no matter how many times you flip the coin. 774 00:39:50,760 --> 00:39:52,620 Autosomal recessive, as you can see 775 00:39:52,620 --> 00:39:54,870 on the right-hand side there, let's say there 776 00:39:54,870 --> 00:39:56,790 are two carriers, the mother and the father 777 00:39:56,790 --> 00:40:00,390 are both carriers of this condition, say cystic fibrosis. 778 00:40:00,390 --> 00:40:02,850 So we would say they're big F, little f. 779 00:40:02,850 --> 00:40:04,463 So neither parent has cystic fibrosis, 780 00:40:04,463 --> 00:40:06,510 they're both carriers for it. 781 00:40:06,510 --> 00:40:09,390 In order to calculate the risk that they would have a child 782 00:40:09,390 --> 00:40:13,350 with cystic fibrosis or a child that is a carrier, 783 00:40:13,350 --> 00:40:15,960 we would do the Punnett square and we would see 784 00:40:15,960 --> 00:40:20,070 that one out of four possibilities would be big F, big F, 785 00:40:20,070 --> 00:40:21,380 or both wild type. 786 00:40:21,380 --> 00:40:23,790 In this case, big F represents wild type 787 00:40:23,790 --> 00:40:26,220 because that's the dominant allele. 788 00:40:26,220 --> 00:40:29,670 So this in the one out of four would be unaffected, 789 00:40:29,670 --> 00:40:30,503 completely unaffected. 790 00:40:30,503 --> 00:40:32,400 So they wouldn't be carrier, they wouldn't have the disease, 791 00:40:32,400 --> 00:40:35,220 so there's a 25% chance for each of their children 792 00:40:35,220 --> 00:40:37,270 that they would be completely unaffected. 793 00:40:38,220 --> 00:40:42,840 There is a two out of four or 50% chance for each child 794 00:40:42,840 --> 00:40:45,210 that they would be carriers that they would've inherited 795 00:40:45,210 --> 00:40:49,410 one disease allele from one parent and one wild type allele 796 00:40:49,410 --> 00:40:50,970 from the other parent. 797 00:40:50,970 --> 00:40:54,600 There's a 25% chance for each one of their children 798 00:40:54,600 --> 00:40:55,433 that they would... 799 00:40:55,433 --> 00:40:56,820 That that child would have cystic fibrosis 800 00:40:56,820 --> 00:41:00,420 or would have inherited the disease allele from each parent. 801 00:41:00,420 --> 00:41:03,960 Okay, X-linked dominant and recessive conditions. 802 00:41:03,960 --> 00:41:05,250 So now, we're talking about X-linked 803 00:41:05,250 --> 00:41:08,345 and males only have one X, females have two 804 00:41:08,345 --> 00:41:11,100 so we have to look at things a little bit differently. 805 00:41:11,100 --> 00:41:13,770 In X-linked dominant conditions, again, 806 00:41:13,770 --> 00:41:16,290 you only have one allele from the father, 807 00:41:16,290 --> 00:41:17,580 you have two alleles from the mother. 808 00:41:17,580 --> 00:41:20,430 Let's say that the mother has this condition and so... 809 00:41:20,430 --> 00:41:22,200 And she's heterozygous for it, 810 00:41:22,200 --> 00:41:24,840 so she would have one disease allele, 811 00:41:24,840 --> 00:41:28,230 which is designated as uppercase, again, big R. 812 00:41:28,230 --> 00:41:30,630 Let's say this is like Rett syndrome 813 00:41:30,630 --> 00:41:35,130 and she would have a wild type or normal allele 814 00:41:35,130 --> 00:41:37,230 as the other allele. 815 00:41:37,230 --> 00:41:39,870 Let's look at all the combinations thereof. 816 00:41:39,870 --> 00:41:42,720 So she could have for daughters, which would be those 817 00:41:42,720 --> 00:41:46,500 that would've inherited an X chromosome from the father, 818 00:41:46,500 --> 00:41:48,240 she would have... 819 00:41:48,240 --> 00:41:51,600 50% of her daughters would have Rett 820 00:41:51,600 --> 00:41:55,330 and 50% of her daughters would be completely unaffected 821 00:41:56,400 --> 00:42:00,300 and for her sons, all of her sons will inherit 822 00:42:00,300 --> 00:42:02,580 one of her two X chromosomes and a Y chromosome 823 00:42:02,580 --> 00:42:03,840 from the father, so we don't... 824 00:42:03,840 --> 00:42:06,240 He doesn't have a second allele, 825 00:42:06,240 --> 00:42:09,300 so we would just look here, these are the sons. 826 00:42:09,300 --> 00:42:13,530 So 50% of her sons would have inherited 827 00:42:13,530 --> 00:42:17,160 the disease allele and in the case of Rett syndrome, 828 00:42:17,160 --> 00:42:19,740 that would be lethal, so it would it... 829 00:42:21,390 --> 00:42:24,810 That son would not make it to term 830 00:42:24,810 --> 00:42:29,810 because having one copy and no normal copy 831 00:42:30,000 --> 00:42:34,320 is lethal in this case and then... 832 00:42:34,320 --> 00:42:37,380 So essentially, what would end up happening 833 00:42:37,380 --> 00:42:42,380 if we look at live births from these two parents, 834 00:42:43,290 --> 00:42:45,270 we would see that 50%, again, 835 00:42:45,270 --> 00:42:46,920 50% of the daughters would have Rett, 836 00:42:46,920 --> 00:42:50,190 50% would be unaffected, and then what we would see actually 837 00:42:50,190 --> 00:42:52,980 is that 100% of the sons would be unaffected. 838 00:42:52,980 --> 00:42:54,120 Why do I say that? 839 00:42:54,120 --> 00:42:59,120 Because the sons that would've inherited her disease allele, 840 00:43:00,060 --> 00:43:03,690 her X chromosome with the disease allele would not have 841 00:43:03,690 --> 00:43:05,703 survived and not have made it to term. 842 00:43:06,720 --> 00:43:10,050 So X-linked recessive conditions, similarly, again, 843 00:43:10,050 --> 00:43:12,270 you know, you only have one allele from the father, 844 00:43:12,270 --> 00:43:14,190 you get two alleles from the mother. 845 00:43:14,190 --> 00:43:17,809 Let's say we have a father that's unaffected 846 00:43:17,809 --> 00:43:20,790 and we have a mother that's a carrier for an X-linked, 847 00:43:20,790 --> 00:43:24,330 let's say it's a hemophilia's example that we gave. 848 00:43:24,330 --> 00:43:26,130 So we would look at the daughters. 849 00:43:26,130 --> 00:43:28,260 50% of the daughters would be unaffected 850 00:43:28,260 --> 00:43:30,483 and 50% would be carriers. 851 00:43:31,680 --> 00:43:32,790 She would not have any daughters 852 00:43:32,790 --> 00:43:34,110 who would have the condition, 853 00:43:34,110 --> 00:43:36,990 assuming that the father does not have the condition 854 00:43:36,990 --> 00:43:40,920 and out of the sons, we would have 50% that are unaffected 855 00:43:40,920 --> 00:43:43,740 because they inherited the wild type allele 856 00:43:43,740 --> 00:43:46,950 and 50% that would have hemophilia of her sons, right? 857 00:43:46,950 --> 00:43:49,350 50% of her sons would have hemophilia 858 00:43:49,350 --> 00:43:52,740 'cause they would've inherited the disease, the X chromosome 859 00:43:52,740 --> 00:43:54,690 with the disease allele on it. 860 00:43:54,690 --> 00:43:57,720 Let's move on then to some exceptions to Mendel, 861 00:43:57,720 --> 00:44:00,813 and these would include different dominance relationships. 862 00:44:01,683 --> 00:44:04,440 It doesn't come up too much in the clinical context, 863 00:44:04,440 --> 00:44:05,790 you might see someone talking 864 00:44:05,790 --> 00:44:08,310 about incomplete or co-dominance so it's included here, 865 00:44:08,310 --> 00:44:09,510 I wouldn't worry about it too much, 866 00:44:09,510 --> 00:44:12,690 but, you know, the idea is that incomplete dominance, 867 00:44:12,690 --> 00:44:14,880 you have sort of a blended phenotype 868 00:44:14,880 --> 00:44:17,730 between both homozygous parents. 869 00:44:17,730 --> 00:44:20,880 In co-dominant situation, you would have patches 870 00:44:20,880 --> 00:44:25,080 or representation of both in the heterozygous child, 871 00:44:25,080 --> 00:44:27,690 which is a result of a cross 872 00:44:27,690 --> 00:44:29,433 between two homozygous parents. 873 00:44:31,650 --> 00:44:33,507 All right, now, let's look at pleiotropy 874 00:44:33,507 --> 00:44:34,980 and genetic heterogeneity. 875 00:44:34,980 --> 00:44:38,070 So a couple of phenomena that I think are actually 876 00:44:38,070 --> 00:44:40,620 more relevant to the clinical context. 877 00:44:40,620 --> 00:44:44,610 Pleiotropy, that is one mutation causing 878 00:44:44,610 --> 00:44:49,610 lots of different phenotypes, and so the example here 879 00:44:49,800 --> 00:44:54,800 is PKU, is a mutation in one gene, the PAH gene, 880 00:44:54,840 --> 00:44:57,330 which results in all these different kinds of phenotypes, 881 00:44:57,330 --> 00:45:00,600 which might appear to be unrelated to one another, 882 00:45:00,600 --> 00:45:05,280 but clearly, the protein encoded by this gene is involved 883 00:45:05,280 --> 00:45:07,770 in pathways that affect each of these kinds of phenotypes, 884 00:45:07,770 --> 00:45:11,760 so that's pleiotropy, one gene, multiple phenotypes. 885 00:45:11,760 --> 00:45:14,160 Genetic heterogeneity is almost kinda like the opposite 886 00:45:14,160 --> 00:45:16,140 of that where you have one phenotype, 887 00:45:16,140 --> 00:45:19,890 in this case, polycystic kidney disease, which would be... 888 00:45:19,890 --> 00:45:21,720 Which could be caused by mutation 889 00:45:21,720 --> 00:45:24,030 in a number of different genes. 890 00:45:24,030 --> 00:45:27,540 Doesn't mean it requires a mutation in each of those genes, 891 00:45:27,540 --> 00:45:28,530 it just means a mutation 892 00:45:28,530 --> 00:45:32,625 in any one of those genes could cause the same phenotype, 893 00:45:32,625 --> 00:45:34,503 which would be a polycystic kidney, 894 00:45:35,490 --> 00:45:38,160 and then finally, we have penetrance and expressivity 895 00:45:38,160 --> 00:45:40,170 as our last two phenomena to talk about, 896 00:45:40,170 --> 00:45:43,140 and I'm just designating these as like in a sort 897 00:45:43,140 --> 00:45:47,460 of abstract colors to look at just maybe a different way 898 00:45:47,460 --> 00:45:50,430 to think about it other than, you know, in addition 899 00:45:50,430 --> 00:45:53,670 to what we had in our slides from the lectures there, 900 00:45:53,670 --> 00:45:55,650 but penetrance you can think of as, 901 00:45:55,650 --> 00:45:58,620 let's say you have this population here 902 00:45:58,620 --> 00:46:01,530 and all of these circles represent people that have 903 00:46:01,530 --> 00:46:04,680 a genotype that indicates they should have 904 00:46:04,680 --> 00:46:06,240 a particular disease, right? 905 00:46:06,240 --> 00:46:10,500 So they have a genotype for Huntington's disease. 906 00:46:10,500 --> 00:46:12,870 All of these people should develop Huntington's disease, 907 00:46:12,870 --> 00:46:15,060 but let's say these two white circles 908 00:46:15,060 --> 00:46:17,640 that are represented in the field of blue circles, 909 00:46:17,640 --> 00:46:20,580 they never actually end up developing Huntington's disease. 910 00:46:20,580 --> 00:46:22,680 That would be incomplete penetrance. 911 00:46:22,680 --> 00:46:25,230 Incomplete penetrance is the... 912 00:46:25,230 --> 00:46:27,060 Basically indicates that there are some members 913 00:46:27,060 --> 00:46:29,100 of the population who have the genotype, 914 00:46:29,100 --> 00:46:31,653 but don't ever end up developing the phenotype. 915 00:46:32,910 --> 00:46:37,910 Expressivity is sort of like the rainbow of possibilities 916 00:46:38,790 --> 00:46:41,370 of different outcomes that you could see associated 917 00:46:41,370 --> 00:46:42,203 with the disease. 918 00:46:42,203 --> 00:46:45,600 So it could be severity of the condition, it could be onset, 919 00:46:45,600 --> 00:46:48,180 you know, whether it's earlier or late onset. 920 00:46:48,180 --> 00:46:51,480 So here, I'm representing it by a bunch of different shades 921 00:46:51,480 --> 00:46:56,310 of, you know, blue that you could see in the disease. 922 00:46:56,310 --> 00:46:57,630 So they all have the disease, 923 00:46:57,630 --> 00:46:59,700 they'll all have some phenotypes of the disease, 924 00:46:59,700 --> 00:47:01,560 it's just that those phenotypes might be different 925 00:47:01,560 --> 00:47:04,380 from one to the other even though their genotypes 926 00:47:04,380 --> 00:47:05,730 are the same. 927 00:47:05,730 --> 00:47:08,133 So that's variable expressivity. 928 00:47:09,480 --> 00:47:11,550 Okay, well, that wraps it up. 929 00:47:11,550 --> 00:47:14,970 Whew, that was a whirlwind, that was a whirlwind. 930 00:47:14,970 --> 00:47:17,640 Okay, so what's in the next module? 931 00:47:17,640 --> 00:47:21,720 Well, we're going to talk about health history 932 00:47:21,720 --> 00:47:25,020 and risk assessment, basically, where do we go from here 933 00:47:25,020 --> 00:47:26,820 and how do we take patient information 934 00:47:26,820 --> 00:47:29,130 and start to turn that into pedigrees 935 00:47:29,130 --> 00:47:32,880 and start to analyze that, so taking us to the next step. 936 00:47:32,880 --> 00:47:36,000 All right, well, with that, I will say goodbye. 937 00:47:36,000 --> 00:47:37,980 Please let me know if you have any questions 938 00:47:37,980 --> 00:47:40,590 and let's, you know, get Blackboard up and running. 939 00:47:40,590 --> 00:47:43,410 If there's some questions that you have along the way 940 00:47:43,410 --> 00:47:45,450 that you want some help with or just want to raise 941 00:47:45,450 --> 00:47:47,940 for discussion, that would be great. 942 00:47:47,940 --> 00:47:50,763 All right, I will talk with you soon, take care.