1 00:00:00,605 --> 00:00:03,634 [Lecturer] Hello and welcome to Module 5. 2 00:00:03,634 --> 00:00:04,891 So, we will go through 3 00:00:04,891 --> 00:00:06,963 three different lectures in this module. 4 00:00:06,963 --> 00:00:09,330 And the first one we're going to start with 5 00:00:09,330 --> 00:00:10,814 really thinking about how to piece together 6 00:00:10,814 --> 00:00:15,564 some of what we've learned in the first couple of modules 7 00:00:17,372 --> 00:00:20,016 expanding that to patterns of inheritance 8 00:00:20,016 --> 00:00:22,711 and the actual traits that you see. 9 00:00:22,711 --> 00:00:23,876 So we're gonna start this with 10 00:00:23,876 --> 00:00:26,315 a lecture called Genotype to Phenotype. 11 00:00:26,315 --> 00:00:27,273 And as you remember, 12 00:00:27,273 --> 00:00:31,299 a genotype is the sequence of a particular gene. 13 00:00:31,299 --> 00:00:32,868 So if someone has, 14 00:00:32,868 --> 00:00:36,368 say a disease mutation that it results in, 15 00:00:37,973 --> 00:00:39,190 it causes a disease, 16 00:00:39,190 --> 00:00:40,269 it's the actual mutation, 17 00:00:40,269 --> 00:00:41,723 the sequence of the gene itself. 18 00:00:41,723 --> 00:00:42,646 That's the genotype. 19 00:00:42,646 --> 00:00:43,962 The phenotype is the trait. 20 00:00:43,962 --> 00:00:46,324 That's actually what you see in a person. 21 00:00:46,324 --> 00:00:48,273 And that might be the disease. 22 00:00:48,273 --> 00:00:51,785 A disease, it might be something else 23 00:00:51,785 --> 00:00:54,586 like eye color, hair color, height. 24 00:00:54,586 --> 00:00:56,377 These are all traits, 25 00:00:56,377 --> 00:01:00,265 these are all phenotypes that are affected 26 00:01:00,265 --> 00:01:02,473 in some cases directly caused by, 27 00:01:02,473 --> 00:01:04,299 and in some cases just affected 28 00:01:04,299 --> 00:01:07,964 by a particular gene sequence or the genotype. 29 00:01:07,964 --> 00:01:10,499 So genotype determines phenotype. 30 00:01:10,499 --> 00:01:12,291 So that we're going to actually take this in 31 00:01:12,291 --> 00:01:14,436 and look into it in a little bit more depth 32 00:01:14,436 --> 00:01:17,863 and better understand how can we transition 33 00:01:17,863 --> 00:01:21,373 from what we've learned about gene sequences 34 00:01:21,373 --> 00:01:22,956 and gene expression 35 00:01:24,974 --> 00:01:29,974 and transition that to the actual traits that we see. 36 00:01:29,998 --> 00:01:32,063 And take that into the next couple of lectures 37 00:01:32,063 --> 00:01:34,775 where we start to think about patterns of inheritance 38 00:01:34,775 --> 00:01:36,608 that you might record, 39 00:01:36,608 --> 00:01:39,409 say in a, in a pedigree from a family history 40 00:01:39,409 --> 00:01:41,909 that a patient might give you. 41 00:01:42,884 --> 00:01:44,348 Let's do a quick review. 42 00:01:44,348 --> 00:01:47,672 DNA sequence is copied into mRNA during transcription. 43 00:01:47,672 --> 00:01:50,036 mRNA sequence is read as codons 44 00:01:50,036 --> 00:01:53,074 or triplets of bases in a specific order. 45 00:01:53,074 --> 00:01:54,226 And this will become really important 46 00:01:54,226 --> 00:01:56,324 when we start talking about different kinds of mutations 47 00:01:56,324 --> 00:02:00,576 and the impact that can have on the protein 48 00:02:00,576 --> 00:02:04,659 that's made from the instructions from this gene. 49 00:02:05,786 --> 00:02:09,412 During translation, each codon encodes for one amino acid 50 00:02:09,412 --> 00:02:12,021 or instructs the ribosome to stop translation. 51 00:02:12,021 --> 00:02:15,411 So you remember that there are 20 different amino acids 52 00:02:15,411 --> 00:02:19,846 and each one of those has a couple of different codons 53 00:02:19,846 --> 00:02:21,457 that can encode for it. 54 00:02:21,457 --> 00:02:22,662 And a codon, as you recall, 55 00:02:22,662 --> 00:02:25,674 is just a set of three bases together 56 00:02:25,674 --> 00:02:28,275 but in a specific order. 57 00:02:28,275 --> 00:02:31,810 So if you remember, there was that codon table 58 00:02:31,810 --> 00:02:33,834 and you can double check that 59 00:02:33,834 --> 00:02:36,150 if you'd like to refresh your memory 60 00:02:36,150 --> 00:02:37,521 of what that actually was. 61 00:02:37,521 --> 00:02:39,114 But that was where you have, 62 00:02:39,114 --> 00:02:42,444 it's that table and you have basically the first base 63 00:02:42,444 --> 00:02:44,975 on the left hand column, 64 00:02:44,975 --> 00:02:47,423 the second base going horizontally across, 65 00:02:47,423 --> 00:02:50,911 and then the third base going down on the right hand column. 66 00:02:50,911 --> 00:02:53,523 And you can look on the table for any combination 67 00:02:53,523 --> 00:02:58,211 of three bases and see which amino acid it encodes, 68 00:02:58,211 --> 00:03:02,211 or if it encodes for a stop signal, for example. 69 00:03:03,386 --> 00:03:05,510 Proteins are made up of a chain of amino acids 70 00:03:05,510 --> 00:03:07,395 strung together in a specific order 71 00:03:07,395 --> 00:03:11,063 to give the protein its specific shape and function. 72 00:03:11,063 --> 00:03:13,421 Proteins do virtually everything in a cell. 73 00:03:13,421 --> 00:03:15,212 So getting the amino acids sequence 74 00:03:15,212 --> 00:03:18,212 exactly correct is really important. 75 00:03:18,212 --> 00:03:19,513 And in some proteins, 76 00:03:19,513 --> 00:03:22,162 in some specific parts of certain proteins, 77 00:03:22,162 --> 00:03:23,525 if there are changes in amino acids, 78 00:03:23,525 --> 00:03:27,353 it may not actually affect the protein's function, 79 00:03:27,353 --> 00:03:32,353 but certainly for others there are regions of the protein 80 00:03:32,576 --> 00:03:36,676 where getting the exact amino acid in the exact right order 81 00:03:36,676 --> 00:03:39,412 is absolutely critical and can completely change 82 00:03:39,412 --> 00:03:44,412 or even eliminate the normal function of the protein. 83 00:03:44,414 --> 00:03:46,565 Here are a few important terms and definitions 84 00:03:46,565 --> 00:03:50,665 that we'll talk about in this particular lecture. 85 00:03:50,665 --> 00:03:52,123 So first of all, genotype. 86 00:03:52,123 --> 00:03:55,039 This is the nucleotide sequence of a gene. 87 00:03:55,039 --> 00:03:59,425 So genotype is the sequence of a particular gene. 88 00:03:59,425 --> 00:04:00,951 The phenotype, this is the trait 89 00:04:00,951 --> 00:04:03,077 or characteristics seen in a person. 90 00:04:03,077 --> 00:04:05,428 So an example would be the presence of a disease. 91 00:04:05,428 --> 00:04:10,351 Another example of a phenotype would be eye color or height 92 00:04:10,351 --> 00:04:14,884 or whether or not a person develops type one diabetes. 93 00:04:14,884 --> 00:04:16,776 These are all called phenotypes. 94 00:04:16,776 --> 00:04:18,385 So it's basically what you would see 95 00:04:18,385 --> 00:04:20,702 or experience in a person. 96 00:04:20,702 --> 00:04:25,272 The genotype is the DNA sequence for the particular genes 97 00:04:25,272 --> 00:04:28,248 that would affect the phenotype. 98 00:04:28,248 --> 00:04:29,976 And allele, this is an important definition 99 00:04:29,976 --> 00:04:34,161 and one I'd like you to try to pick up on, 100 00:04:34,161 --> 00:04:37,348 because we're going to start using this term a lot. 101 00:04:37,348 --> 00:04:40,398 And it's important that you understand what it means because 102 00:04:40,398 --> 00:04:41,798 otherwise it can get kind of confusing. 103 00:04:41,798 --> 00:04:45,086 But an allele is one of the alternate versions of a gene. 104 00:04:45,086 --> 00:04:47,210 And what I mean by that is, 105 00:04:47,210 --> 00:04:50,851 let's take for example the eye color gene let's say. 106 00:04:50,851 --> 00:04:53,649 We actually have a couple of different genes 107 00:04:53,649 --> 00:04:54,635 that affect eye color, 108 00:04:54,635 --> 00:04:57,047 but let's make it simple and just say there's one, 109 00:04:57,047 --> 00:05:00,147 one gene that affects eye color. 110 00:05:00,147 --> 00:05:04,732 So you would have in say, 10 different people, 111 00:05:04,732 --> 00:05:07,075 you might have three or four different eye colors. 112 00:05:07,075 --> 00:05:09,908 You could have green, brown, blue, 113 00:05:10,746 --> 00:05:12,937 even like a grayish color, you know. 114 00:05:12,937 --> 00:05:14,896 There are many other colors. 115 00:05:14,896 --> 00:05:16,322 But basically what we're talking about 116 00:05:16,322 --> 00:05:18,062 when we're talking about an allele, 117 00:05:18,062 --> 00:05:20,961 if we think about that eye color gene, let's say, 118 00:05:20,961 --> 00:05:23,833 so it's a gene which encodes a protein 119 00:05:23,833 --> 00:05:28,036 which impacts directly the eye color of an individual. 120 00:05:28,036 --> 00:05:29,297 And a person who has brown eyes, 121 00:05:29,297 --> 00:05:33,214 they would have an allele for a brown eye color 122 00:05:34,211 --> 00:05:36,124 for that particular eye color gene. 123 00:05:36,124 --> 00:05:40,010 And another person, they might have a blue eye color allele. 124 00:05:40,010 --> 00:05:44,343 So the allele is just basically a different version, 125 00:05:45,210 --> 00:05:49,751 slight modification in the sequence of a gene, 126 00:05:49,751 --> 00:05:52,000 which impacts the phenotype. 127 00:05:52,000 --> 00:05:54,445 So it would give you a different phenotype 128 00:05:54,445 --> 00:05:56,708 or you know, slightly different outcome 129 00:05:56,708 --> 00:05:58,973 for that particular trait. 130 00:05:58,973 --> 00:06:01,986 So alleles, you can have many different alleles 131 00:06:01,986 --> 00:06:04,009 sort of in the general population 132 00:06:04,009 --> 00:06:07,285 for a particular gene, you know. 133 00:06:07,285 --> 00:06:10,687 You might have hundreds or more different versions, 134 00:06:10,687 --> 00:06:13,149 slight variations on a particular gene. 135 00:06:13,149 --> 00:06:15,375 Each individual person, 136 00:06:15,375 --> 00:06:18,738 each person will only have two alleles 137 00:06:18,738 --> 00:06:21,574 because you have two copies of each gene. 138 00:06:21,574 --> 00:06:23,961 So you might have two alleles that are exactly the same. 139 00:06:23,961 --> 00:06:25,809 Let's go back to the eye color example. 140 00:06:25,809 --> 00:06:29,142 Maybe both of your parents had blue eyes 141 00:06:31,337 --> 00:06:35,025 and let's say they both donated to you 142 00:06:35,025 --> 00:06:36,750 the blue eye allele. 143 00:06:36,750 --> 00:06:39,925 So you would have, say you'd have blue eyes in that case, 144 00:06:39,925 --> 00:06:41,311 and both of your alleles, 145 00:06:41,311 --> 00:06:43,436 both of your copies of the eye color gene 146 00:06:43,436 --> 00:06:46,749 would be for the blue eye color. 147 00:06:46,749 --> 00:06:50,312 You can also have two different alleles. 148 00:06:50,312 --> 00:06:51,645 So alleles that, 149 00:06:53,498 --> 00:06:57,781 two slightly different versions of the same gene. 150 00:06:57,781 --> 00:06:59,148 And then the question becomes, 151 00:06:59,148 --> 00:07:01,188 what would your phenotype be 152 00:07:01,188 --> 00:07:03,486 if you have two different alleles? 153 00:07:03,486 --> 00:07:04,812 Well, we'll talk about that 154 00:07:04,812 --> 00:07:08,027 in a lot of detail in the next lecture. 155 00:07:08,027 --> 00:07:10,527 So hold on to those questions. 156 00:07:12,063 --> 00:07:14,778 A SNP or single nucleotide polymorphism 157 00:07:14,778 --> 00:07:17,344 is a single base change in a DNA sequence, 158 00:07:17,344 --> 00:07:20,414 which may or may not be associated with a phenotype. 159 00:07:20,414 --> 00:07:22,015 And what I mean by that is, 160 00:07:22,015 --> 00:07:23,729 there could be a slight change. 161 00:07:23,729 --> 00:07:25,874 It's basically changing one base to another base. 162 00:07:25,874 --> 00:07:29,577 So an A towards to a T or a C to an A 163 00:07:29,577 --> 00:07:31,627 or something like that. 164 00:07:31,627 --> 00:07:34,250 And that may result in a different amino acid 165 00:07:34,250 --> 00:07:37,575 being coded for if this is occurring within a gene. 166 00:07:37,575 --> 00:07:40,790 And that may or may not impact the proteins function, 167 00:07:40,790 --> 00:07:45,074 which may or may not impact the phenotype for a gene 168 00:07:45,074 --> 00:07:49,991 or may not impact the phenotype for that particular allele. 169 00:07:52,514 --> 00:07:53,347 All right. 170 00:07:53,347 --> 00:07:55,082 Wild-type is it what we would call 171 00:07:55,082 --> 00:07:57,385 the most common allele of a gene. 172 00:07:57,385 --> 00:08:00,535 So we would refer to sort of what you might consider 173 00:08:00,535 --> 00:08:01,523 the normal copy, 174 00:08:01,523 --> 00:08:03,422 especially if we're talking about a disease. 175 00:08:03,422 --> 00:08:04,825 Now, this isn't really going to be the case 176 00:08:04,825 --> 00:08:07,882 for something like eye color or hair color 177 00:08:07,882 --> 00:08:08,715 or things like that, 178 00:08:08,715 --> 00:08:11,774 but more when we're talking about a disease 179 00:08:11,774 --> 00:08:15,347 versus non-disease, versus, you know, 180 00:08:15,347 --> 00:08:17,109 sort of a normal functioning copy. 181 00:08:17,109 --> 00:08:18,395 The wild-type is going to really be 182 00:08:18,395 --> 00:08:22,110 the normal functioning version of a gene. 183 00:08:22,110 --> 00:08:24,209 But it's considered wild-type. 184 00:08:24,209 --> 00:08:27,973 And it was given that name by earlier geneticists 185 00:08:27,973 --> 00:08:31,723 who were studying genetics in animal species, 186 00:08:33,760 --> 00:08:35,634 different species of animals. 187 00:08:35,634 --> 00:08:36,799 And they would go out into the wild 188 00:08:36,799 --> 00:08:37,757 and they would, you know, 189 00:08:37,757 --> 00:08:42,075 catch their particular animals that they're studying. 190 00:08:42,075 --> 00:08:43,450 And many of them it was, you know, 191 00:08:43,450 --> 00:08:45,247 fruit flies that they would catch. 192 00:08:45,247 --> 00:08:48,274 And so they would say the most common, 193 00:08:48,274 --> 00:08:51,426 the most common phenotypes or traits that they would see, 194 00:08:51,426 --> 00:08:53,623 they would consider those to be the wild ones. 195 00:08:53,623 --> 00:08:56,101 So what you would see out in the wild. 196 00:08:56,101 --> 00:08:58,709 So that's why it actually has the name, Wild-type. 197 00:08:58,709 --> 00:09:01,408 Wild-type really just means the normal version, 198 00:09:01,408 --> 00:09:02,722 the very common version 199 00:09:02,722 --> 00:09:05,548 that's mostly seen in the population. 200 00:09:05,548 --> 00:09:07,009 Mutant would be the allele 201 00:09:07,009 --> 00:09:09,122 with the change in the sequence compared 202 00:09:09,122 --> 00:09:10,771 to the wild-type sequence. 203 00:09:10,771 --> 00:09:13,021 And this mutant most likely 204 00:09:14,748 --> 00:09:17,498 is related to a phenotype change. 205 00:09:19,200 --> 00:09:23,263 And in the case of diseases, most mutant alleles 206 00:09:23,263 --> 00:09:27,136 are actually associated with a person having a disease 207 00:09:27,136 --> 00:09:30,775 or having a greater susceptibility for a disease. 208 00:09:30,775 --> 00:09:33,086 De novo would be what we would refer to 209 00:09:33,086 --> 00:09:35,075 as a new mutation which occurs 210 00:09:35,075 --> 00:09:36,837 spontaneously in an individual. 211 00:09:36,837 --> 00:09:40,749 So it was not inherited from his or her parents. 212 00:09:40,749 --> 00:09:44,745 Monogenic is a disease which is caused by a single gene. 213 00:09:44,745 --> 00:09:48,578 So one gene, for example, in case of a disease 214 00:09:49,772 --> 00:09:53,220 a mutation in one gene would be sufficient 215 00:09:53,220 --> 00:09:56,637 to cause an individual to have a disease. 216 00:09:58,684 --> 00:10:01,745 Multifactorial diseases, these are diseases which are caused 217 00:10:01,745 --> 00:10:04,510 by multiple genes and or environmental influences. 218 00:10:04,510 --> 00:10:06,596 And this is actually most diseases 219 00:10:06,596 --> 00:10:09,683 would fall into the category of being multifactorial. 220 00:10:09,683 --> 00:10:13,583 So they're influenced not just by one gene, say. 221 00:10:13,583 --> 00:10:15,495 Maybe you have a slight influence 222 00:10:15,495 --> 00:10:18,245 from 10, 15, 100 different genes, 223 00:10:19,604 --> 00:10:21,558 and also could be influenced by the environment. 224 00:10:21,558 --> 00:10:25,641 And that could mean any combination of, you know, 225 00:10:26,508 --> 00:10:28,195 of things in a person, say for example, 226 00:10:28,195 --> 00:10:31,058 their diet, their level of exercise, 227 00:10:31,058 --> 00:10:33,819 any other comorbidities they may have. 228 00:10:33,819 --> 00:10:35,782 All of these may start to impact 229 00:10:35,782 --> 00:10:39,120 and influence a multifactorial disease 230 00:10:39,120 --> 00:10:41,072 as opposed to a monogenic disease, 231 00:10:41,072 --> 00:10:43,020 which is really directly caused 232 00:10:43,020 --> 00:10:46,282 by a mutation in a single gene. 233 00:10:46,282 --> 00:10:47,959 We'll talk more about monogenic diseases 234 00:10:47,959 --> 00:10:50,528 in the next lecture as well. 235 00:10:50,528 --> 00:10:51,670 Multifactorial diseases, 236 00:10:51,670 --> 00:10:54,682 we'll go into those in more detail in the next module. 237 00:10:54,682 --> 00:10:55,765 So next week. 238 00:10:57,295 --> 00:10:58,128 All right. 239 00:10:58,128 --> 00:11:00,321 So I sort of gave you an overview with that, 240 00:11:00,321 --> 00:11:01,498 but let's go back one more time 241 00:11:01,498 --> 00:11:02,755 'cause it is pretty important to get 242 00:11:02,755 --> 00:11:05,646 some of these terms correct. 243 00:11:05,646 --> 00:11:07,946 So as you recall there, you have two copies of each gene, 244 00:11:07,946 --> 00:11:09,208 one from each parent, 245 00:11:09,208 --> 00:11:12,219 and the genotype will be the sequence of the gene. 246 00:11:12,219 --> 00:11:16,845 And so for each of us, if we're talking about a gene 247 00:11:16,845 --> 00:11:19,222 which say is on an autosome, right, 248 00:11:19,222 --> 00:11:21,943 we each have two copies of all of those genes. 249 00:11:21,943 --> 00:11:26,148 So our genotype, we would have the genotype 250 00:11:26,148 --> 00:11:31,148 for both the maternal and our paternal copies of each gene. 251 00:11:31,523 --> 00:11:33,609 The phenotype is the traitor characteristic 252 00:11:33,609 --> 00:11:34,937 seen in the patient. 253 00:11:34,937 --> 00:11:36,788 And that would be in the case 254 00:11:36,788 --> 00:11:39,396 of what we'll be discussing more sensibly, 255 00:11:39,396 --> 00:11:44,396 that would be say, having a disease or not having a disease. 256 00:11:44,707 --> 00:11:47,146 And these copies or alleles may have slight differences. 257 00:11:47,146 --> 00:11:50,059 And we talked about this a moment ago with eye color gene 258 00:11:50,059 --> 00:11:52,522 in the population one allele or sequence variant 259 00:11:52,522 --> 00:11:55,285 codes for, for brown eyes, one for blue, one for green, 260 00:11:55,285 --> 00:11:57,184 but they are all the same genes. 261 00:11:57,184 --> 00:11:58,172 When we're talking about different alleles, 262 00:11:58,172 --> 00:12:01,147 these are different alleles of the same gene. 263 00:12:01,147 --> 00:12:02,999 A protein dysfunction related to a disease 264 00:12:02,999 --> 00:12:05,060 results from the patient having at least 265 00:12:05,060 --> 00:12:07,158 one copy of the gene with the disease 266 00:12:07,158 --> 00:12:09,461 or disrupted sequence or the disease allele 267 00:12:09,461 --> 00:12:13,573 or what could be called the mutant allele. 268 00:12:13,573 --> 00:12:15,856 So I just wanna take one more quick moment 269 00:12:15,856 --> 00:12:19,148 to get the concept of alleles down. 270 00:12:19,148 --> 00:12:20,972 And I apologize if this is really being redundant, 271 00:12:20,972 --> 00:12:23,335 but I'd rather be a little bit redundant here 272 00:12:23,335 --> 00:12:27,345 than to just lose you a little bit when we start 273 00:12:27,345 --> 00:12:29,934 throwing around terms like allele, wild-type, you know, 274 00:12:29,934 --> 00:12:32,684 when we move on in this material. 275 00:12:33,953 --> 00:12:36,492 So here's an analogy that might be useful, 276 00:12:36,492 --> 00:12:38,478 I hope it's useful to you. 277 00:12:38,478 --> 00:12:40,719 If you think of alleles, 278 00:12:40,719 --> 00:12:44,386 let's take example of a deck of cards, okay, 279 00:12:45,667 --> 00:12:46,775 a deck of cards. 280 00:12:46,775 --> 00:12:49,382 So like a regular deck of playing cards. 281 00:12:49,382 --> 00:12:54,215 So there are 52 different cards in a typical playing deck. 282 00:12:56,729 --> 00:13:00,476 If we're using an analogy here, you can think of, 283 00:13:00,476 --> 00:13:02,075 this is basically like saying, 284 00:13:02,075 --> 00:13:05,243 there's the, the card gene, right. 285 00:13:05,243 --> 00:13:07,910 So all of the cards in the deck, 286 00:13:09,037 --> 00:13:11,606 even though there are 52 different cards in the deck, 287 00:13:11,606 --> 00:13:12,771 they're all cards, right. 288 00:13:12,771 --> 00:13:14,413 So let's say they're all 289 00:13:14,413 --> 00:13:16,538 different versions of the card gene. 290 00:13:16,538 --> 00:13:19,569 We can call that the card gene. 291 00:13:19,569 --> 00:13:20,986 And there are 52 different versions of it. 292 00:13:20,986 --> 00:13:21,944 That would be like saying 293 00:13:21,944 --> 00:13:24,004 there are 52 different possible alleles. 294 00:13:24,004 --> 00:13:25,212 You could have the 2 of clubs, 295 00:13:25,212 --> 00:13:26,394 you could have the 5 of spades, 296 00:13:26,394 --> 00:13:27,330 you could have the queen of diamonds, 297 00:13:27,330 --> 00:13:28,417 you could have whatever. 298 00:13:28,417 --> 00:13:31,442 Let's say those are all, there are 52 different alleles 299 00:13:31,442 --> 00:13:33,684 or slightly different versions of cards, 300 00:13:33,684 --> 00:13:35,250 but they're all cards 301 00:13:35,250 --> 00:13:38,673 so that they're all alleles of the same gene. 302 00:13:38,673 --> 00:13:41,147 It's just that they have slight changes. 303 00:13:41,147 --> 00:13:45,276 So, you know, a small percentage of the bases 304 00:13:45,276 --> 00:13:48,728 are different between the different copies. 305 00:13:48,728 --> 00:13:50,790 And the same, you know, could be true 306 00:13:50,790 --> 00:13:52,981 if we go back to that analogy of the cards. 307 00:13:52,981 --> 00:13:56,328 So there are 52 different alleles, let's say, 308 00:13:56,328 --> 00:13:59,245 in our population in the card gene. 309 00:14:01,471 --> 00:14:03,982 So for each person you get to have two, 310 00:14:03,982 --> 00:14:05,107 you get to have two alleles, 311 00:14:05,107 --> 00:14:07,585 assuming this gene is on an autosome, right, 312 00:14:07,585 --> 00:14:08,924 Not on an X chromosome, 313 00:14:08,924 --> 00:14:10,925 but on an autosome, you get to have two copies. 314 00:14:10,925 --> 00:14:14,560 So it's like taking two cards from the deck 315 00:14:14,560 --> 00:14:16,341 and you get whatever you get from that. 316 00:14:16,341 --> 00:14:18,970 And those two cards, and you know, 317 00:14:18,970 --> 00:14:22,403 let's say we have more than one deck of cards 318 00:14:22,403 --> 00:14:23,837 that there are there, 319 00:14:23,837 --> 00:14:25,906 let's say we have five decks of cards, okay. 320 00:14:25,906 --> 00:14:28,376 So there are 52 different cards in the deck, 321 00:14:28,376 --> 00:14:30,076 but each of them is present, you know, 322 00:14:30,076 --> 00:14:32,076 in five different cards. 323 00:14:33,074 --> 00:14:35,146 So when you pull two cards, 324 00:14:35,146 --> 00:14:36,580 you might pull two different cards. 325 00:14:36,580 --> 00:14:40,413 You might pull a 2 of clubs and a 7 of spades, 326 00:14:42,402 --> 00:14:45,152 or you might pull two 2 of clubs. 327 00:14:47,494 --> 00:14:49,941 And what we'll talk about in the next lecture would be 328 00:14:49,941 --> 00:14:54,941 how our phenotype can be affected by the different alleles 329 00:14:55,189 --> 00:14:57,347 that the two different alleles that we have. 330 00:14:57,347 --> 00:14:59,186 So let's go back for a second to that analogy again, 331 00:14:59,186 --> 00:15:01,175 I apologize if this isn't coming out 332 00:15:01,175 --> 00:15:03,441 as clearly as it is in my head. 333 00:15:03,441 --> 00:15:06,024 But it's basically like saying, 334 00:15:07,309 --> 00:15:08,691 alleles are slightly different, 335 00:15:08,691 --> 00:15:11,610 or slightly different versions of the same gene, 336 00:15:11,610 --> 00:15:14,037 but they're all the same gene. 337 00:15:14,037 --> 00:15:16,645 So they're all cards in our analogy. 338 00:15:16,645 --> 00:15:18,526 And you can have many different alleles 339 00:15:18,526 --> 00:15:21,058 or slightly different versions of a particular gene 340 00:15:21,058 --> 00:15:24,058 in the population as a whole, right, 341 00:15:25,094 --> 00:15:29,594 but each individual person only possesses two alleles. 342 00:15:30,542 --> 00:15:32,405 And those two alleles might be different from one another 343 00:15:32,405 --> 00:15:35,249 and they might be the same as one another. 344 00:15:35,249 --> 00:15:36,082 Okay. 345 00:15:36,082 --> 00:15:41,082 I hope that kind of starting to make sense a little bit. 346 00:15:41,413 --> 00:15:43,804 So let's take a quick peek at what this might mean 347 00:15:43,804 --> 00:15:46,129 and what are these changes that we're talking about? 348 00:15:46,129 --> 00:15:50,199 So small changes in the sequence are called mutations. 349 00:15:50,199 --> 00:15:54,731 So we would consider that the most common sequence 350 00:15:54,731 --> 00:15:58,281 for a particular gene, again is called the what? 351 00:15:58,281 --> 00:16:01,075 Is called the wild-type allele. 352 00:16:01,075 --> 00:16:03,945 And any derivation from that in terms of the sequence 353 00:16:03,945 --> 00:16:07,031 would be considered a mutation. 354 00:16:07,031 --> 00:16:11,663 The mutation may be harmful in the end to the person, 355 00:16:11,663 --> 00:16:13,192 it may be completely neutral, 356 00:16:13,192 --> 00:16:16,623 actually most mutations are neutral 357 00:16:16,623 --> 00:16:19,146 or it actually may be slightly beneficial 358 00:16:19,146 --> 00:16:22,396 and that would be what drives evolution 359 00:16:23,321 --> 00:16:26,565 and progression of a species and adaptation. 360 00:16:26,565 --> 00:16:28,006 We're not gonna really get into that. 361 00:16:28,006 --> 00:16:29,975 We're gonna really more so focus 362 00:16:29,975 --> 00:16:33,243 on the detrimental side of mutations. 363 00:16:33,243 --> 00:16:35,511 But just keep in mind that actually mutations 364 00:16:35,511 --> 00:16:39,847 are not entirely a bad thing, certainly not for a species 365 00:16:39,847 --> 00:16:43,765 because it can provide genetic diversity, 366 00:16:43,765 --> 00:16:45,349 which can be quite beneficial in, 367 00:16:45,349 --> 00:16:49,408 that if we're responding to changes in our environment, 368 00:16:49,408 --> 00:16:52,852 those individuals who have an ability to say, 369 00:16:52,852 --> 00:16:55,981 survive specific set of conditions 370 00:16:55,981 --> 00:16:59,011 could survive in our species could propagate. 371 00:16:59,011 --> 00:16:59,844 Anyway, we're not gonna really talk about 372 00:16:59,844 --> 00:17:00,802 beneficial mutations. 373 00:17:00,802 --> 00:17:04,870 We're really going to focus on those mutations 374 00:17:04,870 --> 00:17:07,113 which are detrimental. 375 00:17:07,113 --> 00:17:09,365 So mutation is just a slight change. 376 00:17:09,365 --> 00:17:10,963 And let's see, in this particular example, 377 00:17:10,963 --> 00:17:15,040 it would be like taking this sequence here, 378 00:17:15,040 --> 00:17:16,599 let's say we're just showing the single strand 379 00:17:16,599 --> 00:17:19,266 of say, a gene's sequence, okay. 380 00:17:20,439 --> 00:17:21,602 That's just one strand. 381 00:17:21,602 --> 00:17:23,409 And let's say it was actually mutated. 382 00:17:23,409 --> 00:17:26,482 So that's the wild-type say on the top 383 00:17:26,482 --> 00:17:29,047 and on the bottom, this strand here, 384 00:17:29,047 --> 00:17:32,630 so changing that adenine base to a guanine, 385 00:17:33,911 --> 00:17:36,494 this would be a mutant version. 386 00:17:38,144 --> 00:17:39,545 So these could be two different alleles 387 00:17:39,545 --> 00:17:42,378 if they have different phenotypes. 388 00:17:44,106 --> 00:17:46,099 And this one mutation can result 389 00:17:46,099 --> 00:17:49,189 in big changes to the protein function, 390 00:17:49,189 --> 00:17:50,828 which can cause disease, 391 00:17:50,828 --> 00:17:53,079 or again, it may actually have no impact 392 00:17:53,079 --> 00:17:56,246 or it might just have a slight impact. 393 00:17:59,047 --> 00:18:02,058 So let's just take one quick, a couple of examples here. 394 00:18:02,058 --> 00:18:03,997 So, sickle cell disease. 395 00:18:03,997 --> 00:18:06,440 A mutation in the hemoglobin beta gene 396 00:18:06,440 --> 00:18:09,043 results in a change in the hemoglobin protein, 397 00:18:09,043 --> 00:18:11,130 which affects its shape and function, 398 00:18:11,130 --> 00:18:14,043 the shape and function of hemoglobin. 399 00:18:14,043 --> 00:18:16,630 Mutated hemoglobin forms along in flexible chains 400 00:18:16,630 --> 00:18:19,109 in red blood cells making them stiff and angular 401 00:18:19,109 --> 00:18:22,442 and likely to become stuck in small capillaries 402 00:18:22,442 --> 00:18:24,410 reducing oxygen delivery to organs. 403 00:18:24,410 --> 00:18:27,256 So as you can see up here, 404 00:18:27,256 --> 00:18:30,626 the normal shape of hemoglobin is basically, you know, 405 00:18:30,626 --> 00:18:32,829 a nice sort of balled up shape 406 00:18:32,829 --> 00:18:34,269 and it needs to be that shape 407 00:18:34,269 --> 00:18:37,155 so it can properly bind to oxygen 408 00:18:37,155 --> 00:18:41,775 and can keep the red blood cells in normal shape 409 00:18:41,775 --> 00:18:43,269 that our body has adapted to 410 00:18:43,269 --> 00:18:45,732 and they can flow freely through capillaries 411 00:18:45,732 --> 00:18:49,079 and deliver oxygen to throughout the body. 412 00:18:49,079 --> 00:18:50,454 If however, there is a mutation, 413 00:18:50,454 --> 00:18:53,892 it's just actually a single base change, 414 00:18:53,892 --> 00:18:57,771 single base change in the hemoglobin beta gene. 415 00:18:57,771 --> 00:19:00,473 That can result in a change 416 00:19:00,473 --> 00:19:03,270 in the protein structure for hemoglobin beta, 417 00:19:03,270 --> 00:19:06,440 which can cause it to form these long and flexible chains, 418 00:19:06,440 --> 00:19:08,861 which can affect the shapes of the cell. 419 00:19:08,861 --> 00:19:12,083 And these hemoglobin proteins 420 00:19:12,083 --> 00:19:15,791 no longer bind oxygen as well either. 421 00:19:15,791 --> 00:19:18,785 So you have the combined effect of getting, 422 00:19:18,785 --> 00:19:21,264 of the blood cells getting stuck in capillaries 423 00:19:21,264 --> 00:19:22,501 and not being able to deliver oxygen. 424 00:19:22,501 --> 00:19:23,777 But also when they do get there, 425 00:19:23,777 --> 00:19:26,705 the oxygen is actually not bound as well. 426 00:19:26,705 --> 00:19:30,508 So that's an example of a change in a protein 427 00:19:30,508 --> 00:19:33,758 affecting an outcome for an individual. 428 00:19:36,671 --> 00:19:38,785 So in this particular case, in this particular case, 429 00:19:38,785 --> 00:19:41,699 we could be looking at two different, 430 00:19:41,699 --> 00:19:43,976 at least two different alleles here, 431 00:19:43,976 --> 00:19:46,290 the normal or wild-type allele 432 00:19:46,290 --> 00:19:51,244 which would encode the normal functioning hemoglobin here. 433 00:19:51,244 --> 00:19:54,101 And also an allele that has that point, you know, 434 00:19:54,101 --> 00:19:56,186 has a single base mutation 435 00:19:56,186 --> 00:20:00,519 which would result in the hemoglobin being disrupted 436 00:20:02,108 --> 00:20:06,025 and give the phenotype of sickle cell disease. 437 00:20:08,562 --> 00:20:09,443 All right. 438 00:20:09,443 --> 00:20:12,281 Let's look at one more example, cystic fibrosis. 439 00:20:12,281 --> 00:20:14,391 So mutations in the CFTR gene 440 00:20:14,391 --> 00:20:18,272 affect the CFTR protein's ability to move chloride ions 441 00:20:18,272 --> 00:20:20,571 in and out of the cell resulting in sticky mucus 442 00:20:20,571 --> 00:20:23,252 building up on the outside of the cell. 443 00:20:23,252 --> 00:20:25,716 And in the lungs, this mucus buildup can lead to infections 444 00:20:25,716 --> 00:20:28,785 and in the pancreas, the mucus can block digestive enzymes 445 00:20:28,785 --> 00:20:32,072 from being secreted leading to significant health problems. 446 00:20:32,072 --> 00:20:34,960 So here what we're looking at is on the left hand side, 447 00:20:34,960 --> 00:20:38,066 a drawing of a normal functioning CFTR channel, 448 00:20:38,066 --> 00:20:39,425 which is the protein, 449 00:20:39,425 --> 00:20:42,954 the proteins function is to act as basically like a channel 450 00:20:42,954 --> 00:20:46,551 through which ions can flow in and out of the cell, 451 00:20:46,551 --> 00:20:49,422 but you know, through the cell membrane. 452 00:20:49,422 --> 00:20:50,332 So that's the normal function, 453 00:20:50,332 --> 00:20:54,869 it allows chloride ions in and out as the cell needs it 454 00:20:54,869 --> 00:20:56,601 and you don't get this buildup of mucus. 455 00:20:56,601 --> 00:20:59,489 If however, there is a mutation 456 00:20:59,489 --> 00:21:02,335 in the sequence for the CFTR gene, 457 00:21:02,335 --> 00:21:04,475 so that would be a mutant allele, 458 00:21:04,475 --> 00:21:07,946 If a person has mutant allele for this, 459 00:21:07,946 --> 00:21:11,530 then the CFTR protein that's encoded 460 00:21:11,530 --> 00:21:13,810 would not function properly 461 00:21:13,810 --> 00:21:15,449 because it would not be built properly 462 00:21:15,449 --> 00:21:17,354 because it would be told, 463 00:21:17,354 --> 00:21:21,458 the cell would be told to basically form a protein, 464 00:21:21,458 --> 00:21:25,256 the CFTR protein with some changes in the amino acids 465 00:21:25,256 --> 00:21:27,043 than what it should be. 466 00:21:27,043 --> 00:21:29,663 Then the protein itself doesn't function properly 467 00:21:29,663 --> 00:21:31,361 and the chloride ions get stuck. 468 00:21:31,361 --> 00:21:34,611 And it results in the buildup of mucus. 469 00:21:36,661 --> 00:21:38,516 All right. Let's talk about mutations. 470 00:21:38,516 --> 00:21:41,293 So this is a change in A DNA sequence. 471 00:21:41,293 --> 00:21:42,681 New mutations occur randomly 472 00:21:42,681 --> 00:21:45,003 from uncorrected errors in DNA replication. 473 00:21:45,003 --> 00:21:47,572 You remember that. We talked about that. 474 00:21:47,572 --> 00:21:50,155 I believe that was in Module 3, 475 00:21:51,144 --> 00:21:53,811 and from DNA damage by mutagens. 476 00:21:55,234 --> 00:21:56,676 So we'll talk more about mutagens 477 00:21:56,676 --> 00:21:59,349 when we go into the cancer module. 478 00:21:59,349 --> 00:22:02,486 But mutagens are basically like, 479 00:22:02,486 --> 00:22:04,079 you can kind of think of them as like 480 00:22:04,079 --> 00:22:07,162 some toxins or chemicals or you know, 481 00:22:09,035 --> 00:22:11,430 UV radiation from sunlight. 482 00:22:11,430 --> 00:22:13,866 Those types of things can be considered mutagens. 483 00:22:13,866 --> 00:22:16,865 And they basically are essentially chemical structures 484 00:22:16,865 --> 00:22:21,284 that enter the cell and will damage DNA and cause mutations. 485 00:22:21,284 --> 00:22:23,846 Mutations could have been inherited from a parent 486 00:22:23,846 --> 00:22:27,025 or could also have occurred spontaneously in an individual. 487 00:22:27,025 --> 00:22:29,128 And these spontaneous mutations, 488 00:22:29,128 --> 00:22:34,128 which result in disease are called de novo mutations. 489 00:22:34,263 --> 00:22:36,769 Three basic types of changes can happen. 490 00:22:36,769 --> 00:22:38,982 And these are the three basic types of mutations. 491 00:22:38,982 --> 00:22:41,584 So a point mutation or a change in one base to another base, 492 00:22:41,584 --> 00:22:43,284 and this is sometimes called a SNP, 493 00:22:43,284 --> 00:22:46,777 you remember that from the definitions page, 494 00:22:46,777 --> 00:22:49,681 a single nucleotide polymorphism. 495 00:22:49,681 --> 00:22:51,878 You can probably see why we call it SNPs. 496 00:22:51,878 --> 00:22:53,068 It's a little easier to say that 497 00:22:53,068 --> 00:22:55,472 than single nucleotide polymorphism. 498 00:22:55,472 --> 00:22:58,216 It's kind of a mouthful. 499 00:22:58,216 --> 00:23:00,660 A point mutation is just a single change. 500 00:23:00,660 --> 00:23:02,873 Nothing added, nothing removed. 501 00:23:02,873 --> 00:23:03,716 It's just basically, 502 00:23:03,716 --> 00:23:05,478 in this case what we're looking at here, 503 00:23:05,478 --> 00:23:08,695 instead of the cytosine in the third position 504 00:23:08,695 --> 00:23:12,336 of the short sequence we're looking at, it's now an adenine. 505 00:23:12,336 --> 00:23:15,377 So it's a C to an A point mutation 506 00:23:15,377 --> 00:23:17,521 or change in the sequence. 507 00:23:17,521 --> 00:23:20,694 An insertion would be inserting a new base or bases. 508 00:23:20,694 --> 00:23:23,426 And here we're looking at between the two cytosines, 509 00:23:23,426 --> 00:23:25,698 that third in the fourth, we add a thymine. 510 00:23:25,698 --> 00:23:28,031 So it's now one base longer. 511 00:23:29,586 --> 00:23:33,268 And you could have an insertion of one base of, you know, 512 00:23:33,268 --> 00:23:36,781 any number of bases, 2, 3, 5, 10, 20, however many. 513 00:23:36,781 --> 00:23:39,945 A deletion would be deleting an existing base or bases. 514 00:23:39,945 --> 00:23:44,258 So here we're looking at the TGCCC sequences. 515 00:23:44,258 --> 00:23:49,258 Now we're losing one of those cytosines. So it now is TGC. 516 00:23:49,440 --> 00:23:54,440 So one of the cytosines was lost. That's a deletion. 517 00:23:54,478 --> 00:23:57,324 So some possible effects of single nucleotide polymorphisms 518 00:23:57,324 --> 00:24:00,776 on the encoded protein or those point mutations. 519 00:24:00,776 --> 00:24:05,419 The end result, so what can it possibly due to the protein 520 00:24:05,419 --> 00:24:08,502 that could be encoded from this gene, 521 00:24:09,603 --> 00:24:11,539 the mutations could be silent, 522 00:24:11,539 --> 00:24:12,938 which means that while the sequence has changed, 523 00:24:12,938 --> 00:24:15,822 there is no change in the protein encoded. 524 00:24:15,822 --> 00:24:16,930 So this would be, for example, 525 00:24:16,930 --> 00:24:20,158 like a CGG being changed to a CGT. 526 00:24:20,158 --> 00:24:23,207 But both of these actually encode for alanine, 527 00:24:23,207 --> 00:24:24,426 the amino acid alanine. 528 00:24:24,426 --> 00:24:27,952 Go look at your amino acid chart if that's helpful to you. 529 00:24:27,952 --> 00:24:29,592 And you, so you can see, 530 00:24:29,592 --> 00:24:31,466 so the protein is the same either way. 531 00:24:31,466 --> 00:24:33,492 So there's no effect on phenotype. 532 00:24:33,492 --> 00:24:35,454 So this is a silent mutation. 533 00:24:35,454 --> 00:24:37,021 And we actually have quite a few of these 534 00:24:37,021 --> 00:24:40,753 because there's no selection against those. 535 00:24:40,753 --> 00:24:42,074 So individuals will survive. 536 00:24:42,074 --> 00:24:43,767 There'll be no effect whatsoever 537 00:24:43,767 --> 00:24:47,874 if this particular kind of silent mutation occurs 538 00:24:47,874 --> 00:24:52,220 because the codon still encodes for the same amino acid, 539 00:24:52,220 --> 00:24:54,208 'cause if you remember, there are only 20 amino acids, 540 00:24:54,208 --> 00:24:57,177 but there's 64 different possible 541 00:24:57,177 --> 00:24:59,677 DNA triplets or codons, right? 542 00:25:00,956 --> 00:25:01,789 You remember that? 543 00:25:01,789 --> 00:25:03,692 That occurs in translation where the ribosome 544 00:25:03,692 --> 00:25:08,357 is reading each of the triplets, each of the codons. 545 00:25:08,357 --> 00:25:09,658 And each of those triplets, 546 00:25:09,658 --> 00:25:12,718 it's telling it a specific amino acid to add. 547 00:25:12,718 --> 00:25:14,480 Well, there's what's called redundancy, 548 00:25:14,480 --> 00:25:18,337 which basically means that as we talked about before, 549 00:25:18,337 --> 00:25:19,574 since there are only 20 amino acids 550 00:25:19,574 --> 00:25:22,705 and there's 64 different possible codons, 551 00:25:22,705 --> 00:25:23,844 that each amino acid actually 552 00:25:23,844 --> 00:25:26,723 has multiple different codons that encode it. 553 00:25:26,723 --> 00:25:28,744 So you can have a single base change 554 00:25:28,744 --> 00:25:31,318 and actually have no change whatsoever 555 00:25:31,318 --> 00:25:35,037 in the amino acid that it's encoding. 556 00:25:35,037 --> 00:25:35,870 All right. 557 00:25:35,870 --> 00:25:37,046 See, it's all starting to come together. 558 00:25:37,046 --> 00:25:39,202 Hopefully you're starting to see that, 559 00:25:39,202 --> 00:25:42,320 that all the hard work you put into 560 00:25:42,320 --> 00:25:44,435 learning the material in the first couple of modules 561 00:25:44,435 --> 00:25:49,269 is starting to come back around now and be reinforced. 562 00:25:49,269 --> 00:25:51,211 So that's the idea anyway. 563 00:25:51,211 --> 00:25:55,378 Okay, so the next type of possible effect of a SNP 564 00:25:56,384 --> 00:25:59,774 will be a missense mutation, a missense. 565 00:25:59,774 --> 00:26:02,751 So again, there's some funny words in genetics. 566 00:26:02,751 --> 00:26:05,356 And we talked about the antisense strand. 567 00:26:05,356 --> 00:26:07,615 This is a missense mutation. 568 00:26:07,615 --> 00:26:09,394 And missense, it means it results 569 00:26:09,394 --> 00:26:12,805 in one amino acid change in the protein. 570 00:26:12,805 --> 00:26:16,253 So let's take an example of that CGG sequence, 571 00:26:16,253 --> 00:26:18,564 instead of it being changed to CGT, 572 00:26:18,564 --> 00:26:21,043 which was coding for the same amino acid, 573 00:26:21,043 --> 00:26:22,485 let's say that the mutation 574 00:26:22,485 --> 00:26:25,164 was changing that first C to a T. 575 00:26:25,164 --> 00:26:27,138 So now it's a TGG. 576 00:26:27,138 --> 00:26:28,717 This would change the protein from having 577 00:26:28,717 --> 00:26:31,379 an alanine in that location to having a threonine. 578 00:26:31,379 --> 00:26:33,001 So if you look up on your chart, 579 00:26:33,001 --> 00:26:36,837 you would see that a CGG codes for alanine, 580 00:26:36,837 --> 00:26:38,574 but a TGG codes for threonine, 581 00:26:38,574 --> 00:26:40,658 which is a different amino acid. 582 00:26:40,658 --> 00:26:42,112 But would only affect that one 583 00:26:42,112 --> 00:26:44,983 where the mutation is located. 584 00:26:44,983 --> 00:26:48,304 And this may have an effect on the phenotype, 585 00:26:48,304 --> 00:26:50,529 by possibly changing the protein shape 586 00:26:50,529 --> 00:26:52,183 and therefore its function. 587 00:26:52,183 --> 00:26:54,912 And certainly there are diseases as we already talked about. 588 00:26:54,912 --> 00:26:56,582 Sickle cell disease is the result 589 00:26:56,582 --> 00:26:59,665 of a single amino acid being changed. 590 00:27:00,648 --> 00:27:03,483 Now, that's not the case for most amino acids, 591 00:27:03,483 --> 00:27:05,589 I'd say and most proteins. 592 00:27:05,589 --> 00:27:07,544 There's a little bit of flexibility 593 00:27:07,544 --> 00:27:09,142 in terms of their functions, 594 00:27:09,142 --> 00:27:11,848 so being maintained even if there's a single change. 595 00:27:11,848 --> 00:27:15,529 But there are those very specific amino acids 596 00:27:15,529 --> 00:27:18,775 which are really important to have the right ones there. 597 00:27:18,775 --> 00:27:22,738 And so missense mutations can actually cause 598 00:27:22,738 --> 00:27:25,761 or lead to certainly disease. 599 00:27:25,761 --> 00:27:27,937 A nonsense mutation results in a truncated protein 600 00:27:27,937 --> 00:27:31,270 because of the creation of a stop codon. 601 00:27:32,252 --> 00:27:34,720 So let's take the example of our original, 602 00:27:34,720 --> 00:27:39,163 our wild-type, remember our wild-type sequence is TTT 603 00:27:39,163 --> 00:27:41,955 and that this is now mutated to ATT, 604 00:27:41,955 --> 00:27:43,600 which would result in the ribosomes 605 00:27:43,600 --> 00:27:46,356 reading a stop signal instead of a lysine. 606 00:27:46,356 --> 00:27:48,852 So none of the codons following this mutation 607 00:27:48,852 --> 00:27:52,485 will be read or translated resulting in a shortened protein. 608 00:27:52,485 --> 00:27:55,236 So TTT codes for lysine. 609 00:27:55,236 --> 00:27:56,227 And what you would normally have, 610 00:27:56,227 --> 00:27:59,950 let's say this was part of your mRNA sequence, 611 00:27:59,950 --> 00:28:02,139 or well rather, let's say this is part of your DNA sequence, 612 00:28:02,139 --> 00:28:06,071 it gets transcribed, right, into mRNA. 613 00:28:06,071 --> 00:28:09,821 So the mRNA would read UUU and that would be, 614 00:28:11,768 --> 00:28:15,086 the ribozone would read that and say, okay, that's a lysine, 615 00:28:15,086 --> 00:28:16,742 and then it would move on to the next codon 616 00:28:16,742 --> 00:28:17,575 and move on to the next 617 00:28:17,575 --> 00:28:19,978 and move on to the next, move on to the next. 618 00:28:19,978 --> 00:28:23,489 Well, in the case of a nonsense mutation, 619 00:28:23,489 --> 00:28:26,516 that changes the codon from a codon 620 00:28:26,516 --> 00:28:31,282 which would normally encode for an amino acid to a stop. 621 00:28:31,282 --> 00:28:34,245 So now the ribosome gets to that sequence 622 00:28:34,245 --> 00:28:37,956 and says, oh, that means stop and it falls off. 623 00:28:37,956 --> 00:28:41,675 And the problem is not only do you not translate 624 00:28:41,675 --> 00:28:44,258 or incorporate that particular, 625 00:28:46,734 --> 00:28:50,502 in this case, lysine into the growing protein chain, 626 00:28:50,502 --> 00:28:53,501 you also don't continue on with the rest of, 627 00:28:53,501 --> 00:28:54,830 reading the rest of that mRNA. 628 00:28:54,830 --> 00:28:56,779 So anything downstream 629 00:28:56,779 --> 00:28:59,862 or that comes after that new mutation 630 00:29:01,124 --> 00:29:04,428 or that that nonsense mutation doesn't get read. 631 00:29:04,428 --> 00:29:09,205 And so the protein basically is short or truncated 632 00:29:09,205 --> 00:29:13,197 because none of the rest of what comes after that stop, 633 00:29:13,197 --> 00:29:16,782 what is now a stop codon gets read by the ribosome. 634 00:29:16,782 --> 00:29:19,990 So this can be a big, big problem. And it often is. 635 00:29:19,990 --> 00:29:22,801 So if there's a nonsense mutation that happens, 636 00:29:22,801 --> 00:29:27,267 basically a protein will be either very, you know, 637 00:29:27,267 --> 00:29:30,781 have a severely reduced function to it, 638 00:29:30,781 --> 00:29:33,636 or it will actually be completely non-functional whatsoever, 639 00:29:33,636 --> 00:29:36,502 which can be a real problem 640 00:29:36,502 --> 00:29:39,867 and can certainly lead to disease. 641 00:29:39,867 --> 00:29:42,339 Let's take a quick peek at what I'm talking about here 642 00:29:42,339 --> 00:29:46,109 so you can see it more visually here. 643 00:29:46,109 --> 00:29:48,732 Silent mutation and let's just orient ourselves 644 00:29:48,732 --> 00:29:50,200 to what we're looking at. 645 00:29:50,200 --> 00:29:53,878 On the top here is the DNA template strand. 646 00:29:53,878 --> 00:29:57,083 So that would be the, you know, the two strands. 647 00:29:57,083 --> 00:30:00,655 And the mRNA that gets transcribed off of that. 648 00:30:00,655 --> 00:30:02,370 And then the protein, 649 00:30:02,370 --> 00:30:05,396 the amino acid sequence, which gets read, 650 00:30:05,396 --> 00:30:08,563 and again, you can go back to your amino acid table 651 00:30:08,563 --> 00:30:12,107 to confirm that these, this is what it basically would read. 652 00:30:12,107 --> 00:30:14,247 But let's say that this is, you know, this is the wild-type. 653 00:30:14,247 --> 00:30:18,117 Again, remember wild-type for normal functioning sequence. 654 00:30:18,117 --> 00:30:21,534 And here you have the, the normal, let's say, 655 00:30:21,534 --> 00:30:23,449 I mean this would be extremely short word protein. 656 00:30:23,449 --> 00:30:26,397 This is just for demonstration purposes only. 657 00:30:26,397 --> 00:30:30,314 Normal proteins are I think in the range of, 658 00:30:30,314 --> 00:30:34,524 I mean at least three, 400 amino acids usually. 659 00:30:34,524 --> 00:30:36,574 So they're much, much longer than this. 660 00:30:36,574 --> 00:30:38,332 And some of them are are, you know, 661 00:30:38,332 --> 00:30:41,161 even in thousands of amino acids long. 662 00:30:41,161 --> 00:30:42,871 But let's just look at this. 663 00:30:42,871 --> 00:30:44,844 This is just for demonstration purposes. 664 00:30:44,844 --> 00:30:49,742 You have your methionine, lysine, phenylalanine, glycine, 665 00:30:49,742 --> 00:30:52,992 and then it reads this stop codon here. 666 00:30:53,875 --> 00:30:54,800 Well, in this case, 667 00:30:54,800 --> 00:30:59,467 let's say that the guanine here was mutated to an adine, 668 00:31:01,048 --> 00:31:02,699 so an A instead of a G. 669 00:31:02,699 --> 00:31:04,782 So this gets read as GGU, 670 00:31:06,581 --> 00:31:09,774 but that still codes for glycine. 671 00:31:09,774 --> 00:31:13,390 GGC and the mRNA and GGU both code for glycine. 672 00:31:13,390 --> 00:31:14,690 So this is a silent mutation. 673 00:31:14,690 --> 00:31:16,693 There's no change in the protein, 674 00:31:16,693 --> 00:31:18,893 in the amino acid sequence and stuff. 675 00:31:18,893 --> 00:31:21,390 So there's no change in the protein whatsoever. 676 00:31:21,390 --> 00:31:24,416 So there's no detriment to this. 677 00:31:24,416 --> 00:31:25,249 Okay. 678 00:31:25,249 --> 00:31:27,951 A missense mutation, a missense mutation. 679 00:31:27,951 --> 00:31:29,044 let's look again, 680 00:31:29,044 --> 00:31:31,286 same type of sequence that we were looking at 681 00:31:31,286 --> 00:31:32,477 the previous slide here. 682 00:31:32,477 --> 00:31:36,548 Let's say instead of the C in this location 683 00:31:36,548 --> 00:31:38,254 and the wild-type strain, 684 00:31:38,254 --> 00:31:41,365 wild-type strand, rather, there's now a T. 685 00:31:41,365 --> 00:31:42,485 So a T instead of a C. 686 00:31:42,485 --> 00:31:43,999 And what does that change? 687 00:31:43,999 --> 00:31:48,999 Well now, instead of it being GGC in the mRNA, it's now AGC, 688 00:31:49,451 --> 00:31:52,789 which is a codon which encodes for serine, 689 00:31:52,789 --> 00:31:55,613 serine as opposed to glycine. 690 00:31:55,613 --> 00:31:59,383 So there is one amino acid difference in this protein 691 00:31:59,383 --> 00:32:01,867 as a result of a missense mutation. 692 00:32:01,867 --> 00:32:03,762 So generally missense mutations, 693 00:32:03,762 --> 00:32:05,998 so silent mutations are really, you know, 694 00:32:05,998 --> 00:32:08,707 not going to have any effect whatsoever on a person. 695 00:32:08,707 --> 00:32:10,374 A missense mutation, 696 00:32:12,835 --> 00:32:17,329 very specific ones can have detriments to a person. 697 00:32:17,329 --> 00:32:19,425 But generally, they're more tolerable 698 00:32:19,425 --> 00:32:21,779 because it's single amino acid be changed. 699 00:32:21,779 --> 00:32:23,018 And unless that amino acid 700 00:32:23,018 --> 00:32:25,767 is in a really important location for the protein, 701 00:32:25,767 --> 00:32:29,243 then the protein and overall the cell 702 00:32:29,243 --> 00:32:30,779 and therefore the individual might be able 703 00:32:30,779 --> 00:32:33,424 to tolerate in a missense mutation. 704 00:32:33,424 --> 00:32:35,334 A nonsense mutation, this is the one that results 705 00:32:35,334 --> 00:32:38,762 in the truncated protein because you're adding, 706 00:32:38,762 --> 00:32:41,429 you're now creating a stop codon 707 00:32:42,758 --> 00:32:45,859 earlier on in the chain, right, 708 00:32:45,859 --> 00:32:47,513 remember because it gets read 709 00:32:47,513 --> 00:32:52,359 just like you're reading a sentence from left to right. 710 00:32:52,359 --> 00:32:56,108 The ribosome is also reading the mRNA from left to right. 711 00:32:56,108 --> 00:32:59,328 So as soon as it hits what it reads as a stop codon, 712 00:32:59,328 --> 00:33:02,954 it stops, the ribosome falls off and the protein is done. 713 00:33:02,954 --> 00:33:05,259 No matter what stage it's at, it doesn't keep going 714 00:33:05,259 --> 00:33:07,390 because it reads that as a stop codon. 715 00:33:07,390 --> 00:33:11,553 So in this case, instead of the T located here, 716 00:33:11,553 --> 00:33:13,981 this is now mutated to an A, 717 00:33:13,981 --> 00:33:17,898 and this gets read as a UAG in the mRNA rather. 718 00:33:20,049 --> 00:33:23,775 And so, basically the protein stops being formed right here, 719 00:33:23,775 --> 00:33:25,319 and there's really nothing to it. 720 00:33:25,319 --> 00:33:28,275 It doesn't have the meat of the protein. 721 00:33:28,275 --> 00:33:31,912 So any amino acids that would be encoded, 722 00:33:31,912 --> 00:33:35,330 any past this stop codon just will never 723 00:33:35,330 --> 00:33:36,561 see the light of day. 724 00:33:36,561 --> 00:33:38,120 They'll never be read by the ribosomes. 725 00:33:38,120 --> 00:33:39,702 'cause the ribosomes reach that stop, 726 00:33:39,702 --> 00:33:41,407 'cause again, remember they're moving left to right, 727 00:33:41,407 --> 00:33:43,761 they're sliding along, read three, move up, 728 00:33:43,761 --> 00:33:46,345 slide along, read three, get up, move read three. 729 00:33:46,345 --> 00:33:49,809 But here it reads three, it puts methionine, 730 00:33:49,809 --> 00:33:50,923 it moves over to the next three 731 00:33:50,923 --> 00:33:53,821 and it reads up, stop, our job's done, you know. 732 00:33:53,821 --> 00:33:55,234 It's quitting time 733 00:33:55,234 --> 00:33:58,236 and the ribosome drops off and that's it for the protein. 734 00:33:58,236 --> 00:33:59,646 It's basically doesn't get 735 00:33:59,646 --> 00:34:02,563 any more amino acids added onto it. 736 00:34:03,794 --> 00:34:04,627 All right. 737 00:34:04,627 --> 00:34:07,208 Let's think about insertions and deletions. 738 00:34:07,208 --> 00:34:09,310 So there's a couple of different effects that can happen 739 00:34:09,310 --> 00:34:10,877 and these tend to be more severe. 740 00:34:10,877 --> 00:34:13,230 So when there's an insertion or a deletion, 741 00:34:13,230 --> 00:34:14,643 these tend to be more severe 742 00:34:14,643 --> 00:34:16,757 and we'll talk about why in a moment 743 00:34:16,757 --> 00:34:21,169 it's more severe than a point mutation or a SNP. 744 00:34:21,169 --> 00:34:22,625 So an in-frame insertion, 745 00:34:22,625 --> 00:34:24,555 this would be one or more complete codons 746 00:34:24,555 --> 00:34:27,551 inserted without disrupting any of the existing codons 747 00:34:27,551 --> 00:34:30,781 resulting in one or more added amino acids to the protein. 748 00:34:30,781 --> 00:34:32,019 Okay. That's a lot of words. 749 00:34:32,019 --> 00:34:34,945 And I'll show you visually what this means in a moment. 750 00:34:34,945 --> 00:34:36,316 So just hang with me for a second. 751 00:34:36,316 --> 00:34:38,964 Just wanna get a few definitions out of the way. 752 00:34:38,964 --> 00:34:41,720 An in-frame deletion would be deleting 753 00:34:41,720 --> 00:34:44,126 one or more complete codons without disrupting 754 00:34:44,126 --> 00:34:45,738 any of the existing codons, 755 00:34:45,738 --> 00:34:47,421 which results in one or more amino acids 756 00:34:47,421 --> 00:34:50,736 removed from the protein, okay. 757 00:34:50,736 --> 00:34:53,020 So remember before when we were talking about, 758 00:34:53,020 --> 00:34:55,242 say, a missense mutation, 759 00:34:55,242 --> 00:34:57,864 which would be changing one amino acid 760 00:34:57,864 --> 00:34:59,053 to a different amino acid. 761 00:34:59,053 --> 00:35:02,047 In this case where with in-frame insertions or deletions, 762 00:35:02,047 --> 00:35:05,216 you're adding, adding one more amino acid 763 00:35:05,216 --> 00:35:07,563 or taking away one amino acid. 764 00:35:07,563 --> 00:35:09,271 It's not that you're changing one, 765 00:35:09,271 --> 00:35:12,213 you're just adding one or you're taking one away. 766 00:35:12,213 --> 00:35:14,244 A frame shift insertion or deletion, 767 00:35:14,244 --> 00:35:15,911 which is actually the most likely 768 00:35:15,911 --> 00:35:18,598 kind of insertion or deletion 769 00:35:18,598 --> 00:35:21,610 results in all codons following the insertion or deletion 770 00:35:21,610 --> 00:35:23,402 of one or more bases 771 00:35:23,402 --> 00:35:25,193 and that disrupts the codons following 772 00:35:25,193 --> 00:35:27,738 the insertion or deletion to be incorrect. 773 00:35:27,738 --> 00:35:29,572 So all of the amino acids in the protein 774 00:35:29,572 --> 00:35:32,682 coded for after the mutation will be incorrect. 775 00:35:32,682 --> 00:35:35,735 So that means all the triplets are off by one or two. 776 00:35:35,735 --> 00:35:38,156 And as you can imagine, that's a real problem. 777 00:35:38,156 --> 00:35:39,126 Let's take a look at that. 778 00:35:39,126 --> 00:35:40,071 But first, let's take a peek 779 00:35:40,071 --> 00:35:43,488 at the in-frame insertions and deletions. 780 00:35:44,592 --> 00:35:46,709 So in-frame versus frameshift, 781 00:35:46,709 --> 00:35:49,873 frameshift is bad news for the protein. 782 00:35:49,873 --> 00:35:52,038 it really, really is. 783 00:35:52,038 --> 00:35:54,100 So, let's take a look at why that might be. 784 00:35:54,100 --> 00:35:55,867 And if you think about this, 785 00:35:55,867 --> 00:35:57,873 if you use the analogy of thinking about 786 00:35:57,873 --> 00:36:02,873 reading an mRNA as if you were reading words in a sentence, 787 00:36:02,972 --> 00:36:05,256 the order of the letters that compose 788 00:36:05,256 --> 00:36:08,307 the sentence are very important. 789 00:36:08,307 --> 00:36:09,295 And it's also important 790 00:36:09,295 --> 00:36:11,955 where you put the spaces between those words. 791 00:36:11,955 --> 00:36:13,257 And that's kind of like thinking 792 00:36:13,257 --> 00:36:16,786 of the letters and the words being like each base 793 00:36:16,786 --> 00:36:19,363 and the space between them being like, 794 00:36:19,363 --> 00:36:22,101 reading one versus the next versus the next. 795 00:36:22,101 --> 00:36:24,086 So if in the wild-type, 796 00:36:24,086 --> 00:36:26,921 let's say that the wild-type would be like the sentence. 797 00:36:26,921 --> 00:36:29,733 So we're using sentences made up of three letter words 798 00:36:29,733 --> 00:36:30,956 because it's like, 799 00:36:30,956 --> 00:36:33,696 sort of like the three base codons, right. 800 00:36:33,696 --> 00:36:36,218 So each letter is like a base 801 00:36:36,218 --> 00:36:38,735 and each word here is like a codon, okay. 802 00:36:38,735 --> 00:36:41,832 And let's say that the sentence is like the protein. 803 00:36:41,832 --> 00:36:43,162 All right. 804 00:36:43,162 --> 00:36:45,290 So if we were reading the wild-type, let's say, 805 00:36:45,290 --> 00:36:50,119 the wild-type sentence is, the red bug bit the dog. 806 00:36:50,119 --> 00:36:52,850 For an in-frame insertion, 807 00:36:52,850 --> 00:36:56,325 we're adding in another three bases, say, 808 00:36:56,325 --> 00:36:59,573 we're adding in a a basically one additional codon, 809 00:36:59,573 --> 00:37:01,600 so it would be in inserting three bases 810 00:37:01,600 --> 00:37:05,601 and it doesn't change, basically adjust 811 00:37:05,601 --> 00:37:07,399 how the rest of the codons are read. 812 00:37:07,399 --> 00:37:10,642 So in this case it would be like adding the word top. 813 00:37:10,642 --> 00:37:14,006 So now it would be, the red top bug bit the dog. 814 00:37:14,006 --> 00:37:15,442 So that's a little bit different, 815 00:37:15,442 --> 00:37:17,602 a little bit different than the wild-type sentence, 816 00:37:17,602 --> 00:37:19,980 so, the red bug bit the dog. 817 00:37:19,980 --> 00:37:22,551 Now it reads, the red top bug bit the dog. 818 00:37:22,551 --> 00:37:23,554 So that might make a difference 819 00:37:23,554 --> 00:37:25,120 in terms of the proteins function. 820 00:37:25,120 --> 00:37:26,791 An in-frame deletion would be like 821 00:37:26,791 --> 00:37:30,482 removing one of the words or one of the codons. 822 00:37:30,482 --> 00:37:33,131 So now it would read, the bug bit the dog. 823 00:37:33,131 --> 00:37:34,734 So you're missing some information here, right? 824 00:37:34,734 --> 00:37:37,168 So before it was, the red bug bit the dog, 825 00:37:37,168 --> 00:37:39,129 now it's just, the bug bit the dog. 826 00:37:39,129 --> 00:37:40,916 So we lost red. 827 00:37:40,916 --> 00:37:43,102 But you can still kind of understand the sentence. 828 00:37:43,102 --> 00:37:45,513 I mean, it still makes sense. 829 00:37:45,513 --> 00:37:47,080 It's still providing you some information, 830 00:37:47,080 --> 00:37:48,424 just a little less. 831 00:37:48,424 --> 00:37:51,223 So most likely an in-frame deletion like this, 832 00:37:51,223 --> 00:37:54,794 that's especially one that's just deleting a single codon 833 00:37:54,794 --> 00:37:56,754 would really probably not have 834 00:37:56,754 --> 00:38:00,170 a dramatic impact on the proteins function. 835 00:38:00,170 --> 00:38:02,522 However, if we start messing around 836 00:38:02,522 --> 00:38:06,022 with the frame of how the codons are read, 837 00:38:07,743 --> 00:38:09,520 here, you get into some trouble. 838 00:38:09,520 --> 00:38:10,910 So a frameshift insertion, 839 00:38:10,910 --> 00:38:14,284 so let's say we're adding in a single nucleotide. 840 00:38:14,284 --> 00:38:17,789 Let's say, in this case you're adding a single base. 841 00:38:17,789 --> 00:38:20,518 So we'll use, and this is our analogy 842 00:38:20,518 --> 00:38:22,161 of using letters instead of bases. 843 00:38:22,161 --> 00:38:25,046 So let's just like adding the letter F 844 00:38:25,046 --> 00:38:28,264 into the sentence that we had before. 845 00:38:28,264 --> 00:38:32,801 But you still have to read each of these in groups of three. 846 00:38:32,801 --> 00:38:36,634 So now it would be, the ref dbu gbi tth edo g. 847 00:38:40,267 --> 00:38:42,899 Okay, that doesn't make any sense, right? 848 00:38:42,899 --> 00:38:44,891 I mean you still get the word the, 849 00:38:44,891 --> 00:38:45,724 that kind of makes sense. 850 00:38:45,724 --> 00:38:47,172 That's fine. That's just the same. 851 00:38:47,172 --> 00:38:51,149 But anything that comes after that frameshift insertion 852 00:38:51,149 --> 00:38:52,548 gets all totally screwed up. 853 00:38:52,548 --> 00:38:56,328 And now, the ribosomes rather, are reading these codons 854 00:38:56,328 --> 00:38:59,678 which are now all off by one, which totally screws it up 855 00:38:59,678 --> 00:39:01,672 because now when it goes to read that, 856 00:39:01,672 --> 00:39:04,131 it's coding for completely different amino acids, 857 00:39:04,131 --> 00:39:06,846 which means the protein's totally different. 858 00:39:06,846 --> 00:39:08,271 It makes no sense. 859 00:39:08,271 --> 00:39:10,037 The same thing is true for a deletion, 860 00:39:10,037 --> 00:39:12,527 let's say deleting a single nucleotide. 861 00:39:12,527 --> 00:39:15,234 And again, we're demonstrating that 862 00:39:15,234 --> 00:39:18,033 through taking out one of the letters. 863 00:39:18,033 --> 00:39:22,033 Now what it would be is, the reb ugb itt hed og. 864 00:39:23,590 --> 00:39:26,181 Yeah, that doesn't make any sense either. 865 00:39:26,181 --> 00:39:30,211 Same thing with in insertion for a frameshift deletion, 866 00:39:30,211 --> 00:39:32,063 you know, anything that comes after 867 00:39:32,063 --> 00:39:34,873 where that deletion occurred doesn't make any sense anymore. 868 00:39:34,873 --> 00:39:36,698 And now the protein's totally different, 869 00:39:36,698 --> 00:39:38,961 probably loses its function altogether 870 00:39:38,961 --> 00:39:42,412 or starts doing something crazy that it shouldn't be doing. 871 00:39:42,412 --> 00:39:45,541 And this can definitely lead to disease. 872 00:39:45,541 --> 00:39:47,712 Let's take a quick peek at what we're talking about here. 873 00:39:47,712 --> 00:39:49,488 So in-frame insertion, 874 00:39:49,488 --> 00:39:50,821 here you have the wild-type sequence, 875 00:39:50,821 --> 00:39:53,118 the DNA sequence on the top in blue, 876 00:39:53,118 --> 00:39:54,408 followed by the mRNA sequence in red, 877 00:39:54,408 --> 00:39:55,654 and then the protein sequence, 878 00:39:55,654 --> 00:39:56,487 and I'm writing that out 879 00:39:56,487 --> 00:40:01,487 as the three letter designation for each amino acid. 880 00:40:01,607 --> 00:40:03,733 So this is our wild-type sequence. 881 00:40:03,733 --> 00:40:04,930 Then an in-frame insertion 882 00:40:04,930 --> 00:40:06,942 means we're adding exactly three bases 883 00:40:06,942 --> 00:40:09,025 or something divisible by 884 00:40:09,968 --> 00:40:12,864 or number divisible by three number of bases. 885 00:40:12,864 --> 00:40:15,663 And you're also maintaining the frame. 886 00:40:15,663 --> 00:40:18,369 So here we're adding in a TCT, let's say, 887 00:40:18,369 --> 00:40:22,202 or an AGA right in between codons two and four 888 00:40:24,637 --> 00:40:25,901 or two and three rather. 889 00:40:25,901 --> 00:40:28,865 So basically now our protein, 890 00:40:28,865 --> 00:40:30,872 what does our protein look like? 891 00:40:30,872 --> 00:40:35,607 So methionine, glutamine, now there's an arginine 892 00:40:35,607 --> 00:40:37,713 and then it's followed by the rest of the, you know, 893 00:40:37,713 --> 00:40:38,975 the regular sequence of the protein. 894 00:40:38,975 --> 00:40:43,142 Cystine, prolene, prolene, leucine, glutamic acid. 895 00:40:44,947 --> 00:40:45,780 All right. 896 00:40:45,780 --> 00:40:47,458 So the protein has one additional amino acid 897 00:40:47,458 --> 00:40:48,563 is the end result. 898 00:40:48,563 --> 00:40:49,572 Similarly for deletion, 899 00:40:49,572 --> 00:40:51,822 it's basically like taking out exactly 900 00:40:51,822 --> 00:40:53,955 the three nucleotides, 901 00:40:53,955 --> 00:40:55,887 which would encode for a single codon. 902 00:40:55,887 --> 00:40:57,941 So nothing gets shifted around, 903 00:40:57,941 --> 00:41:00,241 but you have one fewer amino acid there. 904 00:41:00,241 --> 00:41:03,221 So now we've lost our cysteine. 905 00:41:03,221 --> 00:41:06,090 And so it's methionine, glutamine, proline, proline, 906 00:41:06,090 --> 00:41:10,736 leucine, glutamic acid, and the cysteine is now gone. 907 00:41:10,736 --> 00:41:13,770 So this can have an impact on the protein certainly, 908 00:41:13,770 --> 00:41:17,264 but it's not totally screwing everything up. 909 00:41:17,264 --> 00:41:19,186 Now if we wanna start screwing stuff up, 910 00:41:19,186 --> 00:41:22,678 let's take a look at what a frameshift insertion would do. 911 00:41:22,678 --> 00:41:24,992 What would insertion do? 912 00:41:24,992 --> 00:41:26,965 Well, let's say, we're just adding one nucleotide. 913 00:41:26,965 --> 00:41:28,522 Like what can that hurt, right? 914 00:41:28,522 --> 00:41:29,681 Just putting one base in those. 915 00:41:29,681 --> 00:41:31,887 Those other two examples, you're adding three bases. 916 00:41:31,887 --> 00:41:34,099 Shouldn't that have a bigger impact? 917 00:41:34,099 --> 00:41:36,340 Well, no, because it totally changes 918 00:41:36,340 --> 00:41:39,813 and shifts the way the ribosomes are reading 919 00:41:39,813 --> 00:41:41,030 those triplets of bases, 920 00:41:41,030 --> 00:41:44,124 which is so important, so important. 921 00:41:44,124 --> 00:41:47,525 So one little base off and everything gets screwed up. 922 00:41:47,525 --> 00:41:49,571 Just like those words in the sentence 923 00:41:49,571 --> 00:41:51,166 that we were just talking about, 924 00:41:51,166 --> 00:41:54,230 you shift things over one to the left or one to the right 925 00:41:54,230 --> 00:41:56,483 and it doesn't make any sense anymore, right? 926 00:41:56,483 --> 00:41:57,566 It's gibberish. 927 00:41:57,566 --> 00:42:01,191 And that's kind of what happens to the protein. 928 00:42:01,191 --> 00:42:02,840 So let's take this example. 929 00:42:02,840 --> 00:42:04,757 We're adding an A here. 930 00:42:05,707 --> 00:42:08,314 And so everything basically 931 00:42:08,314 --> 00:42:10,977 gets shifted over to the right by one 932 00:42:10,977 --> 00:42:14,452 as far as how the ribosome is going to read the sequence. 933 00:42:14,452 --> 00:42:17,725 So now the ribosome reads a UG, yep, same as before, 934 00:42:17,725 --> 00:42:20,820 CAA, yep, same as before, but now it's reading AUG, 935 00:42:20,820 --> 00:42:23,404 which is methionine as a cysteine. 936 00:42:23,404 --> 00:42:27,487 So, it basically has totally shifted over by one. 937 00:42:28,417 --> 00:42:31,358 So instead of reading it the normal way it's supposed to, 938 00:42:31,358 --> 00:42:33,967 now everything gets shifted, 939 00:42:33,967 --> 00:42:36,053 gets basically shifted over one. 940 00:42:36,053 --> 00:42:38,886 So now instead of reading TGT CCG, 941 00:42:38,886 --> 00:42:43,303 it's now going to read TCC, GCC, see what I'm saying? 942 00:42:44,436 --> 00:42:47,769 ATT, and that's what you have down here. 943 00:42:50,301 --> 00:42:51,134 All right. 944 00:42:51,134 --> 00:42:52,756 And that results in completely different, 945 00:42:52,756 --> 00:42:55,672 completely different amino acids being read 946 00:42:55,672 --> 00:42:57,505 after the frame shift. 947 00:42:59,659 --> 00:43:01,607 A deletion, same thing, delete. 948 00:43:01,607 --> 00:43:03,121 You just taken out one little base. 949 00:43:03,121 --> 00:43:04,322 What can that hurt? Right? 950 00:43:04,322 --> 00:43:06,134 Well, there's a lot because now 951 00:43:06,134 --> 00:43:08,583 everything gets screwed up after that. 952 00:43:08,583 --> 00:43:10,951 And the, again, same thing. 953 00:43:10,951 --> 00:43:14,422 So let's say we're removing this T here, 954 00:43:14,422 --> 00:43:18,005 so everything moves back over this way one. 955 00:43:19,195 --> 00:43:21,605 So everything gets moved over one again. 956 00:43:21,605 --> 00:43:24,283 And here you have the same problems, 957 00:43:24,283 --> 00:43:25,794 everything following, 958 00:43:25,794 --> 00:43:27,669 all the amino acids following that frameshift 959 00:43:27,669 --> 00:43:28,593 are completely different. 960 00:43:28,593 --> 00:43:31,151 And then the protein gets totally screwed up. 961 00:43:31,151 --> 00:43:33,283 So as you might be able to start imagining, 962 00:43:33,283 --> 00:43:35,050 since it's everything that follows that mutation 963 00:43:35,050 --> 00:43:38,883 gets screwed up, the closer to the start codon 964 00:43:40,549 --> 00:43:42,367 that a frameshift mutation happens, 965 00:43:42,367 --> 00:43:44,306 the more detrimental it is to the protein. 966 00:43:44,306 --> 00:43:48,456 Similarly, the closer to the start codon, 967 00:43:48,456 --> 00:43:52,871 the start of translation that a nonsense mutation happens. 968 00:43:52,871 --> 00:43:54,303 So inserting a, 969 00:43:54,303 --> 00:43:58,432 basically changing a codon for an amino acid 970 00:43:58,432 --> 00:44:00,071 to a stop codon, 971 00:44:00,071 --> 00:44:03,220 the closer that that happens to the start codon, 972 00:44:03,220 --> 00:44:05,015 the more screwed up the protein's going to be 973 00:44:05,015 --> 00:44:07,097 'cause the shorter the protein's going to be. 974 00:44:07,097 --> 00:44:09,336 Same thing here in a frame shift. 975 00:44:09,336 --> 00:44:12,625 The closer that that mutation happens 976 00:44:12,625 --> 00:44:16,708 to the start of translation, that means that the, 977 00:44:18,737 --> 00:44:20,067 all of the amino acids following it 978 00:44:20,067 --> 00:44:20,919 are going to be screwed up. 979 00:44:20,919 --> 00:44:25,458 So the the worst in it actually is for the protein. 980 00:44:25,458 --> 00:44:26,294 Okay. 981 00:44:26,294 --> 00:44:27,333 Let's talk about a little nomenclature 982 00:44:27,333 --> 00:44:30,852 for mutations which result in changes to the protein. 983 00:44:30,852 --> 00:44:33,179 So this is definitely not all of it. It's not. 984 00:44:33,179 --> 00:44:35,166 Unfortunately, it's not all totally standardized. 985 00:44:35,166 --> 00:44:37,099 So you might see this in different ways. 986 00:44:37,099 --> 00:44:38,598 I just want to give you at least one way 987 00:44:38,598 --> 00:44:40,269 that you might start to see some of these. 988 00:44:40,269 --> 00:44:42,987 I'm not going to go in a lot of gory detail here 989 00:44:42,987 --> 00:44:45,244 'cause it gets to just be like a lot of memorization 990 00:44:45,244 --> 00:44:47,424 and it's not totally necessary. 991 00:44:47,424 --> 00:44:49,974 I just want you to, when you see something 992 00:44:49,974 --> 00:44:52,464 say on a chart or you know, in a test result or something, 993 00:44:52,464 --> 00:44:55,027 I want you to be able to recognize it at least 994 00:44:55,027 --> 00:44:57,370 and then you can kind of look up what it means 995 00:44:57,370 --> 00:44:59,075 specifically in that context. 996 00:44:59,075 --> 00:45:02,531 But to give you a sense of what you might see, 997 00:45:02,531 --> 00:45:04,984 the nomenclature likely denotes the changes 998 00:45:04,984 --> 00:45:08,127 in the amino acid sequence not the DNA sequence. 999 00:45:08,127 --> 00:45:09,538 And they may use a single letter 1000 00:45:09,538 --> 00:45:12,005 or the three letter amino acid designation 1001 00:45:12,005 --> 00:45:13,870 as you saw I was using 1002 00:45:13,870 --> 00:45:16,716 the three letter amino acid designation, 1003 00:45:16,716 --> 00:45:17,973 but there's also single letters, 1004 00:45:17,973 --> 00:45:21,670 which is what I have down here. And you can look those up, 1005 00:45:21,670 --> 00:45:23,870 just so you can look up a table of that online, you know, 1006 00:45:23,870 --> 00:45:25,198 for the 20 amino acids, 1007 00:45:25,198 --> 00:45:27,635 what the single letter and three letter designations 1008 00:45:27,635 --> 00:45:29,468 are for each of those. 1009 00:45:30,413 --> 00:45:31,942 For a nonsense mutation, 1010 00:45:31,942 --> 00:45:36,586 it's designated as the amino acid which is changed 1011 00:45:36,586 --> 00:45:40,228 and its location along the chain of amino acids. 1012 00:45:40,228 --> 00:45:41,882 And it's followed by the letter X. 1013 00:45:41,882 --> 00:45:44,513 And that x basically means it's a stop codon. 1014 00:45:44,513 --> 00:45:47,705 So nothing else follows that. 1015 00:45:47,705 --> 00:45:50,205 So in this case we have G542x. 1016 00:45:51,995 --> 00:45:56,096 If you see that, then you know that it is the glycine, 1017 00:45:56,096 --> 00:45:57,456 which is the amino acid, 1018 00:45:57,456 --> 00:46:00,266 which is designated by the letter G. 1019 00:46:00,266 --> 00:46:01,934 Glycine at location, 1020 00:46:01,934 --> 00:46:05,286 at the 542nd amino acid in the chain 1021 00:46:05,286 --> 00:46:08,839 of amino acids for this protein is normally a glycine. 1022 00:46:08,839 --> 00:46:11,172 So the wild-type is glycine. 1023 00:46:12,365 --> 00:46:15,336 But now, in this individual who has nonsense mutation 1024 00:46:15,336 --> 00:46:17,545 that it is now a stop codon. 1025 00:46:17,545 --> 00:46:19,371 So it is designated as an X 1026 00:46:19,371 --> 00:46:21,990 because no amino acids have Xs there. 1027 00:46:21,990 --> 00:46:25,448 Single, single letter designation, okay. 1028 00:46:25,448 --> 00:46:27,534 And this sense mutation is designated 1029 00:46:27,534 --> 00:46:30,618 by the wild-type or the old amino acid. 1030 00:46:30,618 --> 00:46:32,641 You can think of it that way, it's location. 1031 00:46:32,641 --> 00:46:34,654 And then the new or mutant amino acid 1032 00:46:34,654 --> 00:46:36,042 that's now in its place. 1033 00:46:36,042 --> 00:46:40,125 In this example would be glycine at location 176. 1034 00:46:42,085 --> 00:46:47,085 So the 176 amino acid in the chain is no longer glycine. 1035 00:46:47,381 --> 00:46:51,381 It's now F which stands for phenylalanine, okay. 1036 00:46:52,754 --> 00:46:54,660 And in-frame deletion is denoted 1037 00:46:54,660 --> 00:46:57,248 by a delta or could be denoted 1038 00:46:57,248 --> 00:46:59,915 as the letters DEL for deletion. 1039 00:47:02,523 --> 00:47:06,332 But you may see it as the the delta symbol, 1040 00:47:06,332 --> 00:47:10,684 then the amino acid, which is deleted and its location. 1041 00:47:10,684 --> 00:47:12,087 So this would be a deletion 1042 00:47:12,087 --> 00:47:15,087 of the phenylalanine at location 508 1043 00:47:15,945 --> 00:47:18,213 in that particular protein. 1044 00:47:18,213 --> 00:47:21,325 An in-frame insertion, it would basically, 1045 00:47:21,325 --> 00:47:23,187 here's where we're supposed to get a little ugly 1046 00:47:23,187 --> 00:47:24,580 with in-frame insertions and frames just, 1047 00:47:24,580 --> 00:47:27,281 it just gets really, (chuckles) 1048 00:47:27,281 --> 00:47:31,373 it gets really hairy with how it's designated 1049 00:47:31,373 --> 00:47:34,475 and it's designated different ways depending upon, 1050 00:47:34,475 --> 00:47:35,456 I don't know, 1051 00:47:35,456 --> 00:47:37,078 what the person ate for breakfast that morning. 1052 00:47:37,078 --> 00:47:38,925 Honestly like, there doesn't seem to be 1053 00:47:38,925 --> 00:47:40,832 a lot of rhyme or reason to it sometimes. 1054 00:47:40,832 --> 00:47:42,858 But here's at least one way in which, 1055 00:47:42,858 --> 00:47:46,281 an in-frame insertion can be denoted. 1056 00:47:46,281 --> 00:47:49,288 It would be denoted as the amino acid before 1057 00:47:49,288 --> 00:47:51,371 and the amino acid after. 1058 00:47:53,163 --> 00:47:55,588 And so it would be denoted as the wild-type, 1059 00:47:55,588 --> 00:47:59,353 which would normally be leucine at location 21, 1060 00:47:59,353 --> 00:48:01,856 followed by a lysine at location 22. 1061 00:48:01,856 --> 00:48:04,423 And there's an insertion now of a threonine. 1062 00:48:04,423 --> 00:48:07,556 So in this individual it would now read, 1063 00:48:07,556 --> 00:48:10,484 if you were reading their amino acids in this protein, 1064 00:48:10,484 --> 00:48:13,444 it would read as starting at amino acid 21 1065 00:48:13,444 --> 00:48:16,777 would read as leucine, threonine, lysine 1066 00:48:18,441 --> 00:48:20,464 and then all the rest of the amino acids 1067 00:48:20,464 --> 00:48:22,309 are in the normal order, 1068 00:48:22,309 --> 00:48:24,508 as you would expect for this protein. 1069 00:48:24,508 --> 00:48:26,625 Frame shifts, it gets more complicated. 1070 00:48:26,625 --> 00:48:29,743 But if you see the letters FS in the designation, 1071 00:48:29,743 --> 00:48:31,978 that means there is a frame shift at that location 1072 00:48:31,978 --> 00:48:33,525 that they are specifying. 1073 00:48:33,525 --> 00:48:36,858 But again, yeah, it gets a little weird. 1074 00:48:37,923 --> 00:48:39,869 I still haven't quite figured out if there's, 1075 00:48:39,869 --> 00:48:42,764 it doesn't seem like there's a standard way to do it. 1076 00:48:42,764 --> 00:48:44,293 So if you see the letters FS, 1077 00:48:44,293 --> 00:48:47,794 that likely means it's referring to a frame shift. 1078 00:48:47,794 --> 00:48:50,283 And I apologize, I can't give you more direction than that. 1079 00:48:50,283 --> 00:48:55,283 I've seen it so many different ways that it would really, 1080 00:48:55,428 --> 00:48:56,421 I think, be a waste of time 1081 00:48:56,421 --> 00:48:58,926 to try to go through all of them. 1082 00:48:58,926 --> 00:49:00,490 So, but anyway, if you see those, 1083 00:49:00,490 --> 00:49:05,490 at least you'll be familiar with what those may indicate. 1084 00:49:05,634 --> 00:49:06,819 All right. 1085 00:49:06,819 --> 00:49:10,039 Let's move on to some categories of genetic disease. 1086 00:49:10,039 --> 00:49:10,872 Chromosomal disorders, 1087 00:49:10,872 --> 00:49:13,004 which we talked about a lot in the last module. 1088 00:49:13,004 --> 00:49:15,132 These are polygenic. 1089 00:49:15,132 --> 00:49:16,342 And by that I mean, 1090 00:49:16,342 --> 00:49:18,743 they're involved with multiple genes 1091 00:49:18,743 --> 00:49:21,993 and that would be all of the genes in the chromosome, 1092 00:49:21,993 --> 00:49:23,418 if it's aneuploidy. 1093 00:49:23,418 --> 00:49:26,501 Basically, the disorder itself may be 1094 00:49:28,412 --> 00:49:29,548 the phenotype of the disorder. 1095 00:49:29,548 --> 00:49:33,745 So let's say the phenotype would be down syndrome. 1096 00:49:33,745 --> 00:49:37,662 The genotype would be trisomy of chromosome 21. 1097 00:49:40,458 --> 00:49:41,915 So the phenotype would be the characteristic, 1098 00:49:41,915 --> 00:49:43,438 which would be down syndrome, 1099 00:49:43,438 --> 00:49:45,414 all that's associated with that. 1100 00:49:45,414 --> 00:49:47,373 The genotype would be what caused it 1101 00:49:47,373 --> 00:49:48,999 from a sequence perspective. 1102 00:49:48,999 --> 00:49:51,784 and that would be a trisomy of chromosome 21. 1103 00:49:51,784 --> 00:49:54,352 So chromosomal disorders are polygenic, right? 1104 00:49:54,352 --> 00:49:56,060 So they involve many different genes, 1105 00:49:56,060 --> 00:49:57,071 however many different genes 1106 00:49:57,071 --> 00:50:00,389 are either on the chromosome itself, if it's an aneuploidy, 1107 00:50:00,389 --> 00:50:05,061 or in the region where there's a chromosomal disorder. 1108 00:50:05,061 --> 00:50:07,837 And that contributes to all of the different 1109 00:50:07,837 --> 00:50:09,728 and various symptoms that you see 1110 00:50:09,728 --> 00:50:12,895 associated with chromosomal disorders. 1111 00:50:13,753 --> 00:50:16,792 A single gene disorder will be considered monogenic. 1112 00:50:16,792 --> 00:50:19,118 There are over 6,000 different identified disorders 1113 00:50:19,118 --> 00:50:20,686 that fall into this category. 1114 00:50:20,686 --> 00:50:24,037 They're often called Mendelian disorders as well. 1115 00:50:24,037 --> 00:50:24,960 You might hear that. 1116 00:50:24,960 --> 00:50:28,349 We'll talk about that a lot in the next lecture. 1117 00:50:28,349 --> 00:50:29,766 And then there are multifactorial, 1118 00:50:29,766 --> 00:50:32,385 which is nearly all diseases to varying degrees, 1119 00:50:32,385 --> 00:50:33,916 which could be considered multifactorial, 1120 00:50:33,916 --> 00:50:37,348 which means they are involved with multiple genes 1121 00:50:37,348 --> 00:50:40,918 to different extents and influence from the environment. 1122 00:50:40,918 --> 00:50:45,918 We'll talk about this in the next module. Next module. 1123 00:50:46,131 --> 00:50:50,546 And those would be diseases like cardiovascular disease, 1124 00:50:50,546 --> 00:50:52,019 cancer for example, 1125 00:50:52,019 --> 00:50:55,436 is also a multifactorial genetic disease, 1126 00:50:57,343 --> 00:51:01,926 you know, stroke risk, all of these are multifactorial. 1127 00:51:03,418 --> 00:51:05,519 Chromosomal disorders as you recall, 1128 00:51:05,519 --> 00:51:08,431 these would be either a full on aneuploidy 1129 00:51:08,431 --> 00:51:13,246 or it could be a portion of a chromosome is deleted, 1130 00:51:13,246 --> 00:51:14,996 duplicated, inverted, 1131 00:51:18,038 --> 00:51:19,786 transferred from one chromosome to another. 1132 00:51:19,786 --> 00:51:24,786 You remember all of those from the last module hopefully. 1133 00:51:25,337 --> 00:51:27,709 So this is excess or lack of a whole chromosome 1134 00:51:27,709 --> 00:51:29,890 or segment of a chromosome. 1135 00:51:29,890 --> 00:51:31,309 So phenotype is the net effect 1136 00:51:31,309 --> 00:51:35,107 of changes in many different genes, okay. 1137 00:51:35,107 --> 00:51:36,222 Single gene disorders, 1138 00:51:36,222 --> 00:51:39,381 these would be disorders like cystic fibrosis, 1139 00:51:39,381 --> 00:51:42,056 which occurs when both copies of the CFTR gene are mutated. 1140 00:51:42,056 --> 00:51:45,195 And we will go into that in the next lecture. 1141 00:51:45,195 --> 00:51:46,457 This would be a mutation or disruption 1142 00:51:46,457 --> 00:51:49,814 in a single gene which results in the disease. 1143 00:51:49,814 --> 00:51:52,897 So for a person who has the genotype, 1144 00:51:54,899 --> 00:51:57,809 the genotype which determines cystic fibrosis, 1145 00:51:57,809 --> 00:52:00,766 it doesn't matter what that person does, right? 1146 00:52:00,766 --> 00:52:05,766 So they could live the healthiest life they possibly could, 1147 00:52:06,024 --> 00:52:07,343 they're still going to develop 1148 00:52:07,343 --> 00:52:10,786 at least some of the symptoms of cystic fibrosis. 1149 00:52:10,786 --> 00:52:12,890 They're still going to develop cystic fibrosis 1150 00:52:12,890 --> 00:52:15,211 because getting that particular disease, 1151 00:52:15,211 --> 00:52:20,211 the manifestation of that disease is 100% determinant on, 1152 00:52:20,916 --> 00:52:25,542 determined by the genotype for the cystic fibrosis gene. 1153 00:52:25,542 --> 00:52:28,494 So it's monogenic, single gene influencing it. 1154 00:52:28,494 --> 00:52:30,440 And in particular mutations in that gene 1155 00:52:30,440 --> 00:52:32,082 will give you the disease. 1156 00:52:32,082 --> 00:52:35,783 The disease will absolutely manifest 1157 00:52:35,783 --> 00:52:38,950 as opposed to multifactorial disorders 1158 00:52:39,915 --> 00:52:42,252 where you can have really a combination of effects. 1159 00:52:42,252 --> 00:52:44,621 And again, this is most of what you see 1160 00:52:44,621 --> 00:52:46,230 certainly on a day-to-day basis. 1161 00:52:46,230 --> 00:52:48,470 And this will be most diseases 1162 00:52:48,470 --> 00:52:50,555 are influenced by many different factors. 1163 00:52:50,555 --> 00:52:52,834 So if you take hypertension for example, 1164 00:52:52,834 --> 00:52:54,293 well as you know, right, 1165 00:52:54,293 --> 00:52:56,661 that's going to be influenced dramatically 1166 00:52:56,661 --> 00:53:00,830 by a person's diet by whether they smoke or not, 1167 00:53:00,830 --> 00:53:04,037 by their lifestyle, so whether they're sedentary 1168 00:53:04,037 --> 00:53:06,870 or do regular amounts of exercise. 1169 00:53:09,341 --> 00:53:13,012 But it's also influenced by a variety of different genes 1170 00:53:13,012 --> 00:53:15,487 and different mutations in those genes. 1171 00:53:15,487 --> 00:53:18,749 They all contribute a little bit to the risk associated 1172 00:53:18,749 --> 00:53:23,416 with potentially developing something like hypertension. 1173 00:53:24,333 --> 00:53:25,166 Okay. 1174 00:53:25,166 --> 00:53:27,220 Yes, and hypertension involves over 15 genes 1175 00:53:27,220 --> 00:53:31,057 as well as diet, exercise, and smoking exposure. 1176 00:53:31,057 --> 00:53:34,516 And we'll get into a little more of that in the next module. 1177 00:53:34,516 --> 00:53:37,474 These become a lot more difficult to nail down 1178 00:53:37,474 --> 00:53:40,122 and give, you know, give precise estimates 1179 00:53:40,122 --> 00:53:42,613 to patients as far as what's their risk 1180 00:53:42,613 --> 00:53:44,629 because there are a lot of factors contributing 1181 00:53:44,629 --> 00:53:46,604 a little bit of risk. 1182 00:53:46,604 --> 00:53:49,346 And it's really the combination of those 1183 00:53:49,346 --> 00:53:51,125 that will determine whether or not 1184 00:53:51,125 --> 00:53:53,312 a person develops a particular disorder 1185 00:53:53,312 --> 00:53:56,286 and the extent to which they do. 1186 00:53:56,286 --> 00:53:57,915 All right. Let's summarize here. 1187 00:53:57,915 --> 00:53:59,438 Genotype leads to phenotype. 1188 00:53:59,438 --> 00:54:02,232 So your genotype would be 1189 00:54:02,232 --> 00:54:04,192 the sequence of a particular gene, 1190 00:54:04,192 --> 00:54:06,540 and that's going to lead to the phenotype 1191 00:54:06,540 --> 00:54:08,957 or how the gene is basically, 1192 00:54:11,245 --> 00:54:14,167 how the genotype is seen in an individual. 1193 00:54:14,167 --> 00:54:18,888 So their traits are affected by a particular genotype. 1194 00:54:18,888 --> 00:54:20,340 Changes to a gene sequence can result 1195 00:54:20,340 --> 00:54:22,135 in changes to the protein it encodes, 1196 00:54:22,135 --> 00:54:23,591 which can affect phenotype. 1197 00:54:23,591 --> 00:54:25,536 We gave you a few examples there 1198 00:54:25,536 --> 00:54:28,481 of the sickle cell disease and cystic fibrosis, 1199 00:54:28,481 --> 00:54:33,148 how changes in those proteins can affect the individual. 1200 00:54:37,315 --> 00:54:40,370 Mutations include changing a base or point mutation 1201 00:54:40,370 --> 00:54:42,899 or inserting or deleting one or more bases. 1202 00:54:42,899 --> 00:54:44,424 And these mutations can cause 1203 00:54:44,424 --> 00:54:45,596 one amino acid to be different, 1204 00:54:45,596 --> 00:54:47,340 which would be a missense, 1205 00:54:47,340 --> 00:54:48,349 the protein to be truncated, 1206 00:54:48,349 --> 00:54:50,071 which would be nonsense 1207 00:54:50,071 --> 00:54:51,721 and amino acid to be added or removed, 1208 00:54:51,721 --> 00:54:54,411 which would be an in-frame insertion or deletion 1209 00:54:54,411 --> 00:54:56,255 or the protein to be dramatically different, 1210 00:54:56,255 --> 00:54:59,003 which would be from a frame shift. 1211 00:54:59,003 --> 00:55:01,005 Genetic diseases can be monogenic, 1212 00:55:01,005 --> 00:55:03,370 polygenic, or multifactorial. 1213 00:55:03,370 --> 00:55:06,006 All right. So what's up next in this module? 1214 00:55:06,006 --> 00:55:07,672 Well, the remaining two lectures, 1215 00:55:07,672 --> 00:55:12,049 we're going to dive into patterns of inheritance 1216 00:55:12,049 --> 00:55:14,331 that are commonly called Mendelian inheritance, 1217 00:55:14,331 --> 00:55:17,282 which means inheritance of conditions 1218 00:55:17,282 --> 00:55:20,032 that are caused by a single gene, 1219 00:55:21,218 --> 00:55:24,783 so looking at inheritance of a single gene. 1220 00:55:24,783 --> 00:55:26,427 And so we're gonna have two lectures on that. 1221 00:55:26,427 --> 00:55:29,573 The first one is on the basics of Mendelian inheritance. 1222 00:55:29,573 --> 00:55:30,447 And that's where we get those terms 1223 00:55:30,447 --> 00:55:32,139 of dominant and recessive. 1224 00:55:32,139 --> 00:55:33,311 I'm sure you're familiar with. 1225 00:55:33,311 --> 00:55:35,115 And then we're going to move on 1226 00:55:35,115 --> 00:55:36,582 to some extensions to Mendel. 1227 00:55:36,582 --> 00:55:40,028 So we know all too well in genetics, 1228 00:55:40,028 --> 00:55:41,796 there's always exceptions 1229 00:55:41,796 --> 00:55:44,391 and some of them are actually pretty important 1230 00:55:44,391 --> 00:55:48,178 to make sure that you're familiar with and aware of 1231 00:55:48,178 --> 00:55:50,355 in things you might see in your practice 1232 00:55:50,355 --> 00:55:53,403 or patterns of inheritance that might not quite fit exactly 1233 00:55:53,403 --> 00:55:56,968 what we learned about from the Mendelian inheritance. 1234 00:55:56,968 --> 00:55:58,813 So with that, I will say goodbye, 1235 00:55:58,813 --> 00:56:01,223 and we'll talk with you in the next lecture.