So, let's talk a bit about the length of the DNA. I found the DNA as the most fascinating molecule in nature for many reasons. And one of them is the length of the DNA. We are making copies of the DNA by enzymes that are walking step by step on the DNA in a linear fashion. The length of the DNA in human cell, if you take the DNA and stretch it all over, It's two meters long from one cell.
Each cell contains two meters of DNA, which needs to be copied by the enzymes, like DNA polymerase. Now, we are talking about something like two times 10 to the power of 13 kilometers of DNA which is produced in our lifetime so the length of the DNA that we are making Throughout our lifetime is astronomical number. Now, I cannot understand what is 2 times 10 to the power of 13 kilometers.
It's too much, so we can actually translate this to astronomical number by using light years. So, as everybody knows, the speed of light is 300,000 kilometers a second and the length of the DNA that our body is producing during our lifetime is equivalent to two light years. Wow! Now if we really want to make it even more interesting, well, I mean, we are making like 10 billion cells every day just for the immune system. And just for this compartment, we are losing and making 20 million kilometers of DNA every day.
500 times around the globe. Or if you want to make it even more interesting, maybe you want to ask what is the length of the DNA that all the students which are enrolled at York University are going to make throughout their lifetime. So the length of the DNA that 50,000 students and staff are going to make throughout their lifetime is going to cross our galaxy, the Milky Way galaxy, which is 100,000 light years long. Well, I mean, be careful over here, it's a very, very strong Black hole, don't get very close to this.
Okay, let's take it a bit, a bit more seriously, away from this analogy, but to the real life. We are making a huge amount of DNA all the time. A very, very long DNA needs to be packaged correctly. in a very tiny nucleus and also to be synthesized with as few mutations as possible we have a very strong DNA repair mechanism which are going to correct most of the errors that we are making during DNA replication.
Sometimes this system is not working appropriately and we are going to stay with the mutation for the rest of our life or maybe even in our kids and their kids, etc. So our genome is huge, 6 billion nucleotides long, and we need to make as few errors as possible. And in general, we are making like one error, one mutation in every cell. Let's go back to...
packaging of the DNA. The DNA is very long. It needs to be packaged appropriately in the nucleus. So the two meter long packed into the nucleus, which is tiny nucleus.
It's six micron in diameter, which is compared to the two meter long DNA, very very tiny. So the DNA must be packaged. There are different levels that the DNA is to be packaged.
The first one is the nucleosomes. DNA is bound with proteins which reduce the length of the molecule. The first level is nucleosomes and the DNA wrapped around histones which are making the nucleosomes. There are a lot of other... Levels of packaging in order to put the two meter long DNA into this tiny nucleus.
Just to get the idea of how the system is working. Let's unwind a chromosome to see its structure. As we unwind it more and more, we see successive levels of packing of the chromatin. Eventually we see nucleosomes packed in tight coils.
Each nucleosome consists of DNA wrapped around a core of histones. Finally, we see the DNA double here. And the second thing that we need to take care of is mutation. In the living cells, DNA undergoes frequent chemical changes. Most mutations are taking place during replication, but there are other situations that cells that are not replicating can have some DNA modifications.
Most of those changes are quickly repaired. We have a very effective DNA repair mechanism. Those that are not result in mutation.
So, yes, I mean, every cell which is produced more or less have something between one to five mutations changes at the level of the DNA. This is, in most of the cases, is going to hit regions that are not making proteins. Our DNA consists of only 1.5% of the DNA as coding regions, as genes.
Most of the DNA is not coding for anything that can be determined with a product like we discussed earlier. So you... mutations over there in most of the cases are not going to be so effective in changing the phenotype of the organism. In general we can say that mutation is a failure of DNA repair mechanism.
Generally DNA repair mechanism need to take care of most. of the mutation in those cases that the system is not working appropriately like any other system nothing work perfect all the time DNA repair mechanisms from time to time can fail and we can stay with a mutation. DNA is under constant attack from reactive chemicals and natural background radiation. Free radicals are the byproducts of normal metabolism in human cells. Seen here as bright particles, They sometimes react with DNA and cause chemical changes.
Radiation can also affect DNA. For example, ultraviolet light from the sun can cause harmful chemical changes in the DNA of skin. These changes can lead to kinks in the DNA that prevent genes from being correctly read, or deletions that alter the type of protein produced. So let's bring us to the DNA repair mechanisms. Mutation can result from the incorporation of the incorrect bases during DNA replication.
Most such spontaneous changes in DNA are temporary because they are immediately corrected by process collectively called DNA repair. Most damage to the DNA is repaired by removal of the damaged bases followed by resynthesis of the excised region. And just to show you a short example For this process, I want to take you to hhmi.org. There's a polymerase, DNA polymerase, which copies both strands of the DNA, the top strand and the bottom strand.
Sometimes those two strands are called Watson and Crick strand, but they're not perfect, as we just mentioned. Sometimes they make mistakes, and the kind of mistake... They might make, as you'll see in a second, to incorporate the wrong nucleotide.
Normally there's going to be an A opposite a T and a C opposite a G, but suppose it makes a mistake and copies a T where a C should be. That should be GC, but now there's a T. So that's a mistake.
potential mutation. Fortunately, cells have repair systems that can erase those mutations. And those repair proteins indicated here called MSH2, MSH6, MLH1, PMS2, The names don't matter.
What's important is that they recruit another enzyme called exo-1, exonuclease, which chops off the mutant strand. And then it allows a DNA polymerase to come by and synthesize the correct strand, thereby fixing up the DNA and making it normal. So the molecular basis of mutation A mutation is any change in an organism's DNA sequence Mutation is at the level of the DNA and in most of the cases It's not going to reach the level of proteins and it's not going to affect the phenotype of the organism. Proteins encoded by the genotype, by the DNA, produces the phenotype. So proteins are responsible for the phenotype.
and the phenotype is going to be changed only if proteins are affected. Hence, DNA mutations affect phenotype only when the mutation is expressed throughout the entire central dogma. DNA, RNA, proteins and the protein function abnormally.
The mutation must affect the sequence of the protein. And even if the sequence of the protein is being changed, in most of the cases, it's not going to affect the activity of the protein. Most of the proteins can suffer from quite a lot of amino acid changes before they are going to lose their activity. And second... Even if the protein is not working properly, in many cases, we have other proteins that can take its job and the protein that is not working properly is not going to cause a very significant phenotype change.
So not all mutations affect the protein ability. to function and to generate a phenotype. So when a protein is modified at the active center of an enzyme, for example, there is a chance that the protein will not work properly.
But proteins are quite long, there are a lot of regions that can suffer a lot of mutations. Without any major problem with the ability of the protein to fulfill its job. One of the most common type of mutations is the point mutation, which is a change in a single nucleotide. There are a lot of different mutations that we can have in the cell.
Here we will concentrate. on point mutation, a change of a single nucleotide that can be replaced by something else or can be eliminated, deletion, insertion, etc. Point mutations can result from errors in DNA replication or from exposure to mutagenic toxins. Smoking cigarettes, for example, is causing us a lot of mutations, usually in the site which is exposed to the tobacco toxins, lungs, for example.
And cancer is a result of the acceleration of mutations in those regions. We are making more mutations. There is a higher chance to come with cancer in those cases that cigarette smoke can induce those mutations at the very high level.
Let's go back to the genetic code. And as I mentioned earlier, Most amino acids are specified by more than one codon. So with this definition, you can have a lot of mutations, for example here on the last letter, that can still keep the same amino acids in place. So you can change U to C to A to G You are still going to have arginine as the amino acid And this is correct for most amino acids that can suffer some level of mutations mainly on the last codon So those mutations which are not going to change the sequence of the amino acids called silent mutation. So if I have this sequence of DNA and here you have the sequence of the protein produced You can have mutations in arginine, for example, from anything to anything.
You're still going to get arginine at the level of the protein. So this is silent mutation, and we can see it a lot. We don't have a selection against those mutations because there is no effect that can make us not to deliver this mutation to the following generations.
Mutations that do not change the amino acid sequence of the protein are known as silent mutations. Misen's mutation is a mutation that dev... is a change at the level of the amino acids.
For example, if you change the second letter in the codon for serine from C to T, you are going to have different amino acids. So the pole mutation that causes... A change in the amino acid sequence of the protein is missense mutation. A missense mutation is a type of point mutation that results in the appearance of an inappropriate amino acid in the polypeptide product. The wild-type DNA suffers a change in one base pair, causing a change in the resulting mRNA codon.
which in turn codes for a different amino acid at this point in the forming polypeptide. In most of the cases, missense mutations are not going to be involved with a major change in the activity of the protein. So let's move towards more significant mutation and this is nonsense mutation.
Nonsense mutation is where the amino acid codon is changed to stop codon. So a point mutation that creates a new stop codon is nonsense mutation. Again, you have a long protein, somewhere in the middle you have ATG, and this ATG is... mutated to ATT. Here you have a stop codon and when you have a stop codon no more protein is going to be made after the stop codon.
The protein is going to be shorter than the normal protein. A nonsense mutation is a type of point mutation that results in termination of polypeptide synthesis at the affected codon. The wild-type DNA suffers a change in one base pair that results in the appearance of a stop codon in the resulting mRNA.
The stop codon causes premature termination of polypeptide synthesis. In the case of nonsense mutation, the protein is going to be shorter. The question is how short the protein is compared to the original one. If the mutation is at the very, very end of the protein, and you are going to lose 10 amino acids, in most of the cases, it's not such a big issue.
If the mutation takes place at the beginning of the protein, the protein, the... stop codon is going to stop the protein from being made and you're actually going to lose a certain activity that can lead to a change in the phenotype including diseases insertions and deletions are special type of mutations and considered to be more severe than any other mutations that I discussed earlier. The idea is this.
The language of the ribosome is three nucleotides at a time. Three after This is the language of the translation. The translation is based on triplets.
Let's say that we are going to have a language which consists only of words with three letters. We can say the cat saw the dog. Each word has three letters.
And now let's try to change one letter at a time. So if you change the C to B, you have the bat saw the dog, someone saw the dog, the dog was there. Makes sense to some level, right? You can also change the D to H and you can say the cat saw the hog. The cat saw something.
It's another informative information. Our cat can see certain things. Or we can change the W to T and we can get the cat set the dog, the cat and the dog get something to do with each other, there is still some level of information in this type of mutation of the sentence appears here. However, if you are going to delete a letter. You are getting something that is totally gibberish.
If you take the C out, and you are going to keep the rules of three letters, each word, one after the other, you are going to keep the V, but all the rest is totally gibberish, totally meaningless. Or, if you add one nucleotide or if you add one letter, if you're going to add one letter, you're also going to get gibberish. From here towards the end of the sentence, D, and then everything else is meaningless. And this mutation We change the Open Reading Frame called Frame Shift Mutation. So again, we can take our original sequence and we can add the nucleotide C, insertion of a nucleotide, and now when we are going to translate this, You're going to see that this triplet and all the other triplets are going to make totally different sequence of amino acids.
So from here until the end of the protein, you are going to have something which is totally gibberish at the level of the protein. means it's a sequence which is not supposed to be there. The first amino acid that is not affected is going to stay the same, but from the second amino acid, where the triplet was mutated by adding C, everything is going to be changed.
Frame shift mutation is a result of addition or deletion of one or two nucleotides or multiple of them likely to create a new triplet of nucleotides and new useless sequence of proteins from the point of the mutation. And the same thing if you are losing a letter. Let's say that you are losing the A over here, and again, you're going to get the same type of a problem. The arginine, which is before the mutation, is going to stay the same, but the tyrosine is going to turn into phenylalanine, the serine into arginine. And here actually we have a stop codon.
I mean, when we have this type of frame shift mutations, a lot of time we are getting stop codon soon enough. It's probably better than to make a protein that have no meaning whatsoever, and sometimes it can even cause damage. So frame shift mutation is the more severe type of mutation that you can have.
in the cells. And usually those type of mutations, if they are affecting dramatically the survival of the organism, because it can cause a disease, it's not going to be transmitted to the next generation, because if you cannot be a father or mother, you cannot transmit those mutations. So very severe mutations have some selection against them so let's go back to the mcclure hill animation at youtube the nucleotide sequence in dna determines the nucleotide sequence in messenger rna and consequently the sequence of amino acids in a protein A mutation in the DNA can result in a change in the amino acid sequence of a protein.
One type of mutation that can occur, either spontaneously or as the result of a mutagen, is the addition of one or more nucleotides during DNA replication. Because translation of a gene begins with a specific codon and proceeds one codon at a time, the addition of an extra nucleotide shifts the codons in the mRNA. This type of mutation is termed a frame mutation. shift mutation a frame shift affects all amino acids incorporated beyond the original site at which the addition occurred if the new code on generated by the frame shift is a stop code on the protein synthesized will be shortened and is often non-functional another type of frame shift mutation occurs when a nucleotide is deleted during DNA replication Deletion of a nucleotide in DNA results in a change in the codons in messenger RNA from the point of the deletion and changes in the amino acids inserted into the protein.
So the consequence of mutations actually can work for the organism. Selective advantage. Not all mutations are involved with the disease.
Many of them can also make us, the organism, to be better in some ways. Evolution is based on selective advantage by mutations. We are evolved all the time because mutations.
Without mutations, we probably... would be swimming in the ocean like amoeba also. We were evolved very long way since that time that we were amoeba billions years ago.
So one thing is that mutations can help us to do better. All share the same chemical code of life, DNA. All life forms also differ genetically. Whoa, these are new. You know, these skates are kind of like a mutation.
Some organisms experience mutations that may or may not be beneficial, depending on the environment. I can tell you that these skates don't exactly give me an edge in this environment. But if a mutation is select...
That is, if the environment changes to give the mutated organism a selective advantage, like this, well then the mutation not only survives, but eventually spreads. This is the basis for the diversity of life. Different mutations in different environments give rise to different successful strategies for survival. Often, enough of the old conditions remain the same, and some members of the previous community persist.
Perhaps in a more restricted scope. So, as environments change, new niches become available, and organisms adapt to fill them. Evolution is the change in inherited traits.
of a population of organisms through successive generations, mainly by changes of DNA sequences, mutations. When you compare the sequence of the chimpanzee with the sequence of human beings, you are going to find that they are very, very similar to each other. Yes, something like 99% at the level of the nucleotide are going to be the same, more or less.
So, you can imagine those mutations which took place are responsible for certain things. Some of them are... making us to be more technological oriented compared to the chimpanzee.
We can make different type of machines. Chimpanzees are much more limited at this level and others may be affecting us in not the best way. I mean, they can jump on trees much better than we do.
So evolution is about mutations and you can choose on your own what makes you better and what makes you worse. And sometimes it's the same mutation and the same phenotype. And Darwin understood that it is not the strongest of the species that survive, nor the most intelligent that survive.
It is the one that... is most adaptable to changes. You're going to see this slide quite a lot during my lectures because many many things that are related to antibiotic resistance or the way that certain bacterial cells can adapt to a certain environment all of those are about mutations that they were able to acquire.
The consequence of the mutation can be that the activity of a protein is reduced, and in some cases it can cause a disease. Like genetic diseases that can be based on the fact that certain protein in our system is not working appropriately. The cycle cell anemia is quite interesting because this is an example that one missense mutation was able to develop into a very significant disease. So again, we are talking about a change from T to A.
that replace the amino acid glutamic acid with amino acid called valine. So we have a change of glutamic acid to valine and this mutation, one change at the level of the amino acid, make the red blood cells from this phenotype to move to this phenotype of sickle red blood cells that are more fragile that cannot deliver the oxygen as well they have shorter life compared to the normal red blood cells that can be quite a significant disease the consequence of mutations can lead to cancer cancer is about a accumulation of mutations in one cell and if the DNA repair mechanism is not working well in the cell because of mutation in the DNA repair system which can lead to more mutations afterwards the cell will acquire more mutations and it can cause cancer Sometimes it is about more activity of certain enzymes, for example, sending the message to the cell to replicate more than the cell should have. The other option is that we are losing the activity of certain proteins, like proteins that are protecting us from cancer.
We have two more suppressor genes, which are protecting us from cancer if we are losing their activity we can come with a tumor with cancer