Genetic Mutations, Part III: Information

Any change in DNA, whether is brought on by copy error or damage, we can call a mutation. In some cases, such as when mutations arise from mismatch errors, the change may be relatively small. We call those kinds of changes point-mutations. Mutations may also involve other relatively small, but potentially serious consequences, such as the insertion or deletion of a base-pair along the string of DNA.

Damage to DNA can actually cause much larger-scale changes. If the damage causes the DNA double helix to break entirely, then entire segments of the chromosome can be lost. We call those chromosomal deletions. Thousand of base-pairs can just be eliminated. Or, those segments that are broken out of the DNA molecule might get flipped around and put in reverse. We call those “inversions”. Or, those segments might actually be pulled out and moved to other part of the chromosome. We call those “translocation”. They might actually be pulled out and inserted in a number of different places. Those are “duplications”.

What are the consequences of these kinds of mutations? We talked briefly about the negative consequences that can happen if a critical gene in a cell is damaged. Not all mutations, however, have this kind of negative consequence. In fact, some may even have positive consequences, at least over the long run.

Mutations and Functionality of Proteins

The genetic code is redundant. That means that different combinations of bases code for the same amino-acid. For example, codons CCA and CCG both code for proline. If the A is somehow mutated and becomes a G, it doesn’t matter, we still have a code for proline. We call these kinds of mutations “silent mutations”. Unless we look at the DNA sequence itself, we would never know it is there.

If CCA, which codes for proline, is changed to UCA, which codes for serine, then we would have a change that affects the amino-acid sequence. Even a change in amino-acid sequence, however, may not be discernable. It may even have a slightly positive effect. The difference is hard to predict in advance, and it all depends on which amino-acid is substituted for the other, and how that substitution affects the shape, and therefore, the function of the protein.

It’s possible to have one amino-acid substituted for another and finding no noticeable change in the way the protein folds up. It’s also possible that an amino-acid substitution does cause a radical change in protein shape. These kinds of changes are what would lead to serious effects. For example, these are the kinds of change that may cause a cancer. If the amino-acid substituted happens to be a particularly critical one, the whole protein can be screwed up.

Interestingly, there is a third alternative. That is that the change of one amino-acid actually makes the protein work a little better. It is conceivable that a slight shape change would make it more functional. In this case, a mutation would have a positive effect.

Over the long run, mutations are important, because they change genetic information among individuals in populations. In that way, mutations add genetic variation, which is the stuff that natural selection works on. I have to point out, though, that the only mutations that matter are those that can be passed to offspring. Up to this point we were talking only about the cell. If a mutation occurs in a single celled organism, when it reproduces the mutations would be passed on to the offspring. For single celled organisms, any mutation is going to be passed on.

Mutations in Multicellular Organisms

If I have a mutation occurring in my skin cells, my future children don’t have to worry about that. Those mutations will die when I do. Those skin cells have no way of passing that genetic information on to my offspring. Instead, in multicellular organisms, such as ourselves, there are small groups of cells whose sole function is to produce reproductive cells. We call those germ cells. Only mutations occurring in germ cells can be passed on to subsequent generations.

I think that we this series of articles on mutations we’ve clarified the subject a little. Because of the ongoing debate over “information” in organisms, and how it is created in order for evolution to work, I think it is really important to share my little knowledge about the subject. In later articles I want to talk about other mechanisms of evolutionary change, like sexual reproduction and genetic drift. Be sure to check them out, and spread the word out, everyone needs to know this stuff. It's really eye-opening.

Genetic Mutations, Part II: Induced Mutations

It’s not just replication which is responsible for genetic mutations. Other things can happen to DNA as well. DNA does very important things, but one of the things that it isn’t good at is staying intact. DNA is not known for being a durable molecule. It is pretty fragile overall. DNA is constantly in danger of being broken or modified by a variety of physical and chemical agents.

For example, radiation is absorbed by nucleotides, which can break the molecules apart. If this happens, the bases themselves might be damaged, rendering it non-functional. Or, one or more base-pairs might be deleted. Or, they might even be added. Or both strands of the double helix might simply break, causing the entire molecule to split in two.

Many kinds of chemicals would interact with bonds in DNA and break them. For example, chemicals found in tobacco smoke are well-known to be highly reactive with DNA. So-called free radicals, which are produced normally by our own metabolism, also interact with DNA and can potentially damage it.

DNA is under constant assault. Even if replication goes well, once DNA is put together, there are many factors which are assaulting it and potentially damaging it. By one estimate, the DNA in a single human cell may be damaged a thousand times a day. A thousand times a day, something happens to your DNA. As you might imagine, there is molecular machinery that is devoted to detecting and correcting all sorts of errors that creep into DNA.

Most of these repair mechanisms share something in common. They depend on complimentary base-pairing to correct mistakes when they find them. When a mistake is detected, they cut out one or the other of the single strands of the double helix.

In spite of this molecular effort, some damage does remain unrepaired, and there can be consequences. A very high percentage of cancers are caused by genetic errors brought on by exposure to various DNA damaging agents. We call them carcinogens. Usually these cancers are caused by damage to certain classes of genes (antioncogenes or tumor suppressor genes). These genes code for proteins that are involved in regulating the way that cells normally divide and reproduce. They essentially act as ON or OFF switches for cell division. When these genes are damaged, they no longer function appropriately, and the cell begins to divide in an uncontrolled fashion. This is a common defining feature of cancers.

In my next article I will talk about the types of mutations that occur, and their specific consequences.

Genetic Mutations, Part I

Mutations are often described by people as something going “wrong”, or something “bad”. Wrong is relative. From our perspective they are bad. They cause diseases and kill a lot of people. They are, however, responsible for creating the genetic variation on which natural selection works. Who are we to judge the process by which we came into being? How we dare label it “wrong”? The best thing we can do is to be part of it. Go with the flow. Try to understand it, at least. Be an admirer. Here I will try to enlighten this subject, so much debated, and not so much understood.

I have been writing a lot about DNA replication lately. We saw how many enzymes work together in what can be seen as an elegant and orchestrated ballet. As elegant as this process may be, though, replication doesn’t always work exactly right. Sometimes, the wrong base gets inserted in a sequence. DNA may also be damaged in a variety of ways, leading to what are essentially mistakes in the sequence of bases.

The cell puts a lot of effort into avoiding and correcting errors. Errors, however, are unavoidable. Often, when errors do occur, they have serious negative consequences for the individuals in which they occur. Over the long run, however, such errors also provide a source of genetic variation, which is the substrate on which evolution by natural selection acts.

We’ve seen in other article that DNA polymerase depends on complimentary base-pairing to accomplish the task of accurately synthesizing a new DNA molecule. It is the base-pairing that determines which nucleotide is going to be added next to a growing polymer of DNA. DNA polymerase, however, sometimes adds the incorrect base.

When the copying process ends, the number of mistakes in the DNA sequence is amazingly low. It is only about one mistake in every billion bases. On the other hand, if you count how many mistakes are actually made by DNA polymerase during the copying process itself, the number would be much larger: about one in every 10000.

The difference between the final product and the mistakes that are actually made during the copying process is due to the fact that there is an extensive amount of molecular machinery devoted to proofreading and repairing DNA in cells.

Who is to Blame?

I said that DNA polymerase was making mistakes. I should apologize. We can’t blame DNA polymerase. It is not really making the mistakes. The proper alignment of new bases with old bases during replication depends on the bases themselves. Ultimately, they line up because of the hydrogen bonding interactions that are responsible for the base-pairing rules. All that DNA polymerase does is to find what the next base is, and add it to the growing strand. It does that job right. If it happens to find the wrong base, it just adds it anyway. We call that “mismatch error”.

When a mismatch occurs, it means that after the DNA strand is synthesized, it will have somewhere in the sequence a non-complimentary base pair. For example, we may have an A paired with a C.

DNA polymerase itself does look out for these mistakes. DNA polymerase does what we call proofreading repair. We could think of DNA polymerase as walking down the template strand of DNA, it adds a base, but then it looks back over its shoulder and it checks: is it the right base? If it finds that it added the wrong base, it would cut the base out. It will wait for another base to come in and then synthesize.

This proofreading corrects a number of the errors that are introduced. It brings down the number of errors to as low as 1 in ten million. One in ten million seems pretty good. I wish I could make only one mistake in ten million tries, but it is actually still quite a high rate given the size of the task at hand. For example, the amount of DNA found in a human cell is about 3.2 billion base-pairs. If we have a rate of about 1 in ten million, that means every time the DNA in a human cell is replicated, there would be about 300 mistakes. When you consider the fact that over the lifetime of a human there are billions and billions of cell-divisions, the number of mistakes would become astronomical and unworkable. So, this mismatch repair done by DNA polymerase itself really doesn’t take it as far as we need.

Quality Control

Fortunately, there is another backup mechanism for correcting mismatches. There is an ensemble of enzymes that we call (with a touch of originality) “mismatch repair enzymes”. They work together to detect and correct mismatches that are found in newly synthesized DNA. Think as these mismatch repair enzymes as quality control officers. They are constantly inspecting the DNA that has been synthesized, and checking for incorrect base-pairings. If these enzymes do detect a mismatch, they cut out the incorrect nucleotide. They may even remove a section of nucleotides around this incorrect nucleotide, leaving a gap. Once that gat is created, new nucleotides would come in and base-pair with the template strand. DNA polymerase would come back and finish the job.

So, we have a lot of molecular machinery that is involved in finding mismatches and repairing them when they occur. In spite of all of this, some errors do get through. At the end of the day, when the entire mismatch repairing is completed, there is still one in a billion mistakes. This is pretty good. That might me on average three mistakes if an entire set of human DNA is replicated. Over the long time, however, they do add up. We will see the consequences of these mistakes in my next article. Stay tuned.