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.

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