Box 165 Mutations Can Happen Without Any Help From Environmental Exposure

We cannot simply blame our load of mutations on exposures to things around us. A certain amount of mutation goes on no matter what we eat or drink, apparently as a simple result of the rate of errors made by the machinery of the cell as it copies the DNA. Even the most pristine lifestyle will not protect against the fact that the natural machinery by which the genetic blueprint replicates has built into it limits on how perfectly it can carry out its copying functions. As the polymerase moves along the DNA making a new copy, it must correctly read a base and put its correct complement into place, every time, over and over again, for more than a billion bases of sequence if it is going to correctly replicate the entire genome once without making any mistakes. Frankly, without any exposure to chemicals or radiation at all, sometimes the polymerase gets it wrong. At some points in the DNA, the rate at which polymerase makes errors is increased because a naturally occurring chemical modification (that only gets made to some of the bases in the DNA) makes the base "look" like a different base to the polymerase as it comes through making copies. When you take antioxidant vitamins, you are helping your cells to repair oxidative damage to your DNA that your cell machinery must work constantly to repair. So there is already a base-line rate of mutation going on before we ever add in additional insults such as smoking to further aggravate the ability of the cell to get it right, every time, over and over and over.

wonder whether people would react differently to the mutagens and cargino-gens in cigarettes if they were labeled on the packet with the sinister sounds of their chemical names. The fact that something is herbal does not mean that it is inherently either safer or more dangerous—it only means that it was synthesized by a plant instead of a factory and likely contains a relatively complex mixture of biochemicals. Within that herbal preparation are bio-chemicals that have exactly the same chemical structures and names that they would have if they had been synthesized by a pharmaceutical company. The fact that something has been chemically synthesized does not necessarily mean that it is either more or less likely to be a mutagen—it only means that it is a relatively better characterized item that is often less biochemically complex than the same item derived from an herbal source. So the real key to whether something is more or less likely to be harmful or mutagenic depends less on whether you got it from a pharmacy or a health food store and more on what the particular biochemical is (Box 16.5). And some amount of mutation will happen without any chemical exposures at all.

HOW OFTEN DO MUTATIONS HAPPEN?

To some degree, mutation can be considered a spontaneous process. DNA polymerase, the enzyme that executes DNA replication, is an unbelievably accurate enzyme. Still, it inserts the wrong base at a frequency of about one error in every 10 billion bases replicated. That number may seem small, but remember that every time the human genome is replicated, DNA polymerase must copy approximately 6 billion base pairs. Thus, on average, slightly less than one new base pair mutation will occur every time the human DNA complement is replicated. If that number seems small to you, remember that a human being will go through more than 1 quadrillion complete replications of his or her DNA (cell division) in his or her lifetime. Thus a very large fraction of the cells in our bodies might be expected to carry one or more base change mutations, but as we have discussed, only some of those changes will actually make any functional difference to the gene product and cellular functions.

Realize that the vast majority of new mutations will occur in somatic cells and that even those deleterious mutations that do occur will likely have little or no effect because they only exist in the single cell in which the mutation event occurred. In most cases, the resulting impairment in gene function will be "covered" or "masked" by the unmutated copy on the normal homologue. Moreover, even if such mutations were to result in the death or impairment of a single cell and its somatic descendants, it is unlikely that the loss of a single cell or cluster of cells would be terribly deleterious to the organism. (We will, however, consider a rather dramatic exception to this generalization when we discuss the genetics of cancer in Chapter 33).

Perhaps of more interest to us is the frequency of mutations in the germline, mutations that get passed along to a child who then carries the mutation in every cell in the body. What fraction of human gametes might be expected to carry a new mutation that will impair or prevent the proper function of a given gene? Based on assaying the frequency of those new mutations in known genes that have phenotypic consequences, scientists have concluded that each gene in the human genome will be mutated (that is to say functionally altered, not just changed silently) only once in every 100,000 gametes. By this measure, Mendel does not seem to have been so far off—mutation is a very rare process indeed. Remember, however, that the actual frequency of DNA changes in a germline are much higher because of the types of silent mutations mentioned above. The observed mutation rate measures only those changes that dramatically alter gene function. Accordingly, whenever you think about mutation rate, stop and ask yourself whether you are looking at all heritable changes happening to the DNA (many) or whether you are looking at changes that are detectable as a phenotypic change in a living person (a much smaller number). And as we have mentioned, some agents in the environment can greatly increase the mutation rate above the baseline level of errors made by the polymerase during normal copying of the DNA (see Boxes 16.3 to 16.5).

Efforts to discuss functional mutation rates—the rate at which a mutation can cause a change in a protein that will alter some function or structure in the cell—are complicated. The mutation rate relative to a particular disease or gene depends on many variables. It depends on what size of gene we are talking about, what type of mutation we are talking about, and what region of the genome we are looking at. It also depends on whether we are asking about mutations with detectable biochemical effects, mutations that alter the amino acid sequence, or mutations that simply change the DNA sequence. The mutation frequency for a gene that is 900 base pairs long is likely to be quite different from the mutation frequency found for a gene that is 9,000 base pairs in length. The mutation frequency will be different for deletions vs. point mutations. Even different types of point mutations happen at rates that can vary more than tenfold, with an occasional hot spot in the genome showing an unusually high mutation rate that might be a thousand times that of some other bases in the genome.

One mutation in any given gene per 100,000 people might seem like a very rare event, but stop to think about what that number means. If you only had one gene, that mutation rate would mean that your chances of passing a new mutation along to your child would be about the same as the chance of winning one of the big lotteries. But if you had 30,000 genes, suddenly the 1 in 100,000 chance of passing along a mutation in one of those genes somewhere in your genome would not look so rare.

So even in a perfect world with no mutagens at all, we would all still have some amount of mutation going on in our cells over the course of a lifetime. Fortunately, most of the time, most of those mutations fall between genes, or within introns, or bring about silent changes, or happen in a skin cell that then dies and is sloughed off. Much of the time, even if a mutation takes place in one of our cells, we will not pass it along to our children unless the mutation happens to take place in the germline—in the lineage of cells that produces the eggs or sperm that carry the blueprint along to the next generation.

Most of these differences in the DNA sequence have been handed along to us by our parents, but new mutations can arise and be passed along to our children. Although we cannot control what we received from our parents, we can affect the chances of creating a new genetic problem that will plague our descendants. So you are going to be stuck with some level of mutation going on no matter how pristine an existence you live, but working around radiation without taking appropriate protective precautions (see Box 16.3) or living on a toxic waste dump site (see Box 16.4) can actually increase the chances that you will pass a new mutation along to your children. So the next time you find yourself wanting to roll your eyes at what some environmentalist is saying, stop and ask yourself how much you know about what causes mutations and what effects those mutations can have. In some cases the answer will be that the particular environmental situation is actually already safe enough, but sometimes the answer will be that there is something that needs to be cleaner, not only for our protection but also for the protection of future generations.

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