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Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002.

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Molecular Biology of the Cell. 4th edition.

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The Maintenance of DNA Sequences

Although the long-term survival of a species is enhanced by occasional genetic changes, the survival of the individual demands genetic stability. Only rarely do the cell's DNA-maintenance processes fail, resulting in permanent change in the DNA. Such a change is called a mutation, and it can destroy an organism if it occurs in a vital position in the DNA sequence. Before examining the mechanisms responsible for genetic stability, we briefly discuss the accuracy with which DNA sequences are maintained from one generation to the next.

Mutation Rates Are Extremely Low

The mutation rate, the rate at which observable changes occur in DNA sequences, can be determined directly from experiments carried out with a bacterium such as Escherichia coli—a resident of our intestinal tract and a commonly used laboratory organism. Under laboratory conditions, E. coli divides about once every 30 minutes, and a very large population—several billion—can be obtained from a single cell in less than a day. In such a population, it is possible to detect the small fraction of bacteria that have suffered a damaging mutation in a particular gene, if that gene is not required for the survival of the bacterium. For example, the mutation rate of a gene specifically required for cells to utilize the sugar lactose as an energy source can be determined (using indicator dyes to identify the mutant cells), if the cells are grown in the presence of a different sugar, such as glucose. The fraction of damaged genes is an underestimate of the actual mutation rate because many mutations are silent (for example, those that change a codon but not the amino acid it specifies, or those that change an amino acid without affecting the activity of the protein coded for by the gene). After correcting for these silent mutations, a single gene that encodes an average-sized protein (~103 coding nucleotide pairs) is estimated to suffer a mutation (not necessarily one that would inactivate the protein) once in about 106 bacterial cell generations. Stated in a different way, bacteria display a mutation rate of 1 nucleotide change per 109 nucleotides per cell generation.

The germ-line mutation rate in mammals is more difficult to measure directly, but estimates can be obtained indirectly. One way is to compare the amino acid sequences of the same protein in several species. The fraction of the amino acids that are different between any two species can then be compared with the estimated number of years since that pair of species diverged from a common ancestor, as determined from the fossil record. Using this method, one can calculate the number of years that elapse, on average, before an inherited change in the amino acid sequence of a protein becomes fixed in an organism. Because each such change usually reflects the alteration of a single nucleotide in the DNA sequence of the gene encoding that protein, this value can be used to estimate the average number of years required to produce a single, stable mutation in the gene.

These calculations will nearly always substantially underestimate the actual mutation rate, because many mutations will spoil the function of the protein and vanish from the population because of natural selection—that is, by the preferential death of the organisms that contain them. But there is one family of protein fragments whose sequence does not seem to matter, allowing the genes that encode them to accumulate mutations without being selected against. These are the fibrinopeptides, 20 amino-acid fragments that are discarded from the protein fibrinogen when it is activated to form fibrin during blood clotting. Since the function of fibrinopeptides apparently does not depend on their amino acid sequence, they can tolerate almost any amino acid change. Sequence comparisons of the fibrinopeptides indicate that a typical protein 400 amino acids long would be randomly altered by an amino acid change in the germ line roughly once every 200,000 years.

Another way to estimate mutation rates is to use DNA sequencing to compare corresponding nucleotide sequences from different species in regions of the genome that do not carry critical information. Such comparisons produce estimates of the mutation rate that are in good agreement with those obtained from the fibrinopeptide studies.

E. coli and humans differ greatly in their modes of reproduction and in their generation times. Yet, when the mutation rates of each are normalized to a single round of DNA replication, they are found to be similar: roughly 1 nucleotide change per 109 nucleotides each time that DNA is replicated.

Many Mutations in Proteins Are Deleterious and Are Eliminated by Natural Selection

When the number of amino acid differences in a particular protein is plotted for several pairs of species against the time that has elapsed since the pair of species diverged from a common ancestor, the result is a reasonably straight line: the longer the period since divergence, the larger the number of differences. For convenience, the slope of this line can be expressed in terms of a “unit evolutionary time” for that protein, which is the average time required for 1 amino acid change to appear in a sequence of 100 amino acid residues. When various proteins are compared, each shows a different but characteristic rate of evolution (Figure 5-1).

Figure 5-1. Different proteins evolve at very different rates.

Figure 5-1

Different proteins evolve at very different rates. A comparison of the rates of amino acid change found in hemoglobin, histone H4, cytochrome c, and the fibrinopeptides. The first three proteins have changed much more slowly during evolution than the (more...)

Since most DNA nucleotides are thought to be subject to roughly the same rate of random mutation, the different rates observed for different proteins must reflect differences in the probability that an amino acid change will be harmful for each protein. For example, from the data in Figure 5-1, we can estimate that about six of every seven random amino acid changes are harmful in cytochrome c, and that virtually all amino acid changes are harmful in histone H4. The individual animals that carried such harmful mutations were presumably eliminated from the population by natural selection.

Low Mutation Rates Are Necessary for Life as We Know It

Since so many mutations are deleterious, no species can afford to allow them to accumulate at a high rate in its germ cells. Although the observed mutation frequency is low, it is nevertheless thought to limit the number of essential proteins that any organism can encode to perhaps 60,000. By an extension of the same argument, a mutation frequency tenfold higher would limit an organism to about 6000 essential genes. In this case, evolution would probably have stopped at an organism less complex than a fruit fly.

Whereas germ cells must be protected against high rates of mutation to maintain the species, the somatic cells of multicellular organisms must be protected from genetic change to safeguard each individual. Nucleotide changes in somatic cells can give rise to variant cells, some of which, through natural selection, proliferate rapidly at the expense of the rest of the organism. In an extreme case, the result is an uncontrolled cell proliferation known as cancer, a disease that causes about 30% of the deaths each year in Europe and North America. These deaths are due largely to an accumulation of changes in the DNA sequences of somatic cells (discussed in Chapter 23). A significant increase in the mutation frequency would presumably cause a disastrous increase in the incidence of cancer by accelerating the rate at which somatic cell variants arise. Thus, both for the perpetuation of a species with a large number of genes (germ cell stability) and for the prevention of cancer resulting from mutations in somatic cells (somatic cell stability), multicellular organisms like ourselves depend on the remarkably high fidelity with which their DNA sequences are maintained.

As we see in subsequent sections, successful DNA maintenance depends both on the accuracy with which DNA sequences are duplicated and distributed to daughter cells, and on a set of enzymes that repair most of the changes in the DNA caused by radiation, chemicals, or other accidents.

Summary

In all cells, DNA sequences are maintained and replicated with high fidelity. The mutation rate, approximately 1 nucleotide change per 109 nucleotides each time the DNA is replicated, is roughly the same for organisms as different as bacteria and humans. Because of this remarkable accuracy, the sequence of the human genome (approximately 3 × 109 nucleotide pairs) is changed by only about 3 nucleotides each time a cell divides. This allows most humans to pass accurate genetic instructions from one generation to the next, and also to avoid the changes in somatic cells that lead to cancer.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2002, Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walter; Copyright © 1983, 1989, 1994, Bruce Alberts, Dennis Bray, Julian Lewis, Martin Raff, Keith Roberts, and James D. Watson .
Bookshelf ID: NBK26881

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