B. Alberts, A. Johnson, J. Lewis и др. - Molecular Biology of The Cell (6th edition) (1120996), страница 91
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12, e8.Mouse Genome Sequencing Consortium (2002) Initial sequencing andcomparative analysis of the mouse genome. Nature 420, 520–562.Pollard KS, Salama SR, Lambert N et al. (2006) An RNA geneexpressed during cortical development evolved rapidly in humans.Nature 443, 167–172.237DNA Replication, Repair,and RecombinationThe ability of cells to maintain a high degree of order in a chaotic universe dependsupon the accurate duplication of vast quantities of genetic information carried inchemical form as DNA.
This process, called DNA replication, must occur beforea cell can produce two genetically identical daughter cells. Maintaining orderalso requires the continued surveillance and repair of this genetic information,because DNA inside cells is repeatedly damaged by chemicals and radiation fromthe environment, as well as by thermal accidents and reactive molecules generated inside the cell. In this chapter, we describe the protein machines that replicate and repair the cell’s DNA. These machines catalyze some of the most rapidand accurate processes that take place within cells, and their mechanisms illustrate the elegance and efficiency of cell chemistry.While the short-term survival of a cell can depend on preventing changesin its DNA, the long-term survival of a species requires that DNA sequences bechangeable over many generations to permit evolutionary adaptation to changingcircumstances. We shall see that despite the great efforts that cells make to protect their DNA, occasional changes in DNA sequences do occur.
Over time, thesechanges provide the genetic variation upon which selection pressures act duringthe evolution of organisms.We begin this chapter with a brief discussion of the changes that occur inDNA as it is passed down from generation to generation. Next, we discuss the cellmechanisms—DNA replication and DNA repair—that are responsible for minimizing these changes. Finally, we consider some of the most intriguing pathwaysthat alter DNA sequences—in particular, those of DNA recombination includingthe movement within chromosomes of special DNA sequences called transposable elements.THE MAINTENANCE OF DNA SEQUENCESAlthough, as just pointed out, occasional genetic changes enhance the long-termsurvival of a species through evolution, the survival of the individual demands ahigh degree of genetic stability.
Only rarely do the cell’s DNA-maintenance processes fail, resulting in permanent change in the DNA. Such a change is called amutation, and it can destroy an organism if it occurs in a vital position in the DNAsequence.Mutation Rates Are Extremely LowThe mutation rate, the rate at which changes occur in DNA sequences, can bedetermined directly from experiments carried out with a bacterium such as Escherichia coli—a resident of our intestinal tract and a commonly used laboratoryorganism (see Figure 1–24). Under laboratory conditions, E. coli divides aboutonce every 30 minutes, and a single cell can generate a very large population—several billion—in less than a day. In such a population, it is possible to detect thesmall fraction of bacteria that have suffered a damaging mutation in a particulargene, if that gene is not required for the bacterium’s survival.
For example, themutation rate of a gene specifically required for cells to use the sugar lactose as anenergy source can be determined by growing the cells in the presence of a differentCHAPTER5IN THIS CHAPTERTHE MAINTENANCE OF DNASEQUENCESDNA REPLICATION MECHANISMSTHE INITIATION ANDCOMPLETION OF DNAREPLICATION IN CHROMOSOMESDNA REPAIRHOMOLOGOUS RECOMBINATIONTRANSPOSITION ANDCONSERVATIVE SITE-SPECIFICRECOMBINATION238Chapter 5: DNA Replication, Repair, and Recombinationsugar, such as glucose, and testing them subsequently to see how many have lostthe ability to survive on a lactose diet.
The fraction of damaged genes underestimates 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 thatchange an amino acid without affecting the activity of the protein coded for by thegene). After correcting for these silent mutations, one finds that a single gene thatencodes an average-sized protein (~103 coding nucleotide pairs) accumulates amutation (not necessarily one that would inactivate the protein) approximatelyonce in about 106 bacterial cell generations. Stated differently, bacteria displaya mutation rate of about three nucleotide changes per 1010 nucleotides per cellgeneration.Recently, it has become possible to measure the germ-line mutation ratedirectly in more complex, sexually reproducing organisms such as humans.
Inthis case, the complete genomes from a family—parents and offspring—weredirectly sequenced, and a careful comparison revealed that approximately 70 newsingle-nucleotide mutations arose in the germ lines of each offspring. Normalized to the size of the human genome, the mutation rate is one nucleotide changeper 108 nucleotides per human generation. This is a slight underestimate becausesome mutations will be lethal and will therefore be absent from progeny; however,because relatively little of the human genome carries critical information, thisconsideration has only a small effect on the true mutation rate. It is estimated thatapproximately 100 cell divisions occur in the germ line from the time of conception to the time of production of the eggs and sperm that go on to make the nextgeneration. Thus, the human mutation rate, expressed in terms of cell divisions(instead of human generations), is approximately 1 mutation/1010 nucleotides/cell division.Although E.
coli and humans differ greatly in their modes of reproduction andin their generation times, when the mutation rates of each are normalized to asingle round of DNA replication, they are both extremely low and within a factorof three of each other. We shall see later in the chapter that the basic mechanismsthat ensure these low rates of mutation have been conserved since the very earlyhistory of cells on Earth.Low Mutation Rates Are Necessary for Life as We Know ItSince many mutations are deleterious, no species can afford to allow them toaccumulate 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 proteinsthat any organism can depend upon to perhaps 30,000. More than this, and theprobability that at least one critical component will suffer a damaging mutationbecomes catastrophically high. By an extension of the same argument, a mutationfrequency tenfold higher would limit an organism to about 3000 essential genes.In this case, evolution would have been limited to organisms considerably lesscomplex than a fruit fly.The cells of a sexually reproducing animal or plant are of two types: germ cellsand somatic cells.
The germ cells transmit genetic information from parent to offspring; the somatic cells form the body of the organism (Figure 5–1). We haveseen that germ cells must be protected against high rates of mutation to maintainthe species. However, the somatic cells of multicellular organisms must also beprotected from genetic change to properly maintain the organized structure of thebody. Nucleotide changes in somatic cells can give rise to variant cells, some ofwhich, through “local” natural selection, proliferate rapidly at the expense of therest of the organism.
In an extreme case, the result is the uncontrolled cell proliferation that we know as cancer, a disease that causes (in Europe and North America) more than 20% of human deaths each year. These deaths are due largely toan accumulation of changes in the DNA sequences of somatic cells, as discussedin Chapter 20. A significant increase in the mutation frequency would presumably cause a disastrous increase in the incidence of cancer by accelerating the rateat which somatic-cell variants arise.
Thus, both for the perpetuation of a speciesDNA REPLICATION MECHANISMS239Figure 5–1 Germ-line cells and somaticcells carry out fundamentally differentfunctions. In sexually reproducingorganisms, the germ-line cells (red)propagate genetic information into the nextgeneration. Somatic cells (blue), which formthe body of the organism, are necessaryfor the survival of germ-line cells but do notthemselves leave any progeny.gametegerm-line cellsgametegerm-line cellszygotezygotesomatic cellssomatic cellsMOTHERDAUGHTERwith a large number of genes (germ-cell stability) and for the prevention of cancer resulting from mutations in somatic cells (somatic-cell stability), multicellularorganisms like ourselves depend on the remarkably high fidelity with which theirDNA sequences are replicated and maintained.SummaryMBoC6 m5.01/5.01In all cells, DNA sequences are maintained and replicated with high fidelity.
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