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Results are shown for 106 out of thetotal of 141 gene regulatory proteins inSaccharomyces cerevisiae. Each protein inthe set was tested for its ability to bind tothe regulatory DNA of each of the genescoding for this set of proteins. In thediagram, the genes are arranged in acircle, and an arrow pointing from gene Ato gene B means that the proteinencoded by A binds to the regulatoryDNA of B, and therefore presumablyregulates the expression of B. Smallcircles with arrowheads indicate geneswhose products directly regulate theirown expression. Genes governingdifferent aspects of cell behavior areshown in different colors. For amulticellular plant or animal, the numberof gene regulatory proteins is about10 times greater, and the amount ofregulatory DNA perhaps 100 timesgreater, so that the correspondingdiagram would be vastly more complex.(From T.I.
Lee et al., Science 298:799–804,2002. With permission from AAAS.)To Make Sense of Cells, We Need Mathematics, Computers, andQuantitative InformationThrough methods such as these, exploiting our knowledge of complete genomesequences, we can list the genes and proteins in a cell and begin to depict theweb of interactions between them (Figure 1–44). But how are we to turn all thisinformation into an understanding of how cells work? Even for a single cell typebelonging to a single species of organism, the current deluge of data seems overwhelming.
The sort of informal reasoning on which biologists usually rely seemstotally inadequate in the face of such complexity. In fact, the difficulty is morethan just a matter of information overload. Biological systems are, for example,full of feedback loops, and the behavior of even the simplest of systems withfeedback is remarkably difficult to predict by intuition alone (Figure 1–45); smallFigure 1–45 A very simple gene regulatory circuit—a single generegulating its own expression by the binding of its protein product toits own regulatory DNA.
Simple schematic diagrams such as this are oftenused to summarize what we know (as in Figure 1–44), but they leave manyquestions unanswered. When the protein binds, does it inhibit orstimulate transcription? How steeply does the transcription rate dependon the protein concentration? How long, on average, does a molecule ofthe protein remain bound to the DNA? How long does it take to makeeach molecule of mRNA or protein, and how quickly does each type ofmolecule get degraded? Mathematical modeling shows that we needquantitative answers to all these and other questions before we canpredict the behavior of even this single-gene system. For differentparameter values, the system may settle to a unique steady state; or it maybehave as a switch, capable of existing in one or other of a set ofalternative states; or it may oscillate; or it may show large randomfluctuations.regulatoryDNAgenecodingregionmRNAgene regulatoryprotein36Chapter 1: Cells and Genomeschanges in parameters can cause radical changes in outcome.
To go from a circuit diagram to a prediction of the behavior of the system, we need detailedquantitative information, and to draw deductions from that information weneed mathematics and computers.These tools for quantitative reasoning are essential, but they are not allpowerful. You might think that, knowing how each protein influences each otherprotein, and how the expression of each gene is regulated by the products of others, we should soon be able to calculate how the cell as a whole will behave, justas an astronomer can calculate the orbits of the planets, or a chemical engineercan calculate the flows through a chemical plant.
But any attempt to performthis feat for an entire living cell rapidly reveals the limits of our present state ofknowledge. The information we have, plentiful as it is, is full of gaps and uncertainties. Moreover, it is largely qualitative rather than quantitative. Most often,cell biologists studying the cell’s control systems sum up their knowledge in simple schematic diagrams—this book is full of them—rather than in numbers,graphs, and differential equations. To progress from qualitative descriptions andintuitive reasoning to quantitative descriptions and mathematical deduction isone of the biggest challenges for contemporary cell biology.
So far, the challengehas been met only for a few very simple fragments of the machinery of livingcells—subsystems involving a handful of different proteins, or two or threecross-regulatory genes, where theory and experiment can go closely hand inhand. We shall discuss some of these examples later in the book.Arabidopsis Has Been Chosen Out of 300,000 Species As a ModelPlantThe large multicellular organisms that we see around us—the flowers and treesand animals—seem fantastically varied, but they are much closer to one anotherin their evolutionary origins, and more similar in their basic cell biology, thanthe great host of microscopic single-celled organisms. Thus, while bacteria andeucaryotes are separated by more than 3000 million years of divergent evolution, vertebrates and insects are separated by about 700 million years, fish andmammals by about 450 million years, and the different species of floweringplants by only about 150 million years.Because of the close evolutionary relationship between all flowering plants,we can, once again, get insight into the cell and molecular biology of this wholeclass of organisms by focusing on just one or a few species for detailed analysis.Out of the several hundred thousand species of flowering plants on Earth today,molecular biologists have chosen to concentrate their efforts on a small weed, thecommon Thale cress Arabidopsis thaliana (Figure 1–46), which can be grownindoors in large numbers, and produces thousands of offspring per plant after8–10 weeks.
Arabidopsis has a genome of approximately 140 million nucleotidepairs, about 11 times as much as yeast, and its complete sequence is known.The World of Animal Cells Is Represented By a Worm, a Fly, aMouse, and a HumanMulticellular animals account for the majority of all named species of livingorganisms, and for the largest part of the biological research effort. Four specieshave emerged as the foremost model organisms for molecular genetic studies.
Inorder of increasing size, they are the nematode worm Caenorhabditis elegans,the fly Drosophila melanogaster, the mouse Mus musculus, and the human,Homo sapiens. Each of these has had its genome sequenced.Caenorhabditis elegans (Figure 1–47) is a small, harmless relative of the eelworm that attacks crops. With a life cycle of only a few days, an ability to survivein a freezer indefinitely in a state of suspended animation, a simple body plan,and an unusual life cycle that is well suited for genetic studies (described inChapter 23), it is an ideal model organism.
C. elegans develops with clockworkprecision from a fertilized egg cell into an adult worm with exactly 959 body cellsFigure 1–46 Arabidopsis thaliana, theplant chosen as the primary model forstudying plant molecular genetics.(Courtesy of Toni Hayden and the JohnInnes Foundation.)GENETIC INFORMATION IN EUCARYOTES37Figure 1–47 Caenorhabditis elegans, thefirst multicellular organism to have itscomplete genome sequencedetermined. This small nematode, about1 mm long, lives in the soil.
Mostindividuals are hermaphrodites,producing both eggs and sperm. Theanimal is viewed here using interferencecontrast optics, showing up theboundaries of the tissues in bright colors;the animal itself is not colored whenviewed with ordinary lighting.
(Courtesyof Ian Hope.)0.2 mm(plus a variable number of egg and sperm cells)—an unusual degree of regularity for an animal. We now have a minutely detailed description of the sequenceof events by which this occurs, as the cells divide, move, and change their characters according to strict and predictable rules. The genome of 97 millionnucleotide pairs codes for about 19,000 proteins, and many mutants and othertools are available for the testing of gene functions. Although the worm has abody plan very different from our own, the conservation of biological mechanisms has been sufficient for the worm to be a model for many of the developmental and cell-biological processes that occur in the human body.
Studies ofthe worm help us to understand, for example, the programs of cell division andcell death that determine the numbers of cells in the body—a topic of greatimportance in developmental biology and cancer research.Studies in Drosophila Provide a Key to Vertebrate DevelopmentThe fruitfly Drosophila melanogaster (Figure 1–48) has been used as a modelgenetic organism for longer than any other; in fact, the foundations of classicalgenetics were built to a large extent on studies of this insect. Over 80 years ago, itprovided, for example, definitive proof that genes—the abstract units of hereditary information—are carried on chromosomes, concrete physical objects whosebehavior had been closely followed in the eucaryotic cell with the light microscope, but whose function was at first unknown.
The proof depended on one ofthe many features that make Drosophila peculiarly convenient for genetics—theFigure 1–48 Drosophila melanogaster.Molecular genetic studies on this fly haveprovided the main key to understandinghow all animals develop from a fertilizedegg into an adult. (From E.B. Lewis,Science 221:cover, 1983. With permissionfrom AAAS.)38Chapter 1: Cells and Genomesgiant chromosomes, with characteristic banded appearance, that are visible insome of its cells (Figure 1–49). Specific changes in the hereditary information,manifest in families of mutant flies, were found to correlate exactly with the lossor alteration of specific giant-chromosome bands.In more recent times, Drosophila, more than any other organism, has shownus how to trace the chain of cause and effect from the genetic instructionsencoded in the chromosomal DNA to the structure of the adult multicellularbody.
Drosophila mutants with body parts strangely misplaced or mispatternedprovided the key to the identification and characterization of the genes requiredto make a properly structured body, with gut, limbs, eyes, and all the other partsin their correct places. Once these Drosophila genes were sequenced, thegenomes of vertebrates could be scanned for homologs. These were found, andtheir functions in vertebrates were then tested by analyzing mice in which thegenes had been mutated. The results, as we see later in the book, reveal anastonishing degree of similarity in the molecular mechanisms of insect and vertebrate development.The majority of all named species of living organisms are insects.
Even ifDrosophila had nothing in common with vertebrates, but only with insects, itwould still be an important model organism. But if understanding the moleculargenetics of vertebrates is the goal, why not simply tackle the problem head-on?Why sidle up to it obliquely, through studies in Drosophila?Drosophila requires only 9 days to progress from a fertilized egg to an adult;it is vastly easier and cheaper to breed than any vertebrate, and its genome ismuch smaller—about 170 million nucleotide pairs, compared with 3200 millionfor a human.
This genome codes for about 14,000 proteins, and mutants cannow be obtained for essentially any gene. But there is also another, deeper reason why genetic mechanisms that are hard to discover in a vertebrate are oftenreadily revealed in the fly. This relates, as we now explain, to the frequency ofgene duplication, which is substantially greater in vertebrate genomes than inthe fly genome and has probably been crucial in making vertebrates the complex and subtle creatures that they are.The Vertebrate Genome Is a Product of Repeated DuplicationAlmost every gene in the vertebrate genome has paralogs—other genes in thesame genome that are unmistakably related and must have arisen by gene duplication.
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