B. Alberts, A. Johnson, J. Lewis и др. - Molecular Biology of The Cell (6th edition) (1120996), страница 20
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Many mutants are known, andgenetic engineering is relatively easy. The zebrafish has the added virtue that it istransparent for the first two weeks of its life, so that one can watch the behaviorof individual cells in the living organism (see Movie 21.2). All this has made it anincreasingly important model vertebrate (Figure 1–44).The Mouse Is the Predominant Mammalian Model OrganismMammals have typically two times as many genes as Drosophila, a genome thatis 16 times larger, and millions or billions of times as many cells in their adultbodies. In terms of genome size and function, cell biology, and molecular mechanisms, mammals are nevertheless a highly uniform group of organisms.
Evenanatomically, the differences among mammals are chiefly a matter of size andproportions; it is hard to think of a human body part that does not have a counterpart in elephants and mice, and vice versa. Evolution plays freely with quantitative features, but it does not readily change the logic of the structure.Figure 1–42 Two species of the frog genus Xenopus. X. tropicalis, above,has an ordinary diploid genome; X. laevis, below, has twice as much DNA percell. From the banding patterns of their chromosomes and the arrangementof genes along them, as well as from comparisons of gene sequences, it isclear that the large-genome species have evolved through duplications ofthe whole genome.
These duplications are thought to have occurred in theaftermath of matings between frogs of slightly divergent Xenopus species.(Courtesy of E. Amaya, M. Offield, and R. Grainger, Trends Genet. 14:253–255, 1998. With permission from Elsevier.)35Chapter 1: Cells and Genomes36hours06163416 cellsblastulagastrula67962841 mmfertilized eggneurulaFigure 1–43 Stages in the normal development of a frog. These drawingsshow the development of a Rana pipiens tadpole from a fertilized egg. Theentire process takes place outside of the mother, making the mechanismsinvolved readily accessible for experimental studies.
(From W. Shumway,Anat. Rec. 78:139–147, 1940.)For a more exact measure of how closely mammalian species resemble oneanother genetically, we can compare the nucleotide sequences of corresponding(orthologous) genes, or the amino acid sequences of the proteins that these genesencode. The results for individual genes and proteins vary widely. But typically, ifwe line up the amino acid sequence of a human protein with that of the orthologous protein from, say, an elephant, about 85% of the amino acids are identical.A similar comparison between human and bird shows an amino acid identity ofabout 70%—twice as many differences, because the bird and the mammalian lineages have had twice as long to diverge as those of the elephant and the human(Figure 1–45).The mouse, being small, hardy, and a rapid breeder, has become the foremostmodel organism for experimental studies of vertebrate molecular genetics.
Manynaturally occurring mutations are known, often mimicking the effects of corresponding mutations in humans (Figure 1–46). Methods have been developed,moreover, to test the function of any chosen mouse gene, or of any noncodingportion of the mouse genome, by artificiallycreating mutations in it, as we explainMBoC6 n1.201/1.43later in the book.Just one made-to-order mutant mouse can provide a wealth of information forthe cell biologist. It reveals the effects of the chosen mutation in a host of differentcontexts, simultaneously testing the action of the gene in all the different kinds ofcells in the body that could in principle be affected.tail budtadpoleHumans Report on Their Own PeculiaritiesAs humans, we have a special interest in the human genome.
We want to know thefull set of parts from which we are made, and to discover how they work. But even(A)1 cm(B)150 µmFigure 1–44 Zebrafish as a model forstudies of vertebrate development. Thesesmall, hardy tropical fish are convenientfor genetic studies. Additionally, they havetransparent embryos that develop outsideof the mother, so that one can clearlyobserve cells moving and changing theircharacter in the living organism throughoutits development. (A) Adult fish.
(B) Anembryo 24 hours after fertilization. (A, withpermission from Steve Baskauf; B, fromM. Rhinn et al., Neural Dev. 4:12, 2009.)GENETIC INFORMATION IN EUKARYOTES988486Cretaceouspig/whalepig/sheephuman/rabbithuman/elephanthuman/mousehuman/sloth778782838981Jurassichuman/kangaroo81Triassicbird/crocodile76human/lizard57human/chicken70human/frog56human/tuna fish55human/shark51human/lamprey35Tertiary50100100human/orangutanmouse/ratcat/dogtime in millions of years150200250Permian300Carboniferous350Devonian400Silurian450Ordovicianpercent amino acids identical in hemoglobin α chainhuman/chimp037500Cambrian550Proterozoicif you were a mouse, preoccupied with the molecular biology of mice, humanswould be attractive as model genetic organisms, because of one special property:through medical examinations and self-reporting, we catalog our own genetic(and other) disorders. The human population is enormous, consisting todayof some 7 billion individuals, and this self-documenting property means that aMBoC6huge database of information existson m1.52/1.45human mutations.
The human genomesequence of more than 3 billion nucleotide pairs has been determined for thousands of different people, making it easier than ever before to identify at a molecular level the precise genetic change responsible for any given human mutant phenotype.By drawing together the insights from humans, mice, fish, flies, worms, yeasts,plants, and bacteria—using gene sequence similarities to map out the correspondences between one model organism and another—we are enriching our understanding of them all.Figure 1–45 Times of divergence ofdifferent vertebrates. The scale on the leftshows the estimated date and geologicalera of the last common ancestor of eachspecified pair of animals.
Each timeestimate is based on comparisons of theamino acid sequences of orthologousproteins; the longer the animals of a pairhave had to evolve independently, thesmaller the percentage of amino acidsthat remain identical. The time scalehas been calibrated to match the fossilevidence showing that the last commonancestor of mammals and birds lived310 million years ago.The figures on the right give data onsequence divergence for one particularprotein—the α chain of hemoglobin. Notethat although there is a clear general trendof increasing divergence with increasingtime for this protein, there are irregularitiesthat are thought to reflect the action ofnatural selection driving especially rapidchanges of hemoglobin sequence whenthe organisms experienced specialphysiological demands.
Some proteins,subject to stricter functional constraints,evolve much more slowly than hemoglobin,others as much as five times faster. All thisgives rise to substantial uncertainties inestimates of divergence times, and someexperts believe that the major groups ofmammals diverged from one another asmuch as 60 million years more recentlythan shown here. (Adapted from S.
Kumarand S.B. Hedges, Nature 392:917–920,1998. With permission from MacmillanPublishers Ltd.)Figure 1–46 Human and mouse: similargenes and similar development. Thehuman baby and the mouse shownhere have similar white patches on theirforeheads because both have mutations inthe same gene (called Kit), required for thedevelopment and maintenance of pigmentcells. (Courtesy of R.A. Fleischman.)38Chapter 1: Cells and GenomesWe Are All Different in DetailWhat precisely do we mean when we speak of the human genome? Whosegenome? On average, any two people taken at random differ in about one or twoin every 1000 nucleotide pairs in their DNA sequence. The genome of the humanspecies is, properly speaking, a very complex thing, embracing the entire pool ofvariant genes found in the human population.
Knowledge of this variation is helping us to understand, for example, why some people are prone to one disease,others to another; why some respond well to a drug, others badly. It is also providing clues to our history—the population movements and minglings of our ancestors, the infections they suffered, the diets they ate.
All these things have left tracesin the variant forms of genes that survive today in the human communities thatpopulate the globe.To Understand Cells and Organisms Will Require Mathematics,Computers, and Quantitative InformationEmpowered by knowledge of complete genome sequences, we can list the genes,proteins, and RNA molecules in a cell, and we have methods that allow us to beginto depict the complex web of interactions between them. But how are we to turnall this information into an understanding of how cells work? Even for a single celltype belonging to a single species of organism, the current deluge of data seemsoverwhelming. The sort of informal reasoning on which biologists usually relyseems totally inadequate in the face of such complexity.In fact, the difficulty is more than just a matter of information overload. Biological systems are, for example, full of feedback loops, and the behavior of eventhe simplest of systems with feedback is remarkably difficult to predict by intuition alone (Figure 1–47); small changes in parameters can cause radical changesin outcome.
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