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The completehuman genome sequence of more than 3 billion nucleotide pairs has now beendetermined, making it easier than ever before to identify at a molecular level theprecise gene responsible for each human mutant characteristic.By drawing together the insights from humans, mice, flies, worms, yeasts,plants, and bacteria—using gene sequence similarities to map out the correspondences between one model organism and another—we enrich our understanding of them all.Figure 1–51 The consequences of geneduplication for mutational analyses ofgene function. In this hypotheticalexample, an ancestral multicellularorganism has a genome containing asingle copy of gene G, which performs itsfunction at several sites in the body,indicated in green. (A) Through geneduplication, a modern descendant of theancestral organism has two copies ofgene G, called G1 and G2. These havediverged somewhat in their patterns ofexpression and in their activities at thesites where they are expressed, but theystill retain important similarities.
At somesites, they are expressed together, andeach independently performs the sameold function as the ancestral gene G(alternating green and yellow stripes); atother sites, they are expressed alone andmay serve new purposes. (B) Because of afunctional overlap, the loss of one of thetwo genes by mutation (red cross) revealsonly a part of its role; only the loss ofboth genes in the double mutant revealsthe full range of processes for whichthese genes are responsible. Analogousprinciples apply to duplicated genes thatoperate in the same place (for example,in a single-celled organism) but are calledinto action together or individually inresponse to varying circumstances.
Thus,gene duplications complicate geneticanalyses in all organisms.GENETIC INFORMATION IN EUCARYOTES988486Cretaceouspig/whalepig/sheephuman/rabbithuman/elephanthuman/mousehuman/sloth778782838981Jurassichuman/kangaroo81Triassicbird/crocodile76human/lizard57human/chicken70human/frog56human/tuna fish55human/shark51human/lamprey35Tertiary50100100human/orangutanmouse/ratcat/dogtime in millions of years150200250Permean300Carboniferous350Devonian400Silurian450% amino acids identical in hemoglobin α chainhuman/chimp041Ordovician500Cambrian550ProterozoicWe 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 ortwo in every 1000 nucleotide pairs in their DNA sequence.
The Human GenomeProject has arbitrarily selected DNA from a small number of anonymous individuals for sequencing. The human genome—the genome of the humanspecies—is, properly speaking, a more complex thing, embracing the entire poolof variant genes that are found in the human population and continuallyexchanged and reassorted in the course of sexual reproduction. Ultimately, wecan hope to document this variation too. Knowledge of it will help us understand, for example, why some people are prone to one disease, others to another;why some respond well to a drug, others badly. It will also provide new clues toour history—the population movements and minglings of our ancestors, theinfections they suffered, the diets they ate.
All these things leave traces in thevariant forms of genes that have survived in human communities.Figure 1–52 Times of divergence ofdifferent vertebrates. The scale on theleft shows the estimated date andgeological era of the last commonancestor of each specified pair of animals.Each time estimate is based oncomparisons of the amino acidsequences of orthologous proteins; thelonger a pair of animals have had toevolve independently, the smaller thepercentage of amino acids that remainidentical. Data from many differentclasses of proteins have been averaged toarrive at the final estimates, and the timescale has been calibrated to match thefossil evidence that the last commonancestor of mammals and birds lived 310million years ago.
The figures on the rightgive data on sequence divergence forone particular protein (chosenarbitrarily)—the a chain of hemoglobin.Note that although there is a cleargeneral trend of increasing divergencewith increasing time for this protein,there are also some irregularities. Thesereflect the randomness within theevolutionary process and, probably, theaction of natural selection drivingespecially rapid changes of hemoglobinsequence in some organisms thatexperienced special physiologicaldemands. On average, within anyparticular evolutionary lineage,hemoglobins accumulate changes at arate of about 6 altered amino acids per100 amino acids every 100 million years.Some proteins, subject to stricterfunctional constraints, evolve much moreslowly than this, others as much as5 times faster. All this gives rise tosubstantial uncertainties in estimates ofdivergence times, and some expertsbelieve that the major groups ofmammals diverged from one another asmuch as 60 million years more recentlythan shown here.
(Adapted fromS. Kumar and S.B. Hedges, Nature392:917–920, 1998. With permission fromMacmillan Publishers Ltd.)Figure 1–53 Human and mouse: similargenes and similar development. Thehuman baby and the mouse shown herehave 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.)42Chapter 1: Cells and GenomesKnowledge and understanding bring the power to intervene—with humans,to avoid or prevent disease; with plants, to create better crops; with bacteria, toturn them to our own uses. All these biological enterprises are linked, becausethe genetic information of all living organisms is written in the same language.The new-found ability of molecular biologists to read and decipher this language has already begun to transform our relationship to the living world.
Theaccount of cell biology in the subsequent chapters will, we hope, prepare you tounderstand, and possibly to contribute to, the great scientific adventure of thetwenty-first century.SummaryEucaryotic cells, by definition, keep their DNA in a separate membrane-enclosed compartment, the nucleus. They have, in addition, a cytoskeleton for support and movement, elaborate intracellular compartments for digestion and secretion, the capacity(in many species) to engulf other cells, and a metabolism that depends on the oxidation of organic molecules by mitochondria. These properties suggest that eucaryotesmay have originated as predators on other cells. Mitochondria—and, in plants,chloroplasts—contain their own genetic material, and evidently evolved from bacteriathat were taken up into the cytoplasm of the eucaryotic cell and survived as symbionts.Eucaryotic cells have typically 3–30 times as many genes as procaryotes, and oftenthousands of times more noncoding DNA.
The noncoding DNA allows for complex regulation of gene expression, as required for the construction of complex multicellularorganisms. Many eucaryotes are, however, unicellular—among them the yeast Saccharomyces cerevisiae, which serves as a simple model organism for eucaryotic cellbiology, revealing the molecular basis of conserved fundamental processes such as theeucaryotic cell division cycle.
A small number of other organisms have been chosen asprimary models for multicellular plants and animals, and the sequencing of theirentire genomes has opened the way to systematic and comprehensive analysis of genefunctions, gene regulation, and genetic diversity. As a result of gene duplications during vertebrate evolution, vertebrate genomes contain multiple closely relatedhomologs of most genes. This genetic redundancy has allowed diversification and specialization of genes for new purposes, but it also makes gene functions harder to decipher.
There is less genetic redundancy in the nematode Caenorhabditis elegans and thefly Drosophila melanogaster, which have thus played a key part in revealing universalgenetic mechanisms of animal development.Which statements are true? Explain why or why not.1–1The human hemoglobin genes, which are arrangedin two clusters on two chromosomes, provide a good example of an orthologous set of genes.1–2Horizontal gene transfer is more prevalent in singlecelled organisms than in multicellular organisms.1–3Most of the DNA sequences in a bacterial genomecode for proteins, whereas most of the sequences in thehuman genome do not.Discuss the following problems.1–4Since it was deciphered four decades ago, some haveclaimed that the genetic code must be a frozen accident,while others have argued that it was shaped by natural selection.
A striking feature of the genetic code is its inherent resistance to the effects of mutation. For example, a change in thethird position of a codon often specifies the same amino acidor one with similar chemical properties. The natural coderesists mutation more effectively (is less susceptible to error)than most other possible versions, as illustrated in FigureQ1–1. Only one in a million computer-generated “random”codes is more error-resistant than the natural genetic code.Does the extraordinary mutation resistance of the geneticcode argue in favor of its origin as a frozen accident or as aresult of natural selection? Explain your reasoning.number of codes (thousands)PROBLEMS25201510naturalcode50051015susceptibility to mutationFigure Q1–1 Susceptibility ofthe natural code relative tomillions of computergenerated codes (Problem1–4).
Susceptibility measuresthe average change in aminoacid properties caused byrandom mutations. A smallvalue indicates thatmutations tend to cause20 minor changes. (Datacourtesy of Steve Freeland.)1–5You have begun to characterize a sample obtainedfrom the depths of the oceans on Europa, one of Jupiter’smoons. Much to your surprise, the sample contains a lifeform that grows well in a rich broth. Your preliminary analysisEND-OF-CHAPTER PROBLEMS43shows that it is cellular and contains DNA, RNA, and protein.
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