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Oncethe sequence of a newly discovered gene has been determined, a scientist cantap a few keys on a computer to search the entire database of known genesequences for genes related to it. In many cases, the function of one or more ofthese homologs will have been already determined experimentally, and thus,since gene sequence determines gene function, one can frequently make a goodguess at the function of the new gene: it is likely to be similar to that of thealready-known homologs.In this way, it is possible to decipher a great deal of the biology of an organism simply by analyzing the DNA sequence of its genome and using the information we already have about the functions of genes in other organisms thathave been more intensively studied.(A)100 nm(B)100 nmFigure 1–27 The viral transfer of DNAfrom one cell to another.
(A) An electronmicrograph of particles of a bacterialvirus, the T4 bacteriophage. The head ofthis virus contains the viral DNA; the tailcontains the apparatus for injecting theDNA into a host bacterium. (B) A crosssection of a bacterium with a T4bacteriophage latched onto its surface.The large dark objects inside thebacterium are the heads of new T4particles in course of assembly. Whenthey are mature, the bacterium will burstopen to release them.
(A, courtesy ofJames Paulson; B, courtesy of JonathanKing and Erika Hartwig from G. Karp, Celland Molecular Biology, 2nd ed. New York:John Wiley & Sons, 1999. With permissionfrom John Wiley & Sons.)THE DIVERSITY OF GENOMES AND THE TREE OF LIFEMore Than 200 Gene Families Are Common to All Three PrimaryBranches of the Tree of LifeGiven the complete genome sequences of representative organisms from all threedomains—archaea, bacteria, and eucaryotes—we can search systematically forhomologies that span this enormous evolutionary divide.
In this way we can beginto take stock of the common inheritance of all living things. There are considerabledifficulties in this enterprise. For example, individual species have often lost someof the ancestral genes; other genes have almost certainly been acquired by horizontal transfer from another species and therefore are not truly ancestral, eventhough shared. In fact, genome comparisons strongly suggest that both lineagespecific gene loss and horizontal gene transfer, in some cases between evolutionarily distant species, have been major factors of evolution, at least among procaryotes. Finally, in the course of 2 or 3 billion years, some genes that were initiallyshared will have changed beyond recognition by current methods.Because of all these vagaries of the evolutionary process, it seems that onlya small proportion of ancestral gene families have been universally retained in arecognizable form.
Thus, out of 4873 protein-coding gene families defined bycomparing the genomes of 50 species of bacteria, 13 archaea, and 3 unicellulareucaryotes, only 63 are truly ubiquitous (that is, represented in all the genomesanalyzed). The great majority of these universal families include components ofthe translation and transcription systems. This is not likely to be a realisticapproximation of an ancestral gene set. A better—though still crude—idea of thelatter can be obtained by tallying the gene families that have representatives inmultiple, but not necessarily all, species from all three major domains. Such ananalysis reveals 264 ancient conserved families.
Each family can be assigned afunction (at least in terms of general biochemical activity, but usually with moreprecision), with the largest number of shared gene families being involved intranslation and in amino acid metabolism and transport (Table 1–2). This set ofhighly conserved gene families represents only a very rough sketch of the common inheritance of all modern life; a more precise reconstruction of the genecomplement of the last universal common ancestor might be feasible with further genome sequencing and more careful comparative analysis.Mutations Reveal the Functions of GenesWithout additional information, no amount of gazing at genome sequences willreveal the functions of genes.
We may recognize that gene B is like gene A, buthow do we discover the function of gene A in the first place? And even if we knowthe function of gene A, how do we test whether the function of gene B is truly thesame as the sequence similarity suggests? How do we connect the world ofabstract genetic information with the world of real living organisms?The analysis of gene functions depends on two complementary approaches:genetics and biochemistry. Genetics starts with the study of mutants: we eitherfind or make an organism in which a gene is altered, and examine the effects onthe organism’s structure and performance (Figure 1–28).
Biochemistry examines the functions of molecules: we extract molecules from an organism andthen study their chemical activities. By combining genetics and biochemistryand examining the chemical abnormalities in a mutant organism, it is possibleto find those molecules whose production depends on a given gene. At the sametime, studies of the performance of the mutant organism show us what rolethose molecules have in the operation of the organism as a whole. Thus, genetics and biochemistry together provide a way to relate genes, molecules, and thestructure and function of the organism.In recent years, DNA sequence information and the powerful tools of molecular biology have allowed rapid progress.
From sequence comparisons, we canoften identify particular subregions within a gene that have been preservednearly unchanged over the course of evolution. These conserved subregions arelikely to be the most important parts of the gene in terms of function. We can testtheir individual contributions to the activity of the gene product by creating in2324Chapter 1: Cells and GenomesTable 1–2 The Numbers of Gene Families, Classified by Function, That Are Commonto All Three Domains of the Living WorldGENE FAMILY FUNCTIONNUMBER OF“UNIVERSAL” FAMILIESInformation processingTranslationTranscriptionReplication, recombination, and repairCellular processes and signalingCell cycle control, mitosis, and meiosisDefense mechanismsSignal transduction mechanismsCell wall/membrane biogenesisIntracellular trafficking and secretionPost-translational modification, protein turnover, chaperonesMetabolismEnergy production and conversionCarbohydrate transport and metabolismAmino acid transport and metabolismNucleotide transport and metabolismCoenzyme transport and metabolismLipid transport and metabolismInorganic ion transport and metabolismSecondary metabolite biosynthesis, transport, and catabolismPoorly characterizedGeneral biochemical function predicted; specific biological roleunknown63713231248191643152298524For the purpose of this analysis, gene families are defined as “universal” if they are represented inthe genomes of at least two diverse archaea (Archaeoglobus fulgidus and Aeropyrum pernix), twoevolutionarily distant bacteria (Escherichia coli and Bacillus subtilis) and one eucaryote (yeast,Saccharomyces cerevisiae).
(Data from R.L. Tatusov, E.V. Koonin and D.J. Lipman, Science 278:631–637,1997, with permission from AAAS; R.L. Tatusov et al., BMC Bioinformatics 4:41, 2003, with permissionfrom BioMed Central; and the COGs database at the US National Library of Medicine.)the laboratory mutations of specific sites within the gene, or by constructingartificial hybrid genes that combine part of one gene with part of another.Organisms can be engineered to make either the RNA or the protein specified bythe gene in large quantities to facilitate biochemical analysis. Specialists inmolecular structure can determine the three-dimensional conformation of thegene product, revealing the exact position of every atom in it. Biochemists candetermine how each of the parts of the genetically specified molecule contributes to its chemical behavior.
Cell biologists can analyze the behavior of cellsthat are engineered to express a mutant version of the gene.There is, however, no one simple recipe for discovering a gene’s function,and no simple standard universal format for describing it. We may discover, forexample, that the product of a given gene catalyzes a certain chemical reaction,and yet have no idea how or why that reaction is important to the organism. Thefunctional characterization of each new family of gene products, unlike thedescription of the gene sequences, presents a fresh challenge to the biologist’singenuity.
Moreover, we never fully understand the function of a gene until welearn its role in the life of the organism as a whole. To make ultimate sense ofgene functions, therefore, we have to study whole organisms, not just moleculesor cells.Molecular Biologists Have Focused a Spotlight on E. coliBecause living organisms are so complex, the more we learn about any particular species, the more attractive it becomes as an object for further study. Each5 mmFigure 1–28 A mutant phenotypereflecting the function of a gene.A normal yeast (of the speciesSchizosaccharomyces pombe) is comparedwith a mutant in which a change in asingle gene has converted the cell from acigar shape (left) to a T shape (right).
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