document: delivery of the human genome draft sequence by publicly funded   and corporate   projects promises to precipitate significant biomedical advances this century . to rise to this challenge 
   , biologists must become adept at navigating the vast expanses of genomic dna data that may seem , at first glance , to be devoid of features . yet lying beneath this facade of uniformity are rich veins of knowledge awaiting exploitation . surveying and signposting 
   this apparently bland genomic landscape should guide investigators towards experiments that address specific hypotheses about gene function . 
   ? different communities of biologists speak in dialects that are not always mutually comprehensible , particularly with respect to the umbrella term ' function ' . 
   where one investigator might be interested in designing active - site inhibitors using high - resolution protein structural data , another might require information on gene pathways , and another might be focused on relating genotype to phenotype . 
   if the genome is to offer up its secrets to all scientific communities , its surveyors need to adopt universal vocabularies . 
   broadly speaking , there are two common ways of annotating ( assigning names and functions to ) genes . 
   websites such as locuslink , genecards , eugenes   and ensembl   ( see table 1 ) integrate information from diverse sources relevant to individual human genes . 
   thus one may browse sequence information , for example concerning single - nucleotide polymorphisms ( snps ) , alongside both descriptions of molecular and cellular function and information relevant to human disease . 
   such annotation is essential , yet it is currently restricted to the minority of human genes - those that have been characterized experimentally . 
   a key to the databases mentioned in this article the second type of annotation relies not on empirical observations but rather on predicted evolutionary relationships . 
   all genes that are thought to have arisen from a common ancestor are defined as homologs : where additional copies have arisen by gene duplication within a single genome they are defined as paralogs , whereas corresponding genes in different species are orthologs . sometimes homologous gene products have strong sequence similarities , such that an inference of homology is straightforward ; one such example is the drosophila melanogaster gene branchless , which encodes a homolog of human fibroblast growth factor ( fgf ) . on other occasions , 
   protein homologs have subtle or indiscernible sequence similarities that try the patience and expertise of genome wayfarers . 
   for example , human fgf and interleukin-1 have highly similar tertiary structures despite insignificantly similar sequences but , as a result of their similar growth - factor - type functions , they are in fact very likely to be homologs . 
   the importance of annotating the genomic landscape on the basis of homology is that protein homologs invariably have similar tertiary structures and frequently also have similar functions . 
   the surveying and way - marking of each new gene , therefore , need n't always be an arduous process of discovering structure and function from scratch , since clues can be inferred from what has already been experimentally gleaned from its homologs . by applying the concept of homology , the problem of broadly predicting the functions of all genes is brought within the realms of possibility . 
   there is a pitfall to be avoided when annotating genes by homology : homology is defined on the basis of evolution , rather than function . on one hand 
   , homologs may be related only by evolution and not by similarities in molecular mechanism ; relatives of enzymes that now lack catalytic sites are just such examples . on the other hand , examples abound of divergent homologs , or even non - homologs , whose functions overlap . 
   consequently , homology assignment indicates only an approximate direction for future empirical determination of function , perhaps analogous to laying down a compass bearing rather than an exact map reference . 
   the first completely sequenced genomes , such as that of haemophilus influenzae , were annotated following searches of all available sequence databases with each predicted gene product . 
   this approach assumes that matters are straightforward : although homologous genes may not always be similar in function , genes are either homologous or they are not . 
   a major problem in gene annotation arises , however , when one encounters sequence - similar , homologous portions of genes embedded in otherwise sequence - dissimilar , non - homologous contexts . 
   the presence of these domains demonstrates that evolution has constantly fused and divided genes , using a repertoire of pre - existing components ( figure 1 ) . 
   domain architectures of the human signalling proteinsvav , grb2 , nck1 and crk , as predicted using smart . 
   although these proteins share two common domains ( namely src - homology 2 and 3 , or sh2 and sh3 , domains ) they are not all homologous to one another . 
   the complex architectures of these proteinsimply that the co - occurrence of these two domain types has arisen on more than one occasion , and thus that the domain combinations seen in the four proteins are not likely to have arisen from a common ancestor with whom they share a common architecture . 
   domains are homologous portions of sequences that are encoded in different gene contexts and have survived the evolutionary tests of time without fragmentation . in three dimensions , domains are observed to be compact units of structure , often with a hydrophobic interior and a hydrophilic exterior , and they are not divisible into smaller units . 
   consequently , domains represent the finite vocabulary of protein evolution : if domains are words , then multidomain proteins are complete sentences . just as there is a dictionary or lexicon for every language , 
   there is one - or in this case several - for the vocabulary of domains . 
   pfam   is the widest - ranging lexicon of domain families , predicting at least one domain for more than two - thirds of all entries in the swiss - prot   protein database . 
   smart   is a more concise collection , focusing on those domains that are widespread and difficult to detect . 
   prosite   also has a dictionary of domain profiles , as does celera   ( called panther ) and the institute for genomic research , tigr . 
   each of these resources detects domains using numerical representations of multiple sequence alignments , either hidden markov models ( hmms ) or generalized profiles ( gps ) . 
   although the constructions of hmms and gps are very different , formally they are equivalent . 
   homology assignments are guided by comparisons of hmms or gps with protein sequence databases , and by implementation of an upper threshold value for e , the number of unrelated sequences expected purely by chance that are aligned with a particular score , or higher , in the search . 
   this procedure has been shown on many occasions to identify subtle , yet informative , sequence similarities among distant homologs . taken together , pfam , smart   and the other domain resources carry considerable redundancy , although each has its own merits . 
   an additional resource , interpro , has been derived in part to avoid the onerous task of querying each of these domain lexicons separately for each protein sequence of interest . 
   interpro ( release 3.0 ) combines the domain and motif sets of prosite , pfam , prodom , prints   and smart   in a hierarchical manner and is thereby able to provide annotation for 74% of all swiss - prot ( protein database ) and trembl ( translated dna sequence database ) entries . 
   pfam , smart and interpro were recently chosen by the public and private consortia to annotate their human genome draft sequences . to be more precise , 
   annotations were applied to the proteome , the current predicted set of all expressed proteins encoded by the draft . 
   the proportion of the proteome that could be annotated , even minimally , using these resources is low , at approximately 40 - 60% . 
   the resources were used to annotate the proteome according to lists of component domains rather than protein or gene names . 
   thus , protein sequences were identified not , for example , as the product of the lbc oncogene , but rather as containing rhogef ( dbl - homology ) and pleckstrin homology ( ph ) domains ( figure 2 ) . 
   this is protein annotation viewed through the evolutionary lens , rather than faithful extracts from the current body of experimental knowledge . by implication , 
   proteome annotation by domain content implies that a gene product 's function is a synthesis of the generalized functions of its component parts ( see figure 2 ) . 
   although such descriptions of molecular function are approximate and pale in comparison to accounts of experimentally derived characteristics , they provide the best predictions that can be mustered for the uncharacterized majority of human genes . 
   domain architectures of the lbc oncogene product , and the experimentally uncharacterized protein kiaa1415 , as predicted using smart . 
   the predicted domains in kiaa1415 suggest that it facilitates guanine nucleotide exchange on rho - type small gtpases ( it has rho guanine - nucleotide exchange factor , or rhogef , and pleckstrin homology or ph domains ) , it is localized to the plasma membrane ( ph domain ) and it may interact with the carboxyl termini of transmembrane receptors or channels ( it has pdz domains ) . the generalized functions of dep domains are not currently known . 
   it should be noted that prediction of this protein 's domain architecture does not allow prediction of either its cellular function or the phenotypic effect of its deficiency . 
   it is important to emphasize that annotation of individual proteins or complete proteomes using domains is achieved automatically rather than by manual curation . 
   this is relevant , because a newly sequenced genome 's proteome is generally in a high state of flux , with additions and deletions resulting from sequence updates , enhanced understanding of gene structure and identification of previously overlooked genes . 
   the animal genome sequencing projects already underway will proceed in the same manner as the publicly funded human project , through numerous draft stages and on towards completion . providing up - to - date , and necessarily automatic 
   one might suggest that gene annotation by use of domains is a relatively short - term measure that will be made redundant by results from high - throughput studies of non - vertebrate model organisms . 
   it can be argued that detailed predictions of the functions of most human genes can be inferred from studies of their orthologs , as these are the most likely members of a family to have similarities in molecular and cellular roles . 
   in contrast to previous expectations , the human genome draft publications found that the great majority of human genes have no orthologs in each of three important model organisms whose genome sequences are known , namely drosophila ( fruitfly ) , caenorhabditis elegans ( nematode worm ) and saccharomyces cerevisiae ( baker 's yeast ) . 
   thus , the contribution of domain identification to gene - function prediction will remain until such a time as reliable results from high - throughput studies on a more closely related organism , such as the mouse , are available . 
   deconvolution of human proteins into their constituent domains has also played a major role in understanding the evolution of chordates . 
   three significant differences were detected between the repertoires of human domain families and those of the nematode worm , fruitfly , the mustard cress arabidopsis thaliana and yeast . 
   first , only a small proportion ( 7% ) of human domain families are absent from the other proteomes . 
   second , numerous domain families were greatly expanded in terms of the number of members in humans , whereas others were considerably reduced . 
   this finding demonstrated that domain ' invention ' in the chordate lineage has made only a minor contribution to proteome diversity , whereas expansions and contractions of domain families , and domain additions and deletions , have all added greatly to proteome innovation . 
   such studies demonstrate the power of comparative proteomics in relating gene content to the evolution of eukaryotic organisms . 
   but as with the argument that the complexity of organisms is only loosely coupled to total gene number , the question of whether the number of representatives of a domain family in a proteome is directly related to that family 's contribution to cellular and organismal function remains open . 
   it is hoped that future proteome comparisons will progress beyond the simple enumeration of homologous genes and domains towards an understanding of the biology that underlies the variability of domain family sizes . 
   although it provides information about molecular structure , function and evolution , by and large it is unable to predict functional aspects , such as cellular or organismal role , protein - binding partners or post - translational modifications . 
   fortunately , other views that address these aspects have been incorporated with domain predictions into web - based resources such as locuslink , genecards , eugenes   and ensembl . 
   each of these sites represents a confluence of diverse information sources that are mapped to specific regions of genomic sequence . 
   whilst navigating these sites it should be borne in mind that they often fail explicitly to distinguish between annotations that are experimentally derived and those that are predicted by homology - based methods . 
   nevertheless , these sites are a significant boon to biologists since they provide views of genomes from multiple vantage points , from protein tertiary structure through to snps and on to human disease . 
   as viewed now , the human genome appears to be a relatively featureless landscape , punctuated by islands of annotations for well - characterized and biomedically important genes . as biological sciences progress into a more knowledge - rich , as well as data - rich , era , the cartography of this genome will become more complex with numerous different functional characteristics being assigned to a growing fraction of human genes 
   . it will be increasingly important to restrict descriptions of function to a common and broad vocabulary that is compatible with computational approaches . 
   fortunately , a cross - community approach to dealing with this issue is already underway . 
   the gene ontology project ( go )   has created an initial hierarchy of defined terms that encompasses many of the flavours of ' function ' commonly described in biology . 
   go has begun to permeate throughout genomics and it will do so more rapidly as its scope and attention to detail improves . 
   two further domain - centric approaches look set to guide the efficient navigation of genomes : orthology prediction and the partitioning of a domain family into subfamilies with distinct functions . 
   orthology is a valuable concept from which to infer functional information between species , and orthologs from the genomes of 30 bacteria , archaea and the yeast saccharomyces cerevisiae can be predicted directly using the cogs database . 
   pairs of orthologs from animal genomes are also available on the web ( for example from the jackson laboratory ) . 
   no resource is yet available that accurately predict sets of orthologs for several multicellular eukaryotes , however , such as the fruitfly , worm , arabidopsis , mouse and human . 
   a more difficult problem is the partitioning of a homologous domain family into multiple subfamilies representing multiple functions . 
   homologous proteins with divergent sequences frequently have distinct functions   that are characterized by contrasting patterns of conserved amino acids . 
   one productive approach to the analysis and prediction of functional subtypes identified key sites in multiple protein sequence alignments that specify the different functional subtypes . 
   this method has performed well in defining functional subtypes with prediction accuracies of up to 96% . a key element in ensuring 
   a central function will be provided by sophisticated web forums that accumulate and automatically present integrated functional data . 
   the best example so far is the distributed annotation system , or das , which seeks to amalgamate annotations donated by experimentalists worldwide . 
   even these schemes , however , will face a major challenge in integrating functional information from the huge datasets that arise , for example , from microarray   and proteomics   experiments . 
   the human genomic landscape , relatively featureless now , will soon be teeming with evidence , pointers , and clues . 
   ultimately , the success of the genome projects will be measured not in the completion of sequences , but in how access to integrated data opens up new avenues of research and therapy .
summary: the evolutionary history of eukaryotic proteins involves rapid sequence divergence , addition and deletion of domains , and fusion and fission of genes . 
   although the protein repertoires of distantly related species differ greatly , their domain repertoires do not . to account for the great diversity of domain contexts and an unexpected paucity of ortholog conservation 
   , we must categorize the coding regions of completely sequenced genomes into domain families , as well as protein families .