Initial sequencing and analysis of the human genome - Vitagenes

articlesmultifunctional proteins and 3 for cytoskeletal/structural. No suchgroups were found for defence and immunity or cell±cell communication.The 1-1-1-1 groups probably represent key functions that havenot undergone duplication and elaboration in the various lineages.They include many anabolic enzymes responsible for such functionsas respiratory chain and nucleotide biosynthesis. In contrast, thereare few catabolic enzymes. As anabolic pathways branch lessfrequently than catabolic pathways, this indicates that alternativeroutes and displacements are more frequent in catabolic reactions.If proteins from the single-celled yeast are excluded from theanalysis, there are 1,195 1-1-1 groups. The additional groupsinclude many examples of more complex signalling proteins, suchas receptor-type and src-like tyrosine kinases, likely to have arisenearly in the metazoan lineage. The fact that this set comprises only asmall proportion of the proteome of each of the animals indicatesthat, apart from a modest conserved core, there has been extensiveelaboration and innovation within the protein complement.Most proteins do not show simple 1-1-1 orthologous relationshipsacross the three animals. To illustrate this, we investigated thenuclear hormone receptor family. In the human proteome, thisfamily consists of 60 different `classical' members, each with a zinc®nger and a ligand-binding domain. In comparison, the ¯y proteomehas 19 and the worm proteome has 220. As shown in Fig. 39,few simple orthologous relationships can be derived among thesehomologues. And, where potential subgroups of orthologues and(>200)(7)(4) Hepatocyte nuclear factors(3)Steroid(7)hormone(4)(2)(2)Ecdysone(3) Retinoic acids(2)(2)(6) Vitamin D3Ecdysone(3)(3)(3)(3)(3)HumanWormFly(3) Thyroid hormone(3) Retinoic acidsPeroxisomeproliferator activated(2) Apolipoproteinregulatory proteinFigure 39 Simpli®ed cladogram (relationship tree) of the `many-to-many' relationships ofclassical nuclear receptors. Triangles indicate expansion within one lineage; barsrepresent single members. Numbers in parentheses indicate the number of paralogues ineach group.paralogues could be identi®ed, it was apparent that the functions ofthe subgroup members could differ signi®cantly. For example, the¯y receptor for the ¯y-speci®c hormone ecdysone and the humanretinoic acid receptors cluster together on the basis of sequencesimilarity. Such examples underscore that the assignment of functionalsimilarity on the basis of sequence similarities among thesethree organisms is not trivial in most cases.New vertebrate domains and proteins. We then explored how theproteome of vertebrates (as represented by the human) differs fromthose of the other species considered. The 1,262 InterPro familieswere scanned to identify those that contain only vertebrate proteins.Only 94 (7%) of the families were `vertebrate-speci®c'. Theserepresent 70 protein families and 24 domain families. Only one ofthe 94 families represents enzymes, which is consistent with theancient origins of most enzymes 336 . The single vertebrate-speci®cenzyme family identi®ed was the pancreatic or eosinophil-associatedribonucleases. These enzymes evolved rapidly, possibly tocombat vertebrate pathogens 337 .The relatively small proportion of vertebrate-speci®c multicopyfamilies suggests that few new protein domains have been inventedin the vertebrate lineage, and that most protein domains trace atleast as far back as a common animal ancestor. This conclusion mustbe tempered by the fact that the InterPro classi®cation system isincomplete; additional vertebrate-speci®c families undoubtedlyexist that have not yet been recognized in the InterPro system.The 94 vertebrate-speci®c families appear to re¯ect importantphysiological differences between vertebrates and other eukaryotes.Defence and immunity proteins (23 families) and proteins thatfunction in the nervous system (17 families) are particularlyenriched in this set. These data indicate the recent emergence orrapid divergence of these proteins.Representative human proteins were previously known for nearlyall of the vertebrate-speci®c families. This was not surprising, giventhe anthropocentrism of biological research. However, the analysisdid identify the ®rst mammalian proteins belonging to two of thesefamilies. Both of these families were originally de®ned in ®sh. The®rst is the family of polar ®sh antifreeze III proteins. We found ahuman sialic acid synthase containing a domain homologous topolar ®sh antifreeze III protein (BAA91818.1). This ®nding suggeststhat ®sh created the antifreeze function by adaptation of thisdomain. We also found a human protein (CAB60269.1) homologousto the ependymin found in teleost ®sh. Ependymins aremajor glycoproteins of ®sh brains that have been claimed to beinvolved in long-term memory formation 338 . The function of themammalian ependymin homologue will need to be elucidated.New architectures from old domains. Whereas there appears to beonly modest invention at the level of new vertebrate proteindomains, there appears to be substantial innovation in the creationof new vertebrate proteins. This innovation is evident at the level ofdomain architecture, de®ned as the linear arrangement of domainswithin a polypeptide. New architectures can be created by shuf¯ing,adding or deleting domains, resulting in new proteins from oldparts.We quanti®ed the number of distinct protein architectures foundin yeast, worm, ¯y and human by using the SMART annotationresource 339 (Fig. 40). The human proteome set contained 1.8 timesas many protein architectures as worm or ¯y and 5.8 times as manyas yeast. This difference is most prominent in the recent evolution ofnovel extracellular and transmembrane architectures in the humanlineage. Human extracellular proteins show the greatest innovation:the human has 2.3 times as many extracellular architectures as ¯yand 2.0 times as many as worm. The larger number of humanarchitectures does not simply re¯ect differences in the number ofdomains known in these organisms; the result remains qualitativelythe same even if the number of architectures in each organism isnormalized by dividing by the total number of domains (notshown). (We also checked that the larger number of human904 © 2001 Macmillan Magazines Ltd NATURE | VOL 409 | 15 FEBRUARY 2001 | www.nature.com