into biological functions; however, ill-informed extrapo- lation of annotation across species can lead to error propagation. Leaving this to the expert, we merely sum- marize the available functional evidence of orthologous genes that is indicative of their common functional role. GO and protein domain summaries. OrthoDB orthologous group functional annotations are summarized from associated GO and InterPro attributes of individual genes, supplemented by data from representative model organisms. Of the just over 1.4 million orthologous group member genes, almost 95% are classiﬁed in orthologous groups that can be described by either GO terms (molecular function, biological process or cellular component) or InterPro domains, and more than 85% by both attributes (Figure 1, Supplementary Figure S2). For each orthologous group, summarizing the member gene GO (molecular function, biological process and cellular component) and InterPro annotations highlights the functional attributes that describe the orthologous group as a whole (Figure 2). These descriptions identify the frequencies of associated GO terms together with InterPro domains of member genes, and list succinct term and domain descriptions. Model organism phenotypes. Mapping of selected model organism phenotype data identiﬁes a signiﬁcant propor- tion of orthologous groups with genes from model organ- isms that exhibit experimental phenotypes. This approach therefore facilitates querying of OrthoDB with key function-related terms from the respective phenotype ontologies, e.g. sterile, or cell cycle defective (Supplementary Table S2). For the representative model organisms in each lineage (Mus musculus, Drosophila melanogaster or Saccharomyces cerevisiae), gene synonyms and secondary identiﬁers, as well as selected associated phenotypes, are indicated with distinct icons linked to their respective database sources. In addition, for each orthologous group member gene, concise UniProt functional descriptors are provided with links to the mapped entries. InterPro matches are displayed with domains ordered sequentially from the N- to C-terminus, describing the complete domain archi- tecture of multidomain genes. The orthologous group summary annotations together with the attributes of indi- vidual gene members provide a snapshot of the available Vertebrates Arthropods Fungi Nucleic Acids Research, 2011, Vol. 39, Database issue D285 functional information, with extensive links to respective source databases, allowing further investigation of their putative biological roles. Evolutionary annotations of orthologous groups Protein sequence divergence rate among orthologous group member genes, their phyletic gene copy-number proﬁles and their homology to genes in other orthologous groups are indicators of the level of conﬁdence with which functional annotations from genes of well-studied model organisms may be transferred to other species. Evolutionary annotations of orthologous groups therefore complement the functional annotations by presenting these quantiﬁable evolutionary properties (Figure 2). Evolutionary rates. Orthologous groups that exhibit appreciably higher or lower levels of sequence divergence are highlighted through quantiﬁcation of the relative divergence among their member genes. These are computed for each orthologous group as the average of interspecies identities normalized to the average identity of all interspecies BRHs, computed from pairwise Smith–Waterman alignments of protein sequences (Supplementary Figure S3). Phyletic proﬁles. Orthologous group phyletic proﬁles indicate the species coverage for the selected species radiation point and contrast the number of species with single-copy members and with multi-copy members. Related groups. Homologous relations among genes from different orthologous groups identify sets of related orthologous groups delineated for the speciﬁc level of the phylogeny. These relations are deﬁned from pairwise Smith–Waterman comparisons between all members of an orthologous group to all members of any related groups with a cutoff of 1e-3. Related groups are identiﬁed at each level of the phylogeny-deﬁned hierarchy, linking to ‘sibling orthologous groups’ as opposed to parent or child groups that would correspond to moving up or down the phylogeny. OrthoDB access The hierarchy. The phylogeny-deﬁned hierarchy of orthologous groups in OrthoDB allows searches to be Classified Genes with Gene Ontology & InterPro attributes with InterPro with Gene Ontology without attributes non-classified genes Genes: 2,500 5,000 7,500 10,000 12,500 15,000 17,500 Figure 1. Striving for the most complete coverage with acceptable accuracy, OrthoDB provides tentative associations of the vast majority of classiﬁed genes with Gene Ontology (GO) and InterPro functional attributes.