Identity of terminator and selenocysteine UGA codons through characterization of selenoproteomes

In the genetic code, UGA terminates protein synthesis and serves as a selenocysteine codon., but identification of correct functions of UGA codons is extremely difficult. In the present study, this UGA dual-function problem was addressed by identifying all or almost all selenoprotein genes in completely sequenced eukaryotic and archaeal genomes. Selenoproteins lack common amino acid sequence motifs, but 3′-untranslated regions of selenoprotein mRNAs contain a common stem-loop structure, selenocysteine insertion sequence (SECIS) element, that is necessary for decoding UGA as selenocysteine rather than as a stop signal. A computer program, SECISearch, was developed, that identifies selenoprotein genes by recognizing SECIS elements on the basis of primary sequence, secondary structure and free energy criteria. When SECISearch was initially applied to search human Expressed Sequence Tags database, two new mammalian selenoproteins, designated SelT and SelR, were identified. On the basis of domain fusion, gene clustering and correlated evolution analyses, SelR function was predicted to be functionally related to peptide methionine sulfoxide reductase. Subsequently, human, mouse and rat genomes were analyzed for the presence of selenoprotein genes. The computational screen included searches for SECIS elements and analyses of their human/rodent conservation characteristics, as well as an independent approach of characterization of coding potentials of UGA codons and their flanking regions. Seven new human selenoproteins were identified by this approach and subsequently confirmed to be true positives. Finally, the search algorithms were adopted for archaeal systems, and all completed archaeal genomes were analyzed for the presence of selenoprotein genes. A single new selenoprotein was identified. The information on identities of 25 human and 24 mouse selenoproteins should help explain biomedical effects of dietary selenium, whereas new bioinformatics tools may be used for genome-wide screens for other structural RNA elements