Les selenoproteïnes constitueixen una família diversa de proteïnes, caracteritzada per la presència del Seleni (Se), en forma de l'amino àcid atípic, la selenocisteïna (Sec). La selenocisteïna, coneguda com l'amino àcid 21, és similar a la cisteïna (Cys) amb un àtom de seleni en lloc de sofre (S). Les selenoproteïnes són els responsables majoritaris dels efectes biològics del seleni i s'ha observat que poden estar implicades en la infertilitat masculina, el càncer, algunes malalties coronàries,l'activació de virus latents i l'envelliment. La selenocisteïna es codifica pel codó UGA, normalment codó de parada (STOP). Per a la recodificació correcta del UGA són necessaris diversos factors. A la part 3' de la regió no traduïda (UTR) dels transcrits dels gens de selenoproteïnes en organismes eucariotes s'hi troba una estructura de "stem-loop" anomenada SECIS. La proteïna SBP2 interactua amb el SECIS, així com amb el ribosoma, i forma un complex amb el factor d'elongació EFsec i el tRNA de la selenocisteïna, el tRNASec. Donat que el codó TGA normalment significa fi de la traducció, les formes tradicionals de cerca de gens no el reconeixen com a codó codificant. Per aquesta raó ha estat necessari desenvolupar una metodologia específica per a la predicció de gens de selenoproteïnes. En els últims anys, hem contribuït a la descripció del selenoproteoma eucariota amb el descobriment de noves famílies (Castellano et al., 2005), amb l'elaboració de nous mètodes (Taskov et al., 2005; Chapple et al., 2009) i l'anotació de diferents genomes (Jaillon et al., 2004; Drosophila 12 genomes Consortium, 2007; Bovine Genome Sequencing and Analysis Consortium, 2009). Finalment, hem identificat el primer animal que no té selenoproteïnes (Drosophila 12 genomes Consortium, 2007; Chapple and Guigó, 2008), un descobriment soprenent donat que, fins el moment, es creia que les selenoproteïnes eren essencials per la vida animal. / Selenoproteins are a diverse family of proteins containing the trace element Selenium (Se)in the form of the non-canonical amino acid selenocysteine (Sec). Selenocysteine, the 21st amino acid, is similar to cysteine (Cys)but with Se replacing Sulphur. In many cases the homologous gene of a known selenoprotein is present with cysteine in the place of Sec in a different genome. Selenoproteins are believed to be the effectors of the biological functions of Selenium and have been implicated in male infertility, cancer and heart diseases, viral expression and ageing. Selenocysteine is coded by the opal STOP codon (TGA). A number of factors combine to achieve the co-translational recoding of TGA to Sec. The 3' Untranslated regions (UTRs) of eukaryotic selenoprotein transcripts contain a stem-loop structure called a Sec Insertion Sequence (SECIS) element. This is recognised by the Secis Binding Protein 2 (SBP2), which binds to both the SECIS element and the ribosome. SBP2, in turn, recruits the Sec-specific Elongation Factor EFsec, and the selenocysteine transfer RNA, tRNASec. The dual meaning of the TGA codon means that selenoprotein genes are often mispredicted by the standard annotation pipelines. The correct prediction of these genes, therefore, requires the development of specific methods. In the past few years we have contributed significally to the description of the eukaryotic selenoproteome2 with the discovery of novel families (Castellano et al., 2005), the elaboration of novel methods (Taskov et al., 2005; Chapple et al., 2009) and the annotation of different genomes (Jaillon et al., 2004; Drosophila 12 genomes Consortium, 2007; Bovine Genome Sequencing and Analysis Consortium, 2009). Finally, and perhaps most importantly, we have identified the first animal to lack selenoprotein genes (Drosophila 12 genomes Consortium, 2007; Chapple and Guigó, 2008). This last finding is particularly surprising because it had previously been believed that selenoproteins were essential for animal life.

La tesis doctoral con título "Caracterización de la región cromosómica 15q11-13 del genoma humano. Variabilidad genómica en el autismo e identificación de ncRNAs" se basa en el estudio de la región cromosómica 15q11-q13, centrándonos en los aspectos de la variabilidad genómica y su significado funcional. En la primera parte del estudio buscamos reordenamientos de 15q11-q13 en pacientes con autismo, mediante la genotipación de marcadores microsatélites cubriendo dicha región, y definimos una deleción polimórfica de origen y tamaño variable en la región 15q11.2. Según los resultados del test FBAT, la deleción está asociada al trastorno autista. Analizamos la organización de esta región delecionada y encontramos evidencias que sugerían la presencia de ncRNAs en esta región. Identificamos 2 nuevos miRNAs y 19 RNAs funcionales de una clase no conocida hasta hoy, específicos de primates y con bajos niveles de expresión al menos en cerebro, hígado, riñón y testículo. Según los estudios de predicción de targets de los miRNAs identificados en la región 15q11.2 del genoma humano, estos podrían participar en el desarrollo y funcionamiento del sistema nervioso central, así como en el origen del autismo, los síndromes de Angelman y de Prader-Willi y otras enfermedades genómicas

Although the genome sequence and gene content are available for an increasing number of organisms, eukaryotic selenoproteins remain poorly characterized. In these proteins, selenium (Se) is incorporated in the form of selenocysteine(Sec), the 21st amino acid. Selenocysteine is cotranslationally inserted in response to UGA codons (a stop signal in the canonical genetic code). The alternative decoding is mediated by a stem-loop structure in the 3'UTR of selenoprotein mRNAs (the SECIS element). Selenium is implicated in male infertility, cancer and heart diseases, viral expression and ageing. In addition, most selenoproteins have homologues in which Sec is replaced by cysteine (Cys).Genome biologists rely on the high-quality annotation of genomes to bridge the gap from the sequence to the biology of the organism. However, for selenoproteins, which mediate the biological functions of selenium, the dual role of the UGA codon confounds both the automatic annotation pipelines and the human curators. In consequence, selenoproteins are misannotated in the majority of genome projects. Furthermore, the finding of novel selenoprotein families remains a difficult task in the newly released genome sequences.In the last few years, we have contributed to the exhaustive description of the eukaryotic selenoproteome (set of eukaryotic selenoproteins) through the development of a number of ad hoc computational tools. Our approach is based on the capacity of predicting SECIS elements, standard genes and genes with a UGA codon in-frame in one or multiple genomes. Indeed, the comparative analysis plays an essential role because 1) SECIS sequences are conserved between close species (eg. human-mouse); and 2) sequence conservation across a UGA codon between genomes at further phylogenetic distance strongly suggests a coding function (eg. human-fugu). Our analysis of the fly, human and Takifugu and Tetraodon genomes have resulted in 9 novel selenoprotein families. Therefore, 20 distinct selenoprotein families have been described in eukaryotes to date. Most of these families are widely (but not uniformly) distributed across eukaryotes, either as true selenoproteins or Cys-homologues.The correct annotation of selenoproteins is thus providing insight into the evolution of the usage of Sec. Our data indicate a discrete evolutionary distribution of selenoprotein in eukaryotes and suggest that, contrary to the prevalent thinking of an increase in the number of selenoproteins from less to more complex genomes, Sec-containing proteins scatter all along the complexity scale. We believe that the particular distribution of each family is mediated by an ongoing process of Sec/Cys interconversion, in which contingent events could play a role as important as functional constraints. The characterization of eukaryotic selenoproteins illustrates some of the most important challenges involved in the completion of the gene annotation of genomes. Notably among them, the increasing number of exceptions to our standard theory of the eukaryotic gene and the necessity of sequencing genomes at different evolutionary distances towards such a complete annotation.