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Abstract: Mitochondrial DNA disorders – disorders associated with dysfunctions of the oxidative phosphorylation system (OXPHOS) – are caused by inborn metabolism errors and have an estimated frequency of 1 out of 10000 live births. Due to the relevant role played by the OXPHOS system in ATP production, causes and effects of mitochondrial disorders are highly heterogeneous and complex. Major origin of mitochondrial disorders is in both nuclear and mitochondrial DNA mutations. Although prenatal diagnosis is routine for nuclear DNA mutations, the cases of prenatal diagnosis of mtDNA mutations are rare, even though urgent, as no real therapies exist. However thanks to bioinformatics support, the gap may be reduced in a short time. Indeed, up to now, the pathogenicity of mtDNA mutations has been, in most cases, prevalently validated by their segregation with the disease and their consequent loss of function when the mutation involves a structural gene, but no systematic statistical analysis of the mtDNA SNPs has been performed. Moreover the criteria commonly followed to associate a mutation to a given pathology are: - aminoacidic change in a strictly conserved site; - presence in patients only; - heteroplasmy condition; - presence in phenotipically similar, but ethnically different families. However a strict correlation mutation-phenotype in patients is not always verified. Here we propose a statistical approach aimed to contribute in the estimation of the pathogenic variation sites. The analysis is based on the estimation of site-specific relative variability in a sets of homologous sequences, through the application of SiteVarProt and SiteVariability softwares, in order to infer a correlation between site variability and pathogenicity of a given mutation.

Abstract: Population genetics studies based on the analysis of mtDNA and mitochondrial disease studies have produced a huge quantity of sequence data and related information. These data, classified as RFLPs, mtDNA SNPs, pathogenic mutations, HVS1 and HVS2 sequences, and complete mtDNA sequences, are distributed in databases differently organised:: MITOMAP, HVRBASE, mtSNPs and mtDB. The two latter databases more or less report frequency data associated with the mitochondrial SNPs, while MITOMAP simply associates the mtSNP to the different phenotypes. HmtDB, stores human complete mitochondrial genomes annotated with variability data estimated through the application of specific algorithms implemented in an automatically running Variability Generation Work Flow (VGWF). Another Work Flow, called Classification Work Flow (CWF), is implemented to perform the automatic classification of newly sequenced genomes. The aims of HmtDB are to collect and integrate all human mitochondrial genomes publicly available, to produce and provide the scientific community with site-specific nucleotidic and aminoacidic variability data estimated on all available human mitochondrial genome sequences through the automatic application of VGWF, to allow researchers to analyse their own complete or partial mitochondrial genomes in order to automatically detect the nucleotidic variants respect to the revised Cambridge Reference Sequence (rCRS) and to predict their haplogroup paternity. At present, 1255 genomes classified according to their continental origin are stored in HmtDB.

Abstract: Population genetics studies based on the analysis of mtDNA and mitochondrial disease studies have produced a huge quantity of sequence data and related information. These data, classified as RFLPs, mtDNA SNPs, pathogenic mutations, HVS1 and HVS2 sequences, and complete mtDNA sequences, are at present distributed worldwide in differently organised databases and web sites, not well integrated among them. Several mitochondrial specialised databases and databases related with variability data have been designed and implemented, but generally they are structured as simple databases where data are stored, without the possibility to perform any analysis. Moreover it is not generally possible for the user to submit and contemporarily analyse its own data comparing them with the content of a given database and this is valid both for population genetics data, and for mitochondrial disease data. As far as population genetics data, for example, the problem of sequence classification in haplogroups is becoming more and more important as the improvement of sequencing technologies is increasing the availability of new complete mitochondrial genomes. Indeed up to now the only way to establish the haplogroup paternity of a given mitochondrial sequence is to manually observe its variant sites respect to a reference sequence, referring to literature in order to define its haplogroup-specific polymorphisms. Also as far as mitochondrial disease data, despite the large number of disease-associated mutations already discovered in the last few years, the sequencing of the complete human mt genome is allowing the discovery of new pathogenic mutations. Indeed, up to now, the pathogenicity of mtDNA mutations has been, in most cases, prevalently validated by their segregation with the disease and their consequent loss of function when the mutation involves a structural gene. However, no systematic statistical analysis of the mtDNA SNPs has been performed until now. Here we present the design of a Human Mitochondrial genome DataBase (HMDB) that will collect the complete human mitochondrial genomes publicly available interfaced to analysis programs, allowing the classification of newly sequenced human mitochondrial genomes, and the prediction, through site-specific nucleotidic and aminoacidic analysis[, of the pathogenic potential of mitochondrial polymorphisms.

Abstract: MitBASE is an integrated and comprehensive database of mitochondrial DNA data which collects all available information from different organisms and from intraspecies variants and mutants. Excellent research institutions from different countries are involved, each in charge of developing, collecting and annotating data for the organisms they are specialised in. The design of the actual structure of the database and its implementation in a user- friendly format are the care of the European Bioinformatic Institute. The database can be accessed on the Web at the following address: http://www.ebi.ac.uk/htbin/Mitbase/mitbase.pl. The impact of this project is outstanding both for basic and applied research, such as the study of mitochondrial genetic diseases and mitochondrial DNA intraspecies diversity exploited in several biotechnological fields. The database has been funded within the EU Biotechnology programme.

Abstract: Human MitBASE is a database collecting human mtDNA variants. This database is part of a greater mitochondrial genome database (MitBASE) funded within the EU Biotech Program (1). The present paper reports the recent improvements in data structure, data quality and data quantity. As far as the database structure is concerned it is now fully designed and implemented. Based on the previously described structure (2) some changes have been made to optimise both data input and data quality. Cross-referencings with other bio-databases (EMBL, OMIM, MEDLINE) have been implemented. Human MitBASE data can be queried with the MitBASE Simple Query System (http://www.ebi.ac.uk/htbin/Mitbase/mitbase.pl.) and with SRS at the EBI under the ìMutationî section (http://srs.ebi.ac.uk/srs5/ ). At present the Human MitBASE node contains about 5000 variants related to studies investigating population polymorphisms and pathologies.

Abstract: Nell'ultimo ventennio abbiamo assistito a due grandi rivoluzioni tecnologiche, lo sviluppo delle tecniche del DNA ricombinante e lo sviluppo delle Tecnologie informatiche. I metodi di sequenziamento sempre più avanzati hanno reso disponibili una grande quantità di dati ma la loro utilità è strettamente correlata alla disponibilità di strumenti informatici che ne consentano l'immagazzinamento e la catalogazione razionale allo scopo di consentirne l'analisi. Tutto ciò ha fatto nascere la neccessità di creare banche dati specializzate. MitBASE, AMmtDB e MitoNuc sono tre banche dati specializzate mitocondriali sviluppate dal gruppo di bioinformatica di Bari. MitBASE è una banca dati che raccoglie in maniera integrata sequenze di DNA mitocondriale di differenti organismi. La sua realizzazione è stata possibile grazie alla collaborazione tra sette differenti gruppi di ricerca europei ciascuno dei quali si è occupato della raccolta e della codifica dei dati relativi ad uno specifico gruppo di organismi (uomo, vertebrati, invertebrati, protisti, funghi, piante ed alghe). Le sequenze nucleotidiche e le loro eventuali varianti, raccolte dalle banche dati primarie e dalla letteratura, relative ai diversi organismi sono state poi arricchite con informazioni aggiuntive di carattere specifico per ciascun nodo. Il gruppo di ricerca di Bari si è occupato della strutturazione e della codifica dei dati relativi a varianti del DNA mitocondriale di uomo e di altri vertebrati con particolare attenzione ai dati inerenti a studi di genetica di popolazioni umane e a studi correlati alle patologie mitocondriali. Un nodo supplementare è stato inoltre sviluppato per raccogliere sequenze di geni nucleari del lievito Saccharomyces cerevisiae coinvolti nella biogenesi mitocondriale. Il database è disponibile al seguente indirizzo: http://www3.ebi.ac.uk/Research/Mitbase/mitbase.pl. AMmtDB è invece una banca dati costituita da una collezione di sequenze multiallineate di geni mitocondriali di vertebrati e invertebrati. Le sequenze multiallineate si riferiscono a geni che codificano per proteine e tRNA. Sono presenti inoltre anche multiallineamenti della regione del D-loop dei mammiferi. Tutti i dati sono stati strutturati per essere interrogati mediante il sistema di retrieval SRS all'indirizzo: http://bio-www.ba.cnr.it:8000/BioWWW/#AMMTDB. MitoNuc è una banca dati specializzata di geni nucleari di Metazoi coinvolti nella biogenesi dei mitocondri. Le informazioni relative a ciascun gene riguardanti ad esempio la localizzazione submitocondriale del prodotto, la sua eventuale tessuto specificità, il peptide segnale, le regioni 5' e 3' UTR dell'mRNA, sono strutturate in modo tale da consentire un efficace retrieval. Tale banca dati potrà essere proficuamente utilizzata per lo studio delle proprietà strutturali e funzionali dei geni nucleari codificanti per proteine mitocondriali, dei loro prodotti e delle interazioni tra il sistema genetico nucleare e quello mitocondriale. La banca dati è disponibile all'indirizzo: http://bio-www.ba.cnr.it:8000/srs6/

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Abstract: The maintenance of biological databases is at present a problem of great interest since the progress made in many experimental procedures has led to an ever increasing amount of data. These data need to be structured and stored in databases and made accessible to the biological community in user-friendly ways. Although both the interest and the need of accessing biological databases are high, the mechanisms to fund their maintenance are unclear. Funding agencies cannot support data annotation in terms of labour costs and hence the development of new tools based on “data miming” technologies could greatly contribute to keep biological databases updated. Here we present a new approach aimed to contribute to the annotation in the HmtDB resource (http://www.hmdb.uniba.it/) of variability data associated to clinical phenotypes [1]. These data are prevalently available in literature where they are reported in a completely free style. Thus, we suggest the construction of a knowledge base derived from browsing papers on web and to be used in the retrieval phase. Nevertheless, problems in extracting data from literature come not only from the heterogeneity of presentation styles but mainly from the unstructured format (i.e. the natural language) in which they are represented. In this scenario, the goal is to feed a knowledge base by identifying occurrences of specific biological entities and their features as well as the particular method and experimental setting of the scientific study adopted in the publication. In this work, we describe some solutions to the problem of structuring information contained in scientific literature in digital (i.e., pdf) or paper format.

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Abstract: The present paper describes AMmtDB a database collecting the multi-aligned sequences of Vertebrate mitochondrial genes coding for proteins and tRNAs, as well as the multiple alignment of the Mammalian mtDNA main regulatory region (D-loop) sequences. The genes coding for proteins are multi-aligned based on the translated sequences and both the nucleotide and aminoacid multialignments are provided. As far as the genes coding for tRNAs are concerned, the multi-alignments based on the primary and the secondary structures are both provided; for the Mammalian D-loop multialignments we report the conserved regions of the entire D-loop (CSB1, CSB2, CSB3, the Central region, ETAS1 and ETAS2) as defined by Sbis? et al. (1). A flatfile format for AMmtDB has been designed allowing its implementation in SRS (2) (http://bio- www.ba.cnr.it:8000/BioWWW/#AMMTDB). Data selected through SRS can be managed using GeneDoc (3) or other programs for the management of multi-aligned data depending on the userís operative system. The multiple alignments have been produced with CLUSTALV (4) and PILEUP (5) programs and then carefully optimized manually.

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Abstract: The detemination of nucleic acids and protein sequences, made ever easier and faster by modern technologies and instruments, has allowed considerable progress in biomedical research. Nowadays exponential growth in the number of amminoacid and protein sequences needs computer-based technologies and tools for their management and analysis. Furthermore, suitable network infrastructures are also instrumental for researchers to access these data from the PC on their desk and analyse them with specific algorithms. To this purpose we have developed a WEB interface (BioWWW) which allows to access different specialised databases and biosequence analysis methods developed within the research activities of the Italian EMBnet node and of other EU funded projects. Products presently available under BioWWW are the following: - MmtDB, a metazoan mitochondrial DNA variant database; - KEYnet, a hierarchically structured database classifying genes and proteins according to their function; - UTRdb, a non-redundant database of untranslated 5' and 3' sequences of mRNA from eukaryotes; - PLMItRNA, a higher plant mitochondrial tRNA genes and molecules database. - WORDUP, an algorithm to determine statistically significant oligonucleotides in isofuctional sequence collections; - CODONTREE, a programme for the analysis of codon usage in protein coding genes; - PATSCAN, a programme to identify complex patterns in nucleotide and amminoacid sequences. The site BioWWW (http://bio-www.ba.cnr.it:8000/BioWWW/#AMMTDB) is constantly updated as new programs and databases are made available by our research group.

Abstract: La crescita parallela delle tecnologie Informatiche e delle Telecomunicazioni ha sin dalla seconda metà degli anni ‘80 favorito la crescita delle reti Bioinformatiche. La grande quantità di dati, da una parte, e il gran numero di ricercatori interessati a consultare le banche dati biologiche e a svolgere analisi sui dati in esse contenute, dall’altra, ha indotto i ricercatori coinvolti nella gestione dei dati a strutturare reti informatiche. La prima rete Bioinformatica è stata EMBnet (European Molecular Biology Network) costituita nel 1988 su iniziativa del laboratorio Europeo di Biologia Molecolare di Heidelberg (GE) da parte di dodici centri di differente nazionalità europee afferenti al laboratorio stesso. La rete EMBnet rappresenta il primo modello di 'Laboratorio di Bioinformatica distribuito e senza muri'. La finalità di EMBnet è quella di sostenere e far progredire la ricerca nel settore della biologia molecolare e della biotecnologia, nel senso più ampio del termine, attraverso gli sforzi combinati dei rappresentanti di ciascun nodo EMBnet, i quali offrono le loro specifiche competenze a supporto della comunità scientifica. La rete EMBnet attualmente è costituita da trentacinque nodi europei ed extraeuropei. I nodi sono a loro volta classificati in: Nodi Nazionali e Speciale. I nodi nazionali sono centri di bioinformatica, nominati dall’autorità governativa del proprio paese, i quali hanno il compito di fornire alla comunità scientifica accademica e industriale accesso a banche dati di biosequenze e programmi d’analisi, e organizzare corsi di formazione orientati all’utilizzo degli strumenti Bioinformatici. I nodi speciali sono centri di bioinformatica che possiedono delle forti competenze negli aspetti legati allo sviluppo di banche dati di biosequenze e di programmi d’analisi. Nodo Nazionale Italiano EMBnet Il gruppo di Bioinformatica e Genomica, dell’Area di Ricerca CNR di Bari, è responsabile del nodo nazionale Italiano. Il nodo nazionale mette a disposizione dell’utenza, costituita da numerosi laboratori universitari, centri di ricerca pubblici e privati, banche dati primarie di biosequenze (Acidi Nucleici, Proteine), banche dati specializzate e programmi per l’analisi funzionale. Le analisi che i ricercatori possono condurre utilizzando i pacchetti e i programmi d’analisi disponibili presso il nodo nazionale EMBnet sono: Ricerca di similarità tra sequenze e banche dati; Allineamento e multiallineamento di biosequenze; Individuazione di regioni codificanti proteine; Ricerca di elementi funzionali funzionali quali promotori, siti di splicing ecc. ; Predizione di strutture secondarie in sequenze di acidi nucleici e proteine. Evoluzione Molecolare Parte degli strumenti bioinformatici, banche dati e programmi di analisi, (Tabella I) messi a disposizione dell’utenza è il risultato delle attività di ricerca del gruppo. Tutti i servizi forniti dal nodo nazionale sono accessibili per via telematica mediante delle connessioni di lavoro interattive ed utilizzando la rete Internet. Il nodo italiano EMBnet, nell'ambito dell'attività di formazione, organizza periodicamente corsi di formazione presso la sede dell'Area di Ricerca o su richiesta presso le sedi degli utenti.

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