Microbial genotype–phenotype mapping by class association rule mining

Motivation: Microbial phenotypes are typically due to the concerted action of multiple gene functions, yet the presence of each gene may have only a weak correlation with the observed phenotype. Hence, it may be more appropriate to examine co-occurrence between sets of genes and a phenotype (multiple-to-one) instead of pairwise relations between a single gene and the phenotype. Here, we propose an efficient class association rule mining algorithm, netCAR, in order to extract sets of COGs (clusters of orthologous groups of proteins) associated with a phenotype from COG phylogenetic profiles and a phenotype profile. netCAR takes into account the phylogenetic co-occurrence graph between COGs to restrict hypothesis space, and uses mutual information to evaluate the biconditional relation

DMPFinder - Finding differentiating pathways with gaps from two groups of metabolic networks

Session 2B: Biological and Regulatory NetworksWhy some strains of a species exhibit a certain phenotype (e.g. drug resistant) but not the other strains of the same species is a critical question to answer. Studying the metabolism of the two groups of strains may discover the corresponding pathways that are conserved in the first group but not in the second group. However, only a few tools provide functions to compare two groups of metabolic networks which are usually limited to the reaction level, not the pathway level. In this paper, we formulate the DMP (Differentiating Metabolic Pathway) problem for finding conserved pathways exist in first group, but not the second group. The problem also captures the mutation in pathways and derives a measure (p-value and e-score) for evaluating the confident of the pathways. We then developed an algorithm, DMPFinder, to solve the DMP problem. Experimental results show that DMPFinder is able to identify pathways that are critical for the first group to exhibit a certain phenotype which is absent in the other group. Some of these pathways cannot be identified by other tools which only consider reaction level or do not take into account possible mutations among species. The software is available at: http://i.cs.hku.hk/alse/hkubrg/projects/DMPFinder/postprintThe 3rd International Conference on Bioinformatics and Computational Biology (BICoB 2011), New Orleans, LA., 23-25 March 2011

Mining for genotype-phenotype relations in Saccharomyces using partial least squares

<p>Abstract</p> <p>Background</p> <p>Multivariate approaches are important due to their versatility and applications in many fields as it provides decisive advantages over univariate analysis in many ways. Genome wide association studies are rapidly emerging, but approaches in hand pay less attention to multivariate relation between genotype and phenotype. We introduce a methodology based on a BLAST approach for extracting information from genomic sequences and Soft- Thresholding Partial Least Squares (ST-PLS) for mapping genotype-phenotype relations.</p> <p>Results</p> <p>Applying this methodology to an extensive data set for the model yeast <it>Saccharomyces cerevisiae</it>, we found that the relationship between genotype-phenotype involves surprisingly few genes in the sense that an overwhelmingly large fraction of the phenotypic variation can be explained by variation in less than 1% of the full gene reference set containing 5791 genes. These phenotype influencing genes were evolving 20% faster than non-influential genes and were unevenly distributed over cellular functions, with strong enrichments in functions such as cellular respiration and transposition. These genes were also enriched with known paralogs, stop codon variations and copy number variations, suggesting that such molecular adjustments have had a disproportionate influence on <it>Saccharomyces </it>yeasts recent adaptation to environmental changes in its ecological niche.</p> <p>Conclusions</p> <p>BLAST and PLS based multivariate approach derived results that adhere to the known yeast phylogeny and gene ontology and thus verify that the methodology extracts a set of fast evolving genes that capture the phylogeny of the yeast strains. The approach is worth pursuing, and future investigations should be made to improve the computations of genotype signals as well as variable selection procedure within the PLS framework.</p

Frequent associations between CTL and T-Helper epitopes in HIV-1 genomes and implications for multi-epitope vaccine designs

<p>Abstract</p> <p>Background</p> <p>Epitope vaccines have been suggested as a strategy to counteract viral escape and development of drug resistance. Multiple studies have shown that Cytotoxic T-Lymphocyte (CTL) and T-Helper (Th) epitopes can generate strong immune responses in Human Immunodeficiency Virus (HIV-1). However, not much is known about the relationship among different types of HIV epitopes, particularly those epitopes that can be considered potential candidates for inclusion in the multi-epitope vaccines.</p> <p>Results</p> <p>In this study we used association rule mining to examine relationship between different types of epitopes (CTL, Th and antibody epitopes) from nine protein-coding HIV-1 genes to identify strong associations as potent multi-epitope vaccine candidates. Our results revealed 137 association rules that were consistently present in the majority of reference and non-reference HIV-1 genomes and included epitopes of two different types (CTL and Th) from three different genes (<it>Gag, Pol </it>and <it>Nef</it>). These rules involved 14 non-overlapping epitope regions that frequently co-occurred despite high mutation and recombination rates, including in genomes of circulating recombinant forms. These epitope regions were also highly conserved at both the amino acid and nucleotide levels indicating strong purifying selection driven by functional and/or structural constraints and hence, the diminished likelihood of successful escape mutations.</p> <p>Conclusions</p> <p>Our results provide a comprehensive systematic survey of CTL, Th and Ab epitopes that are both highly conserved and co-occur together among all subtypes of HIV-1, including circulating recombinant forms. Several co-occurring epitope combinations were identified as potent candidates for inclusion in multi-epitope vaccines, including epitopes that are immuno-responsive to different arms of the host immune machinery and can enable stronger and more efficient immune responses, similar to responses achieved with adjuvant therapies. Signature of strong purifying selection acting at the nucleotide level of the associated epitopes indicates that these regions are functionally critical, although the exact reasons behind such sequence conservation remain to be elucidated.</p

NIBBS-Search for Fast and Accurate Prediction of Phenotype-Biased Metabolic Systems

Understanding of genotype-phenotype associations is important not only for furthering our knowledge on internal cellular processes, but also essential for providing the foundation necessary for genetic engineering of microorganisms for industrial use (e.g., production of bioenergy or biofuels). However, genotype-phenotype associations alone do not provide enough information to alter an organism's genome to either suppress or exhibit a phenotype. It is important to look at the phenotype-related genes in the context of the genome-scale network to understand how the genes interact with other genes in the organism. Identification of metabolic subsystems involved in the expression of the phenotype is one way of placing the phenotype-related genes in the context of the entire network. A metabolic system refers to a metabolic network subgraph; nodes are compounds and edges labels are the enzymes that catalyze the reaction. The metabolic subsystem could be part of a single metabolic pathway or span parts of multiple pathways. Arguably, comparative genome-scale metabolic network analysis is a promising strategy to identify these phenotype-related metabolic subsystems. Network Instance-Based Biased Subgraph Search (NIBBS) is a graph-theoretic method for genome-scale metabolic network comparative analysis that can identify metabolic systems that are statistically biased toward phenotype-expressing organismal networks. We set up experiments with target phenotypes like hydrogen production, TCA expression, and acid-tolerance. We show via extensive literature search that some of the resulting metabolic subsystems are indeed phenotype-related and formulate hypotheses for other systems in terms of their role in phenotype expression. NIBBS is also orders of magnitude faster than MULE, one of the most efficient maximal frequent subgraph mining algorithms that could be adjusted for this problem. Also, the set of phenotype-biased metabolic systems output by NIBBS comes very close to the set of phenotype-biased subgraphs output by an exact maximally-biased subgraph enumeration algorithm ( MBS-Enum ). The code (NIBBS and the module to visualize the identified subsystems) is available at http://freescience.org/cs/NIBBS

Finite state models in information extraction

Disertacija je posvećena istraživanju naučne oblasti nazvane ekstrakcija informacija (engl. information extraction), koja predstavlja podoblast veštačke inteligencije, a u sebi kombinuje i koristi tehnike i dostignuća više različitih oblasti računarstva. Termin "ekstrakcija informacija" će biti korišćen u dva različita konteksta. U jednom od njih misli se na ekstrakciju informacije kao naučnu oblast i tada će se koristiti skraćenica IE, preuzeta iz anglosaksonske literature u značenju "Information Extraction". U drugom slučaju, kada se bude mislilo na sam proces i postupak izdvajanja informacija iz teksta, koristiće se oblik "ekstrakcija informacija". Ova disertacija predstavlja, pored pregleda postojećih metoda iz ove oblasti, i jedan originalni pristup i metod za ekstrakciju informacija baziran na konačnim transduktorima. Tokom istraživanja i rada na disertaciji, a primenom pomenutog metoda, kao rezultat formirana je baza podataka o mikroorganizmima koja sadrži fenotipske i genotipske karakteristike za 2412 vrsta i 873 rodova, namenjena za istraživanja iz oblasti bioinformatike i genetike. Baza i korišćeni metod su detaljno prikazani u nekoliko radova, publikovanih u časopisima ili izlaganih na međunarodnim konferencijama (Pajić, 2011; Pajić i sar. 2011a; Pajić i sar. 2011b) U glavi 1 dat je uvod u oblast ekstrakcije informacije, unutar koga je opisan istorijat i razvoj metoda ove oblasti. Dalje je opisana klasifikacija tekstualnih resursa nad kojima se vrši ekstrakcija informacija, kao i klasifikacija samih informacija. Na kraju glave 1 oblast ekstrakcije informacije je upoređena sa drugim srodnim disciplinama računarstva. Glava 2 je posvećena prikazu teorijskih osnova na kojima su zasnovana istraživanja ove disertacije. Razmatrana je teorija formalnih jezika i modela konačnih stanja, kao i njihova uzajamna veza i veza sa ekstrakcijom informacija. Akcenat je stavljen na konačne modele i metode koji su zasnovani na modelima konačnih stanja. Ovi metodi pokazuju veću preciznost od drugih metoda za ekstrakciju informacije, te su nezamenljivi u situacijama kada je tačnost izdvojenih podataka iz teksta od presudnog značaja. Pojedini pojmovi ekstrakcije informacija - jezik relevantnih informacija, jezik izdvojenih informacija, pravila ekstrakcije, definisani su iz ugla teorije formalnih jezika. Formulisano je i dokazano osnovno svojstvo relacije transdukcije za zadato pravilo ekstrakcije. Definisan je i pojam jezika konteksta informacija i dokazano je njegovo svojstvo regularnosti...This dissertation is on research and studying in scientific field called information extraction, which can be seen as a sub-area of artificial intelligence and which combines and uses techniques and achievements of several computer science areas. The term „information extraction“ will be used in two different contexts. In the first one, the term will refer to the scientific area and the acronym IE will be used in that case. In the second case, this term will refer to the very process of extracting information. Beside the IE state-of-the-art survey, an original approach and a method for information extraction based on finite state transducers are presented. A database with microbial phenotype and genotype characteristics, for 2412 species and 873 genera has been created, as a result of the research and the work on the dissertation. The database is intended for research, in bioinformatics and genetics. The method used for the creation of the database and the database itself are described in details and published in several journals and conference proceedings (Pajić, 2011; Pajić et al. 2011a; Pajić et al. 2011b). In the Section 1, the introduction to IE is given, together with the history of development of methods in this area. The classification of textual resources that are used for information extraction and classification of the information itself are described. At the end of the Section 1, IE is compared with other related disciplines of computer science. Section 2 contains some excerpts from formal language theory and abstract automata, on which the dissertation is based. The mutual relationship between these two areas and their connection with IE are described. The emphasis is put on the final state models and methods based on them. These methods show higher precision than other methods for extracting information, and are indispensable in situations where the accuracy of data extracted from the text is of crucial importance. Some specific terms of information extraction - the language of the relevant information, the language of extracted information and extraction rules, are defined from the perspective of formal language theory. The basic feature of the transduction relation for the given rule extraction is formulated and proved. The language of information context is defined and its regularilty is proven..