Interactive visualization and exploration of relationships between biological objects

Genome sequencing and microarray technology produce ever-increasing amounts of complex data that need analysis. Visualization is an effective analytical technique that exploits the ability of the human brain to process large amounts of data. Here, we review traditional visualization methods based on clustering and tree representation, and also describe an alternative approach that involves projecting objects onto a Euclidean space in a way that reflects their structural or functional distances. Data are visualized without preclustering and can be dynamically explored by the user using ‘virtual-reality’. We illustrate this approach with two case studies from protein topology and gene expression.     

Identifying functional relationships among human genes by systematic analysis of biological literature

Background  

The availability of biomedical literature in electronic format has made it possible to implement automatic text processing methods to expose implicit relationships among different documents, and more importantly, the functional relationships among the molecules and processes that these documents describe.     

Association between the polymorphisms of glutathione S-transferase genes and rheumatoid arthritis: A meta-analysis

The glutathione S-transferases (GSTs) are a family of phase II xenobiotic metabolizing enzymes known to be involved in the detoxification and elimination of reactive oxygen species (ROS), thus defending tissues against oxidative stress. Recently, several studies have examined the potential contributions of GSTM1 and GSTT1 gene polymorphisms toward susceptibility to rheumatoid arthritis (RA), but these studies have produced diverse results. To verify the association between GSTM1 and GSTT1 gene polymorphisms and susceptibility to RA, we conducted a meta-analysis of all relevant reports cited in MEDLINE/PubMed before April 2012. A meta-analysis on the association between the GSTM1 polymorphism and RA was performed for 4636 patients with RA and 3916 controls from 8 published studies. In addition, a total of 5 studies involving 3174 RA patients and 2958 controls were considered in the meta-analysis of the association between the GSTT1 polymorphism and RA. No significant association was found between the GSTM1 null genotype and RA susceptibility in all subjects; however, a significant increased risk was found in East Asians. The GSTT1 null genotype was not associated with susceptibility to RA in any study subject. No apparent effect of smoking was found in stratified analysis. The results of our meta-analysis indicated that the GSTM1 null genotype is significantly associated with RA in East Asians alone, indicating that GSTM1 is another non-human leukocyte antigen (non-HLA) susceptibility gene for RA in East Asian populations.     

Different relationships between galling and non-galling herbivore richness and plant species richness: a meta-analysis

The plant richness hypothesis (PRH) is used to explain herbivorous insect richness based on the number of plant species, predicting a positive relationship. However, the influence of plant richness on insect distribution can become stronger with greater levels of specialization of herbivores. In this meta-analysis, I tested whether there is any difference in the correlation force recorded between studies that investigated endophagous versus exophagous herbivores, and galling versus non-galling guilds, in order to determine whether more specialized groups have a stronger relationship. Furthermore, I calculated whether effect sizes were homogeneous between galling studies carried out at local and regional scales, and between tropical and temperate regions. A total of 52 correlations were analyzed between plant species richness and herbivore species richness, with 18 correlations derived from galling herbivores and 34 from non-galling herbivores. The effect sizes were significant and positive in all studies, being higher for endophages than for exophages, and for galling than for non-galling studies. These results provide evidence that groups of insects with a higher level of host specialization and specificity (e.g., endophagous and galling) exhibit a greater dependence on plant richness. There was no difference in effect sizes for galling studies between the local and regional level or between tropical and temperate groups. Despite the large variability found for galling studies, effect sizes were consistent independently of climatic region and latitudinal variation. These results suggest that the PRH for galling insects can be generalized to most ecosystem and vegetation types.     

Protein structures and information extraction from biological texts: the PASTA system

MOTIVATION: The rapid increase in volume of protein structure literature means useful information may be hidden or lost in the published literature and the process of finding relevant material, sometimes the rate-determining factor in new research, may be arduous and slow. RESULTS: We describe the Protein Active Site Template Acquisition (PASTA) system, which addresses these problems by performing automatic extraction of information relating to the roles of specific amino acid residues in protein molecules from online scientific articles and abstracts. Both the terminology recognition and extraction capabilities of the system have been extensively evaluated against manually annotated data and the results compare favourably with state-of-the-art results obtained in less challenging domains. PASTA is the first information extraction (IE) system developed for the protein structure domain and one of the most thoroughly evaluated IE system operating on biological scientific text to date. AVAILABILITY: PASTA makes its extraction results available via a browser-based front end: http://www.dcs.shef.ac.uk/nlp/pasta/. The evaluation resources (manually annotated corpora) are also available through the website: http://www.dcs.shef.ac.uk/nlp/pasta/results.html.     

The relationships between intake and net portal fluxes of energy metabolites in ruminants: A meta-analysis

In a research programme aiming at characterising the energy value of ruminant diets by the net portal energy fluxes in ruminants, the present work focused on the relationships between intakes of both dry matter (DMI) and digestible organic matter (DOMI) and the portal blood flow and the net portal fluxes of oxygen (O₂), volatile fatty acids, β-hydroxybutyrate, glucose and lactate in sheep and growing cattle. Response equations were generated, expressed as a function of liveweight (LW), using meta-analysis on published that were compiled into the FLORA (FLux of nutrients through the Organs and tissues of Ruminant Animals) database and that investigated changes in intake at constant dietary metabolisable energy (ME) contents within experimental groups. The experimental groups in the selected data set were predominantly adult sheep (n = 17), with nine experimental groups on growing cattle and only one experimental group on lactating dairy cows. Intake range was larger in sheep than in growing cattle (0–35 g/d/kg LW versus 0–23 g/d/kg LW, respectively), and the types of diets fed also differed, with sheep predominantly being fed forage-rich diets (60% of experimental groups). Blood flow and portal O₂ consumption showed curvilinear relationships; however the response equations generated for nutrients were best described by linear relationships. With the exception of glucose net portal flux, 70–95% of variation was explained by the models generated. The magnitude of the response equations was largely different between species, and this may also include differences in diets and/or physiological state between the datasets. Both DMI and DOMI were good predictors of the influence of a change in intake level on net portal fluxes of energy metabolites. Subsequent work needs to focus on the influence of diet composition (i.e., dietary ME content).     

A biological relativity view of the relationships between genomes and phenotypes

This article explores the relativistic principle that there is no privileged scale of causality in biology to clarify the relationships between genomes and phenotypes. The idea that genetic causes are primary views the genome as a program. Initially, that view was vindicated by the discovery of mutations and knockouts that have large and specific effects on the phenotype. But we now know that these form the minority of cases. Many changes at the genome level are buffered by robust networks of interactions in cells, tissues and organs. The ‘differential’ view of genetics therefore fails because it is too restrictive. An ‘integral’ view, using reverse engineering from systems biological models to quantify contributions to function, can solve this problem. The article concludes by showing that far from breaking the supervenience principle, downward causation requires that it should be obeyed.     

Functional relationships between genes of the Shaker gene complex of Drosophila

Different mutations belonging to the HLI and HLII complementation groups of the haplolethal (HL) region of the Shaker complex (ShC) are described. The HLI complementation group includes viable (hdp), recessive lethals [l(1)1614], semidominant lethals [l(1)8384] and dominant lethals [l(1)5051,l(1)9916, l(1)13193], lack-of-function alleles that affect nervous system, cuticle and muscle development. The HLI complementation group encodes troponin I. HLII lack-of-function mutations [l(1)174 and l(l)4058] affect nervous system development. The semidominant lethal HLI mutation 1(1)8384 shows differential complementation with other mutations in the ME and HL regions of ShC. Thus, heterozygous combinations of l(1)8384 with ME mutations l(1)162 and l(1)387 are poorly viable. The same phenomenon is observed for heterozygotes of l(1)8384 with HL mutations l(1)1199, l(1)2288 and l(1)3014. These specific interactions indicate the existence of functional relationships among the genetic elements of ShC. The implications for the understanding of the functional organization of ShC are discussed.     

MedEvi: retrieving textual evidence of relations between biomedical concepts from Medline

Search engines running on MEDLINE abstracts have been widely used by biologists to find publications that are related to their research. The existing search engines such as PubMed, however, have limitations when applied for the task of seeking textual evidence of relations between given concepts. The limitations are mainly due to the problem that the search engines do not effectively deal with multi-term queries which may imply semantic relations between the terms. To address this problem, we present MedEvi, a novel search engine that imposes positional restriction on occurrences matching multi-term queries, based on the observation that terms with semantic relations which are explicitly stated in text are not found too far from each other. MedEvi further identifies additional keywords of biological and statistical significance from local context of matching occurrences in order to help users reformulate their queries for better results. AVAILABILITY: http://www.ebi.ac.uk/tc-test/textmining/medevi/     

Phylogenetic relationships based on two mitochondrial genes and hybridization patterns in Anatidae

We produced DNA sequence data from two mitochondrial genes (cytochrome b and the NADH dehydrogenase subunit 2) to reconstruct the phylogenetic relationships among 121 species of the Anseriformes (waterfowls including ducks, geese, swans, the magpie goose and screamers). Phylogenetic analyses converged into a congruent topology and defined several well-supported clades. We calibrated a molecular clock and reconstructed ancestral biogeographical areas using Bayesian inference supporting an austral continental (Gondwanaland) origin of the waterfowls. Ducks, swans and geese might have diversified during the Miocene (23–5 Myr ago) reaching northern distributions in Holarctic and Afrotropical regions. The evolution of hybridization patterns in Anseriformes has been investigated using a cladistic analysis (morphology), which may underestimate or overestimate the phylogenetic divergence among species, or restricted only to ducks. Using a phylogenetic framework, genetic-based distances and a Bayesian time calibration, our data support the hypothesis based on immunological distances of slow rate of appearance of reproductive incompatibilities in waterfowls compared with other vertebrates and the view that these birds may be like frogs in having lost their interspecific hybridization potential more slowly than mammals.     

Asthma susceptible genes in Chinese population: A meta-analysis

Background

Published data regarding the associations between genetic variants and asthma risk in Chinese population were inconclusive. The aim of this study was to investigate asthma susceptible genes in Chinese population.

Methods

The authors conducted 18 meta-analyzes for 18 polymorphisms in 13 genes from eighty-two publications.

Results

Seven polymorphisms were found being associated with risk of asthma, namely: A Disintegrin and Metalloprotease 33 (ADAM33) T1-C/T (odds ratio [OR] = 6.07, 95% confidence interval [CI]: 2.69-13.73), Angiotensin-Converting Enzyme (ACE) D/I (OR = 3.85, 95%CI: 2.49-5.94), High-affinity IgE receptor β chain (FcεRIβ) -6843G/A (OR = 1.49, 95%CI: 1.01-2.22), Interleukin 13(IL-13) -1923C/T (OR = 2.99, 95%CI: 2.12-4.24), IL-13 -2044A/G (OR = 1.49, 95%CI: 1.07-2.08), Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES) -28C/G (OR = 1.64, 95%CI: 1.09-2.46), Tumor Necrosis Factor-α (TNF-α) -308G/A(OR = 1.42, 95%CI: 1.09, 1.85). After subgroup analysis by age, the ACE D/I, β2-Adrenergic Receptor (β2-AR) -79G/C, TNF-α -308G/A, Interleukin 4 receptor(IL-4R) -1902G/A and IL-13 -1923C/T polymorphisms were found significantly associated with asthma risk in Chinese children. In addition, the ACE D/I, FcεRIβ -6843G/A, TNF-α -308G/A, IL-13 -1923C/T and IL-13 -2044A/G polymorphisms were associated with asthma risk in Chinese adults.

Conclusion

ADAM33, FcεRIβ, RANTES, TNF-α, ACE, β2-AR, IL-4R and IL-13 genes could be proposed as asthma susceptible genes in Chinese population. Given the limited number of studies, more data are required to validate these associations.     

Phylogenetic relationships of glassfrogs (Centrolenidae) based on mitochondrial and nuclear genes

Glassfrogs (family Centrolenidae) represent an exceptionally diverse group among Neotropical anurans, but their evolutionary relationships never have been assessed from a molecular perspective. Mitochondrial and nuclear markers were used to develop a novel hypothesis of centrolenid phylogeny. Ingroup sampling included 100 terminals, with 78 (53%) of the named species in the family, representing most of the phenotypic diversity described for the group. Thirty-five species representing taxa traditionally associated with glassfrogs were used as outgroups. Gene sampling consisted of complete or partial sequences of three mitochondrial (12S, 16S, ND1) and three nuclear markers (c-myc exon 2, RAG1, POMC) for a total of 4362 bp. Phylogenies were estimated using maximum parsimony, maximum likelihood, and Bayesian analyses for individual genes and combined datasets. The separate analysis of mitochondrial and nuclear datasets allowed us to clarify the relationships within glassfrogs; also, we corroborate the sister-group relationship between Allophryne ruthveni and glassfrogs. The new phylogeny differs significantly from all previous morphology-based hypotheses of relationships, and shows that hypotheses based on few traits are likely to misrepresent evolutionary history. Traits previously hypothesized as unambiguous synapomorphies are shown to be homoplastic, and all genera in the current taxonomy (Centrolene, Cochranella, Hyalinobatrachium, Nymphargus) are found to be poly- or paraphyletic. The new topology implies a South American origin of glassfrogs and reveals allopatric speciation as the most important speciation mechanism. The phylogeny profoundly affects the traditional interpretations of glassfrog taxonomy, character evolution, and biogeography—topics that now require more extensive evaluation in future studies.