On the limitations of standard statistical modeling in biological systems: A full Bayesian approach for biology

One of the most important scientific challenges today is the quantitative and predictive understanding of biological function. Classical mathematical and computational approaches have been enormously successful in modeling inert matter, but they may be inadequate to address inherent features of biological systems. We address the conceptual and methodological obstacles that lie in the inverse problem in biological systems modeling. We introduce a full Bayesian approach (FBA), a theoretical framework to study biological function, in which probability distributions are conditional on biophysical information that physically resides in the biological system that is studied by the scientist.     

A kinematic method for computing the motion of the body centre-of-mass (CoM) during walking: a Bayesian approach

The gait pattern of a particular patient can be altered in a large set of pathologies. Tracking the body centre-of-mass (CoM) during the gait allows a quantitative evaluation of these diseases at comparing the gait with normal patterns. A correct estimation of this variable is still an open question because of its non-linearity and inaccurate location. This paper presents a novel strategy for tracking the CoM, using a biomechanical gait model whose parameters are determined by a Bayesian strategy. A particle filter is herein implemented for predicting the model parameters from a set of markers located at the sacral zone. The present approach is compared with other conventional tracking methods and decreases the calculated root mean squared error in about a 56% in the x-axis and 59% in the y-axis.     

BGX: a fully Bayesian integrated approach to the analysis of Affymetrix GeneChip data

We present Bayesian hierarchical models for the analysis of Affymetrix GeneChip data. The approach we take differs from other available approaches in two fundamental aspects. Firstly, we aim to integrate all processing steps of the raw data in a common statistically coherent framework, allowing all components and thus associated errors to be considered simultaneously. Secondly, inference is based on the full posterior distribution of gene expression indices and derived quantities, such as fold changes or ranks, rather than on single point estimates. Measures of uncertainty on these quantities are thus available. The models presented represent the first building block for integrated Bayesian Analysis of Affymetrix GeneChip data: the models take into account additive as well as multiplicative error, gene expression levels are estimated using perfect match and a fraction of mismatch probes and are modeled on the log scale. Background correction is incorporated by modeling true signal and cross-hybridization explicitly, and a need for further normalization is considerably reduced by allowing for array-specific distributions of nonspecific hybridization. When replicate arrays are available for a condition, posterior distributions of condition-specific gene expression indices are estimated directly, by a simultaneous consideration of replicate probe sets, avoiding averaging over estimates obtained from individual replicate arrays. The performance of the Bayesian model is compared to that of standard available point estimate methods on subsets of the well known GeneLogic and Affymetrix spike-in data. The Bayesian model is found to perform well and the integrated procedure presented appears to hold considerable promise for further development.     

GEFs, GAPs, GDIs and effectors: taking a closer (3D) look at the regulation of Ras-related GTP-binding proteins

Cell biology depends on the interactions of macromolecules, such as protein—DNA, protein—protein or protein—nucleotide interactions. GTP-binding proteins are no exception to the rule. They regulate cellular processes as diverse as protein biosynthesis and intracellular membrane trafficking. Recently, a large number of genes encoding GTP-binding proteins and the proteins that interact witht these molecular switches have been cloned and expressed. The 3D structures of some of these have also been elucidated     

A new look at geographic and phylogenetic relationships within the species group surrounding Octopus vulgaris (Mollusca, Cephalopoda): indications of very wide distribution from mitochondrial DNA sequences

The distribution of Octopus vulgaris has not yet been completely clarified. For a long time, a cosmopolitan distribution with unknown distribution limits had been assumed. This assumption has recently been questioned and it has been postulated that the distribution is restricted to the Mediterranean and the northeastern Atlantic. However, as our previous studies show, the existence of O. vulgaris can be confirmed for the Mediterranean and the whole eastern Atlantic, and evidence is provided for its occurrence in the western Atlantic. The aim of the present work is to extend our previous data matrix and to clarify whether O. vulgaris exists in the northwestern Pacific. Therefore, the sequence variation in ostensible O. vulgaris from 13 localities in the Mediterranean (France), the Atlantic Ocean [Lanzarote, Senegal, South Africa (Atlantic, Indian Ocean), Tristan da Cunha, north, middle and south Brazil], the Caribbean Sea (Venezuela) and the Pacific Ocean (Taiwan, Japan and Costa Rica) was examined using the mitochondrial genes coding for the 16S rRNA and cytochrome oxidase subunit III (COIII). Sequence divergence was relatively low between populations of O. vulgaris from the Mediterranean, the eastern and western Atlantic (except north Brazil), Venezuela, Taiwan and Japan compared with other species of the genus Octopus . Trees constructed by using maximum likelihood, neighbour joining and maximum parsimony algorithms (PAUP) show the above-mentioned populations from the Mediterranean, the western and eastern Atlantic, Venezuela and the northwestern Pacific (Japan and Taiwan) as a monophyletic cluster. Thus, even if the Octopus vulgaris -like octopus from north Brazil should turn out a cryptic species, the data of this work not only support our hypothesis of the distribution of O. vulgaris in the Mediterranean, the eastern and western Atlantic but also show that O. vulgaris is present in the northwestern Pacific, namely in the waters of Taiwan and Japan.     

A kinematic method for computing the motion of the body centre-of-mass (CoM) during walking: a Bayesian approach

The gait pattern of a particular patient can be altered in a large set of pathologies. Tracking the body centre-of-mass (CoM) during the gait allows a quantitative evaluation of these diseases at comparing the gait with normal patterns. A correct estimation of this variable is still an open question because of its non-linearity and inaccurate location. This paper presents a novel strategy for tracking the CoM, using a biomechanical gait model whose parameters are determined by a Bayesian strategy. A particle filter is herein implemented for predicting the model parameters from a set of markers located at the sacral zone. The present approach is compared with other conventional tracking methods and decreases the calculated root mean squared error in about a 56% in the x-axis and 59% in the y-axis.     

A molecular phylogenetic analysis of the "true thrushes" (Aves: Turdinae)

The true thrushes (Passeriformes: Muscicapidae, subfamily Turdinae) are a speciose and widespread avian lineage presumed to be of Old World origin. Phylogenetic relationships within this assemblage were investigated using mitochondrial DNA (mtDNA) sequence data that included the cytochrome b and ND2 genes. Our ingroup sampling included 54 species representing 17 of 20 putative turdine genera. Phylogenetic trees derived via maximum parsimony and maximum likelihood were largely congruent. Most of the Turdine taxa sampled can be placed into one of six well supported clades. Our data indicate a polyphyletic Zoothera which can be divided into at least two (Afro-Asian and Austral-Asian) main clades. The genus Turdus, as presently recognized, is paraphyletic but forms a well supported clade with the addition of three mostly monotypic genera (Platycichla, Nesocichla, and Cichlherminia). We identify an exclusively New World clade that includes a monophyletic Catharus, Hylocichla, Cichlopsis, Entomodestes, Ridgwayia, and Ixoreus. Members of the morphologically and behaviorally distinct genera Sialia, Myadestes, and Neocossyphus unexpectedly form a basal clade. Using multiple outgroup choices, we show that this group is distantly related, but unequivocally the sister group to the remaining Turdines sampled. The Turdinae appear to be a relatively old songbird lineage, originating in the mid to late Miocene. If the Turdinae are indeed Old World in origin, our data indicate a minimum of three separate invasions of the New World.     

Accounting for phylogenetic uncertainty in biogeography: a Bayesian approach to dispersal-vicariance analysis of the thrushes (Aves: Turdus)

The phylogeny of the thrushes (Aves: Turdus) has been difficult to reconstruct due to short internal branches and lack of node support for certain parts of the tree. Reconstructing the biogeographic history of this group is further complicated by the fact that current implementations of biogeographic methods, such as dispersal-vicariance analysis (DIVA; Ronquist, 1997), require a fully resolved tree. Here, we apply a Bayesian approach to dispersal-vicariance analysis that accounts for phylogenetic uncertainty and allows a more accurate analysis of the biogeographic history of lineages. Specifically, ancestral area reconstructions can be presented as marginal distributions, thus displaying the underlying topological uncertainty. Moreover, if there are multiple optimal solutions for a single node on a certain tree, integrating over the posterior distribution of trees often reveals a preference for a narrower set of solutions. We find that despite the uncertainty in tree topology, ancestral area reconstructions indicate that the Turdus clade originated in the eastern Palearctic during the Late Miocene. This was followed by an early dispersal to Africa from where a worldwide radiation took place. The uncertainty in tree topology and short branch lengths seems to indicate that this radiation took place within a limited time span during the Late Pliocene. The results support the role of Africa as a probable source area for intercontinental dispersals as suggested for other passerine groups, including basal diversification within the songbird tree.     

The evolution of ecomorphological traits within the Abrothrichini (Rodentia: Sigmodontinae): a Bayesian phylogenetics approach

The generally accepted hypothesis regarding the origin of fossorial mammals proposes adaptive convergence from open environments towards the use of subterranean environments. We evaluated this hypothesis for South American mole-mice using conventional and Bayesian frameworks, with independent evidence. By using a molecular approach based on Cytochrome b and IRBP sequences, we evaluated phylogenetic relationships, time of origin, the ancestral trait of fossoriality, and ancestral distributions of species belonging to the Andean Clade (Rodentia: Sigmodontinae). Our results indicate that the Andean Clade is highly sustained; with one clade grouping all fossorial forms and another grouping all cursorial species. We hypothesized that fossoriality originated in the Miocene/Pliocene transition, in the Temperate Forests of southern South America. We conclude that the origin of fossorial ecomorphological traits did not necessarily occur under a general model of open environments, the origin of these traits depends on the ecological-historical relationship of the taxon with the environment.     

Colonization history of the Swiss Rhine basin by the bullhead (Cottus gobio): inference under a Bayesian spatially explicit framework

The present distribution of freshwater fish in the Alpine region has been strongly affected by colonization events occurring after the last glacial maximum (LGM), some 20 000 years ago. We use here a spatially explicit simulation framework to model and better understand their colonization dynamics in the Swiss Rhine basin. This approach is applied to the European bullhead ( Cottus gobio ), which is an ideal model organism to study fish past demographic processes since it has not been managed by humans. The molecular diversity of eight sampled populations is simulated and compared to observed data at six microsatellite loci under an approximate Bayesian computation framework to estimate the parameters of the colonization process. Our demographic estimates fit well with current knowledge about the biology of this species, but they suggest that the Swiss Rhine basin was colonized very recently, after the Younger Dryas some 6600 years ago. We discuss the implication of this result, as well as the strengths and limits of the spatially explicit approach coupled to the approximate Bayesian computation framework.     

Shallow subtidal macroalgae in the North-eastern Atlantic archipelagos (Macaronesian region): a spatial approach to community structure

Shallow subtidal macroalgal communities in the North-eastern Atlantic archipelagos (Azores, Madeira, Canaries and Cape Verde) were studied in order to identify their spatial organization patterns and the main drivers of change. Fifteen islands and 145 sites across 15º of latitude and 2850 km were sampled. We found high spatial variability across the scales considered (archipelago, island and site). The structure of macroalgal communities differed among archipelagos, except between Madeira and the Canaries, which were similar. Across a latitudinal gradient, macroalgal communities in the Azores were clearly separated from the other archipelagos; communities in Madeira and the Canaries occupied an intermediate position, while those in Cape Verde appeared at the opposite end of the gradient. In the Azores, species with warm-temperate affinities dominated communities. Cape Verde communities were, in contrast, dominated by tropical taxa, whereas in the subtropical Canaries and Madeira there was a mixture of species with colder and warmer affinities. Apart from crustose coralline algae, the Dictyotales were the group with greatest cover; larger and longer-lived species were progressively replaced by short-lived species along a latitudinal gradient from north to south. The perennial species Zonaria tournefortii dominated the sea-bottom in the Azores, the semi-perennial Lophophora variegata in the Canaries, the filamentous algae in Madeira and the ephemeral Dictyota dichotoma in Cape Verde. We hypothesized that the differences among archipelagos could be explained by synergies between temperature and herbivory, which increased in diversity southwards, especially in Cape Verde. This was supported by the predominance of non-crustose macroalgae in the Azores and of crustose macroalgae in Cape Verde, as would be predicted from the greater herbivore activity. At the scale of islands and sites, the same set of environmental variables drove differences in macroalgal community structure across all the Macaronesian archipelagos.     

The historical biogeography of the freshwater knifefishes using mitogenomic approaches: A Mesozoic origin of the Asian notopterids (Actinopterygii: Osteoglossomorpha)

The continental distributions of freshwater fishes in the family Notopteridae (Osteoglossomorpha) across Africa, India, and Southeast Asia constitute a long standing and enigmatic problem of freshwater biogeography. The migrational pathway of the Asian notopterids has been discussed in light of two competing schemes: the first posits recent transcontinental dispersal while the second relies on distributions being shaped by ancient vicariance associated with plate-tectonic events. In this study, we determined complete mitochondrial DNA sequences from 10 osteoglossomorph fishes to estimate phylogenetic relationships using partitioned Bayesian and maximum likelihood methods and divergence dates of the family Notopteridae with a partitioned Bayesian approach. We used six species representing the major lineages of the Notopteridae and seven species from the remaining osteoglossomorph families. Fourteen more-derived teleosts, nine basal actinopterygians, two coelacanths, and one shark were used as outgroups. Phylogenetic analyses indicated that the African and Asian notopterids formed a sister group to each other and that these notopterids were a sister to a clade comprising two African families (Mormyridae and Gymnarchidae). Estimated divergence time between the African and Asian notopterids dated back to the early Cretaceous when India–Madagascar separated from the African part of Gondwanaland. Thus, estimated time of divergence based on the molecular evidence is at odds with the recent dispersal model. It can be reconciled with the geological and paleontological evidence to support the vicariance model in which the Asian notopterids diverged from the African notopterids in Gondwanaland and migrated into Eurasia on the Indian subcontinent from the Cretaceous to the Tertiary. However, we could not exclude an alternative explanation that the African and Asian notopterids diverged in Pangea before its complete separation into Laurasia and Gondwanaland, to which these two lineages were later confined, respectively.     

Environmental constraints at the edge of a species distribution, the Eurasian badger (Meles meles L.): a biogeographic approach

Aim This paper describes the distribution pattern (occurrence) of badgers (Meles meles L. 1758) in a Mediterranean mountain area of central Spain, in relation to landscape characteristics and climatic data. We test the fit of the badger occurrence pattern to the niche hypothesis predictions. Location We sampled twenty-four survey plots randomly distributed in the mountains of central Spain (Sierra de Guadarrama, Madrid): ten in the north and fourteen in the south slopes. All habitat types and climatic conditions typical of central Spain can be found. Methods The ocurrence of badgers in the plots were recorded through an exhaustive search of setts and latrines in four different (and evenly spaced) points in each plot. The index of occurrence was made by dividing the number of positive points (badger presence) by the total number of points sampled (four in all plots). Landscape patterns (% type of habitat in each plot) were obtained from detailed maps and climate data from meteorological stations placed in the plot. We analyse the contribution of landscape variables and climate data to explain the differences in badger occurrence through Pearson correlations and fixed one-way ANCOVA with climatic data as fixed factor, vegetation cover as covariates and badger occurrence as response variable. Additionally, we use an one-way ANOVA to check the differences in occurrence between north and south plots with the location of each plot as fixed factor. Results The results indicate that the badger is more abundant in rainy areas of the mountains, and in open landscapes vegetated by ash-tree forests than in closed landscapes vegetated by holm oak forests. In addition, the species is more abundant in the northern plots than in the southern ones. Northern plots were homogeneous areas characterized by their open landscape and wet climate, while southern plots were characterized by their dry climate and closed landscapes. In addition, climate (measured as summer rain) is more determinant than habitat type (holm oak cover) to explain the pattern of badger occurrence. Main conclusions Overall, we consider that the typical Mediterranean landscapes are poor habitats for badgers due to changes in the environmental conditions associated with concomitant changes in food resources. These data support the niche hypothesis to explain the changes in abundance or occurrence close to the edge of the distribution of species, and in particular, in Palearctic species in the Mediterranean area.     

Assessing the sequence specificity in the binding of Co(III) to DNA via a thermodynamic approach

The interaction specificities of Co(III) with DNA were investigated via consideration of thermodynamic characteristics of the duplex to single strand transition for DNA oligomers incubated in the presence of [Co(NH₃)₅(OH₂)] (ClO₄)₃. It has previously been demonstrated that incubation of the DNA oligomer [(5medC-dG)₄]₂ with this cobalt complex leads to coordination of the cobalt center to the DNA, presumably at N7 of guanine bases [D. C. Calderone, E. J. Mantilla, M. Hicks, D. H. Huchital, W. R. Murphy, Jr. and R. D. Sheardy, (1995) Biochemistry 34, 13841]. In this report, DNA oligomers of different sequence were incubated with [Co(NH₃)₅(OH₂)] (ClO₄)₃ via protocols developed previously and the treated oligomers were subjected to thermal denaturation for comparison to the untreated oligomers. The DNA oligomers were designed in order to investigate the sequence specificity, if any, in the reaction of the cobalt complex with DNA. The values of T_m, ΔH_uH, and Δn (the differential ion binding term) obtained from the thermal denaturations were used to assess the sequence specificity of the interaction. For all oligomers, treated or untreated, T_m and Δ_uH vary linearly with log [Na⁺] and hence the value of Δn is a function of the Na⁺ concentration. The results indicate no significant reaction between the cobalt complex and oligomers possessing isolated -GA- or -CG- sites; however, the thermodynamic characteristics of DNA oligomers possessing either an isolated -GG- site or an isolated -GC- site were altered by the treatment. Atomic absorption studies of the treated oligomers demonstrate that only the DNA oligomers possessing isolated -GG- or -GC- sites bind cobalt. Hence, the changes in the thermodynamic properties of these oligomers are a result of cobalt binding with a remarkable sequence specificity. © 1997 John Wiley & Sons, Inc. Biopoly 42: 549–599, 1997     

Site-directed mutations in the third intracellular loop of the serotonin 5-HT(1A) receptor alter G protein coupling from G(i) to G(s) in a ligand-dependent manner

The effect of mutations (V344E and T343A/V344E) in the third intracellular loop of the serotonin 5-HT(1A) receptor expressed transiently in human embryonic kidney 293 cells have been examined in terms of receptor/G protein interaction and signaling. Serotonin, (R)-8-hydroxy-2-dipropylaminotetralin [(R)-8-OH-DPAT], and buspirone inhibited cyclic AMP production in cells expressing native and mutant 5-HT(1A) receptors. Serotonin, however, produced inverse bell-shaped cyclic AMP concentration-response curves at native and mutant 5-HT(1A) receptors, indicating coupling not only to G(i)/G(o), but also to G(s). (R)-8-OH-DPAT, however, induced stimulation of cyclic AMP production only after inactivation of G(i)/G(o) proteins by pertussis toxin and only at the mutant receptors. The partial agonist buspirone was unable to induce coupling to G(s) at any of the receptors, even after pertussis toxin treatment. The basal activities of native and mutant 5-HT(1A) receptors in suppressing cyclic AMP levels were not found to be significantly different. The receptor binding characteristics of the native and mutant receptors were investigated using the novel 5-HT(1A) receptor antagonist [(3)H]NAD-299. For other receptors, analogous mutations have produced constitutive activation. This does not occur for the 5-HT(1A) receptor, and for this receptor the mutations seem to alter receptor/G protein coupling, allowing ligand-dependent coupling of receptor to G(s) in addition to G(i)/G(o) proteins.     

A multi-gene phylogeny of Clavicipitaceae (Ascomycota, Fungi): identification of localized incongruence using a combinational bootstrap approach

Multi-gene phylogenetic analyses were conducted to address the evolution of Clavicipitaceae (Ascomycota). Data are presented here for approximately 5900 base pairs from portions of seven loci: the nuclear ribosomal small and large subunit DNA (nrSSU and nrLSU), beta-tubulin, elongation factor 1alpha (EF-1alpha), the largest and second largest subunits of RNA polymerase II (RPB1 and RPB2), and mitochondrial ATP Synthase subunit 6 (mtATP6). These data were analyzed in a complete 66-taxon matrix and 91-taxon supermatrix that included some missing data. Separate phylogenetic analyses, with data partitioned according to genes, produced some conflicting results. The results of separate analyses from RPB1 and RPB2 are in agreement with the combined analyses that resolve a paraphyletic Clavicipitaceae comprising three well-supported clades (i.e., Clavicipitaceae clade A, B, and C), whereas the tree obtained from mtATP6 is in strong conflict with the monophyly of Clavicipitaceae clade B and the sister-group relationship of Hypocreaceae and Clavicipitaceae clade C. The distribution of relative contribution of nodal support for each gene partition was assessed using both partitioned Bremer support (PBS) values and combinational bootstrap (CB) analyses, the latter of which analyzed bootstrap proportions from all possible combinations of the seven gene partitions. These results suggest that CB analyses provide a more consistent estimate of nodal support than PBS and that combining heterogeneous gene partitions, which individually support a limited number of nodes, results in increased support for overall tree topology. Analyses of the 91-taxa supermatrix data sets revealed that some nodes were more strongly supported by increased taxon sampling. Identifying the localized incongruence of mtATP6 and analyses of complete and supermatrix data sets strengthen the evidence for rejecting the monophyly of Clavicipitaceae and much of the current subfamilial classification of the family. Although the monophyly of the grass-associated subfamily Clavicipitoideae (e.g., Claviceps, Balansia, and Epichlo?) is strongly supported, the subfamily Cordycipitoideae (e.g., Cordyceps and Torrubiella) is not monophyletic. In particular, species of the genus Cordyceps, which are pathogens of arthropods and truffles, are found in all three clavicipitaceous clades. These results imply that most characters used in the current familial classification of Clavicipitaceae are not diagnostic of monophyly.