Model Selection in Systems Biology Depends on Experimental Design

Experimental design attempts to maximise the information available for modelling tasks. An optimal experiment allows the inferred models or parameters to be chosen with the highest expected degree of confidence. If the true system is faithfully reproduced by one of the models, the merit of this approach is clear - we simply wish to identify it and the true parameters with the most certainty. However, in the more realistic situation where all models are incorrect or incomplete, the interpretation of model selection outcomes and the role of experimental design needs to be examined more carefully. Using a novel experimental design and model selection framework for stochastic state-space models, we perform high-throughput in-silico analyses on families of gene regulatory cascade models, to show that the selected model can depend on the experiment performed. We observe that experimental design thus makes confidence a criterion for model choice, but that this does not necessarily correlate with a model''s predictive power or correctness. Finally, in the special case of linear ordinary differential equation (ODE) models, we explore how wrong a model has to be before it influences the conclusions of a model selection analysis.     

Isocitrate dehydrogenase 1 R132C mutation occurs exclusively in microsatellite stable colorectal cancers with the CpG island methylator phenotype

The CpG Island Methylator Phenotype (CIMP) is fundamental to an important subset of colorectal cancer; however, its cause is unknown. CIMP is associated with microsatellite instability but is also found in BRAF mutant microsatellite stable cancers that are associated with poor prognosis. The isocitrate dehydrogenase 1 (IDH1) gene causes CIMP in glioma due to an activating mutation that produces the 2-hydroxyglutarate oncometabolite. We therefore examined IDH1 alteration as a potential cause of CIMP in colorectal cancer. The IDH1 mutational hotspot was screened in 86 CIMP-positive and 80 CIMP-negative cancers. The entire coding sequence was examined in 81 CIMP-positive colorectal cancers. Forty-seven cancers varying by CIMP-status and IDH1 mutation status were examined using Illumina 450K DNA methylation microarrays. The R132C IDH1 mutation was detected in 4/166 cancers. All IDH1 mutations were in CIMP cancers that were BRAF mutant and microsatellite stable (4/45, 8.9%). Unsupervised hierarchical cluster analysis identified an IDH1 mutation-like methylation signature in approximately half of the CIMP-positive cancers. IDH1 mutation appears to cause CIMP in a small proportion of BRAF mutant, microsatellite stable colorectal cancers. This study provides a precedent that a single gene mutation may cause CIMP in colorectal cancer, and that this will be associated with a specific epigenetic signature and clinicopathological features.     

Associations between abundances of free‐roaming gamebirds and common buzzards Buteo buteo are not driven by consumption of gamebirds in the buzzard breeding season

Releasing gamebirds in large numbers for sport shooting may directly or indirectly influence the abundance, distribution and population dynamics of native wildlife. The abundances of generalist predators have been positively associated with the abundance of gamebirds. These relationships have implications for prey populations, with the potential for indirect impacts of gamebird releases on wider biodiversity. To understand the basis of these associations, we investigated variation in territory size, prey provisioning to chicks, and breeding success of common buzzards Buteo buteo, and associations with variation in the abundances of free‐roaming gamebirds, primarily pheasants Phasianus colchicus, and of rabbits Oryctolagus cuniculus and field voles Microtus agrestis, as important prey for buzzards. The relative abundance of gamebirds, but not those of rabbits or voles, was weakly but positively correlated with our index of buzzard territory size. Gamebirds were rarely brought to the nest. Rabbits and voles, and not gamebirds, were provisioned to chicks in proportion to their relative abundance. The number of buzzard chicks increased with provisioning rates of rabbits, in terms of both provisioning frequency and biomass, but not with provisioning rates for gamebirds or voles. Associations between the abundances of buzzards and gamebirds may not be a consequence of the greater availability of gamebirds as prey during the buzzard breeding season. Instead, the association may arise either from habitat or predator management leading to higher densities of alternative prey (in this instance, rabbits), or from greater availability of gamebirds as prey or carrion during the autumn and winter shooting season. The interactions between gamebird releases and associated practices of predator control and shooting itself require better understanding to more effectively intervene in any one aspect of this complex social‐ecological system.     

Rates of root and organism growth, soil conditions, and temporal and spatial development of the rhizosphere

BACKGROUND: Roots growing in soil encounter physical, chemical and biological environments that influence their rhizospheres and affect plant growth. Exudates from roots can stimulate or inhibit soil organisms that may release nutrients, infect the root, or modify plant growth via signals. These rhizosphere processes are poorly understood in field conditions. SCOPE AND AIMS: We characterize roots and their rhizospheres and rates of growth in units of distance and time so that interactions with soil organisms can be better understood in field conditions. We review: (1) distances between components of the soil, including dead roots remnant from previous plants, and the distances between new roots, their rhizospheres and soil components; (2) characteristic times (distance(2)/diffusivity) for solutes to travel distances between roots and responsive soil organisms; (3) rates of movement and growth of soil organisms; (4) rates of extension of roots, and how these relate to the rates of anatomical and biochemical ageing of root tissues and the development of the rhizosphere within the soil profile; and (5) numbers of micro-organisms in the rhizosphere and the dependence on the site of attachment to the growing tip. We consider temporal and spatial variation within the rhizosphere to understand the distribution of bacteria and fungi on roots in hard, unploughed soil, and the activities of organisms in the overlapping rhizospheres of living and dead roots clustered in gaps in most field soils. CONCLUSIONS: Rhizosphere distances, characteristic times for solute diffusion, and rates of root and organism growth must be considered to understand rhizosphere development. Many values used in our analysis were estimates. The paucity of reliable data underlines the rudimentary state of our knowledge of root-organism interactions in the field.     

Empirical evidence of a convection–diffusion model for pH patterns in the rhizospheres of root tips

A recently formulated convection–diffusion model predicted that root growth plus diffusion of protons in the neighbouring soil would lead to particular pH patterns around the moving root tip. To test the predictions of this theory, pH was measured at differing radial distances from the root surface after 24 h of growth in a medium with low diffusivity (sandy soil) and after a shorter period (55 min of growth) in a medium with high diffusivity (agar). In agreement with the theory, the growth zone was found to influence the pH of the soil for distances less than 1 mm from the root surface (even after many hours) and the pH of the agar for a distance of at least 5 mm (after only 1 h). The axial pattern of pH along the surface of soil‐grown Zea mays L. root tips was found to be the same for roots growing at different rates under different temperatures (2·23  mm h^?1 at 26 °C or 1·27 mm h^?1 at 20 °C). Thus, the plant can synchronize proton flux with growth to maintain a particular surface pH pattern within the growth zone. This implies that root tips growing at different rates in response to different temperatures can carry the same microenvironment of pH through a homogeneous soil.     

MECHANICAL PROPERTIES WITHIN THE GROWTH ZONE OF CORN ROOTS INVESTIGATED BY BENDING EXPERIMENTS I. PRELIMINARY OBSERVATIONS

Bending experiments were performed to analyze mechanical properties within the apical 15 mm of the primary root of corn, Zea mays. Force required to maintain a root in a bent shape declined with the logarithm of time, indicating significant stress relaxation. Spatial distributions of local curvature, strain due to bending, and geometrical moment of inertia were calculated from digitized photographs of mechanically bent roots during and after imposition of a bending moment. When roots were bent to nonuniform curvature (maximum K = 3 cm^–1 at the location 8 mm from the root tip), “irreversible” curvature (residual curvature 4 hr after release of the bending moment) was approximately 44% of initial curvature. This percentage of irreversible curvature (and associated bending strain) was uniform throughout the growth zone. When roots were bent to uniform curvature of either 1 cm^–1 or 1.67 cm^–1, “springback” curvature (residual curvature after two minutes of bending) varied from 60% of initial curvature in the apical regions (at 4 mm) to 85% of initial curvature at the base of the growth zone. The results are consistent with a model in which total strain is proportional to stress, and irreversible strain at a particular location is proportional to total strain at the same location.