Knowledge-based computational mutagenesis for predicting the disease potential of human non-synonymous single nucleotide polymorphisms

Certain genetic variations in the human population are associated with heritable diseases, and single nucleotide polymorphisms (SNPs) represent the most common form of such differences in DNA sequence. In particular, substantial interest exists in determining whether a non-synonymous SNP (nsSNP), leading to a single residue replacement in the translated protein product, is neutral or disease-related. The nature of protein structure-function relationships suggests that nsSNP effects, either benign or leading to aberrant protein function possibly associated with disease, are dependent on relative structural changes introduced upon mutation. In this study, we characterize a representative sampling of 1790 documented neutral and disease-related human nsSNPs mapped to 243 diverse human protein structures, by quantifying environmental perturbations in the associated proteins with the use of a computational mutagenesis methodology that relies on a four-body, knowledge-based, statistical contact potential. These structural change data are used as attributes to generate a vector representation for each nsSNP, in combination with additional features reflecting sequence and structure of the corresponding protein. A trained model based on the random forest supervised classification algorithm achieves 76% cross-validation accuracy. Our classifier performs at least as well as other methods that use significantly larger datasets of nsSNPs for model training, and the novelty of our attributes differentiates the model as an orthogonal approach that can be utilized in conjunction with other techniques. A dedicated server for obtaining predictions, as well as supporting datasets and documentation, is available at http://proteins.gmu.edu/automute.     

Clarifications on habitat complexity: A response to technical note by Madin et al.

In a critique of our recent review on measuring habitat complexity in ecology, Madin et al. (2023) advocate the use of fractal dimension in ecology and defend their geometric constraint theory of habitat complexity. We explain the flaws in their arguments and highlight points where they misinterpreted our statements.     

Estimating person view-factors from fish-eye lens photographs

A simple technique is described whereby view-factors can be estimated for a person at locations where the building geometry is complex. Procedures are outlined for the construction of a polar diagram whose grid cells give equal person view-factors: the diagram is designed to overlay a fish-eye lens photograph, enabling the estimation of view-factors of distinctive surfaces in the photograph image for standing and seated people.     

The rational parameterisation theorem for multisite post-translational modification systems

Post-translational modification of proteins plays a central role in cellular regulation but its study has been hampered by the exponential increase in substrate modification forms (“modforms”) with increasing numbers of sites. We consider here biochemical networks arising from post-translational modification under mass-action kinetics, allowing for multiple substrates, having different types of modification (phosphorylation, methylation, acetylation, etc.) on multiple sites, acted upon by multiple forward and reverse enzymes (in total number L), using general enzymatic mechanisms. These assumptions are substantially more general than in previous studies. We show that the steady-state modform concentrations constitute an algebraic variety that can be parameterised by rational functions of the L free enzyme concentrations, with coefficients which are rational functions of the rate constants. The parameterisation allows steady states to be calculated by solving L algebraic equations, a dramatic reduction compared to simulating an exponentially large number of differential equations. This complexity collapse enables analysis in contexts that were previously intractable and leads to biological predictions that we review. Our results lay a foundation for the systems biology of post-translational modification and suggest deeper connections between biochemical networks and algebraic geometry.     

Simple temporal models for ecological systems with complex spatial patterns

Spatial patterns are ubiquitous in nature. Because these patterns modify the temporal dynamics and stability properties of population densities at a range of spatial scales, their effects must be incorporated in temporal ecological models that do not represent space explicitly. We demonstrate a connection between a simple parameterization of spatial effects and the geometry of clusters in an individual‐based predator–prey model that is both nonlinear and stochastic. Specifically we show that clusters exhibit a power‐law scaling of perimeter to area with an exponent close to unity. In systems with a high degree of patchiness, similar power‐law scalings can provide a basis for applying simple temporal models that assume well‐mixed conditions.     

Cross sectional geometry of the forelimb skeleton and flight mode in pelecaniform birds

Avian wing elements have been shown to experience both dorsoventral bending and torsional loads during flapping flight. However, not all birds use continuous flapping as a primary flight strategy. The pelecaniforms exhibit extraordinary diversity in flight mode, utilizing flapping, flap‐gliding, and soaring. Here we (1) characterize the cross‐sectional geometry of the three main wing bone (humerus, ulna, carpometacarpus), (2) use elements of beam theory to estimate resistance to loading, and (3) examine patterns of variation in hypothesized loading resistance relative to flight and diving mode in 16 species of pelecaniform birds. Patterns emerge that are common to all species, as well as some characteristics that are flight‐ and diving‐mode specific. In all birds examined, the distal most wing segment (carpometacarpus) is the most elliptical (relatively high I_max/I_min) at mid‐shaft, suggesting a shape optimized to resist bending loads in a dorsoventral direction. As primary flight feathers attach at an oblique angle relative to the long axis of the carpometacarpus, they are likely responsible for inducing bending of this element during flight. Moreover, among flight modes examined the flapping group (cormorants) exhibits more elliptical humeri and carpometacarpi than other flight modes, perhaps pertaining to the higher frequency of bending loads in these elements. The soaring birds (pelicans and gannets) exhibit wing elements with near‐circular cross‐sections and higher polar moments of area than in the flap and flap‐gliding birds, suggesting shapes optimized to offer increased resistance to torsional loads. This analysis of cross‐sectional geometry has enhanced our interpretation of how the wing elements are being loaded and ultimately how they are being used during normal activities. J. Morphol., 2011. © 2011 Wiley‐Liss,Inc.