Focusing on the genetics of hearing: you ain't heard nothin' yet

The complexity of genetic pathways for hearing is beginning to be amenable to unraveling by systematic functional genomic analysis. Genome-wide mutagenesis studies in the mouse are beginning to shed further light on the structure and regulation of the machinery of hearing.     

Monitoring ungulates in steep non-forest habitat: a comparison of faecal pellet and helicopter counts

Faecal pellet counts have been widely used to monitor the abundances of introduced ungulates in New Zealand, but ground-based sampling cannot be conducted safely in the steep non-forest habitats that are common in New Zealand's Southern Alps. Helicopter counts may be an effective technique for monitoring ungulates in steep non-forest habitat. We evaluated the relationship between faecal pellet and helicopter counts of ungulates (primarily feral goat Capra hircus) at 12 non-forest sites in the Southern Alps. Within each site we counted the numbers of ungulates from a helicopter on three occasions and the number of intact faecal pellets along 30 transects. Mean observed densities of feral goats derived from helicopter counts ranged from 0.0 to 20.2 km^?2. There was a positive curvilinear (concave down) relationship between faecal pellet and helicopter counts. Compared with faecal pellet counts, helicopter counts were cheaper, could identify ungulate species and provided estimates of absolute density. Helicopter counts are a cost-effective method for monitoring ungulates in the steep non-forest habitats of New Zealand's Southern Alps.     

Effect of cholesterol depletion on the pore dilation of TRPV1

The TRPV1 ion channel is expressed in nociceptors, where pharmacological modulation of its function may offer a means of alleviating pain and neurogenic inflammation processes in the human body. The aim of this study was to investigate the effects of cholesterol depletion of the cell on ion-permeability of the TRPV1 ion channel. The ion-permeability properties of TRPV1 were assessed using whole-cell patch-clamp and YO-PRO uptake rate studies on a Chinese hamster ovary (CHO) cell line expressing this ion channel. Prolonged capsaicin-induced activation of TRPV1 with N-methyl-D-glucamine (NMDG) as the sole extracellular cation, generated a biphasic current which included an initial outward current followed by an inward current. Similarly, prolonged proton-activation (pH 5.5) of TRPV1 under hypocalcemic conditions also generated a biphasic current including a fast initial current peak followed by a larger second one. Patch-clamp recordings of reversal potentials of TRPV1 revealed an increase of the ion-permeability for NMDG during prolonged activation of this ion channel under hypocalcemic conditions. Our findings show that cholesterol depletion inhibited both the second current, and the increase in ion-permeability of the TRPV1 channel, resulting from sustained agonist-activation with capsaicin and protons (pH 5.5). These results were confirmed with YO-PRO uptake rate studies using laser scanning confocal microscopy, where cholesterol depletion was found to decrease TRPV1 mediated uptake rates of YO-PRO. Hence, these results propose a novel mechanism by which cellular cholesterol depletion modulates the function of TRPV1, which may constitute a novel approach for treatment of neurogenic pain.     

Visualizing fitness landscapes

Fitness landscapes are a classical concept for thinking about the relationship between genotype and fitness. However, because the space of genotypes is typically high-dimensional, the structure of fitness landscapes can be difficult to understand and the heuristic approach of thinking about fitness landscapes as low-dimensional, continuous surfaces may be misleading. Here, I present a rigorous method for creating low-dimensional representations of fitness landscapes. The basic idea is to plot the genotypes in a manner that reflects the ease or difficulty of evolving from one genotype to another. Such a layout can be constructed using the eigenvectors of the transition matrix describing the evolution of a population on the fitness landscape when mutation is weak. In addition, the eigendecomposition of this transition matrix provides a new, high-level view of evolution on a fitness landscape. I demonstrate these techniques by visualizing the fitness landscape for selection for the amino acid serine and by visualizing a neutral network derived from the RNA secondary structure genotype-phenotype map.     

ON THE FINDABILITY OF GENOTYPES

Can we define a measure that describes how easy or difficult it is for a population to evolve to a specific genotype? For populations evolving under weak mutation on a time‐invariant fitness landscape, I argue that one appropriate measure is the expected waiting time, starting from equilibrium, for a population to become fixed for a given genotype. Under this definition for the “findability” of genotypes, I show that for any pair of genotypes (1) a population at equilibrium is always more likely to fix at the more findable before the less findable genotype and (2) the expected time to evolve from the more findable to the less findable genotype is always greater that the expected time to evolve in the opposite direction. Although increasing the fitness of a genotype always increases its findability, in general there is no simple relationship between the rank ordering of genotypes by fitness and the rank ordering of genotypes by findability. I also present a method for quantifying the relative contributions of mutation, selection, substitution rate, and probability of reversion to a genotype's findability.     

TBMap: a taxonomic perspective on the phylogenetic database TreeBASE

Background  

TreeBASE is currently the only available large-scale database of published organismal phylogenies. Its utility is hampered by a lack of taxonomic consistency, both within the database, and with names of organisms in external genomic, specimen, and taxonomic databases. The extent to which the phylogenetic knowledge in TreeBASE becomes integrated with these other sources is limited by this lack of consistency.     

CoMEt: a statistical approach to identify combinations of mutually exclusive alterations in cancer

Cancer is a heterogeneous disease with different combinations of genetic alterations driving its development in different individuals. We introduce CoMEt, an algorithm to identify combinations of alterations that exhibit a pattern of mutual exclusivity across individuals, often observed for alterations in the same pathway. CoMEt includes an exact statistical test for mutual exclusivity and techniques to perform simultaneous analysis of multiple sets of mutually exclusive and subtype-specific alterations. We demonstrate that CoMEt outperforms existing approaches on simulated and real data. We apply CoMEt to five different cancer types, identifying both known cancer genes and pathways, and novel putative cancer genes.

Electronic supplementary material

The online version of this article (doi:10.1186/s13059-015-0700-7) contains supplementary material, which is available to authorized users.     

Detecting epistasis from an ensemble of adapting populations

The role that epistasis plays during adaptation remains an outstanding problem, which has received considerable attention in recent years. Most of the recent empirical studies are based on ensembles of replicate populations that adapt in a fixed, laboratory controlled condition. Researchers often seek to infer the presence and form of epistasis in the fitness landscape from the time evolution of various statistics averaged across the ensemble of populations. Here, we provide a rigorous analysis of what quantities, drawn from time series of such ensembles, can be used to infer epistasis for populations evolving under weak mutation on finite‐site fitness landscapes. First, we analyze the mean fitness trajectory—that is, the time course of the ensemble average fitness. We show that for any epistatic fitness landscape and starting genotype, there always exists a non‐epistatic fitness landscape that produces the exact same mean fitness trajectory. Thus, the presence of epistasis is not identifiable from the mean fitness trajectory. By contrast, we show that two other ensemble statistics—the time evolution of the fitness variance across populations, and the time evolution of the mean number of substitutions—can detect certain forms of epistasis in the underlying fitness landscape.     

Effects of PM10 in human peripheral blood monocytes and J774 macrophages

Background

Asthma is characterized by type 2 T-helper cell (Th2) inflammation, goblet cell hyperplasia, airway hyperreactivity, and airway fibrosis. Monocyte chemoattractant protein-1 (MCP-1 or CCL2) and its receptor, CCR2, have been shown to play important roles in the development of Th2 inflammation. CCR2-deficient mice have been found to have altered inflammatory and physiologic responses in some models of experimental allergic asthma, but the role of CCR2 in contributing to inflammation and airway hyperreactivity appears to vary considerably between models. Furthermore, MCP-1-deficient mice have not previously been studied in models of experimental allergic asthma.

Methods

To test whether MCP-1 and CCR2 are each required for the development of experimental allergic asthma, we applied an Aspergillus antigen-induced model of Th2 cytokine-driven allergic asthma associated with airway fibrosis to mice deficient in either MCP-1 or CCR2. Previous studies with live Aspergillus conidia instilled into the lung revealed that MCP-1 and CCR2 play a role in anti-fungal responses; in contrast, we used a non-viable Aspergillus antigen preparation known to induce a robust eosinophilic inflammatory response.

Results

We found that wild-type C57BL/6 mice developed eosinophilic airway inflammation, goblet cell hyperplasia, airway hyperreactivity, elevations in serum IgE, and airway fibrosis in response to airway challenge with Aspergillus antigen. Surprisingly, mice deficient in either MCP-1 or CCR2 had responses to Aspergillus antigen similar to those seen in wild-type mice, including production of Th2 cytokines.

Conclusion

We conclude that robust Th2-mediated lung pathology can occur even in the complete absence of MCP-1 or CCR2.