Temporal estimates of effective population size in species with overlapping generations

The standard temporal method for estimating effective population size (N(e)) assumes that generations are discrete, but it is routinely applied to species with overlapping generations. We evaluated bias in the estimates N(e) caused by violation of this assumption, using simulated data for three model species: humans (type I survival), sparrow (type II), and barnacle (type III). We verify a previous proposal by Felsenstein that weighting individuals by reproductive value is the correct way to calculate parametric population allele frequencies, in which case the rate of change in age-structured populations conforms to that predicted by discrete-generation models. When the standard temporal method is applied to age-structured species, typical sampling regimes (sampling only newborns or adults; randomly sampling the entire population) do not yield properly weighted allele frequencies and result in biased N(e). The direction and magnitude of the bias are shown to depend on the sampling method and the species' life history. Results for populations that grow (or decline) at a constant rate paralleled those for populations of constant size. If sufficient demographic data are available and certain sampling restrictions are met, the Jorde-Ryman modification of the temporal method can be applied to any species with overlapping generations. Alternatively, spacing the temporal samples many generations apart maximizes the drift signal compared to sampling biases associated with age structure.     

A potential bias in the temporal method for estimating Ne in admixed populations under natural selection

Indirect genetic methods are frequently used to estimate the effective population size (N(e)) or effective number of breeders (N(b)) in natural populations. Although assumptions behind these methods are often violated, there have been few attempts to evaluate how accurate these estimates really are in practice. Here we investigate the influence of natural selection following a population admixture on the temporal method for estimating N(e). Our analytical and simulation results suggest that N(e) is often underestimated in this method when subpopulations differ substantially in allele frequencies and in reproductive success. The underestimation is exacerbated when true N(e) and the fraction of the low-fitness group are large. As an empirical example, we compared N(b) estimated in natural populations of steelhead trout (Oncorhynchus mykiss) using the temporal method (N(b[temp])) with estimates based on direct demographic methods (N(b[demo])) and the linkage disequilibrium method (N(b[LD])). While N(b[LD]) was generally in close agreement with N(b[demo]), N(b[temp]) was much lower in sample sets that were dominated by nonlocal hatchery fish with low reproductive success, as predicted by the analytical results. This bias in the temporal method, which arises when genes associated with a particular group of parents are selected against in the offspring sample, has not been widely appreciated before. Such situations may be particularly common when artificial propagation or translocations are used for conservation. The linkage disequilibrium method, which requires data from only one sample, is robust to this type of bias, although it can be affected by other factors.     

Paralogs are revealed by proportion of heterozygotes and deviations in read ratios in genotyping‐by‐sequencing data from natural populations

Whole‐genome duplications have occurred in the recent ancestors of many plants, fish, and amphibians, resulting in a pervasiveness of paralogous loci and the potential for both disomic and tetrasomic inheritance in the same genome. Paralogs can be difficult to reliably genotype and are often excluded from genotyping‐by‐sequencing (GBS) analyses; however, removal requires paralogs to be identified which is difficult without a reference genome. We present a method for identifying paralogs in natural populations by combining two properties of duplicated loci: (i) the expected frequency of heterozygotes exceeds that for singleton loci, and (ii) within heterozygotes, observed read ratios for each allele in GBS data will deviate from the 1:1 expected for singleton (diploid) loci. These deviations are often not apparent within individuals, particularly when sequence coverage is low; but, we postulated that summing allele reads for each locus over all heterozygous individuals in a population would provide sufficient power to detect deviations at those loci. We identified paralogous loci in three species: Chinook salmon (Oncorhynchus tshawytscha) which retains regions with ongoing residual tetrasomy on eight chromosome arms following a recent whole‐genome duplication, mountain barberry (Berberis alpina) which has a large proportion of paralogs that arose through an unknown mechanism, and dusky parrotfish (Scarus niger) which has largely rediploidized following an ancient whole‐genome duplication. Importantly, this approach only requires the genotype and allele‐specific read counts for each individual, information which is readily obtained from most GBS analysis pipelines.     

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.     

Parallel signatures of selection in temporally isolated lineages of pink salmon

Studying the effect of similar environments on diverse genetic backgrounds has long been a goal of evolutionary biologists with studies typically relying on experimental approaches. Pink salmon, a highly abundant and widely ranging salmonid, provide a naturally occurring opportunity to study the effects of similar environments on divergent genetic backgrounds due to a strict two‐year semelparous life history. The species is composed of two reproductively isolated lineages with overlapping ranges that share the same spawning and rearing environments in alternate years. We used restriction‐site‐associated DNA (RAD) sequencing to discover and genotype approximately 8000 SNP loci in three population pairs of even‐ and odd‐year pink salmon along a latitudinal gradient in North America. We found greater differentiation within the odd‐year than within the even‐year lineage and greater differentiation in the southern pair from Puget Sound than in the northern Alaskan population pairs. We identified 15 SNPs reflecting signatures of parallel selection using both a differentiation‐based method (BAYESCAN) and an environmental correlation method (BAYENV). These SNPs represent genomic regions that may be particularly informative in understanding adaptive evolution in pink salmon and exploring how differing genetic backgrounds within a species respond to selection from the same natural environment.     

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.     

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.