The sampling theory of neutral alleles and an urn model in population genetics

The behaviour of a Pólya-like urn which generates Ewens' sampling formula in population genetics is investigated. Connections are made with work of Watterson and Kingman and to the Poisson-Dirichlet distribution. The order in which novel types occur in the urn is shown to parallel the age distribution of the infinitely many alleles diffusion model and consequences of this property are explored. Finally the urn process is related to Kingman's coalescent with mutation to provide a rigorous basis for this parallel.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46946/1/285_2004_Article_BF00276386.pd

Recombination facilitates neofunctionalization of duplicate genes via originalization

<p>Abstract</p> <p>Background</p> <p>Recently originalization was proposed to be an effective way of duplicate-gene preservation, in which recombination provokes the high frequency of original (or wild-type) allele on both duplicated loci. Because the high frequency of wild-type allele might drive the arising and accumulating of advantageous mutation, it is hypothesized that recombination might enlarge the probability of neofunctionalization (P_neo) of duplicate genes. In this article this hypothesis has been tested theoretically.</p> <p>Results</p> <p>Results show that through originalization recombination might not only shorten mean time to neofunctionalizaiton, but also enlarge P_neo.</p> <p>Conclusions</p> <p>Therefore, recombination might facilitate neofunctionalization via originalization. Several extensive applications of these results on genomic evolution have been discussed: 1. Time to nonfunctionalization can be much longer than a few million generations expected before; 2. Homogenization on duplicated loci results from not only gene conversion, but also originalization; 3. Although the rate of advantageous mutation is much small compared with that of degenerative mutation, P_neocannot be expected to be small.</p

The Met Office Global Coupled model 3.0 and 3.1 (GC3.0 & GC3.1) configurations

The Global Coupled 3 (GC3) configuration of the Met Office Unified Model is presented. Amongst other applications, GC3 is the basis of the United Kingdom's submission to the Coupled Model Intercomparison Project 6 (CMIP6). This paper documents the model components that make up the configuration (although the scientific description of these components are in companion papers), and details the coupling between them. The performance of GC3 is assessed in terms of mean biases and variability in long climate simulations using present-day forcing. The suitability of the configuration for predictability on shorter timescales (weather and seasonal forecasting) is also briefly discussed. The performance of GC3 is compared against GC2, the previous Met Office coupled model configuration, and against an older configuration (HadGEM2-AO) which was the submission to CMIP5. In many respects, the performance of GC3 is comparable with GC2, however there is a notable improvement in the Southern Ocean warm sea surface temperature bias which has been reduced by 75%, and there are improvements in cloud amount and some aspects of tropical variability. Relative to HadGEM2-AO, many aspects of the present-day climate are improved in GC3 including tropospheric and stratospheric temperature structure, most aspects of tropical and extra-tropical variability and top-of-atmosphere & surface fluxes. A number of outstanding errors are identified including a residual asymmetric sea surface temperature bias (cool northern hemisphere, warm Southern Ocean), an overly strong global hydrological cycle and insufficient European blocking

Multichromosomal median and halving problems under different genomic distances

<p>Abstract</p> <p>Background</p> <p>Genome median and genome halving are combinatorial optimization problems that aim at reconstructing ancestral genomes as well as the evolutionary events leading from the ancestor to extant species. Exploring complexity issues is a first step towards devising efficient algorithms. The complexity of the median problem for unichromosomal genomes (permutations) has been settled for both the breakpoint distance and the reversal distance. Although the multichromosomal case has often been assumed to be a simple generalization of the unichromosomal case, it is also a relaxation so that complexity in this context does not follow from existing results, and is open for all distances.</p> <p>Results</p> <p>We settle here the complexity of several genome median and halving problems, including a surprising polynomial result for the breakpoint median and guided halving problems in genomes with circular and linear chromosomes, showing that the multichromosomal problem is actually easier than the unichromosomal problem. Still other variants of these problems are NP-complete, including the DCJ double distance problem, previously mentioned as an open question. We list the remaining open problems.</p> <p>Conclusion</p> <p>This theoretical study clears up a wide swathe of the algorithmical study of genome rearrangements with multiple multichromosomal genomes.</p

Spectators’ Negotiations of Risk, Masculinity and Performative Mobilities at the TT Races

This paper explores the particular assemblage of place, event and individual identity performances that occur each year in the Isle of Man in and through the TT (Tourist Trophy) motorcycle races. These road races are associated with a high degree of risk for the racers and the confluence of over 30,000 visitors and 10,000 motorcycles also presents potential risks for spectators and residents alike. Both motorcycling and risk-taking have been associated with particular forms of masculinity, notably hegemonic, working class and youthful masculinities. Using detailed surveys of spectators we argue that the TT races, while undoubtedly dominated by men and predicated on a cultural privileging of speed and skill, are grounded in varying combinations of determinate and reflexive attitudes to risk, reflecting the performance of a variety of gendered, ‘biker’ and wider identity-based positionalities. Findings also highlight a particular inter-relation of mobilities and place identities at the TT races and bring to light the highly significant and under-researched embodied, performative and emotional mobilities of spectators. The conceptual and methodological importance of (a) situated research of both mobilities and gender in specific place-temporalities and (b) wider surveys of motorcyclists to complement ethnographic studies of small cohorts are also stressed

A Naturally Occurring Polymorphism at Drosophila melanogaster Lim3 Locus, a Homolog of Human LHX3/4, Affects Lim3 Transcription and Fly Lifespan

Lim3 encodes an RNA polymerase II transcription factor with a key role in neuron specification. It was also identified as a candidate gene that affects lifespan. These pleiotropic effects indicate the fundamental significance of the potential interplay between neural development and lifespan control. The goal of this study was to analyze the causal relationships between Lim3 structural variations, and gene expression and lifespan changes, and to provide insights into regulatory pathways controlling lifespan. Fifty substitution lines containing second chromosomes from a Drosophila natural population were used to analyze the association between lifespan and sequence variation in the 5′-regulatory region, and first exon and intron of Lim3A, in which we discovered multiple transcription start sites (TSS). The core and proximal promoter organization for Lim3A and a previously unknown mRNA named Lim3C were described. A haplotype of two markers in the Lim3A regulatory region was significantly associated with variation in lifespan. We propose that polymorphisms in the regulatory region affect gene transcription, and consequently lifespan. Indeed, five polymorphic markers located within 380 to 680 bp of the Lim3A major TSS, including two markers associated with lifespan variation, were significantly associated with the level of Lim3A transcript, as evaluated by real time RT-PCR in embryos, adult heads, and testes. A naturally occurring polymorphism caused a six-fold change in gene transcription and a 25% change in lifespan. Markers associated with long lifespan and intermediate Lim3A transcription were present in the population at high frequencies. We hypothesize that polymorphic markers associated with Lim3A expression are located within the binding sites for proteins that regulate gene function, and provide general rather than tissue-specific regulation of transcription, and that intermediate levels of Lim3A expression confer a selective advantage and longer lifespan

Pervasive Hitchhiking at Coding and Regulatory Sites in Humans

Much effort and interest have focused on assessing the importance of natural selection, particularly positive natural selection, in shaping the human genome. Although scans for positive selection have identified candidate loci that may be associated with positive selection in humans, such scans do not indicate whether adaptation is frequent in general in humans. Studies based on the reasoning of the MacDonald–Kreitman test, which, in principle, can be used to evaluate the extent of positive selection, suggested that adaptation is detectable in the human genome but that it is less common than in Drosophila or Escherichia coli. Both positive and purifying natural selection at functional sites should affect levels and patterns of polymorphism at linked nonfunctional sites. Here, we search for these effects by analyzing patterns of neutral polymorphism in humans in relation to the rates of recombination, functional density, and functional divergence with chimpanzees. We find that the levels of neutral polymorphism are lower in the regions of lower recombination and in the regions of higher functional density or divergence. These correlations persist after controlling for the variation in GC content, density of simple repeats, selective constraint, mutation rate, and depth of sequencing coverage. We argue that these results are most plausibly explained by the effects of natural selection at functional sites—either recurrent selective sweeps or background selection—on the levels of linked neutral polymorphism. Natural selection at both coding and regulatory sites appears to affect linked neutral polymorphism, reducing neutral polymorphism by 6% genome-wide and by 11% in the gene-rich half of the human genome. These findings suggest that the effects of natural selection at linked sites cannot be ignored in the study of neutral human polymorphism

Electrotonic Signals along Intracellular Membranes May Interconnect Dendritic Spines and Nucleus

Synapses on dendritic spines of pyramidal neurons show a remarkable ability to induce phosphorylation of transcription factors at the nuclear level with a short latency, incompatible with a diffusion process from the dendritic spines to the nucleus. To account for these findings, we formulated a novel extension of the classical cable theory by considering the fact that the endoplasmic reticulum (ER) is an effective charge separator, forming an intrinsic compartment that extends from the spine to the nuclear membrane. We use realistic parameters to show that an electrotonic signal may be transmitted along the ER from the dendritic spines to the nucleus. We found that this type of signal transduction can additionally account for the remarkable ability of the cell nucleus to differentiate between depolarizing synaptic signals that originate from the dendritic spines and back-propagating action potentials. This study considers a novel computational role for dendritic spines, and sheds new light on how spines and ER may jointly create an additional level of processing within the single neuron

Genetic Differentiation of the Western Capercaillie Highlights the Importance of South-Eastern Europe for Understanding the Species Phylogeography

The Western Capercaillie (Tetrao urogallus L.) is a grouse species of open boreal or high altitude forests of Eurasia. It is endangered throughout most mountain range habitat areas in Europe. Two major genetically identifiable lineages of Western Capercaillie have been described to date: the southern lineage at the species' southernmost range of distribution in Europe, and the boreal lineage. We address the question of genetic differentiation of capercaillie populations from the Rhodope and Rila Mountains in Bulgaria, across the Dinaric Mountains to the Slovenian Alps. The two lineages' contact zone and resulting conservation strategies in this so-far understudied area of distribution have not been previously determined. The results of analysis of mitochondrial DNA control region sequences of 319 samples from the studied populations show that Alpine populations were composed exclusively of boreal lineage; Dinaric populations of both, but predominantly (96%) of boreal lineage; and Rhodope-Rila populations predominantly (>90%) of southern lineage individuals. The Bulgarian mountains were identified as the core area of the southern lineage, and the Dinaric Mountains as the western contact zone between both lineages in the Balkans. Bulgarian populations appeared genetically distinct from Alpine and Dinaric populations and exhibited characteristics of a long-term stationary population, suggesting that they should be considered as a glacial relict and probably a distinct subspecies. Although all of the studied populations suffered a decline in the past, the significantly lower level of genetic diversity when compared with the neighbouring Alpine and Bulgarian populations suggests that the isolated Dinaric capercaillie is particularly vulnerable to continuing population decline. The results are discussed in the context of conservation of the species in the Balkans, its principal threats and legal protection status. Potential conservation strategies should consider the existence of the two lineages and their vulnerable Dinaric contact zone and support the specificities of the populations

The Effect of Macromolecular Crowding, Ionic Strength and Calcium Binding on Calmodulin Dynamics

The flexibility in the structure of calmodulin (CaM) allows its binding to over 300 target proteins in the cell. To investigate the structure-function relationship of CaM, we combined methods of computer simulation and experiments based on circular dichroism (CD) to investigate the structural characteristics of CaM that influence its target recognition in crowded cell-like conditions. We developed a unique multiscale solution of charges computed from quantum chemistry, together with protein reconstruction, coarse-grained molecular simulations, and statistical physics, to represent the charge distribution in the transition from apoCaM to holoCaM upon calcium binding. Computationally, we found that increased levels of macromolecular crowding, in addition to calcium binding and ionic strength typical of that found inside cells, can impact the conformation, helicity and the EF hand orientation of CaM. Because EF hand orientation impacts the affinity of calcium binding and the specificity of CaM's target selection, our results may provide unique insight into understanding the promiscuous behavior of calmodulin in target selection inside cells.Comment: Accepted to PLoS Comp Biol, 201