So, let's see what's new in PLoS Genetics, PLoS Computational Biology, PLoS Pathogens and PLoS Neglected Tropical Diseases this week. As always, you should rate the articles, post notes and comments and send trackbacks when you blog about the papers. Here are my own picks for the week - you go and look for your own favourites:
Patterns of Positive Selection in Six Mammalian Genomes:
Populations evolve as mutations arise in individual organisms and, through hereditary transmission, gradually become "fixed" (shared by all individuals) in the population. Many mutations have essentially no effect on organismal fitness and can become fixed only by the stochastic process of neutral drift. However, some mutations produce a selective advantage that boosts their chances of reaching fixation. Genes in which new mutations tend to be beneficial, rather than neutral or deleterious, tend to evolve rapidly and are said to be under positive selection. Genes involved in immunity and defense are a well-known example; rapid evolution in these genes presumably occurs because new mutations help organisms to prevail in evolutionary "arms races" with pathogens. Many mammalian genes show evidence of positive selection, but open questions remain about the overall impact of positive selection in mammals. For example, which key differences between species can be attributed to positive selection? How have patterns of selection changed across the mammalian phylogeny? What are the effects of population size and gene expression patterns on positive selection? Here we attempt to shed light on these and other questions in a comprehensive study of ~16,500 genes in six mammalian genomes.
Engaging the Community: An Interview with Uche Amazigo:
Walking purposefully towards the shabby grey concrete structure that functions as the main health centre of Kyenjojo district in western Uganda, public health doctor Andrew Byamungu makes a trip he has done many times before since joining the vector control department of the Ugandan Ministry of Health. Fighting his way through the crowds of waiting patients and relatives, he greets the tired-looking health staff who, among their many other duties, are responsible for education and drug distribution in the country's onchocerciasis control programme, which is one of the most advanced of the 19 country projects of the African Programme for Onchocerciasis Control (APOC).
Patients who succumbed to influenza during the pandemic from 1918 to 1919 had severe lung pathology marked by extensive inflammatory infiltrate, indicating a robust immune response in the lung. Similar findings have been reported from H5N1-infected patients, raising the question as to why people expire in the presence of a strong immune response. We addressed this question by characterizing the immune cell populations in the mouse lung following infection with the 1918 pandemic virus and two H5N1 viruses isolated from fatal cases. We found that certain cells of the innate immune system, specifically macrophages and neutrophils, increase significantly early during infection but that the cells responsible for bridging the innate and adaptive immune responses, dendritic cells and the orchestrators of viral clearance, T cells, did not differ significantly between infection groups. Dendritic cells and mouse lung macrophages were shown to be susceptible to 1918 and H5N1 virus infection in vitro, suggesting a possible mechanism of pathogenesis. Our data shows excessive immune cell infiltration in the lungs contributing to severe consolidation and tissue architecture destruction in mice infected with highly pathogenic influenza viruses, supporting the histopathological observations of lung tissue from 1918 and H5N1 fatalities. Identification of the precise inflammatory cells associated with lung inflammation will be important for the development of treatments that could potentially enhance or modulate host innate immune responses.
Until recently, sequencing the entire genome of an organism was a major endeavor. New technologies are transforming this task into routine practice and launching a new assault on whole-genome sequencing.
It is more than 30 years since Sir Fred Sanger and colleagues published their method for sequencing DNA [1]. This Nobel Prize-winning work formed the basis of the vast majority of subsequent sequencing methodologies, albeit with some crucial technical innovations. Despite the great utility of Sanger sequencing, its scalability is inherently limited, and therefore the creation of warehouse-sized facilities was required to accomplish whole-genome sequencing projects. As a result, sequencing more than a few kilobases of DNA--a requirement for all but the simplest genomes--has long remained the province of a few dedicated sequencing centers. Within the last year, however, things have begun to change in dramatic ways. New sequencing technologies are emerging, announced in an assortment of reports, conference presentations, and press releases. In this issue of PLoS Genetics, Srivatsan et al. [2] report the resequencing of several genomes of the bacterium Bacillus subtilis using one of these new technologies. A new battle at the frontier of DNA sequencing has commenced.
A Model of Stimulus-Specific Neural Assemblies in the Insect Antennal Lobe:
It has been proposed that synchronized neural assemblies in the antennal lobe of insects encode the identity of olfactory stimuli. In response to an odor, some projection neurons exhibit synchronous firing, phase-locked to the oscillations of the field potential, whereas others do not. Experimental data indicate that neural synchronization and field oscillations are induced by fast GABAA-type inhibition, but it remains unclear how desynchronization occurs. We hypothesize that slow inhibition plays a key role in desynchronizing projection neurons. Because synaptic noise is believed to be the dominant factor that limits neuronal reliability, we consider a computational model of the antennal lobe in which a population of oscillatory neurons interact through unreliable GABAA and GABAB inhibitory synapses. From theoretical analysis and extensive computer simulations, we show that transmission failures at slow GABAB synapses make the neural response unpredictable. Depending on the balance between GABAA and GABAB inputs, particular neurons may either synchronize or desynchronize. These findings suggest a wiring scheme that triggers stimulus-specific synchronized assemblies. Inhibitory connections are set by Hebbian learning and selectively activated by stimulus patterns to form a spiking associative memory whose storage capacity is comparable to that of classical binary-coded models. We conclude that fast inhibition acts in concert with slow inhibition to reformat the glomerular input into odor-specific synchronized neural assemblies.
High-Precision, Whole-Genome Sequencing of Laboratory Strains Facilitates Genetic Studies:
In this manuscript, we describe novel applications of the newly developed Solexa sequencing technology. We aim to provide insights into the following questions: (1) Can whole-genome sequencing, while rapidly surveying mega-bases of genome information, also reliably identify variations at the base-pair resolution? (2) Can it be used to identify the differences between isolates of the same laboratory strain and between different laboratory strains? (3) Can it be used as a genetic tool to predict phenotypes and identify suppressors? To this end, we performed whole-genome shotgun sequencing of several related strains of the widely studied model bacterium Bacillus subtilis, we identified genomic variations that potentially underlie strain-specific phenotypes, which occur frequently in biological studies, and we found multiple suppressor mutations within a single strain that are difficult to discern through traditional methods. We conclude that whole-genome sequencing can be directly used to guide genetic studies.
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