So, let's see what's new in PLoS Genetics, PLoS Computational Biology, PLoS Pathogens, PLoS ONE 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:
An End to Endless Forms: Epistasis, Phenotype Distribution Bias, and Nonuniform Evolution:
At the very end of his On the Origin of Species, Charles Darwin wrote, "from so simple a beginning endless forms most beautiful and most wonderful have been, and are being, evolved." Nature truly displays a bewildering variety of shapes and forms. Yet, with all its magnificence, this diversity still represents only a tiny fraction of the endless "space" of possibilities; research on the evolution of development has revealed that observed common morphologies and body plans (or, more generally, phenotypes) occupy only small, dense patches in the abstract phenotypic space. In this paper, we introduce a simple model of evolving gene regulation and show that these empirically identified patterns can be attributed, at least in part, to interaction between genes (epistasis) in the developmental network. Our model further predicts that early developmental programs with low levels of interaction would span most of the variation found in extant species. The theory presented in our paper complements the view of development as a key component in the production of endless forms and highlights the crucial role of development in constraining (as well as generating) biotic diversity.
When performing reaching and grasping movements, the brain has to choose one trajectory among an infinite set of possibilities. Nevertheless, because human and animal movements provide highly stereotyped features, motor strategies used by the brain were assumed to be optimal according to certain optimality criteria. In this study, we propose a theoretical model for motor planning of arm movements that minimizes a compromise between the absolute work exerted by the muscles and the integral of the squared acceleration. We demonstrate that under these assumptions agonistic and antagonistic muscles are inactivated during overlapping periods of time for quick enough movements. Moreover, it is shown that only this type of criterion can predict these inactivation periods. Finally, experimental evidence is in agreement with the predictions of the model. Indeed, we report the existence of simultaneous inactivation of opposing muscles during fast vertical arm movements. Therefore, this study suggests that biological movements partly optimize the energy expenditure, integrating both inertial and gravitational forces during the motor planning process.
Genetical Genomics: Spotlight on QTL Hotspots:
Genetical genomics aims at identifying quantitative trait loci (QTLs) for molecular traits such as gene expression or protein levels (eQTL and pQTL, respectively). One of the central concepts in genetical genomics is the existence of hotspots [1], where a single polymorphism leads to widespread downstream changes in the expression of distant genes, which are all mapping to the same genomic locus. Several groups have hypothesized that many genetic polymorphisms--e.g., in major regulators or transcription factors--would lead to large and consistent biological effects that would be visible as eQTL hotspots.
Horizontal versus Familial Transmission of Helicobacter pylori:
More than half of the world population is infected with Helicobacter pylori. It was widely believed that the primary mode of transmission is intra-familial, but the chains of infection are poorly understood. We have applied multilocus sequence analysis to H. pylori from two large multi-generation families in rural South Africa. Observations were compared with H. pylori from small, nuclear families in urban areas of the United States, United Kingdom, Colombia, and Korea, as well as with a large global collection from unrelated individuals. Intra-familial transmission of H. pylori was common in urban families but less common in the rural South African families. Instead, the South African families were infected with widely diverse strains, and multiple infections were common. We argue that the apparent predominance of intra-familial transmission in urban societies is a result of good socioeconomic conditions. In high-prevalence areas, opportunities for horizontal transmission are higher, which can result in greater diversity of H. pylori within a family. The patterns of frequent horizontal spread in rural South African families may be representative of large parts of the developing world. This interpretation is supported by the global sample which yielded ample evidence for horizontal inter-familial transmission in many areas of the world.
Predicting Unobserved Phenotypes for Complex Traits from Whole-Genome SNP Data:
Results from recent genome-wide association studies indicate that for most complex traits, there are many loci that contribute to variation in observed phenotype and that the effect of a single variant (single nucleotide polymorphism, SNP) on a phenotype is small. Here, we propose a method that combines the effects of multiple SNPs to make a prediction of a phenotype that has not been observed. We apply the method to data on mice, using phenotypic and genomic data from some individuals to predict phenotypes in other, either related or unrelated, individuals. We find that correlations between predicted and actual phenotypes are in the range of 0.4 to 0.9. The method also shows that the SNPs used in the prediction appear in regions that are known to contain genes associated with the traits studied. The prediction of unobserved phenotypes from high-density SNP data and appropriate statistical methodology is feasible and can be applied in human medicine, forensics, or artificial breeding programs.
Bacterial infections often involve more than one species. The lung disease of cystic fibrosis (CF) patients provides examples of polymicrobial infections whereby diverse and dynamic microbial communities are a characteristic of CF airways. The significance of microbe-microbe interactions and the interplay of the communities with the host have not been thoroughly investigated. We describe a novel Drosophila model to discern the biological interactions between microbes within microbial communities, as well as the interactions between the communities and the innate immune system. Using fly survival as a readout of relevant interactions, we show that mixed infections may additively or synergistically enhance the pathogenicity of a microbial community. The polymicrobial infection model was used to differentiate the bacterial flora in CF sputum, revealing that a large proportion of the organisms in CF airways has the ability to influence the outcome of an infection when in combination with the principal CF pathogen Pseudomonas aeruginosa. We show that during the synergistic-type mixed infections, P. aeruginosa virulence gene expression is altered within live Drosophila compared to mono-species infections. The immune response to microbial communities takes many forms and can include synergistic activation of antimicrobial peptide gene expression. We postulate that the biological interactions exposed using this model may contribute to the transition from chronic stable infections to acute pulmonary exacerbation infections in CF.
The Anticonvulsant Ethosuximide Disrupts Sensory Function to Extend C. elegans Lifespan:
Aging is a major factor that contributes to disease and disability in humans, but no medicines have been demonstrated to delay human aging. We previously conducted a screen for FDA-approved drugs that can extend the lifespan of the nematode worm C. elegans, resulting in the identification of ethosuximide, a medicine used to treat epilepsy. To elucidate the mechanism of action of ethosuximide in lifespan extension, we conducted a genetic screen for C. elegans mutations that cause resistance to ethosuximide. Here, we describe the identification of genes that are critical for ethosuximide sensitivity. These genes are necessary for the function of neurons that mediate sensory perception. Furthermore, ethosuximide treatment caused defects in sensory perception. These results indicate that ethosuximide affects lifespan by inhibiting neurons that function in the perception of sensory cues. These studies highlight the importance of sensory neurons in lifespan determination and demonstrate that a drug can act on specific cells within the nervous system to extend lifespan. Sensory perception also modulates Drosophila lifespan, suggesting this is an evolutionarily conserved relationship. Our results indicate that sensory perception may be a promising target for pharmacological extension of lifespan in a variety of animals.
Web-Based Virtual Microscopy for Parasitology: A Novel Tool for Education and Quality Assurance:
Here, we describe a novel tool to observe parasites by virtual microscopy on the Internet. Microscopy-based identification of parasites is the basis for both diagnostics and epidemiological assessment of parasite burden globally. Yet, quality assessment of diagnostic parasitology laboratories is difficult, as delivering identical educational specimens has been impossible. In this study, a series of parasite specimens on ordinary glass slides were digitized using a recently developed microscope scanner technique. Up to 50,000 images captured at high magnification are digitally stitched together to form a representation of the entire glass slide. These "virtual slides" digitized at a thousand-fold magnification can hold more than 60 gigabytes of data. Handling such large amounts of data was made possible because of efficient compression techniques and a viewing system adopted from the geospatial imaging industry. Viewing the samples on the Internet very much resembles, for example, the use of Google Maps, and puts only modest requirements on the viewer's computer. In addition, we captured image stacks at different focal planes, and developed a web-based viewing system for three-dimensional navigation in the specimens. This novel technique is especially valuable for detailed visualization of large objects such as helminth eggs in stool specimens.
Genome-wide data provide a powerful tool for inferring patterns of genetic variation and structure of human populations. In this study, we analysed almost 250,000 SNPs from a total of 945 samples from Eastern and Western Finland, Sweden, Northern Germany and Great Britain complemented with HapMap data. Small but statistically significant differences were observed between the European populations (FST = 0.0040, p
The sialic acid present in the protective surface mucin coat of Trypanosoma cruzi is added by a membrane anchored trans-sialidase (TcTS), a modified sialidase that is expressed from a large gene family. In this work, we analyzed single domain camelid antibodies produced against trans-sialidase. Llamas were immunized with a recombinant trans-sialidase and inhibitory single-domain antibody fragments were obtained by phage display selection, taking advantage of a screening strategy using an inhibition test instead of the classic binding assay. Four single domain antibodies displaying strong trans-sialidase inhibition activity against the recombinant enzyme were identified. They share the same complementarity-determining region 3 length (17 residues) and have very similar sequences. This result indicates that they likely derived from a unique clone. Probably there is only one structural solution for tight binding inhibitory antibodies against the TcTS used for immunization. To our surprise, this single domain antibody that inhibits the recombinant TcTS, failed to inhibit the enzymatic activity present in parasite extracts. Analysis of individual recombinant trans-sialidases showed that enzymes expressed from different genes were inhibited to different extents (from 8 to 98%) by the llama antibodies. Amino acid changes at key positions are likely to be responsible for the differences in inhibition found among the recombinant enzymes. These results suggest that the presence of a large and diverse trans-sialidase family might be required to prevent the inhibitory response against this essential enzyme and might thus constitute a novel strategy of T. cruzi to evade the host immune system.
Searching for the Majority: Algorithms of Voluntary Control:
Voluntary control of information processing is crucial to allocate resources and prioritize the processes that are most important under a given situation; the algorithms underlying such control, however, are often not clear. We investigated possible algorithms of control for the performance of the majority function, in which participants searched for and identified one of two alternative categories (left or right pointing arrows) as composing the majority in each stimulus set. We manipulated the amount (set size of 1, 3, and 5) and content (ratio of left and right pointing arrows within a set) of the inputs to test competing hypotheses regarding mental operations for information processing. Using a novel measure based on computational load, we found that reaction time was best predicted by a grouping search algorithm as compared to alternative algorithms (i.e., exhaustive or self-terminating search). The grouping search algorithm involves sampling and resampling of the inputs before a decision is reached. These findings highlight the importance of investigating the implications of voluntary control via algorithms of mental operations.
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