PLoS Biology

The Challenge of Conserving Amphibian Megadiversity in Madagascar.

Publication Date: 2008 May 6 PMID: 18462021
Authors: Andreone, F. - Carpenter, A. I. - Cox, N. - du Preez, L. - Freeman, K. - Furrer, S. - Garcia, G. - Glaw, F. - Glos, J. - Knox, D. - Kohler, J. - Mendelson, J. R. - Mercurio, V. - Mittermeier, R. A. - Moore, R. D. - Rabibisoa, N. H. - Randriamahazo, H. - Randrianasolo, H. - Raminosoa, N. R. - Ramilijaona, O. R. - Raxworthy, C. J. - Vallan, D. - Vences, M. - Vieites, D. R. - Weldon, C.
Journal: PLoS Biol

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Interesting Structures: Education and Outreach at the RCSB Protein Data Bank.

Publication Date: 2008 May 6 PMID: 18462020
Authors: Zardecki, C.
Journal: PLoS Biol

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The Parasexual Cycle in Candida albicans Provides an Alternative Pathway to Meiosis for the Formation of Recombinant Strains.

Publication Date: 2008 May 6 PMID: 18462019
Authors: Forche, A. - Alby, K. - Schaefer, D. - Johnson, A. D. - Berman, J. - Bennett, R. J.
Journal: PLoS Biol

Candida albicans has an elaborate, yet efficient, mating system that promotes conjugation between diploid a and alpha strains. The product of mating is a tetraploid a/alpha cell that must undergo a reductional division to return to the diploid state. Despite the presence of several "meiosis-specific" genes in the C. albicans genome, a meiotic program has not been observed. Instead, tetraploid products of mating can be induced to undergo efficient, random chromosome loss, often producing strains that are diploid, or close to diploid, in ploidy. Using SNP and comparative genome hybridization arrays we have now analyzed the genotypes of products from the C. albicans parasexual cycle. We show that the parasexual cycle generates progeny strains with shuffled combinations of the eight C. albicans chromosomes. In addition, several isolates had undergone extensive genetic recombination between homologous chromosomes, including multiple gene conversion events. Progeny strains exhibited altered colony morphologies on laboratory media, demonstrating that the parasexual cycle generates phenotypic variants of C. albicans. In several fungi, including Saccharomyces cerevisiae and Schizosaccharomyces pombe, the conserved Spo11 protein is integral to meiotic recombination, where it is required for the formation of DNA double-strand breaks. We show that deletion of SPO11 prevented genetic recombination between homologous chromosomes during the C. albicans parasexual cycle. These findings suggest that at least one meiosis-specific gene has been re-programmed to mediate genetic recombination during the alternative parasexual life cycle of C. albicans. We discuss, in light of the long association of C. albicans with warm-blooded animals, the potential advantages of a parasexual cycle over a conventional sexual cycle.

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Allele-Specific Up-Regulation of FGFR2 Increases Susceptibility to Breast Cancer.

Publication Date: 2008 May 6 PMID: 18462018
Authors: Meyer, K. B. - Maia, A. T. - O'Reilly, M. - Teschendorff, A. E. - Chin, S. F. - Caldas, C. - Ponder, B. A.
Journal: PLoS Biol

The recent whole-genome scan for breast cancer has revealed the FGFR2 (fibroblast growth factor receptor 2) gene as a locus associated with a small, but highly significant, increase in the risk of developing breast cancer. Using fine-scale genetic mapping of the region, it has been possible to narrow the causative locus to a haplotype of eight strongly linked single nucleotide polymorphisms (SNPs) spanning a region of 7.5 kilobases (kb) in the second intron of the FGFR2 gene. Here we describe a functional analysis to define the causative SNP, and we propose a model for a disease mechanism. Using gene expression microarray data, we observed a trend of increased FGFR2 expression in the rare homozygotes. This trend was confirmed using real-time (RT) PCR, with the difference between the rare and the common homozygotes yielding a Wilcox p-value of 0.028. To elucidate which SNPs might be responsible for this difference, we examined protein-DNA interactions for the eight most strongly disease-associated SNPs in different breast cell lines. We identify two cis-regulatory SNPs that alter binding affinity for transcription factors Oct-1/Runx2 and C/EBPbeta, and we demonstrate that both sites are occupied in vivo. In transient transfection experiments, the two SNPs can synergize giving rise to increased FGFR2 expression. We propose a model in which the Oct-1/Runx2 and C/EBPbeta binding sites in the disease-associated allele are able to lead to an increase in FGFR2 gene expression, thereby increasing the propensity for tumour formation.

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Mapping the Genetic Architecture of Gene Expression in Human Liver.

Publication Date: 2008 May 6 PMID: 18462017
Authors: Schadt, E. E. - Molony, C. - Chudin, E. - Hao, K. - Yang, X. - Lum, P. Y. - Kasarskis, A. - Zhang, B. - Wang, S. - Suver, C. - Zhu, J. - Millstein, J. - Sieberts, S. - Lamb, J. - Guhathakurta, D. - Derry, J. - Storey, J. D. - Avila-Campillo, I. - Kruger, M. J. - Johnson, J. M. - Rohl, C. A. - van Nas, A. - Mehrabian, M. - Drake, T. A. - Lusis, A. J. - Smith, R. C. - Guengerich, F. P. - Strom, S. C. - Schuetz, E. - Rushmore, T. H. - Ulrich, R.
Journal: PLoS Biol

Genetic variants that are associated with common human diseases do not lead directly to disease, but instead act on intermediate, molecular phenotypes that in turn induce changes in higher-order disease traits. Therefore, identifying the molecular phenotypes that vary in response to changes in DNA and that also associate with changes in disease traits has the potential to provide the functional information required to not only identify and validate the susceptibility genes that are directly affected by changes in DNA, but also to understand the molecular networks in which such genes operate and how changes in these networks lead to changes in disease traits. Toward that end, we profiled more than 39,000 transcripts and we genotyped 782,476 unique single nucleotide polymorphisms (SNPs) in more than 400 human liver samples to characterize the genetic architecture of gene expression in the human liver, a metabolically active tissue that is important in a number of common human diseases, including obesity, diabetes, and atherosclerosis. This genome-wide association study of gene expression resulted in the detection of more than 6,000 associations between SNP genotypes and liver gene expression traits, where many of the corresponding genes identified have already been implicated in a number of human diseases. The utility of these data for elucidating the causes of common human diseases is demonstrated by integrating them with genotypic and expression data from other human and mouse populations. This provides much-needed functional support for the candidate susceptibility genes being identified at a growing number of genetic loci that have been identified as key drivers of disease from genome-wide association studies of disease. By using an integrative genomics approach, we highlight how the gene RPS26 and not ERBB3 is supported by our data as the most likely susceptibility gene for a novel type 1 diabetes locus recently identified in a large-scale, genome-wide association study. We also identify SORT1 and CELSR2 as candidate susceptibility genes for a locus recently associated with coronary artery disease and plasma low-density lipoprotein cholesterol levels in the process.

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Biogenesis of the Trypanosome Endo-Exocytotic Organelle Is Cytoskeleton Mediated.

Publication Date: 2008 May 6 PMID: 18462016
Authors: Bonhivers, M. - Nowacki, S. - Landrein, N. - Robinson, D. R.
Journal: PLoS Biol

Trypanosoma brucei is a protozoan parasite that is used as a model organism to study such biological phenomena as gene expression, protein trafficking, and cytoskeletal biogenesis. In T. brucei, endocytosis and exocytosis occur exclusively through a sequestered organelle called the flagellar pocket (FP), an invagination of the pellicular membrane. The pocket is the sole site for specific receptors thus maintaining them inaccessible to components of the innate immune system of the mammalian host. The FP is also responsible for the sorting of protective parasite glycoproteins targeted to, or recycling from, the pellicular membrane, and for the removal of host antibodies from the cell surface. Here, we describe the first characterisation of a flagellar pocket cytoskeletal protein, BILBO1. BILBO1 functions to form a cytoskeleton framework upon which the FP is made and which is also required and essential for FP biogenesis and cell survival. Remarkably, RNA interference (RNAi)-mediated ablation of BILBO1 in insect procyclic-form parasites prevents FP biogenesis and induces vesicle accumulation, Golgi swelling, the aberrant repositioning of the new flagellum, and cell death. Cultured bloodstream-form parasites are also nonviable when subjected to BILBO1 RNAi. These results provide the first molecular evidence for cytoskeletally mediated FP biogenesis.

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One rhodopsin per photoreceptor: Iro-C genes break the rule.

Publication Date: 2008 Apr 29 PMID: 18447588
Authors: Stavenga, D. G. - Arikawa, K.
Journal: PLoS Biol

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Polycomb group genes: keeping stem cell activity in balance.

Publication Date: 2008 Apr 29 PMID: 18447587
Authors: Sauvageau, M. - Sauvageau, G.
Journal: PLoS Biol

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Cellular conductors: glial cells as guideposts during neural circuit development.

Publication Date: 2008 Apr 29 PMID: 18447586
Authors: Colon-Ramos, D. A. - Shen, K.
Journal: PLoS Biol

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A competition between stimulators and antagonists of Upf complex recruitment governs human nonsense-mediated mRNA decay.

Publication Date: 2008 Apr 29 PMID: 18447585
Authors: Singh, G. - Rebbapragada, I. - Lykke-Andersen, J.
Journal: PLoS Biol

The nonsense-mediated decay (NMD) pathway subjects mRNAs with premature termination codons (PTCs) to rapid decay. The conserved Upf1-3 complex interacts with the eukaryotic translation release factors, eRF3 and eRF1, and triggers NMD when translation termination takes place at a PTC. Contrasting models postulate central roles in PTC-recognition for the exon junction complex in mammals versus the cytoplasmic poly(A)-binding protein (PABP) in other eukaryotes. Here we present evidence for a unified model for NMD, in which PTC recognition in human cells is mediated by a competition between 3' UTR-associated factors that stimulate or antagonize recruitment of the Upf complex to the terminating ribosome. We identify cytoplasmic PABP as a human NMD antagonizing factor, which inhibits the interaction between eRF3 and Upf1 in vitro and prevents NMD in cells when positioned in proximity to the termination codon. Surprisingly, only when an extended 3' UTR places cytoplasmic PABP distally to the termination codon does a downstream exon junction complex enhance NMD, likely through increasing the affinity of Upf proteins for the 3' UTR. Interestingly, while an artificial 3' UTR of >420 nucleotides triggers NMD, a large subset of human mRNAs contain longer 3' UTRs but evade NMD. We speculate that these have evolved to concentrate NMD-inhibiting factors, such as PABP, in spatial proximity of the termination codon.

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Why we sleep: the temporal organization of recovery.

Publication Date: 2008 Apr 29 PMID: 18447584
Authors: Mignot, E.
Journal: PLoS Biol

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Bergmann glia and the recognition molecule CHL1 organize GABAergic axons and direct innervation of Purkinje cell dendrites.

Publication Date: 2008 Apr 29 PMID: 18447583
Authors: Ango, F. - Wu, C. - Van der Want, J. J. - Wu, P. - Schachner, M. - Huang, Z. J.
Journal: PLoS Biol

The geometric and subcellular organization of axon arbors distributes and regulates electrical signaling in neurons and networks, but the underlying mechanisms have remained elusive. In rodent cerebellar cortex, stellate interneurons elaborate characteristic axon arbors that selectively innervate Purkinje cell dendrites and likely regulate dendritic integration. We used GFP BAC transgenic reporter mice to examine the cellular processes and molecular mechanisms underlying the development of stellate cell axons and their innervation pattern. We show that stellate axons are organized and guided towards Purkinje cell dendrites by an intermediate scaffold of Bergmann glial (BG) fibers. The L1 family immunoglobulin protein Close Homologue of L1 (CHL1) is localized to apical BG fibers and stellate cells during the development of stellate axon arbors. In the absence of CHL1, stellate axons deviate from BG fibers and show aberrant branching and orientation. Furthermore, synapse formation between aberrant stellate axons and Purkinje dendrites is reduced and cannot be maintained, leading to progressive atrophy of axon terminals. These results establish BG fibers as a guiding scaffold and CHL1 a molecular signal in the organization of stellate axon arbors and in directing their dendritic innervation.

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Compilation and network analyses of cambrian food webs.

Publication Date: 2008 Apr 29 PMID: 18447582
Authors: Dunne, J. A. - Williams, R. J. - Martinez, N. D. - Wood, R. A. - Erwin, D. H.
Journal: PLoS Biol

A rich body of empirically grounded theory has developed about food webs--the networks of feeding relationships among species within habitats. However, detailed food-web data and analyses are lacking for ancient ecosystems, largely because of the low resolution of taxa coupled with uncertain and incomplete information about feeding interactions. These impediments appear insurmountable for most fossil assemblages; however, a few assemblages with excellent soft-body preservation across trophic levels are candidates for food-web data compilation and topological analysis. Here we present plausible, detailed food webs for the Chengjiang and Burgess Shale assemblages from the Cambrian Period. Analyses of degree distributions and other structural network properties, including sensitivity analyses of the effects of uncertainty associated with Cambrian diet designations, suggest that these early Paleozoic communities share remarkably similar topology with modern food webs. Observed regularities reflect a systematic dependence of structure on the numbers of taxa and links in a web. Most aspects of Cambrian food-web structure are well-characterized by a simple "niche model," which was developed for modern food webs and takes into account this scale dependence. However, a few aspects of topology differ between the ancient and recent webs: longer path lengths between species and more species in feeding loops in the earlier Chengjiang web, and higher variability in the number of links per species for both Cambrian webs. Our results are relatively insensitive to the exclusion of low-certainty or random links. The many similarities between Cambrian and recent food webs point toward surprisingly strong and enduring constraints on the organization of complex feeding interactions among metazoan species. The few differences could reflect a transition to more strongly integrated and constrained trophic organization within ecosystems following the rapid diversification of species, body plans, and trophic roles during the Cambrian radiation. More research is needed to explore the generality of food-web structure through deep time and across habitats, especially to investigate potential mechanisms that could give rise to similar structure, as well as any differences.

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High-throughput SHAPE analysis reveals structures in HIV-1 genomic RNA strongly conserved across distinct biological states.

Publication Date: 2008 Apr 29 PMID: 18447581
Authors: Wilkinson, K. A. - Gorelick, R. J. - Vasa, S. M. - Guex, N. - Rein, A. - Mathews, D. H. - Giddings, M. C. - Weeks, K. M.
Journal: PLoS Biol

Replication and pathogenesis of the human immunodeficiency virus (HIV) is tightly linked to the structure of its RNA genome, but genome structure in infectious virions is poorly understood. We invent high-throughput SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) technology, which uses many of the same tools as DNA sequencing, to quantify RNA backbone flexibility at single-nucleotide resolution and from which robust structural information can be immediately derived. We analyze the structure of HIV-1 genomic RNA in four biologically instructive states, including the authentic viral genome inside native particles. Remarkably, given the large number of plausible local structures, the first 10% of the HIV-1 genome exists in a single, predominant conformation in all four states. We also discover that noncoding regions functioning in a regulatory role have significantly lower (p-value < 0.0001) SHAPE reactivities, and hence more structure, than do viral coding regions that function as the template for protein synthesis. By directly monitoring protein binding inside virions, we identify the RNA recognition motif for the viral nucleocapsid protein. Seven structurally homologous binding sites occur in a well-defined domain in the genome, consistent with a role in directing specific packaging of genomic RNA into nascent virions. In addition, we identify two distinct motifs that are targets for the duplex destabilizing activity of this same protein. The nucleocapsid protein destabilizes local HIV-1 RNA structure in ways likely to facilitate initial movement both of the retroviral reverse transcriptase from its tRNA primer and of the ribosome in coding regions. Each of the three nucleocapsid interaction motifs falls in a specific genome domain, indicating that local protein interactions can be organized by the long-range architecture of an RNA. High-throughput SHAPE reveals a comprehensive view of HIV-1 RNA genome structure, and further application of this technology will make possible newly informative analysis of any RNA in a cellular transcriptome.

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Posttranscriptional gene regulation by spatial rearrangement of the 3' untranslated region.

Publication Date: 2008 Apr 29 PMID: 18447580
Authors: Eberle, A. B. - Stalder, L. - Mathys, H. - Orozco, R. Z. - Muhlemann, O.
Journal: PLoS Biol

Translation termination at premature termination codons (PTCs) triggers degradation of the aberrant mRNA, but the mechanism by which a termination event is defined as premature is still unclear. Here we show that the physical distance between the termination codon and the poly(A)-binding protein PABPC1 is a crucial determinant for PTC recognition in human cells. "Normal" termination codons can trigger nonsense-mediated mRNA decay (NMD) when this distance is extended; and vice versa, NMD can be suppressed by folding the poly(A) tail into proximity of a PTC or by tethering of PABPC1 nearby a PTC, indicating an evolutionarily conserved function of PABPC1 in promoting correct translation termination and antagonizing activation of NMD. Most importantly, our results demonstrate that spatial rearrangements of the 3' untranslated region can modulate the NMD pathway and thereby provide a novel mechanism for posttranscriptional gene regulation.

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A microtubule interactome: complexes with roles in cell cycle and mitosis.

Publication Date: 2008 Apr 22 PMID: 18433294
Authors: Hughes, J. R. - Meireles, A. M. - Fisher, K. H. - Garcia, A. - Antrobus, P. R. - Wainman, A. - Zitzmann, N. - Deane, C. - Ohkura, H. - Wakefield, J. G.
Journal: PLoS Biol

The microtubule (MT) cytoskeleton is required for many aspects of cell function, including the transport of intracellular materials, the maintenance of cell polarity, and the regulation of mitosis. These functions are coordinated by MT-associated proteins (MAPs), which work in concert with each other, binding MTs and altering their properties. We have used a MT cosedimentation assay, combined with 1D and 2D PAGE and mass spectrometry, to identify over 250 MAPs from early Drosophila embryos. We have taken two complementary approaches to analyse the cellular function of novel MAPs isolated using this approach. First, we have carried out an RNA interference (RNAi) screen, identifying 21 previously uncharacterised genes involved in MT organisation. Second, we have undertaken a bioinformatics analysis based on binary protein interaction data to produce putative interaction networks of MAPs. By combining both approaches, we have identified and validated MAP complexes with potentially important roles in cell cycle regulation and mitosis. This study therefore demonstrates that biologically relevant data can be harvested using such a multidisciplinary approach, and identifies new MAPs, many of which appear to be important in cell division.

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Iroquois complex genes induce co-expression of rhodopsins in Drosophila.

Publication Date: 2008 Apr 22 PMID: 18433293
Authors: Mazzoni, E. O. - Celik, A. - Wernet, M. F. - Vasiliauskas, D. - Johnston, R. J. - Cook, T. A. - Pichaud, F. - Desplan, C.
Journal: PLoS Biol

The Drosophila eye is a mosaic that results from the stochastic distribution of two ommatidial subtypes. Pale and yellow ommatidia can be distinguished by the expression of distinct rhodopsins and other pigments in their inner photoreceptors (R7 and R8), which are implicated in color vision. The pale subtype contains ultraviolet (UV)-absorbing Rh3 in R7 and blue-absorbing Rh5 in R8. The yellow subtype contains UV-absorbing Rh4 in R7 and green-absorbing Rh6 in R8. The exclusive expression of one rhodopsin per photoreceptor is a widespread phenomenon, although exceptions exist. The mechanisms leading to the exclusive expression or to co-expression of sensory receptors are currently not known. We describe a new class of ommatidia that co-express rh3 and rh4 in R7, but maintain normal exclusion between rh5 and rh6 in R8. These ommatidia, which are localized in the dorsal eye, result from the expansion of rh3 into the yellow-R7 subtype. Genes from the Iroquois Complex (Iro-C) are necessary and sufficient to induce co-expression in yR7. Iro-C genes allow photoreceptors to break the "one receptor-one neuron" rule, leading to a novel subtype of broad-spectrum UV- and green-sensitive ommatidia.

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