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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2018

Species composition and altitudinal distribution of bumble bees (Hymenoptera: Apidae: Bombus) in the East Himalaya, Arunachal Pradesh, India

The East Himalaya is one of the worlds most biodiverse ecosystems. Yet, very little is known about the abundance and distribution of many plant and animal taxa in this region. Bumble bees are a group of cold-adapted and high altitude insects that fulfill an important ecological and economical function as pollinators of wild and agricultural flowering plants and crops. The Himalayan mountain range provides ample suitable habitats for bumble bees. Himalayan bumble bees have been studied systematically for a few decades now, with the main focus on the western region, while the eastern part of the mountain range received little attention and only a few species are genuinely reported. During a three-year survey, we collected more than 700 bumble bee specimens of 21 species in Arunachal Pradesh, the largest of the north-eastern states of India. We collected a range of species that were previously known from a very limited number of collected specimens, which highlights the unique character of the East Himalayan ecosystem. Our results are an important first step towards a future assessment of species distribution, threat and conservation. We observed clear altitudinal patterns of species diversity, which open important questions about the functional adaptations that allow bumble bees to thrive in this particularly moist region in the East Himalaya.

zoology↗

bioRxiv2018

Entomopathogenic nematodes increase predation success by inducing specific cadaver volatiles that attract healthy herbivores

Herbivore natural enemies, including predators, parasitoids and parasites, protect plants by regulating herbivore populations. Some parasites can increase their transmission efficiency by manipulating host behavior. Whether natural enemies can manipulate herbivore behavior to increase top-down control, however, is unknown. Here, we investigate if and how the entomopathogenic nematode Heterorhabditis bacteriophora, an important biocontrol agent, modulates the behavior of the western corn rootworm, Diabrotica virgifera virgifera, a major maize pest, and how these behavioral changes affect the capacity of the nematode to control the rootworm. We found that healthy rootworm larvae are attracted to nematode-infected cadavers shortly before the emergence of the next generation of nematodes. Nematode-infected rootworms release distinct volatile bouquets, including butylated hydroxytoluene (BHT), which attracts rootworms to infected cadavers. In a soil setting, BHT attracts rootworms and reduces nematode resistance, resulting in increased infection rates and rootworm mortality as well as increased nematode reproductive success. Five out of seven tested insect species were found to be attracted to nematode-infected conspecifics, suggesting that attraction of healthy hosts to nematode-infected cadavers is widespread. This study reveals a new facet of the biology of entomopathogenic nematodes that increases their capacity to control a major root pest by increasing the probability of host encounters.

ecology↗

bioRxiv2018

Sulfated RaxX, which represents an unclassified group of ribosomally synthesized post-translationally modified peptides, binds a host immune receptor

The rice immune receptor XA21 is activated by the sulfated microbial peptide RaxX (required for activation of XA21-mediated immunity X) produced by Xanthomonas oryzae pv. oryzae (Xoo). Mutational studies and targeted proteomics revealed that RaxX is processed and secreted by the protease/transporter RaxB, whose function can be partially fulfilled by a noncognate peptidase-containing transporter B (PctB). RaxX is cleaved at a Gly-Gly motif, yielding a mature peptide that retains the necessary elements for RaxX function as an immunogen and host peptide hormone mimic. These results indicate that RaxX is a founding member of a previously unclassified and understudied group of tyrosine sulfated RiPPs (ribosomally synthesized, post-translationally modified peptides). We further demonstrate that sulfated RaxX directly binds XA21 with high affinity. This work reveals a complete, previously uncharacterized biological process: bacterial RiPP biosynthesis, secretion, binding to a eukaryotic receptor and triggering of a robust host immune response.

microbiology↗

bioRxiv2018

Response of extremophile microbiome to a rare rainfall reveals a two-step adaptation mechanism

Understanding the mechanisms underlying microbial resistance and resilience to perturbations is essential to predict the impact of climate change on Earths ecosystems. However, the resilience and adaptation mechanisms of microbial communities to natural perturbations remain relatively unexplored, particularly in extreme environments. The response of an extremophile community inhabiting halite (salt rocks) in the Atacama Desert to a catastrophic rainfall provided the opportunity to characterize and de-convolute the temporal response of a highly specialized community to a major disturbance. With shotgun metagenomic sequencing, we investigated the halite microbiome taxonomic composition and functional potential over a 4-year longitudinal study, uncovering the dynamics of the initial response and of the recovery of the community after a rainfall event. The observed changes can be recapitulated by two general modes of community shifts - a rapid Type 1 shift and a more gradual Type 2 adjustment. In the initial response, the community entered an unstable intermediate state after stochastic niche re-colonization, resulting in broad predicted protein adaptations to increased water availability. In contrast, during recovery, the community returned to its former functional potential by a gradual shift in abundances of the newly acquired taxa. The general characterization and proposed quantitation of these two modes of community response could potentially be applied to other ecosystems, providing a theoretical framework for prediction of taxonomic and functional flux following environmental changes.

microbiology↗

bioRxiv2018

Periplasmic protein EipA determines envelope stress resistance and virulence in Brucella abortus

Molecular components of the Brucella abortus cell envelope play a major role in its ability to infect, colonize and survive inside mammalian host cells. In this study, we have defined a role for a conserved gene of unknown function in B. abortus envelope stress resistance and infection. Expression of this gene, which we name eipA, is directly activated by the essential cell cycle regulator, CtrA. eipA encodes a soluble periplasmic protein that adopts an unusual eight-stranded {beta}-barrel fold. Deletion of eipA attenuates replication and survival in macrophage and mouse infection models, and results in sensitivity to treatments that compromise the integrity of the cell envelope. Transposon disruption of genes required for LPS O-polysaccharide biosynthesis is synthetically lethal with eipA deletion. This genetic connection between O-polysaccharide and eipA is corroborated by our discovery that eipA is essential in Brucella ovis, a naturally rough species that harbors mutations in several genes required for O-polysaccharide production. Conditional depletion of eipA expression in B. ovis results in a cell chaining phenotype, providing evidence that eipA directly or indirectly influences cell division in Brucella. We conclude that EipA is a molecular determinant of Brucella virulence that functions to maintain cell envelope integrity and influences cell division.

microbiology↗

bioRxiv2018

Automatic navigation system for the mouse brain

Identification and delineation of brain regions in histologic mouse brain sections is especially pivotal for many neurogenomics, transcriptomics, proteomics and connectomics studies, yet this process is prone to observer error and bias. Here we present a novel brain navigation system, named NeuroInfo, whose general principle is similar to that of a global positioning system (GPS) in a car. NeuroInfo automatically navigates an investigator through the complex microscopic anatomy of histologic sections of mouse brains (thereafter: \"experimental mouse brain sections\"). This is achieved by automatically registering a digital image of an experimental mouse brain section with a three-dimensional (3D) digital mouse brain atlas that is essentially based on the third version of the Allen Mouse Brain Common Coordinate Framework (CCF v3), retrieving graphical region delineations and annotations from the 3D digital mouse brain atlas, and superimposing this information onto the digital image of the experimental mouse brain section on a computer screen. By doing so, NeuroInfo helps in solving the long-standing problem faced by researchers investigating experimental mouse brain sections under a light microscope--that of correctly identifying the distinct brain regions contained within the experimental mouse brain sections. Specifically, NeuroInfo provides an intuitive, readily-available computer microscopy tool to enhance researchers ability to correctly identify specific brain regions in experimental mouse brain sections. Extensive validation studies of NeuroInfo demonstrated that this novel technology performs remarkably well in accurately delineating regions that are large and/or located in the dorsal parts of mouse brains, independent on whether the sections were imaged with fluorescence or brightfield microscopy. This novel navigation system provides a highly efficient way for registering a digital image of an experimental mouse brain section with the 3D digital mouse brain atlas in a minute and accurate delineation of the image in real-time.

neuroscience↗

bioRxiv2018

Assembly of Yeast Spindle Pole Body and its Components Revealed by Electron Cryo-Tomography

Spindle pole body (SPB) is the microtubule organizing center (MTOC) in yeast. It plays essential roles during many cellular processes, ranging from mitosis to karyogamy. Here, we used electron cryo-tomography (cryo-ET) and image processing to study SPB and its component purified from the budding yeast. The 3D images and models of SPB at various cell cycle stages were reconstructed by cryo-ET and were analyzed. The results reveal SPB as a cylindrical shaped structure composed of multiple layers. The central layers are arranged with a degree of crystalline order. By using subtomogram averaging methods, we studied the purified \"sheet\" from over-expressed Spc42p. Our analysis of the SPBs and its components provides new insights into the assembly of this organelle and its cellular function as an MTOC.

cell biology↗

bioRxiv2018

Genes with high network connectivity are enriched for disease heritability

Recent studies have highlighted the role of gene networks in disease biology. To formally assess this, we constructed a broad set of pathway, network, and pathway+network annotations and applied stratified LD score regression to 42 independent diseases and complex traits (average N=323K) to identify enriched annotations. First, we constructed annotations from 18,119 biological pathways, including 100kb windows around each gene. We identified 156 pathway-trait pairs whose disease enrichment was statistically significant (FDR < 5%) after conditioning on all genes and on annotations from the baseline-LD model, a stringent step that greatly reduced the number of pathways detected; most of the significant pathway-trait pairs were previously unreported. Next, for each of four published gene networks, we constructed probabilistic annotations based on network connectivity using closeness centrality, a measure of how close a gene is to other genes in the network. For each gene network, the network connectivity annotation was strongly significantly enriched. Surprisingly, the enrichments were fully explained by excess overlap between network annotations and regulatory annotations from the baseline-LD model, validating the informativeness of the baseline-LD model and emphasizing the importance of accounting for regulatory annotations in gene network analyses. Finally, for each of the 156 enriched pathway-trait pairs, for each of the four gene networks, we constructed pathway+network annotations by annotating genes with high network connectivity to the input pathway. For each gene network, these pathway+network annotations were strongly significantly enriched for the corresponding traits. Once again, the enrichments were largely explained by the baseline-LD model. In conclusion, gene network connectivity is highly informative for disease architectures, but the information in gene networks may be subsumed by regulatory annotations, such that accounting for known annotations is critical to robust inference of biological mechanisms.

genetics↗

bioRxiv2018

A prognostic signature for lower-grade gliomas based on expression of long noncoding RNAs

Diffuse low-grade and intermediate-grade gliomas (together known as lower-grade gliomas, WHO grade II and III) develop in the supporting glial cells of brain and are the most common types of primary brain tumor. Despite a better prognosis for lower-grade gliomas, 70% of patients undergo high-grade transformation within 10 years, stressing the importance of better prognosis. Long non-coding RNAs (lncRNAs) are gaining attention as potential biomarkers for cancer diagnosis and prognosis. We have developed a computational model, UVA8, for prognosis of lower-grade gliomas by combining lncRNA expression, Cox regression and L1-LASSO penalization. The model was trained on a subset of patients in TCGA. Patients in TCGA, as well as a completely independent validation set (CGGA) could be dichotomized based on their risk score, a linear combination of the level of each prognostic lncRNA weighted by its multivariable cox regression coefficient. UVA8 is an independent predictor of survival and outperforms standard epidemiological approaches and previous published lncRNA-based predictors as a survival model. Guilt-by-association studies of the lncRNAs in UVA8, all of which predict good outcome, suggest they have a role in suppressing interferon stimulated response and epithelial to mesenchymal transition. The expression levels of 8 lncRNAs can be combined to produce a prognostic tool applicable to diverse populations of glioma patients. The 8 lncRNA (UVA8) based score can identify grade II and grade III glioma patients with poor outcome and thus identify patients who should receive more aggressive therapy at the outset.

genomics↗

bioRxiv2018

Tropical arboreal ants form dominance hierarchies over nesting resources in agroecosystems

Interspecific dominance hierarchies have been widely reported across animal systems. While some dominant individuals (winners) get to monopolize resources, during dyadic interactions, they can increase their relative fitness as compared to subdominant individuals (losers). In some ant species, dominance hierarchies have been used to explain species coexistence and community structure. However, it remains unclear whether or in what contexts dominance hierarchies occur in tropical ant communities. Furthermore, it can be challenging to infer and quantify reliable dominance hierarchies from observed interactions. This study seeks to examine whether arboreal twig-nesting ants competing for nesting resources in a Mexican coffee agricultural ecosystem are arranged in a dominance hierarchy. Using network analysis, we quantified interactions between ten species by measuring the uncertainty and steepness in the dominance hierarchy. We also assessed the orderliness of the hierarchy by considering species interactions at the network level. Based on the Elo-ranking method, we found that the twig-nesting ant species Myrmelachista mexicana ranked highest in the ranking, while Pseudomyrmex ejectus was ranked as the lowest in the hierarchy. We quantified the uncertainty in the dominance hierarchy and found that the hierarchy was intermediate in its steepness, suggesting that the probability of higher ranked individuals winning contests against lower ranked individuals was fairly high. Motif analysis and significant excess of triads further revealed that the species networks were largely transitive. This study highlights that some tropical arboreal ant communities self-organize into dominance hierarchies.

ecology↗

bioRxiv2018

Potentially repurposable drugs for schizophrenia identified from its interactome

From the schizophrenia drug-target interactome,1 we studied the drugs that targeted multiple proteins in the interactome, or those that target proteins with many targets, or those that target novel (computationally predicted) interactors of schizophrenia associated proteins. In schizophrenia, gene expression has been described as a measurable aspect of the disease reflecting the action of risk genes. We studied each of the selected drugs using the NextBio software suite, and shortlisted those that had a negative correlation with gene expression of schizophrenia. This analysis resulted in 12 drugs whose differential gene expression (drug versus normal) had an anti-correlation with differential expression for schizophrenia (disorder versus normal). Some of these drugs were already being tested for their clinical activity in schizophrenia and other neuropsychiatric disorders. Several proteins in the protein interactome of the targets of several of these drugs were associated with various neuropsychiatric disorders. The network of genes which were differentially expressed on drug treatment, and had an anti-correlation with gene expression in schizophrenia, were significantly enriched in pathways relevant to schizophrenia etiology and GWAS genes associated with traits or diseases that had pathophysiological overlap with schizophrenia. Drugs that are structurally similar to the shortlisted drugs, or targeted the same genes as these drugs, have also demonstrated clinical activity in schizophrenia and other related disorders. This integrated computational analysis may help translate insights from the schizophrenia drug-protein interactome to clinical research - an important step, especially in the field of psychiatric drug development, facing a high failure rate.

neuroscience↗

bioRxiv2018

Subclonal architecture, evolutionary trajectories and patterns of inheritance of germline variants in pediatric glioblastoma

Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. Intratumoral genetic heterogeneity and mode of tumor evolution have not been systematically addressed for this cancer. Whole-genome sequencing of germline-tumor pairs showed that pGBM is characterized by intratumoral genetic heterogeneity and consequent subclonal architecture. We found that pGBM undergoes extreme evolutionary trajectories, with primary and recurrent tumors having different subclonal compositions. Analysis of variant allele frequencies supported a model of tumor growth involving slow-cycling cancer stem cells that give rise to fast-proliferating progenitor-like cells and to non-dividing cells. pGBM patients germlines had subclonal structural variants, some of which underwent dynamic frequency fluctuations during tumor evolution. By sequencing germlines of mother-father-patient trios, we found that inheritance of deleterious germline variants from healthy parents cooperate with de novo germline and somatic events to the tumorigenic process. Our studies therefore challenge the current notion that pGBM is a relatively homogeneous molecular entity.

cancer biology↗

bioRxiv2018

The Dynamic Conformational Landscapes of the Protein Methyltransferase SETD8

Elucidating conformational heterogeneity of proteins is essential for understanding protein functions and developing exogenous ligands for chemical perturbation. While structural biology methods can provide atomic details of static protein structures, these approaches cannot in general resolve less populated, functionally relevant conformations and uncover conformational kinetics. Here we demonstrate a new paradigm for illuminating dynamic conformational landscapes of target proteins. SETD8 (Pr-SET7/SET8/KMT5A) is a biologically relevant protein lysine methyltransferase for in vivo monomethylation of histone H4 lysine 20 and nonhistone targets. Utilizing covalent chemical inhibitors and depleting native ligands to trap hidden high-energy conformational states, we obtained diverse novel X-ray structures of SETD8. These structures were used to seed massively distributed molecular simulations that generated six milliseconds of trajectory data of SETD8 in the presence or absence of its cofactor. We used an automated machine learning approach to reveal slow conformational motions and thus distinct conformational states of SETD8, and validated the resulting dynamic conformational landscapes with multiple biophysical methods. The resulting models provide unprecedented mechanistic insight into how protein dynamics plays a role in SAM binding and thus catalysis, and how this function can be modulated by diverse cancer-associated mutants. These findings set up the foundation for revealing enzymatic mechanisms and developing inhibitors in the context of conformational landscapes of target proteins.

biophysics↗

bioRxiv2018

Measures of neural similarity

One fundamental question is what makes two brain states similar. For example, what makes the activity in visual cortex elicited from viewing a robin similar to a sparrow? One common assumption in fMRI analysis is that neural similarity is described by Pearson correlation. However, there are a host of other possibilities, including Minkowski and Mahalanobis measures, with each differing in its mathematical, theoretical, neural computational assumptions. Moreover, the operable measures may vary across brain regions and tasks. Here, we evaluated which of several competing similarity measures best captured neural similarity. Our technique uses a decoding approach to assess the information present in a brain region and the similarity measures that best correspond to the classifiers confusion matrix are preferred. Across two published fMRI datasets, we found the preferred neural similarity measures were common across brain regions, but differed across tasks. Moreover, Pearson correlation was consistently surpassed by alternatives.

neuroscience↗

bioRxiv2018

Knockout of the gene encoding the extracellular matrix protein Sned1 results in craniofacial malformations and early neonatal lethality.

BackgroundThe extracellular matrix (ECM) is a fundamental component of multicellular organisms that orchestrates developmental processes and controls cell and tissue organization. We previously identified the novel ECM protein SNED1 as a promoter of breast cancer metastasis and showed that its level of expression negatively correlated with survival of breast cancer patients. Here we sought to identify the roles of SNED1 during murine development and in physiology. ResultsWe generated two novel Sned1 knockout mouse strains and showed that Sned1 is essential since homozygous ablation of the gene led to ~67% early neonatal lethality. Phenotypic analysis of the surviving knockout mice obtained revealed a role for SNED1 in the development of craniofacial and skeletal structures since Sned1 knockout resulted in growth defects, nasal cavity occlusion, and craniofacial malformations. Sned1 is widely expressed in embryos, notably in neural-crest derivatives. We further show here that mice with a neural-crest-cell-specific deletion of Sned1 survive, but display facial anomalies partly phenocopying the global knockout mice. ConclusionsOur results demonstrate requisite roles for SNED1 during development and neonatal survival. Importantly, the deletion of 2q37.3 in humans, a region that includes the SNED1 locus, has been associated with facial dysmorphism and short stature.

developmental biology↗

bioRxiv2018

Segregated encoding of spatiotemporal features in the mouse visual cortex

Visual processing and behavior depend on specialized neural representations and information channels that encode distinct visual information and enable distinct computations. Our understanding of the neural substrate, however, remain severely limited by sparse recordings and the restricted range of visual areas and visual stimuli considered. We characterized in the mouse the multidimensional spatiotemporal tuning properties of > 30,000 layer 2/3 pyramidal neurons across seven areas of the cortex. The dataset reveals population specialized for processing of oriented and non-oriented contrast, spatiotemporal frequency, and motion speed. Areal analysis reveals profound functional diversity and specificity as well as highly specific representations of visual processing channels in distinct visual areas. Clustering analysis shows a branching of visual representations along the posterior to anterior axis, and between lateral and dorsal areas. Overall, this dataset provides a cellular-resolution atlas for understanding organizing principles underlying sensory representations across the cortex. SummaryVisual representations and visual channels are the cornerstones of mammalian visual processing and critical for a range of life sustaining behaviors. However, the lack of data sets spanning multiple visual areas preclude unambiguous identification of visual processing streams and the sparse, singular recording data sets obtained thus far are insufficient to reveal the functional diversity of visual areas and to study visual information channels. We characterized the tunings of over 30,000 cortical excitatory neurons from 7 visual areas to a broad array of stimuli and studied their responses in terms of their ability to encode orientation, spatiotemporal contrast and visual motion speed. We found all mouse visual cortical areas convey diverse information but show distinct biases in terms of numbers of neurons tuned to particular spatiotemporal features. Neurons in visual areas differ in their spatiotemporal tuning but also in their relative response to oriented and unoriented contrast. We uncovered a population that preferentially responds to unoriented contrast and shows only weak responses to oriented stimuli. This population is strongly overrepresented in certain areas (V1, LM and LI) and underrepresented in others (AL, RL, AM, and PM). Spatiotemporal tunings are broadly distributed in all visual areas indicating that all areas have access to broad spatiotemporal information. However, individual areas show specific biases. While V1 is heavily biased in favor of low spatial and temporal frequencies, area LM responds more strongly to mid-range frequencies. Areas PM and LI are biased in favor of slowly-varying high-resolution signals. By comparison, anterior areas AL, RL and AM are heavily biased in favor of fast-varying, low to mid spatial frequency signals. Critically, theses biases express themselves in vastly different number of cells tuned to particular features, suggesting differential sampling of visual processing channels across areas. Comparing across areas, we found divergent visual representations between anterior and posterior areas, and between lateral and dorsal areas, suggesting the segregated organization of cortical streams for distinct information processing.

neuroscience↗

bioRxiv2018

Motile curved bacteria are Pareto-optimal

Curved-rods are a ubiquitous bacterial phenotype, but the fundamental question of why they are shaped this way remains unanswered. Through in silico experiments, we assessed freely swimming straight- and curved-rod bacteria of a wide diversity of equal-volume shapes parameterized by elongation and curvature, and predicted their performances in tasks likely to strongly influence overall fitness. Performance tradeoffs between these tasks lead to a variety of shapes that are Pareto-optimal, including coccoids, all straight rods, and a range of curvatures. Comparison with an extensive morphological survey of motile curved-rod bacteria indicates that the vast majority of species fall within the Pareto-optimal region of morphospace. This result is consistent with evolutionary tradeoffs between just three tasks: efficient swimming, chemotaxis, and low cell construction cost. We thus reveal the underlying selective pressures driving morphological diversity in a wide-spread component of microbial ecosystems.\n\nSignificance StatementBacteria exhibit a bewildering diversity of morphologies but despite their impact on nearly all aspects of life, they are frequently classified into a few general categories, usually just spheres and rods. Curved-rod bacteria are one simple variation and are widespread, particularly in the ocean. However, why so many species have evolved this shape is unknown. We show that curvature can increase swimming efficiency, revealing a widely-applicable selective advantage. Furthermore, we show that the distribution of cell lengths and curvatures observed across bacteria in nature are predicted by evolutionary tradeoffs between three tasks influenced by shape: efficient swimming, the ability to detect chemical gradients, and reduced cost of cell construction. We therefore reveal shape as an important component of microbial fitness.

biophysics↗

bioRxiv2018

Cyclin B2 is required for progression through meiosis in mouse oocytes

Cyclins associate with CDK1 to generate the M-phase-promoting factor (MPF) essential for progression through mitosis and meiosis. Previous studies concluded that CCNB2 is dispensable for cell cycle progression. Given our findings of high translation rates of CcnB2 mRNA in prophase-arrested oocytes, we have reevaluated its role during meiosis. CcnB2-/- oocytes undergo delayed germinal vesicle breakdown followed by a defective M-phase due to reduced pre-MPF activity. This disrupted maturation is associated with compromised CcnB1 and Mos mRNA translation and delayed spindle assembly. Given these defects, a significant population of oocytes fail to complete meiosis I because SAC remains activated and APC function is inhibited. In vivo, CCNB2 depletion leads to decreased oocyte developmental competence, compromised fecundity, and premature ovarian failure. These findings demonstrate that CCNB2 is required to assemble sufficient pre-MPF for timely meiosis reentry and progression. Although endogenous cyclins cannot compensate, overexpression of CCNB1 rescues the meiotic phenotypes, demonstrating similar molecular properties but divergent modes of regulation of these cyclins.

developmental biology↗