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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2017

A Two-Process Model for Circadian and Sleep-dependent Modulation of Pain Sensitivity

Pain sensitivity is strongly modulated by time of day and by prior sleep behavior. These two factors, governed by the circadian rhythm and homeostatic sleep drive, respectively, likewise dictate the timing and duration of sleep. The fields of sleep and circadian research have identified much of the physiology underlying the circadian rhythm and homeostatic sleep drive with mathematical modeling playing an important role in understanding how these two processes interact to affect sleep behavior. We hypothesize that the daily rhythm of pain sensitivity and its sleep-dependent modulation reflect an interaction of the circadian rhythm and homeostatic sleep drive. To investigate this hypothesis, we adapt the formalism of a classic mathematical model for the regulation of sleep behavior by the circadian rhythm and homeostatic sleep drive, called the Two Process model, to simulate the interaction of these two processes on pain sensitivity. To construct the model, we utilize data from experimental reports on the daily rhythmicity of pain sensitivity in humans to define a \"daily pain sensitivity\" function. We decompose this function into two processes: a sleep-dependent process S(t) that follows the homeostatic sleep drive and a circadian process C(t) that is dictated by the circadian rhythm. By simulating different sleep schedules with the original Two Process model, we compute changes in the sleep-dependent process S(t) that modulates pain sensitivity. By combining S(t) with the circadian process C(t), our model predicts resultant changes in the daily pain sensitivity rhythm. We illustrate model predictions for changes in pain sensitivity due to sleep deprivation, sleep restriction and shift work schedules. We believe that this model may be a useful tool for pain management by providing predictions of the variations in pain sensitivity due to changing sleep schedules.

neuroscience↗

bioRxiv2017

Lineage-specific rediploidization is a mechanism to explain time-lags between genome duplication and evolutionary diversification

The functional divergence of duplicate genes (ohnologues) retained from whole genome duplication (WGD) is thought to promote evolutionary diversification. However, species radiation and phenotypic diversification is often highly temporally-detached from WGD. Salmonid fish, whose ancestor experienced WGD by autotetraploidization ~95 Ma (i.e. Ss4R), fit such a time-lag model of post-WGD radiation, which occurred alongside a major delay in the rediploidization process. Here we propose a model called Lineage-specific Ohnologue Resolution (LORe) to address the phylogenetic and functional consequences of delayed rediploidization. Under LORe, speciation precedes rediploidization, allowing independent ohnologue divergence in sister lineages sharing an ancestral WGD event. Using cross-species sequence capture, phylogenomics and genome-wide analyses of ohnologue expression divergence, we demonstrate the major impact of LORe on salmonid evolution. One quarter of each salmonid genome, harbouring at least 4,500 ohnologues, has evolved under LORe, with rediploidization and functional divergence occurring on multiple independent occasions > 50 Myr post-WGD. We demonstrate the existence and regulatory divergence of many LORe ohnologues with functions in lineage-specific physiological adaptations that promoted salmonid species radiation. We show that LORe ohnologues are enriched for different functions than older ohnologues that began diverging in the salmonid ancestor. LORe has unappreciated significance as a nested component of post-WGD divergence that impacts the functional properties of genes, whilst providing ohnologues available solely for lineage-specific adaptation. Under LORe, which is predicted following many WGD events, the functional outcomes of WGD need not appear explosively, but can arise gradually over tens of Myr, promoting lineage-specific diversification regimes under prevailing ecological pressures.

genomics↗

bioRxiv2017

Epistatic networks jointly influence phenotypes related to metabolic disease and gene expression in Diversity Outbred mice

Genetic studies of multidimensional phenotypes can potentially link genetic variation, gene expression, and physiological data to create multi-scale models of complex traits. Multi-parent populations provide a resource for developing methods to understand these relationships. In this study, we simultaneously modeled body composition, serum biomarkers, and liver transcript abundances from 474 Diversity Outbred mice. This population contained both sexes and two dietary cohorts. Using weighted gene co-expression network analysis (WGCNA), we summarized transcript data into functional modules which we then used as summary phenotypes representing enriched biological processes. These module phenotypes were jointly analyzed with body composition and serum biomarkers in a combined analysis of pleiotropy and epistasis (CAPE), which inferred networks of epistatic interactions between quantitative trait loci that affect one or more traits. This network frequently mapped interactions between alleles of different ancestries, providing evidence of both genetic synergy and redundancy between haplotypes. Furthermore, a number of loci interacted with sex and diet to yield sex-specific genetic effects. We were also able to identify alleles that potentially protect individuals from the effects of a high-fat diet. Although the epistatic interactions explained small amounts of trait variance, the combination of directional interactions, allelic specificity, and high genomic resolution provided context to generate hypotheses for the roles of specific genes in complex traits. Our approach moves beyond the cataloging of single loci to infer genetic networks that map genetic etiology by simultaneously modeling all phenotypes.

genetics↗

bioRxiv2017

Biocuration as an undergraduate training experience: Improving the annotation of the insect vector of Citrus greening disease

The Asian citrus psyllid (Diaphorina citri Kuwayama) is the insect vector of the bacterium Candidatus Liberibacter asiaticus (CLas), the pathogen associated with citrus Huanglongbing (HLB, citrus greening). HLB threatens citrus production worldwide. Suppression or reduction of the insect vector using chemical insecticides has been the primary method to inhibit the spread of citrus greening disease. Accurate structural and functional annotation of the Asian citrus psyllid genome, as well as a clear understanding of the interactions between the insect and CLas, are required for development of new molecular-based HLB control methods. A draft assembly of the D. citri genome has been generated and annotated with automated pipelines. However, knowledge transfer from well-curated reference genomes such as that of Drosophila melanogaster to newly sequenced ones is challenging due to the complexity and diversity of insect genomes. To identify and improve gene models as potential targets for pest control, we manually curated several gene families with a focus on genes that have key functional roles in D. citri biology and CLas interactions. This community effort produced 530 manually curated gene models across developmental, physiological, RNAi regulatory, and immunity-related pathways. As previously shown in the pea aphid, RNAi machinery genes putatively involved in the microRNA pathway have been specifically duplicated. A comprehensive transcriptome enabled us to identify a number of gene families that are either missing or misassembled in the draft genome. In order to develop biocuration as a training experience, we included undergraduate and graduate students from multiple institutions, as well as experienced annotators from the insect genomics research community. The resulting gene set (OGS v1.0) combines both automatically predicted and manually curated gene models. All data are available on https://citrusgreening.org/.

genomics↗

bioRxiv2017

Multivariate cross-frequency coupling via generalized eigendecomposition

This paper presents a new framework for analyzing cross-frequency coupling in multichannel electrophysiological recordings. The generalized eigendecomposition-based cross-frequency coupling framework (gedCFC) is inspired by source separation algorithms combined with dynamics of mesoscopic neurophysiological processes. It is unaffected by factors that confound traditional CFC methods such as non-stationarities, non-sinusoidality, and non-uniform phase angle distributions--attractive properties considering that brain activity is neither stationary nor perfectly sinusoidal. The gedCFC framework opens new opportunities for conceptualizing CFC as network interactions with diverse spatial/topographical distributions. five specific methods within the gedCFC framework are detailed, with validations in simulated data and applications in several empirical datasets. gedCFC accurately recovers physiologically plausible CFC patterns embedded in noise where traditional CFC methods perform poorly. It is also demonstrated that spike-field coherence in multichannel local field potential data can be analyzed using the gedCFC framework, with significant advantages over traditional spike-field coherence analyses. Null-hypothesis testing is also discussed.

neuroscience↗

bioRxiv2017

Local Control of Intracellular Microtubule Dynamics by End Binding Protein 1 (EB1) Photo-Dissociation

Dynamic remodelling of the microtubule cytoskeleton and local interactions with intracellular targets are central to many polarized cell biological processes, an idea first formalized as search-and-capture hypothesis three decades ago1. However, because of the rapid timescale of microtubule polymerization dynamics, it is difficult to directly ask how, when and where dynamic microtubules participate in specific biological processes. Here, we employ a blue light-sensitive interaction with the oat phototropin LOV2 domain2 to generate a photo-inactivated variant of the microtubule end-binding protein EB1, a small adaptor that is central to the interaction of functionally and structurally diverse proteins with growing microtubule ends3,4, that can replace endogenous EB1 function. Acute and reversible blue light-mediated n-EB1 photo-dissociation allows spatially and temporally precise control of intracellular microtubule polymerization dynamics. In addition to demonstrating that neither the GTP cap nor the MT polymerase CKAP5 are sufficient to sustain persistent MT polymerization at physiological growth rates, our data illustrate accurate subcellular control of a freely diffusible, cytoplasmic protein at the second and micrometer scale. This novel design may serve as a template for precise control of many other intracellular protein activities.

cell biology↗

bioRxiv2017

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Over 95% of human multi-exon genes undergo alternative splicing, a process important in normal development and often dysregulated in disease. We sought to analyze the global splicing regulatory network of CELF2 in human T cells, a well-studied splicing regulator critical to T cell development and function. By integrating high-throughput sequencing data for binding and splicing quantification with sequence features and probabilistic splicing code models, we find evidence of splicing antagonism between CELF2 and the RBFOX family of splicing factors. We validate this functional antagonism through knockdown and overexpression experiments in human cells and find CELF2 represses RBFOX2 mRNA and protein levels. Because both families of proteins have been implicated in the development and maintenance of neuronal, muscle, and heart tissues, we analyzed publicly available data in these systems. Our analysis suggests global, antagonistic co-regulation of splicing by the CELF and RBFOX proteins in mouse muscle and heart in several physiologically relevant targets including proteins involved in calcium signaling and members of the MEF2 family of transcription factors. Importantly, a number of these co-regulated events are aberrantly spliced in mouse models and human patients with diseases that affect these tissues including heart failure, diabetes, or myotonic dystrophy. Finally, analysis of exons regulated by ancient CELF family homologs in chicken, and Drosophila suggests this antagonism is conserved through evolution.

genomics↗

bioRxiv2017

Estrogen and Soy Isoflavonoids Decrease Sensitivity of Medulloblastoma and Central Nervous System Primitive Neuroectodermal Tumor Cells to Chemotherapeutic Cytotoxicity

BackgroundOur previous studies demonstrated that growth and migration of medulloblastoma (MB), the most common malignant brain tumor in children, are stimulated by 17{beta}-estradiol. The growth stimulating effects of estrogens are mediated through ER{beta} and insulin-like growth factor 1 signaling to inhibit caspase 3 activity and reduce tumor cell apoptosis. The objective of this study was to determine whether estrogens decreased sensitivity of MB cells to cytotoxic actions of chemotherapeutic drugs.\n\nMethodsUsing in vitro cell viability and clonogenic survival assays, concentration response analysis was used to determine whether the cytoprotective effects of estradiol protected human D283 Med MB cells from the cytotoxic actions of the MB chemotherapeutic drugs cisplatin, vincristine, or lomustine. Additional experiments were done to determine whether the ER antagonist fulvestrant or the selective ER modulator tamoxifen blocked the cytoprotective actions of estradiol. ER-selective agonists and antagonists were used to define receptor specificity, and the impacts of the soy-derived phytoestrogens genistein, daidzein, and s-equol on chemosensitivity were evaluated.\n\nResultsIn D283 Med cells the presence of 10 nM estradiol increased the IC50 for cisplatin-induced inhibition of viability 2-fold from ~5 M to >10 M. In clonogenic survival assays estradiol decreased the chemosensitivity of D283 Med exposed to cisplatin, lomustine and vincristine. The ER{beta} selective agonist DPN and low physiological concentrations of the soy-derived phytoestrogens genistein, daidzein, and s-equol also decreased sensitivity of D283 Med cells to cisplatin. The protective effects of estradiol were blocked by the antiestrogens 4-hydroxytamoxifen, fulvestrant (ICI 182,780) and the ER{beta} selective antagonist PPHTP. Whereas estradiol also decreased chemosensitivity of PFSK1 cells, estradiol increased sensitivity of Daoy cell to cisplatin, suggesting that ER{beta} mediated effects may vary in different subtypes of MB.\n\nConclusionsThese findings demonstrate that E2 and environmental estrogens decrease sensitivity of MB to cytotoxic chemotherapeutics, and that ER{beta} selective and non-selective inhibition of estrogen receptor activity blocks these cytoprotective actions. These findings support the therapeutic potential of antiestrogen adjuvant therapies for MB, and findings that soy phytoestrogens also decrease sensitivity of MB cells to cytotoxic chemotherapeutics suggest that decreased exposure to environmental estrogens may benefit MB patient responses to chemotherapy.

pharmacology and toxicology↗

bioRxiv2017

Evolution of Reduced Co-Activator Dependence Led to Target Expansion of a Starvation Response Pathway

In S. cerevisiae, the phosphate starvation (PHO) responsive transcription factors Pho4 and Pho2 are jointly required for induction of phosphate response genes and survival in phosphate starvation conditions. In the related human commensal and pathogen C. glabrata, Pho4 is required but Pho2 is dispensable for survival in phosphate-limited conditions and is only partially required for inducing the phosphate response genes. This reduced dependence on Pho2 evolved in C. glabrata and closely related species. Pho4 orthologs that are less dependent on Pho2 induce more genes when introduced into the S. cerevisiae background, and Pho4 in C. glabrata both binds to more sites and induces more genes with expanded functional roles compared to Pho4 in S. cerevisiae. Our work reveals an evolutionary mechanism for rapidly expanding the targets of a transcription factor by changing its dependence on a co-activator, potentially refining the physiological response it regulates.

evolutionary biology↗

bioRxiv2017

Targeted gene correction of FKRP by CRISPR/Cas9 restores functional glycosylation of α-dystroglycan in cortical neurons derived from human induced pluripotent stem cells

Mutations in genes required for functional glycosylation of -dystroglycan cause a group of congenital muscular dystrophies associated with brain malformations, referred to as dystroglycanopathies. The lack of isogenic, physiology-relevant human cellular models has limited our understanding of the cortical abnormalities in dystroglycanopathies. Here we generate induced pluripotent stem cells (iPSCs) from a severe dystroglycanopathy patient with homozygous mutations in the ribitol-5-phosphate transferase gene, FKRP. We carry out targeted gene correction in FKRP-iPSCs using CRISPR/Cas9-mediated genome editing. We characterise the directed differentiation of FKRP- and corrected-iPSCs to neural stem cells, cortical progenitors and cortical neurons. Importantly, we show that targeted gene correction of FKRP restores functional glycosylation of -dystroglycan in iPSC-derived cortical neurons. We independently validate this result by showing targeted gene mutation of FKRP disrupts functional glycosylation of -dystroglycan. This work demonstrates the feasibility of using CRISPR/Cas9-engineered human iPSCs for modelling dystroglycanopathies and provides a foundation for therapeutic development.\n\nHighlightsO_LIGeneration of FKRP-iPSCs for modelling cortical abnormalities in dystroglycanopathies\nC_LIO_LIPrecise gene correction by CRISPR/Cas9-mediated genome editing\nC_LIO_LIDirected differentiation of isogenic control and FKRP-iPSC to cortical neurons\nC_LIO_LIFunctional glycosylation of -dystroglycan is restored in cortical neurons derived from CRISPR/Cas9-corrected iPSCs\nC_LIO_LITargeted gene mutation of FKRP disrupts functional glycosylation of -dystroglycan in cortical neurons\nC_LI

molecular biology↗

bioRxiv2017

Experience-induced forgetting by WT1 enables learning of sequential tasks.

Under physiological conditions, strength and persistence of memory must be regulated in order to produce behavioral flexibility. In fact, impairments in memory flexibility are associated with pathologies such as post-traumatic stress disorder or autism; however the underlying mechanisms that enable memory flexibility are still poorly understood. Here we identified the transcriptional repressor Wilms Tumor 1 (WT1) as a critical synaptic plasticity regulator that decreases memory strength, promoting memory flexibility. WT1 was activated in the hippocampus following induction of long-term potentiation (LTP) or learning. WT1 knockdown enhanced CA1 neuronal excitability, LTP and long-term memory whereas its over-expression weakened memory retention. Moreover, forebrain WT1-deficient mice showed deficits in both reversal, sequential learning tasks and contextual fear extinction, exhibiting impaired memory flexibility. We conclude that WT1 limits memory strength or promotes memory weakening, thus enabling memory flexibility, a process that is critical for learning from new experience.

neuroscience↗

bioRxiv2017

Structural and functional dissection of the interplay between lipid and Notch binding by human Notch ligands

AbstractRecent data have expanded our understanding of Notch signaling by identifying a C2 domain at the N-terminus of Notch ligands which has both lipid- and receptor-binding properties. We present novel structures of human ligands Jagged2 and DLL4 and human Notch-2, together with functional assays, which suggest that ligand-mediated coupling of membrane recognition and Notch binding is likely to be critical in establishing the optimal context for Notch signaling. Comparisons between the Jagged and Delta family show a huge diversity in the structures of the loops at the apex of the C2 domain implicated in membrane recognition and Jagged1 missense mutations which affect these loops and are associated with extrahepatic biliary atresia lead to a loss of membrane recognition, but do not alter Notch binding. Taken together, these data suggest that C2 domain binding to membranes is an important element in tuning ligand-dependent Notch signaling in different physiological contexts.

biochemistry↗

bioRxiv2017

DNA-dependent RNA cleavage by the Natronobacterium gregoryi Argonaute

We show here that, unlike most other prokaryotic Argonaute (Ago) proteins, which are DNA-guided endonucleases, the Natronobacterium gregoryi-derived Ago (NgAgo) can function as a DNA-guided endoribonuclease, cleaving RNA, rather than DNA, in a targeted manner. The NgAgo protein, in complex with 5-hydroxylated or 5-phosphrylated oligodeoxyribonucleotides (ODNs) of variable lengths, split RNA targets into two or more fragments in vitro, suggesting its physiological role in bacteria and demonstrating a potential for degrading RNA molecules such as mRNA or lncRNA in eukaryotic cells in a targeted manner.

biochemistry↗

bioRxiv2017

Glycolytic reliance promotes anabolism in photoreceptors

Sensory neurons capture information from the environment and convert it into signals that can greatly impact the survival of an organism. These systems are thus under heavy selective pressure, including for the most efficient use of energy to support their sensitivity and efficiency1. In this regard, the vertebrate photoreceptor cells face a dual challenge. They not only need to preserve their membrane excitability via ion pumps by ATP hydrolysis2 but also maintain a highly membrane rich organelle, the outer segment, which is the primary site of phototransduction, creating a considerable biosynthetic demand. How photoreceptors manage carbon allocation to balance their catabolic and anabolic demands is poorly understood. One metabolic feature of the retina is its ability to convert the majority of its glucose into lactate3,4 even in the presence of oxygen. This phenomenon, aerobic glycolysis, is found in cancer and proliferating cells, and is thought to promote biomass buildup to sustain proliferation5,6. The purpose of aerobic glycolysis in the retina, its relevance to photoreceptor physiology, and its regulation, are not understood. Here, we show that rod photoreceptors rely on glycolysis for their outer segment (OS) biogenesis. Genetic perturbations targeting allostery or key regulatory nodes in the glycolytic pathway impacted the OS size. Fibroblast growth factor (FGF) signaling was found to regulate glycolysis, with antagonism of this pathway resulting in anabolic deficits. These data demonstrate the cell autonomous role of the glycolytic pathway in OS maintenance and provide evidence that aerobic glycolysis is part of a metabolic program that supports the biosynthetic needs of a normal neuronal cell type.

cell biology↗

bioRxiv2017

Basal forebrain gating by somatostatin neurons drives cortical activity

The basal forebrain provides modulatory input to the cortex regulating brain states and cognitive processing. Somatostatin-expressing cells constitute a local GABAergic source known to functionally inhibit the major cortically-projecting cell types. However, it remains unclear if somatostatin cells can regulate the basal forebrains synaptic output and thus control cortical dynamics. Here, we demonstrate in mice that somatostatin neurons regulate the corticopetal synaptic output of the basal forebrain impinging on cortical activity and behavior. Optogenetic inactivation of somatostatin neurons in vivo increased spiking of some basal forebrain cells, rapidly enhancing and desynchronizing neural activity in the prefrontal cortex, inhibiting slow rhythms and increasing gamma oscillations. Locomotor activity was specifically increased in quiescent animals, but not in active mice. Altogether, we provide physiological and behavioral evidence indicating that somatostatin cells are pivotal in gating the synaptic output of the basal forebrain, thus indirectly controlling cortical operations via both cholinergic and non-cholinergic mechanisms.

neuroscience↗

bioRxiv2017

Diverse yet highly selective interorgan crosstalk mechanisms shape the bodywide transcriptome landscape

The cardiovascular system facilitates body-wide distribution of oxygen, a vital process for development and survival of virtually all vertebrates. However, zebrafish, a vertebrate model organism, appears to form organs and survive mid-larval periods without the functional cardiovascular system. Despite such dispensability, it is the first organ to develop. Such enigma prompted us to hypothesize yet other cardiovascular functions that are important for developmental and/or physiological processes. Hence, systematic cellular ablations and functional perturbations are performed on zebrafish cardiovascular system to gain comprehensive and body-wide understanding of such functions and to elucidate underlying mechanisms. This approach identifies a set of organ-specific genes, each implicated for important functions. The study also unveils distinct cardiovascular mechanisms, each differentially regulating their expressions in organ-specific and oxygen-independent manners. Such mechanisms are mediated by organ-vessel interactions, circulation-dependent signals, and circulation-independent beating-heart-derived signals. Hence, a comprehensive and body-wide functional landscape of the cardiovascular system reported herein may provide a clue as to why it is the first organ to develop. Furthermore, the dataset herein could serve as a resource for the study of organ development and function.\n\nSUMMARY STATEMENTThe body-wide landscape of the cardiovascular functions during development is reported. Such landscape may provide a clue as to why the cardiovascular system is the first organ to develop.

systems biology↗

bioRxiv2017

Translating ceRNA susceptibilities into correlation functions

Competition to bind microRNAs induces an effective positive crosstalk between their targets, therefore known as competing endogenous RNAs or ceRNAs. While such an effect is known to play a significant role in specific situations, estimating its strength from data and, experimentally, in physiological conditions appears to be far from simple. Here we show that the susceptibility of ceRNAs to different types of perturbations affecting their competitors (and hence their tendency to crosstalk) can be encoded in quantities as intuitive and as simple to measure as correlation functions. We confirm this scenario by extensive numerical simulations and validate it by re-analyzing PTENs crosstalk pattern from TCGA breast cancer database. These results clarify the links between different quantities used to estimate the intensity of ceRNA crosstalk and provide new keys to analyze transcriptional datasets and effectively probe ceRNA networks in silico.

systems biology↗

bioRxiv2017

Contemporary evolution of a Lepidopteran species, Heliothis virescens, in response to modern agricultural practices

Adaptation to human-induced environmental change has the potential to profoundly influence the genomic architecture of affected species. This is particularly true in agricultural ecosystems, where anthropogenic selection pressure is strong. Heliothis virescens feeds on cotton in its larval stages and US populations have been declining since the widespread planting of transgenic cotton, which endogenously express proteins derived Bacillus thuringiensis (Bt). No physiological adaptation to Bt toxin has been found in the field, so adaptation to this altered environment could involve: 1) shifts in host plant selection mechanisms to avoid cotton, 2) changes in detoxification mechanisms required for cotton-feeding versus feeding on other host plants, or 3) loss of resistance to previously used management practices including insecticides. Here we begin to address the question of whether such changes occurred in H. virescens populations between the years 1997 and 2012. As part of our study, we produced an H. virescens genome assembly and used this in concert with a ddRAD-seq enabled genome scan to identify loci with significant allele frequency changes over the 15 year period after Bt crops became widespread in the agricultural landscape. Confirmation that a known genetic change at a previously described H. virescens target of selection was detectable in our genome scan increased our confidence in this methodology. We quantified the strength of selection required to elicit the observed allele frequency changes at loci under selection. Potential contributions of genes near the loci under selection to adaptive phenotypes in the H. virescens cotton system are discussed.

evolutionary biology↗