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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.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

Genetic networks of the oxytocin system in the human brain: A gene expression and large-scale fMRI meta-analysis study

Oxytocin is a neuropeptide involved in animal and human reproductive and social behaviour, with potential implications for a range of psychiatric disorders. However, the therapeutic potential of oxytocin in mental health care suggested by animal research has not been successfully translated into clinical practice, partly due to a poor understanding of the expression and distribution of the oxytocin signaling pathway in the human brain, and its complex interactions with other biological systems. Among the genes involved in the oxytocin signaling pathway, three genes have been frequently implicated in human social behavior: OXT (structural gene for oxytocin), OXTR (oxytocin receptor), and CD38 (central oxytocin secretion). We characterized the distribution of the OXT, OXTR, and CD38 mRNA across the brain, identified putative gene pathway interactions by comparing gene expression patterns across 29131 genes, and assessed associations between gene expression patterns and cognitive states via large-scale fMRI meta-analysis. In line with the animal literature, oxytocin pathway gene expression was enriched in central, temporal, and olfactory regions. Across the brain, there was high co-expression of the oxytocin pathway genes with both dopaminergic (DRD2) and muscarinic acetylcholine (CHRM4) genes, reflecting an anatomical basis for critical gene pathway interactions. Finally, fMRI meta-analysis revealed that oxytocin pathway maps correspond with motivation and emotion processing, demonstrating the value of probing gene expression maps to identify brain functional targets for future pharmacological trials.

neuroscience↗

bioRxiv2017

Sparse genetic tracing reveals regionally specific functional organization of mammalian nociceptors

The human distal limbs have a high spatial acuity for noxious stimuli but a low density of pain-sensing neurites. To elucidate mechanisms underlying the pain fovea, we sparsely traced non-peptidergic nociceptors across the body using a newly generated MrgprDCreERT2 mouse line. We found that mouse plantar paw skin also has a low density of MrgprD+ neurites, and individual arbors in different locations are comparable in size. Surprisingly, the central arbors of plantar paw and trunk innervating nociceptors have distinct morphologies in the spinal cord. This regional difference is well correlated with a heightened signal transmission for plantar paw circuits, as revealed by both spinal cord slice recordings and behavior assays. Taken together, our results elucidate a novel somatotopic functional organization of the mammalian pain system and suggest that regional central arbor structure could facilitate the magnification of plantar paw regions to contribute to the pain fovea.

neuroscience↗

bioRxiv2017

Developmental switching in Physarum polycephalum: Petri net analysis of single cell trajectories of gene expression indicates responsiveness and genetic plasticity of the Waddington quasipotential landscape

The developmental switch to sporulation in Physarum polycephalum is a phytochrome-mediated far-red light-induced cell fate decision that synchronously encompasses the entire multinucleate plasmodial cell and is associated with extensive reprogramming of the transcriptome. By repeatedly taking samples of single cells after delivery of a light stimulus pulse, we analysed differential gene expression in two mutant strains and in a heterokaryon of the two strains all of which display a different propensity for making the cell fate decision. Multidimensional scaling of the gene expression data revealed individually different single cell trajectories eventually leading to sporulation. Characterization of the trajectories as walks through states of gene expression discretized by hierarchical clustering allowed the reconstruction of Petri nets that model and predict the observed behavior. Structural analyses of the Petri nets indicated stimulus- and genotype-dependence of both, single cell trajectories and of the quasipotential landscape through which these trajectories are taken. The Petri net-based approach to the analysis and decomposition of complex cellular responses and of complex mutant phenotypes may provide a scaffold for the data-driven reconstruction of causal molecular mechanisms that shape the topology of the quasipotential landscape.

systems biology↗

bioRxiv2017

The Molecular Genetic Basis of Herbivory between Butterflies and their Host-Plants

Interactions between herbivorous insects and their host-plants are a central component of terrestrial food webs and a critical topic in agriculture, where a substantial fraction of potential crop yield is lost annually to pests. Important insights into plant-insect interactions have come from research on specific plant defenses and insect detoxification mechanisms. Yet, much remains unknown about the molecular mechanisms that mediate plant-insect interactions. Here we use multiple genome-wide approaches to map the molecular basis of herbivory from both plant and insect perspectives, focusing on butterflies and their larval host-plants. Parallel genome-wide association studies in the Cabbage White butterfly, Pieris rapae, and its host-plant, Arabidopsis thaliana, pinpointed a small number of butterfly and plant genes that influenced herbivory. These genes, along with much of the genome, were regulated in a dynamic way over the time course of the feeding interaction. Comparative analyses, including diverse butterfly/plant systems, showed a variety of genome-wide responses to herbivory, yet a core set of highly conserved genes in butterflies as well as their host-plants. These results greatly expand our understanding of the genomic causes and evolutionary consequences of ecological interactions across two of Natures most diverse taxa, butterflies and flowering plants.

genomics↗

bioRxiv2017

Worldwide genetic variation of the IGHV and TRBV immune receptor gene families in humans

The immunoglobulin heavy variable (IGHV) and T cell beta variable (TRBV) loci are among the most complex and variable regions in the human genome. Generated through a process of gene duplication/deletion and diversification, these loci can vary extensively between individuals in copy number and contain genes that are highly similar, making their analysis technically challenging. Here, we present a comprehensive study of the functional gene segments in the IGHV and TRBV loci, quantifying their copy number and single nucleotide variation in a globally diverse sample of 109 (IGHV) and 286 (TRBV) humans from over a hundred populations. We find that the IGHV and TRBV gene families exhibit starkly different patterns of variation. In particular, with hundreds of copy number haplotypes (instances that have differences in the number of functional gene segments), the IGHV locus has undergone more frequent gene duplication/deletion compared to the TRBV locus, which has only a few copy number haplotypes. In contrast, the TRBV locus has a greater or at least equal propensity to mutate, as evidenced by greater single nucleotide variation, compared to the IGHV locus. Thus, despite common molecular and functional characteristics, the genes that comprise the IGHV and TRBV loci have evolved in strikingly different ways. As well as providing insight into the different evolutionary paths the IGHV and TRBV loci have taken, our results are also important to the adaptive immune repertoire sequencing community, where the lack of frequencies of common alleles and copy number variants is hampering existing analytical pipelines.

genomics↗

bioRxiv2017

Integration of multiple data sources for gene network inference using genetic perturbation data

BackgroundThe inference of gene regulatory networks is of great interest and has various applications. The recent advances in high-throughout biological data collection have facilitated the construction and understanding of gene regulatory networks in many model organisms. However, the inference of gene networks from large-scale human genomic data can be challenging. Generally, it is difficult to identify the correct regulators for each gene in the large search space, given that the high dimensional gene expression data only provides a small number of observations for each gene.\n\nResultsWe present a Bayesian approach integrating external data sources with knockdown data from human cell lines to infer gene regulatory networks. In particular, we assemble multiple data sources including gene expression data, genome-wide binding data, gene ontology, known pathways and use a supervised learning framework to compute prior probabilities of regulatory relationships. We show that our integrated method improves the accuracy of inferred gene networks. We apply our method to two different human cell lines, which illustrates the general scope of our method.\n\nConclusionsWe present a flexible and systematic framework for external data integration that improves the accuracy of human gene network inference while retaining efficiency. Integrating various data sources of biological information also provides a systematic way to build on knowledge from existing literature.

systems biology↗

bioRxiv2017

IW-Scoring: an Integrative Weighted Scoring framework for annotating and prioritizing genetic variations in the noncoding genome

IW-Scoring represents a new Integrative Weighted Scoring model to annotate and prioritise functionally relevant noncoding variations. The pipeline integrates 11 popular algorithms and outperforms individual methods in three independent data sets, including variants in ClinVar database and GWAS studies, and cancer mutations. Using IW-Scoring, we located 11 recurrently mutated noncoding regions enriched for at least three functional mutations in 14 follicular lymphoma genomes, and validated 9 clusters (82%) in the International Cancer Genome Consortium cohort (n=36), including promoter and enhancer regions of PAX5. IW-Scoring offers greater versatility to identify trait and disease associated noncoding variants.

bioinformatics↗

bioRxiv2017

Functional consequences of genetic loci associated with intelligence in a meta-analysis of 87,740 individuals

Variance in IQ is associated with a wide range of health outcomes, and 1% of the population are affected by intellectual disability. Despite a century of research, the fundamental neural underpinnings of intelligence remain unclear. We integrate results from genome-wide association studies (GWAS) of intelligence with brain tissue and single cell gene expression data to identify tissues and cell types associated with intelligence. GWAS data for IQ (N = 78,308) were meta-analyzed with an extreme-trait cohort of 1,247 individuals with mean IQ [~]170 and 8,185 controls. Genes associated with intelligence implicate pyramidal neurons of the somatosensory cortex and CA1 region of the hippocampus, and midbrain embryonic GABAergic neurons. Tissue-specific analyses find the most significant enrichment for frontal cortex brain expressed genes. These results suggest specific neuronal cell types and genes may be involved in intelligence and provide new hypotheses for neuroscience experiments using model systems.

genomics↗

bioRxiv2017

Differences in the genetic control of early egg development and reproduction between C. elegans and its parthenogenetic relative D. coronatus

BackgroundThe free-living nematode Diploscapter coronatus is the closest known relative of C. elegans with parthenogenetic reproduction. It shows several developmental idiosyncracies, for example concerning the control of meiosis and embryonic axis formation [1]. Our recent genome analysis [2] provided some support for the view that D. coronatus is a product of interspecies hybridization. Here we present additional data towards this assumption. Based on genomic and transcriptomic data we try to better understand the molecular basis of developmental idiosyncrasies in this species in an evolutionary context by comparison with selected other nematodes.\n\nResultsIn a genomic comparison between D. coronatus, C. elegans, other representatives of the genus Caenorhabditis and the more distantly related Pristionchus pacificus and Panagrellus redivivus, certain genes required for normal embryogenesis in C. elegans were found to be restricted to the genus Caenorhabditis. The mRNA content of early D. coronatus embryos was sequenced and compared with similar stages in C. elegans and Ascaris suum. We identified 350 gene families transcribed in the early embryo of D. coronatus but not in the other two nematodes. Looking at individual genes transcribed early in D. coronatus but not in C. elegans and A. suum we found that orthologs of most of these are present in the genomes of the latter species as well, suggesting heterochronic shifts with respect to expression behavior. Considerable divergence between alleles lends further support to the view that D. coronatus may be the result of an interspecies hybridization. Expression analysis of early acting single copy genes yield no indication for silencing of one parental genome.\n\nConclusionsOur comparative cellular and molecular studies support the view that the genus Caenorhabditis differs considerably from the other studied nematodes in its control of development and reproduction. The easy-to-culture parthenogenetic D. coronatus, with its high quality draft genome and only a single chromosome when haploid, offers many new starting points on the cellular, molecular, and genomic level to better understand alternative routes of nematode development and reproduction.

evolutionary biology↗

bioRxiv2017

A genetic screen suggests an alternative mechanism for inhibition of SecA by azide

Sodium azide prevents bacterial growth by inhibiting the activity of SecA, which is required for translocation of proteins across the cytoplasmic membrane. Azide inhibits ATP turnover in vitro, but its mechanism of action in vivo is unclear. To investigate how azide inhibits SecA in cells, we used transposon directed insertion-site sequencing (TraDIS) to screen a library of transposon insertion mutants for mutations that affect the susceptibility of E. coli to azide. Insertions disrupting components of the Sec machinery generally increased susceptibility to azide, but insertions truncating the C-terminal tail (CTT) of SecA decreased susceptibility of E. coli to azide. Treatment of cells with azide caused increased aggregation of the CTT, suggesting that azide disrupts its structure. Analysis of the metal-ion content of the CTT indicated that SecA binds to iron and the azide disrupts the interaction of the CTT with iron. Azide also disrupted binding of SecA to membrane phospholipids, as did alanine substitutions in the metal-coordinating amino acids. Furthermore, treating purified phospholipid-bound SecA with azide in the absence of added nucleotide disrupted binding of SecA to phospholipids. Our results suggest that azide does not inhibit SecA by inhibiting the rate of ATP turnover in vivo. Rather, azide inhibits SecA by causing it to \"backtrack\" from the ADP-bound to the ATP-bound conformation, which disrupts the interaction of SecA with the cytoplasmic membrane.\n\nSignificance statementSecA is a bacterial ATPase that is required for the translocation of a subset of secreted proteins across the cytoplasmic membrane. Sodium azide is a well-known inhibitor of SecA, but its mechanism of action in vivo is poorly understood. To investigate this mechanism, we examined the effect of azide on the growth of a library of [~]1 million transposon insertion mutations. Our results suggest that azide causes SecA to backtrack in its ATPase cycle, which disrupts binding of SecA to the membrane and to its metal cofactor, which is iron. Our results provide insight into the molecular mechanism by which SecA drives protein translocation and how this essential biological process can be disrupted.

microbiology↗

bioRxiv2017

Evolutionary genetics of cytoplasmic incompatibility genes cifA and cifB in prophage WO of Wolbachia

The bacterial endosymbiont Wolbachia manipulates arthropod reproduction to facilitate its maternal spread through populations. The most common manipulation is cytoplasmic incompatibility (CI): Wolbachia-infected males produce modified sperm that cause embryonic mortality, unless rescued by eggs harboring the same Wolbachia. The genes underlying CI, cifA and cifB, were recently identified in the eukaryotic association module of Wolbachias prophage WO. Here, we use transcriptomic and genomic approaches to address three important evolutionary facets of these genes. First, we assess whether or not cifA and cifB comprise a classic toxin-antitoxin operon, and show they do not form an operon in strain wMel. They coevolve but exhibit strikingly distinct expression across host development. Second, we provide new domain and functional predictions across homologs within Wolbachia, and we show amino acid sequences vary substantially across the genus. Lastly, we investigate conservation of cifA and cifB and find degradation and loss of the genes is common in strains that no longer induce CI. Taken together, we find no evidence for the operon hypothesis in wMel, provide functional annotations that broaden the potential mechanisms of CI induction, illuminate recurrent erosion of cifA and cifB in non-CI strains, and advance an understanding of the most widespread form of reproductive parasitism.

evolutionary biology↗

bioRxiv2017

Comment on "A genetic signature of the evolution of loss of flight in the Galapagos cormorant"

Burga et al. could not identify gene regulatory regions which might contribute to flightlessness in the Galapagos cormorant. Using a bird-specific alignment we discover 48 limb enhancers showing strong accelerated evolution in P. harrisi, including enhancers of key cilia development, hedgehog signaling, and planar cell polarity genes, such as Prickle1, Twist2 and Ndk1, extending Burga's proposed mechanism into the non-coding genome.

genomics↗

bioRxiv2017

An integrated analysis of the epigenetic, genetic, and transcriptional patterns associated with outcome across cancer types

Successful treatment decisions in cancer depend on the accurate assessment of patient risk. To improve our understanding of the molecular alterations that underlie deadly malignancies, we analyzed genomic profiles from 33,036 solid tumors with known patient outcomes. Contrary to expectations, we find that mutations in cancer driver genes are almost never associated with patient survival time. In contrast, copy number changes in these same genes are broadly prognostic. Analysis of methylation, microRNA, mRNA, and protein expression patterns in primary tumors define several additional prognostic patterns, including signatures of tumor mitotic activity and tissue de-differentiation. Co-expression analysis with a cell cycle meta-gene distinguished proliferation-dependent and -independent prognostic features, allowing us to construct multivariate survival models with improved stratification power. In total, our analysis provides a comprehensive resource for biomarker and therapeutic target identification, and suggests that copy number and methylation profiling should complement tumor sequencing efforts to improve patient risk assessment.

cancer biology↗

bioRxiv2017

LDJump: Estimating Variable Recombination Rates from Population Genetic Data

As recombination plays an important role in evolution, its estimation, as well as, the identification of hotspot positions is of considerable interest. We propose a novel approach for estimating historical recombination along a chromosome that involves a sequential multiscale change point estimator. Our method also permits to take demography into account. It uses a composite likelihood estimate and other summary statistics within a regression model fitted on suitable scenarios. Our proposed method is accurate, computationally fast, and provides a parsimonious solution by ensuring a type I error control against too many changes in the recombination rate. An application to human genome data suggests a good congruence between our estimated and experimentally identified hotspots. Our method is implemented in the R-package LDJump, which is freely available from https://github.com/PhHermann/LDJump.

bioinformatics↗

bioRxiv2017

Genetic drivers of repeat expansion disorders localize to 3-D chromatin domain boundaries

More than 25 inherited neurological disorders are caused by the unstable expansion of repetitive DNA sequences termed short tandem repeats (STRs). A fundamental unresolved question is why specific STRs are susceptible to unstable expansion leading to severe pathology, whereas tens of thousands of normal-length repeat tracts across the human genome are relatively stable. Here, we unexpectedly discover that nearly all STRs associated with repeat expansion diseases are located at boundaries demarcating 3-D chromatin domains. We find that boundaries exhibit markedly higher CpG island density compared to loci internal to domains. Importantly, disease-associated STRs are specifically localized to ultra-dense CpG island-rich boundaries, suggesting that these loci might be hotspots for epigenetic instability and topological disruption upon unstable expansion. In Fragile X Syndrome, mutation-length expansion at the Fmr1 gene results in severe disruption of the boundary between TADs. Our data uncover higher-order chromatin architecture as a new dimension in understanding the mechanistic basis of repeat expansion disorders.

genomics↗

bioRxiv2017

Genetic differences in the aryl hydrocarbon receptor and CYP1A2 affect susceptibility to developmental polychlorinated biphenyl exposure in mice: Relevance to studies of human neurological disorders

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that remain a human health concern with the discovery of new sources of contamination and ongoing bioaccumulation and biomagnification. Children exposed during early brain development are at highest risk of neurological deficits, but there is some evidence that high PCB exposure in adults increases the risk of Parkinsons disease. Our previous studies found allelic differences in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) affect susceptibility to developmental PCB exposure, resulting in cognitive deficits and motor dysfunction. High-affinity AhrbCyp1a2(-/-) mice were most susceptible compared with poor-affinity AhrdCyp1a2(-/-) and wild type AhrbCyp1a2(+/+) mice. Our follow-up studies assessed biochemical, histological and gene expression changes to identify the brain regions and pathways affected. We also measured PCB and metabolite levels in multiple tissues to determine if genotype altered toxicokinetics. We found evidence of AHR-mediated immune suppression with reduced thymus and spleen weights and significantly reduced thyroxine at P14. In the brain, the greatest changes were seen in the cerebellum where a foliation defect was over-represented in Cyp1a2(-/-) mice. In contrast, we found no difference in tyrosine hydroxylase immuno-staining in the striatum. Gene expression patterns varied across the three genotypes, but there was clear evidence of AHR activation. Distribution of parent PCB congeners also varied by genotype with strikingly high levels of PCB 77 in poor-affinity AhrdCyp1a2(-/-) while AhrbCyp1a2(+/+) mice effectively sequestered coplanar PCBs in the liver. Together, our data suggest that the AHR pathway plays a role in developmental PCB neurotoxicity, but we found little evidence that developmental exposure is a risk factor for Parkinsons disease.

pharmacology and toxicology↗

bioRxiv2017

Genetic reagents for making split-GAL4 lines in Drosophila

The ability to reproducibly target expression of transgenes to small, defined subsets of cells is a key experimental tool for understanding many biological processes. The Drosophila nervous system contains thousands of distinct cell types and it has generally not been possible to limit expression to one or a few cell types when using a single segment of genomic DNA as an enhancer to drive expression. Intersectional methods, in which expression of the transgene only occurs where two different enhancers overlap in their expression patterns, can be used to achieve the desired specificity. This report describes a set of over 2,800 transgenic lines for use with the split-GAL4 intersectional method.

neuroscience↗

bioRxiv2017

The response to selection in Glycoside Hydrolase Family 13 structures: A comparative quantitative genetics approach

Glycoside Hydrolase Family 13 (GH13) structures are responsible for the hydrolysis of starch into smaller carbohydrates. They important in industrial applications and evolutionary studies. This family has been thoroughly documented in the the Carbohydrate-Active enZYmes Database (CAZY), and divided into subfamilies based mainly in sequence information. Here we give structural evidence into GH13 classification and evolution using structural information. Here we proposed a novel method that is sensitive enough to identify miss-classifications, or to provide evidence for further partition that can be of interests to bio-engineers and evolutionary biologists. We also introduced a method to explore the relative importance of residues with respect to the overall deformation that it causes to the overall structure in an evolutionary time scale. We found that the GH13 family can be classified into three main structural groups. There is a hierarchical structure within these clusters that can be use to inform other classification schemes. We also found that by using structural information, subtle structural shifts can be identified and that can be missed in sequence/phylogeny-only based classifications. When each structural group is explored, we found that identifying the most structurally variable sites can lead to identification of functionally (both catalytically and structurally) important residues.

bioinformatics↗