Biology subjects

Yang, J.

Publications and source records attributed to Yang, J..

At least 19 recordsLinked to original sources

bioRxiv2018

Bayesian phylodynamics of avian influenza virus H9N2 in Asia with time-dependent predictors of migration

Model-based phylodynamic approaches recently employed generalized linear models (GLMs) to uncover potential predictors of viral spread. Very recently some of these models have allowed both the predictors and their coefficients to be time-dependent. However, these studies mainly focused on predictors that are assumed to be constant through time. Here we inferred the phylodynamics of H9N2 viruses isolated in 12 Asian countries and regions under both discrete trait analysis (DTA) and structured coalescent (MASCOT) approaches. Using MASCOT we applied a new time-dependent GLM to uncover the underlying factors behind H9N2 spread. We curated a rich set of time-series predictors including annual international live poultry trade and national poultry production figures. This time-dependent phylodynamic prediction model was compared to commonly employed time-independent alternatives. Additionally the time-dependent MASCOT model allowed for the estimation of viral effective sub-population sizes and their changes through time and these effective population dynamics within each country were predicted by a GLM. International annual poultry trade is a strongly supported predictor of virus migration rates. There was also strong support for geographic proximity as a predictor of migration rate in all GLMs investigated. In time-dependent MASCOT models, national poultry production was also identified as a predictor of virus genetic diversity through time and this signal was obvious in mainland China and Bangladesh. Our application of a recently introduced time-dependent GLM predictors integrated rich time-series data in Bayesian phylodynamic prediction. We demonstrated the contribution of poultry trade and geographic proximity (potentially unheralded wild bird movements) to avian influenza spread in Asia. To gain a better understanding of the drivers of H9N2 spread, we suggest increased surveillance of the H9N2 virus in countries that are currently under-sampled as well as in wild bird populations in the most affected countries.\n\nAuthor summaryWhat drives the geographic dispersal and genetic diversity of H9N2 avian influenza virus in Asia? We used two model-based approaches, DTA and MASCOT, to reconstruct the phylogeographic dynamics of the virus. Further, multiple potential predictors were used to inform the virus spread and population dynamics by GLMs. Here, we maximised the power of time-series predictors in Bayesian phylodynamic prediction. For the first time, we were able to quantify the contribution of both time-series and constant predictors to both migration rates and effective population sizes in a structured population. We identified a positive association of international poultry trade and national poultry production time-series with virus migration rates and effective population sizes respectively. We also identify geographic proximity as a strongly supported driver to virus migration rates and this points to the potential role of wild bird populations in virus dispersal across countries. Our study is a practical exemplar of the use of temporal information in predictors to model heterogeneous spatial diffusion and population dynamic processes and provides direction to H9N2 control efforts in Asia.

epidemiology↗

bioRxiv2018

OSCA: a tool for omic-data-based complex trait analysis

The rapid increase of omic data in the past decades has greatly facilitated the investigation of associations between omic profiles such as DNA methylation (DNAm) and complex traits in large cohorts. Here, we proposed a mixed-linear-model-based method (called MOMENT) that tests for association between a DNAm probe and trait with all other distal probes fitted in multiple random-effect components to account for the effects of unobserved confounders as well as the correlations between distal probes induced by the confounders. We demonstrated by simulations that MOMENT showed a lower false positive rate and more robustness than existing methods. MOMENT has been implemented in a versatile software package (called OSCA) together with a number of other implementations for omic-data-based analysis including the estimation of variance in a trait captured by all measures of multiple omic profiles, omic-data-based quantitative trait locus (xQTL) analysis, and meta-analysis of xQTL data.

bioinformatics↗

bioRxiv2018

Murine MPDZ-Linked Hydrocephalus is Caused by Hyperpermeability of the Choroid Plexus

Though congenital hydrocephalus is heritable, it has been linked only to eight genes, one of which is MPDZ. Humans and mice that carry a truncated version of MPDZ incur severe hydrocephalus resulting in acute morbidity and lethality. We show by magnetic resonance imaging that contrast-medium penetrates into the brain ventricles of mice carrying a Mpdz loss-of-function mutation, whereas none is detected in the ventricles of normal mice, implying that the permeability of the choroid plexus epithelial cell monolayer is abnormally high. Comparative proteomic analysis of the cerebrospinal fluid of normal and hydrocephalic mice revealed up to a 53-fold increase in protein concentration, suggesting that transcytosis through the choroid plexus epithelial cells of Mpdz KO mice is substantially higher than in normal mice. These conclusions are supported by ultrastructural evidence, and by immunohistochemistry and cytology data. Our results provide a straight-forward and concise explanation for the pathophysiology of Mpdz-linked hydrocephalus.

neuroscience↗

bioRxiv2018

The effect of X-linked dosage compensation on complex trait variation

Quantitative genetics theory predicts that X-chromosome dosage compensation between sexes will have a detectable effect on the amount of genetic and therefore phenotypic trait variances at associated loci in males and females. Here, we systematically examine the role of dosage compensation in complex trait variation in humans in 20 complex traits in a sample of more than 450,000 individuals from the UK Biobank and in 1,600 gene expression traits from a sample of 2,000 individuals as well as across-tissue gene expression from the GTEx resource. We find, on average, twice as much genetic variation for complex traits due to X-linked loci in males compared to females, consistent with a negligible effect of predicted escape from X-inactivation on complex trait variation across traits and also detect biologically relevant X-linked heterogeneity between the sexes for a number of complex traits.

genetics↗

bioRxiv2018

Inhibition of nucleotide synthesis mediates replicative senescence of human mammary epithelial cells

Cellular senescence is a mechanism by which cells permanently withdraw from the cell cycle in response to stresses including telomere shortening, DNA damage, or oncogenic signaling. Senescent cells contribute to both age-related degeneration and hyperplastic pathologies, including cancer. In culture, normal human epithelial cells enter senescence after a limited number of cell divisions, known as replicative senescence. Here, to investigate how metabolic pathways regulate replicative senescence, we used LC-MS-based metabolomics to analyze senescent primary human mammary epithelial cells (HMECs). We did not observe significant changes in glucose uptake or lactate secretion in senescent HMECs. However, analysis of intracellular metabolite pool sizes indicated that senescent cells exhibit depletion of metabolites from nucleotide synthesis pathways. Furthermore, stable isotope tracing with 13C-labeled glucose or glutamine revealed a dramatic blockage of flux of these two metabolites into nucleotide synthesis pathways in senescent HMECs. To test whether cellular immortalization would reverse these observations, we expressed telomerase in HMECs. In addition to preventing senescence, telomerase expression maintained metabolic flux from glucose into nucleotide synthesis pathways. Finally, we investigated whether inhibition of nucleotide synthesis in proliferating HMECs is sufficient to induce senescence. In proliferating HMECs, both pharmacological and genetic inhibition of ribonucleotide reductase regulatory subunit M2 (RRM2), a rate-limiting enzyme in dNTP synthesis, induced premature senescence with concomitantly decreased metabolic flux from glucose into nucleotide synthesis. Taken together, our results suggest that nucleotide synthesis inhibition plays a causative role in the establishment of replicative senescence in HMECs.

systems biology↗

bioRxiv2018

Systematic Prediction of Regulatory Motifs from Human ChIP-Sequencing Data Based on a Deep Learning Framework

Identification of transcription factor binding sites (TFBSs) and cis-regulatory motifs (motifs for short) from genomics datasets, provides a powerful view of the rules governing the interactions between TFs and DNA. Existing motif prediction methods however, are limited by high false positive rates in TFBSs identification, contributions from non-sequence-specific binding, and complex and indirect binding mechanisms. High throughput next-generation sequencing data provides unprecedented opportunities to overcome these difficulties, as it provides multiple whole-genome scale measurements of TF binding information. Uncovering this information brings new computational and modeling challenges in high-dimensional data mining and heterogeneous data integration. To improve TFBS identification and novel motifs prediction accuracy in the human genome, we developed an advanced computational technique based on deep learning (DL) and high-performance computing, named DESSO. DESSO utilizes deep neural network and binomial distribution to optimize the motif prediction. Our results showed that DESSO outperformed existing tools in predicting distinct motifs from the 690 in vivo ENCODE ChIP-Sequencing (ChIP-Seq) datasets for 161 human TFs in 91 cell lines. We also found that protein-protein interactions (PPIs) are prevalent among human TFs, and a total of 61 potential tethering binding were identified among the 100 TFs in the K562 cell line. To further expand DESSOs deep-learning capabilities, we included DNA shape features and found that (i) shape information has a strong predictive power for TF-DNA binding specificity; and (ii) it aided in identification of the shape motifs recognized by human TFs which in turn contributed to the interpretation of TF-DNA binding in the absence of sequence recognition. DESSO and the analyses it enabled will continue to improve our understanding of how gene expression is controlled by TFs and the complexities of DNA binding. The source code and the predicted motifs and TFBSs from the 690 ENCODE TF ChIP-Seq datasets are freely available at the DESSO web server: http://bmbl.sdstate.edu/DESSO.

bioinformatics↗

bioRxiv2018

Carbohydrate activity regulation of floral quantity during the juvenile phase in black pepper (Piper nigrum L.)

Black pepper plants maintain synchronous vegetative growth and flowering during their lifetimes, even in the juvenile phase. How to limit the duration of flowering, facilitate a return to vegetative development should be studied. Light intensity has been reported to affect the levels of stored carbohydrates in some horticultural trees. However, it is unclear whether increased flowering intensity in adaptable light intensity is due to the regulation of carbohydrates in black pepper. Here, we report the characterization of carbohydrates and enzyme turnover in major source leaves under shading treatments during the juvenile phase of pepper. In addition to the previous finding that carbohydrate levels are correlated with flowering time, we report the novel finding that carbohydrate contents in the leaves control floral quantity. To gain insights into the underlying physiological mechanisms, we analyzed the effect of shading on sugar contents and floral transition, which revealed that shading regulated carbohydrate levels, an increase in starch accumulation improved floral quantity, and sucrose-starch ratio played a negative role in inflorescence quantity. Based on this analysis, we characterized the changes in enzyme activities in the leaves that affect carbohydrate dynamics and identified the key indicator enzymes and optimal shading intensity for the five developmental periods.\n\nHighlightWe identified the key carbohydrates, indicator enzymes and optimal shading intensity to control inflorescence quantity during the juvenile phase in black pepper for labor-saving.

biophysics↗

bioRxiv2018

A draft reference genome sequence for Scutellaria baicalensis Georgi

Scutellaria baicalensis Georgi is an important medicinal plant used worldwide. Information about the genome of this species is important for scientists studying the metabolic pathways that synthesise the bioactive compounds in this plant. Here, we report a draft reference genome sequence for S. baicalensis obtained by a combination of Illumina and PacBio sequencing, which was assembled using 10 X Genomics and Hi-C technologies. We assembled 386.63 Mb of the 408.14 Mb genome, amounting to about 94.73% of the total genome size, and the sequences were anchored onto 9 pseudochromosomes with a super-N50 of 33.2 Mb. The reference genome sequence of S. baicalensis offers an important foundation for understanding the biosynthetic pathways for bioactive compounds in this medicinal plant and for its improvement through molecular breeding.

plant biology↗

bioRxiv2018

Efficient Multivariate Analysis Algorithms for Longitudinal Genome-wide Association Studies

MotivationCurrent dynamic phenotyping system introduces time as an extra dimension to genome-wide association studies (GWAS), which helps to explore the mechanism of dynamical genetic control for complex longitudinal traits. However, existing methods for longitudinal GWAS either ignore the covariance among observations of different time points or encounter computational efficiency issues.\n\nResultsWe herein developed efficient genome-wide multivariate association algorithms (GMA) for longitudinal data. In contrast to existing univariate linear mixed model analyses, the proposed new method has improved statistic power for association detection and computational speed. In addition, the new method can analyze unbalanced longitudinal data with thousands of individuals and more than ten thousand records within a few hours. The corresponding time for balanced longitudinal data is just a few minutes.\n\nAvailability and ImplementationWe wrote a software package to implement the efficient algorithm named GMA (https://github.com/chaoning/GMA), which is available freely for interested users in relevant fields.

bioinformatics↗

bioRxiv2018

Parkinson’s disease genetics: identifying novel risk loci, providing causal insights and improving estimates of heritable risk

We performed the largest genome-wide association study of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases, and 1.4M controls. We identified 90 independent genome-wide significant signals across 78 loci, including 38 independent risk signals in 37 novel loci. These variants explained 26-36% of the heritable risk of PD. Tests of causality within a Mendelian randomization framework identified putatively causal genes for 70 risk signals. Tissue expression enrichment analysis suggested that signatures of PD loci were heavily brain-enriched, consistent with specific neuronal cell types being implicated from single cell expression data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. In sum, these data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified.

genetics↗

bioRxiv2018

Natural selection on TMPRSS6 associated with the blunted erythropoiesis and improved blood viscosity in Tibetan Pigs

Tibetan pigs, indigenous to Tibetan plateau, are well adapted to hypoxia. So far, there have been not any definitively described genes and functional sites responsible for hypoxia adaptation for the Tibetan pig. Here we conducted resequencing of the nearly entire genomic region (40.1 kb) of the candidate gene TMPRSS6 (Transmembrane protease, serine 6) associated with hemoglobin concentration (HGB) and red blood cell count (RBC) in 40 domestic pigs and 40 wild boars from five altitudes along the Tea-horse ancient road and identified 708 SNPs, in addition to an indel (CGTG/----) in the intron 10. Both the CGTG deletion frequency and the pairwise r2 linkage disequilibrium showed an increase with elevated altitudes in 838 domestic pigs from five altitudes, suggesting that TMPRSS6 has been under Darwinian positive selection. As the conserved core sequence of hypoxia-response elements (HREs), the deletion of CGTG in Tibetan pigs decreased the expression levels of TMPRSS6 mRNA and protein in the liver revealed by real-time quantitative PCR and western blot, respectively. To explore whether reduced TMPRSS6 expression level could improve blood viscosity, the relationship between CGTG indel and hematologic and hemorheologic parameters in 482 domestic pigs from continuous altitudes was detected and dissected a genetic effect on reducing HGB by 13.25g/L in Gongbogyamda Tibetan pigs and decreasing MCV by 4.79 fl in Diqing Tibetan pigs. In conclusion, the CGTG deletion of TMPRSS6 resulted in lower HGB and smaller MCV, thereby blunting erythropoiesis and improving blood viscosity as well as erythrocyte deformability.

physiology↗

bioRxiv2018

Flexibility and rigidity index for chromosome packing, flexibility and dynamics analysis

MotivationThe packing of genomic DNA from double string into highly-order hierarchial assemblies has great impact on chromosome flexibility, dynamics and functions. The open and accessible regions of chromosome are the primary binding positions for regulatory elements and are crucial to nuclear processes and biological functions.\n\nResultsMotivated by the success of flexibility-rigidity index (FRI) in biomolecular flexibility analysis and drug design, we propose a FRI based model for quantitatively characterizing the chromosome flexibility. Based on the Hi-C data, a flexibility index for each locus can be evaluated. Physically, the flexibility is tightly related to the packing density. Highly compacted regions are usually more rigid, while loosely packed regions are more flexible. Indeed, a strong correlation is found between our flexibility index and DNase and ATAC values, which are measurements for chromosome accessibility. Recently, Gaussian network model (GNM) is applied to analyze the chromosome accessibility and a mobility profile has been proposed to characterize the chromosome flexibility. Compared with GNM, our FRI is slightly more accurate (1% to 2% increase) and significantly more efficient in both computational time and costs. For a 5kb resolution Hi-C data, the flexibility evaluation process only takes FRI a few minutes on a single-core processor. In contrast, GNM requires 1.5 hours on 10 CPUs. Moreover, interchromosome information can be easily incorporated into the flexibility evaluation, thus further enhance the accuracy of our FRI. In contrast, the consideration of interchromosome information into GNM will significantly increase the size of its Laplacian matrix, thus computationally extremely challenging for the current GNM.\n\nAvailabilityThe software is available at https://github.com/jiajiepeng/FRI_chrFle.\n\nContactxiakelin@ntu.edu.sg; jiajiepeng@nwpu.edu.cn

bioinformatics↗

bioRxiv2018

Hierarchical Domain Structure Reveals the Divergence of Activity among TADs and Boundaries

The spatial organization of chromatin in the nucleus has been implicated in many aspects of regulated gene expression. Maps of high frequency interactions between different segments of chromatin have revealed Topologically Associating Domains (TADs), within which most of the regulatory interactions are thought to occur. Recent studies have shown that TADs are not homogeneous structural units, but rather they appear to be organized into a hierarchy. However, precise identification of hierarchical TAD structures remains a challenge. We present OnTAD, an Optimized Nested TAD caller from Hi-C data, to identify hierarchical TADs. Compared to existing methods, OnTAD has significantly improved accuracy and running speed. Results from OnTAD reveal new biological insights on the role of different TAD levels, boundary usage in gene regulation, the loop extrusion model, and compartmental domains. The software and documentation for OnTAD are available at: https://github.com/anlin00007/OnTAD

bioinformatics↗

bioRxiv2018

Yeast replicative aging leads to permanent cell cycle arrest in G1 effectuated by the start repressor Whi5

Yeast replicative aging has been a canonical model for aging research. Since replicative aging eventually leads to permanent cell cycle arrest, a fundamental question is how cells sense the signals from aging and communicate that to the cell cycle control machineries. Using microfluidic devices to track individual mother cells labeled by two different cell cycle markers Whi5-tdTomato and Myo1-EGFP, we measured the length of different cell cycle phases as a function of age and the distribution of cell death in different cell cycle phases. We found that the majority of the cells died in the G1 phase, and their G1 cell cycle length increased drastically in the last few cell divisions. This increase of G1 length correlates with the increase of the nuclear concentration of Whi5, which is a major transcriptional suppressor of the cell cycle start check point. Interestingly, this correlation is apparent only above a threshold concentration of Whi5. We show that in response to external stress, Whi5 concentration increases and cell growth slows down in a Whi5 dependent manner, and that Whi5 deletion significantly extends the lifespan. Together these data suggest the existence of a programmed control to arrest cell cycle in G1 in response to stress signals due to aging, and that Whi5 is a major mediator of this process. Our findings may have important implications in understanding senescence and cancer in mammalian cells, which have a parallel G1/S control system with Rb (a well known tumor suppressor) as the analog of Whi5.\n\nSignificance statementIn this work, we used microfluidic devices to track individual mother cells labeled by two cell cycle markers Whi5-tdTomato and Myo1-EGFP. We found that aging leads to significant lengthening of G1 phase in old cells and the eventual permanent cell cycle arrest in G1, and Whi5 plays an important role in implementing such a program. We show that oxidative stress can lead to the increase of Whi5 expression and the slow-down of cell division. Furthermore, Whi5 deletion significantly extends the lifespan. The result suggest the existence of a programmed control to arrest cell cycle in G1 in response to stress signals due to aging, and that Whi5 is a major mediator of this process.

cell biology↗

bioRxiv2018

G-quadruplex DNA drives genomic instability and represents a targetable molecular abnormality in ATRX-deficient malignant glioma

Mutational inactivation of ATRX (-thalassemia mental retardation X-linked) represents a defining molecular alteration in large subsets of malignant glioma. Yet the pathogenic consequences of ATRX deficiency remain unclear, as do tractable mechanisms for its therapeutic targeting. Here we report that ATRX loss in isogenic glioma model systems induces replication stress and DNA damage by way of G-quadruplex (G4) DNA secondary structure. Moreover, these effects are associated with the acquisition of disease-relevant copy number alterations over time. We then demonstrate, both in vitro and in vivo, that ATRX deficiency selectively enhances DNA damage and cell death following chemical G4 stabilization. Finally, we show that G4 stabilization synergizes with other DNA-damaging therapies, including ionizing radiation, in the ATRX-deficient context. Our findings reveal novel pathogenic mechanisms driven by ATRX deficiency in glioma, while also pointing to tangible strategies for drug development.

cancer biology↗

bioRxiv2018

The key lethal effect existed in the antibacterial behavior of short, medium, and long chain fatty acid monoglycerides on Escherichia coli

Monoglyceride is an amphiphilic molecule with promising antimicrobial activity for bacteria; however, the key lethal effect in its antibacterial behavior was still unknown. In the study, monobutyrate (MB), monolaurate (ML), monomyristate (MM) were selected to represent the short, medium, and long chain monoglycerides to compare their inhibitory effect against Escherichia coli, and a new dose-dependent inhibitory mechanism was proposed by the key lethal effect. The minimal inhibitory concentration and antibacterial curve showed a huge diversity existed in biology activity of MB, ML and MM. The results in scanning electron microscopy and flow cytometry assay indicated that the interference level of MB on cell membrane was obviously weaker than that of ML and MM, while the latter two had similar performance in increasing cell permeability at low doses. The results presented in UV-Vis spectroscopy, cell cycle and biomacromolecules synthesis inhibition assay showed that the cell cycle of Escherichia coli was obviously affected by three monoglycerides at doses near MIC, which was therefore regarded as the key lethal effect. The reason for the better biological activity of MM than ML was the stronger interference ability on bacterial cell cycle. In addition, an expanded antibacterial mode was raised that cell permeability increase at low doses was antimicrobial basis, cell cycle arrest at medium doses played the key lethal effect, and cell lysis at high doses was the result of combined action.

microbiology↗

bioRxiv2018

Overexpressed microRNA-141-3p enhance proliferation via targeting PLAG1 in non-diabetic macrosomia

Several studies have shown microRNAs (miRNAs) could regulate the placental development, yet the role and mechanism of miRNAs in the development of non-diabetic macrosomia (NDFMS) remains unclear. The key miRNA that abnormal expressed in NDFMS placentas was screened out by miRNA microarray and verified using qRT-PCR in 91 subjects. The effects of the key miRNA were verified by proliferation assay and invasion assay in HTR-8/SVneo cell, and also in pregnant C57BL/6J mice. miR-141-3p was determined as the key miRNA with the most significant difference, which could promote the proliferation and invasion by regulating the expression of target gene PLAG1. Overexpression of PLAG1 could reverse the effect of cell proliferation and invasion ability caused by miR-141-3p overexpression. Significant difference in fetal birth weight was observed between the control group and treated group with miR-141-3p agomir in late pregnancy, but not in early pregnancy. This study revealed miR-141-3p could increase the proliferation of placenta to participate in the occurrence and development of NDFMS through regulating PLAG1 expression.

developmental biology↗

bioRxiv2018

The identification of critical lethal action in antimicrobial mechanism of glycerol monomyristate against foodborne pathogens

Glycerol monomyristate (GMM) is a promising antimicrobial substance due to its broad antibacterial spectrum: however, the critical lethal action in its antimicrobial mechanism for foodborne pathogens remains unclear. In the present study, the inhibitory activities of GMM on Escherichia coli (E. coli), Staphylococcus aureus (S. aureus) and Candida albicans (C. albicans) were compared, and its membrane and intracellular action mechanism was investigated. The results showed that the susceptibility of E. coli to GMM was the highest, followed by S. aureus, and C. albicans being the poorest. Using flow cytometry, the GMM dose causing above 50% permeability ratio on E. coli was lower than that on S. aureus. The images from scanning electron microscope revealed no doses difference existed between the two strains when the obvious cell damage occurred. Furthermore, cell cycle and multiple fluorescent staining assays showed only the cell division of E. coli and S. aureus, excluding that of C. albicans, was obviously affected at 1/4 MIC and 1/2 MIC, indicating that the DNA interfere and subsequent cell division inhibition was likely to be the critical lethal action with doses near MIC, which can also explain the poor sensitivity of C. albicans.\n\nImportanceFoodborne pathogens, as a common source of biological pollution in the food industry, can cause millions of food poisoning incidents each year, which poses great risks to consumers health and safety. The use of monoglyceride as an edible surfactant to inhibit the growth of food-borne microorganisms has been a long time, but the relevant antibacterial mechanism is too broad to accurately grasp its key lethal effect and its action doses, which not only affects the antibacterial efficiency, but also may result in the abnormalities of food flavor when adding at overdoses. The significance of the study is to identify the key lethal effect and its action doses, which will greatly enhance the understanding of the response mechanism of different types of foodborne pathogens to monoglycerides, and provide a more reasonable reference for differential control and treatment of different gastrointestinal infections when combined with antibiotics in clinical.

microbiology↗