Biology subjects

Yu, H.

Publications and source records attributed to Yu, H..

At least 469 records · Page 26Linked to original sources

bioRxiv2019

A chromosome-level genome of black rockfish, Sebastes schlegelii, provides insights into the evolution of live birth

Black rockfish (Sebastes schlegelii) is a teleost species where eggs are fertilized internally and retained in the maternal reproductive system, where they undergo development until live birth (termed viviparity). In the present study, we report a chromosome-level black rockfish genome assembly. High-throughput transcriptome analysis (RNA-seq and ATAC-seq), coupled with in situ hybridization (ISH) and immunofluorescence, identify several candidate genes for maternal preparation, sperm storage and release, and hatching. We propose that zona pellucida (ZP) genes retain sperm at the oocyte envelope, while genes in two distinct astacin metalloproteinase subfamilies serve to release sperm from the ZP and free the embryo from chorion at pre-hatching stage. Finally, we present a model of black rockfish reproduction, and propose that the rockfish ovarian wall has a similar function to uterus of mammals. Taken together, these genomic data reveal unprecedented insights into the evolution of an unusual teleost life history strategy, and provide a sound foundation for studying viviparity in non-mammalian vertebrates and an invaluable resource for rockfish ecology and evolution research.

genomics↗

bioRxiv2019

Comparative Population Genomics of Bread Wheat (Triticum aestivum) Reveals Its Cultivation and Breeding History in China

The evolution of bread wheat (Triticum aestivum) is distinctive in that domestication, natural hybridization, and allopolyploid speciation have all had significant effects on the diversification of its genome. Wheat was spread around the world by humans and has been cultivated in China for ~4,600 years. Here, we report a comprehensive assessment of the evolution of wheat based on the genome-wide resequencing of 120 representative landraces and elite wheat accessions from China and other representative regions. We found substantially higher genetic diversity in the A and B subgenomes than in the D subgenome. Notably, the A and B subgenomes of the modern Chinese elite cultivars were mainly derived from European landraces, while Chinese landraces had a greater contribution to their D subgenomes. The duplicated copies of homoeologous genes from the A, B, and D subgenomes were commonly found to be under different levels of selection. Our genome-wide assessment of the genetic changes associated with wheat breeding in China provides new strategies and practical targets for future breeding.

plant biology↗

bioRxiv2018

Hyocholic acid species and the risk of type 2 diabetes

Hyocholic acid (HCA) and its derivatives are found in only trace amounts in human blood, but constitute approximately 76 % of the bile acid (BA) pool in the pig, a species known for its exceptional resistance to type 2 diabetes mellitus (T2DM). Here we show that HCA species play a crucial role in maintaining glucose homeostasis and preventing T2DM. We found that in two cohort studies (n=1,213), both obesity and diabetes were associated with lower serum concentrations of HCA species. Serum HCA levels in apparently healthy individuals (n=132) were found to be strong predictors for metabolic health 10 years later. Oral administration of HCA increased serum fasting GLP-1, to a greater extent than metformin, in healthy and diabetic mouse models. HCA upregulated GLP-1 secretion in intestinal enteroendocrine cells via simultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoid X receptor, a unique mechanism that is not found in other BA species.

systems biology↗

bioRxiv2018

Comparative Transcriptomes Analysis of Taenia pisiformis at Different Development Stages

To understand the characteristics of the transcriptional group of Taenia pisiformis at different developmental stages, and to lay the foundation for the screening of vaccine antigens and drug target genes, the transcriptomes of adult and larva of T. pisiformis were assembled and analyzed using bioinformatic tools. A total of 36,951 unigenes with a mean length of 950bp were formed, among which 12,665, 8,188, 7,577, and 6,293 unigenes have been annotated respectively by sequence similarity analysis with four databases (NR, Swiss-Prot, KOG, and KEGG). It should be noted there are 5,662 unigenes that share good similarity with the four databases and get a relatively perfect functional annotation. Besides, a total of 10,247 differentially expressed genes were screened. To be specific, 6,910 unigenes were up-regulated in the larva stage while 3,337 were down-regulated in the adult stage. To sum up, this study sequenced and analyzed the transcriptomes of the larval and adult stages of T. pisiformis. The results of differentially expressed genes in these two stages could provide basis for functional genomics, immunology and gene expression profiles of T. pisiformis.

molecular biology↗

bioRxiv2018

Engineering a decoy substrate in soybean to enable recognition of the Soybean Mosaic Virus NIa protease

In Arabidopsis, recognition of the AvrPphB effector protease from Pseudomonas syringae is mediated by the disease resistance (R) protein RPS5, which is activated by AvrPphB-induced cleavage of the Arabidopsis protein kinase PBS1. The recognition specificity of RPS5 can be altered by substituting the AvrPphB cleavage site within PBS1 with cleavage sequences for other proteases, including proteases from viruses. AvrPphB also activates defense responses in soybean (Glycine max), suggesting that soybean may contain an R protein analogous to RPS5. It was unknown, however, whether this response is mediated by cleavage of a soybean PBS1-like protein. Here we show that soybean contains three PBS1 orthologs and that their products are cleaved by AvrPphB. Further, transient expression of soybean PBS1 derivatives containing a five-alanine insertion at their AvrPphB cleavage sites activated cell death in soybean protoplasts, demonstrating that soybean likely contains an AvrPphB-specific resistance protein that is activated by a conformational change in soybean PBS1 proteins. Significantly, we show that a soybean PBS1 decoy protein modified to contain a cleavage site for the Soybean mosaic virus (SMV) NIa protease triggers cell death in soybean protoplasts when cleaved by this protease, indicating that the PBS1 decoy approach will work in soybean using endogenous PBS1 genes. Lastly, we show that activation of the AvrPphB-dependent cell death response effectively inhibits systemic spread of SMV in soybean. These data also indicate that decoy engineering may be feasible in other crop plant species that recognize AvrPphB protease activity.

plant biology↗

bioRxiv2018

GRAM: A generalized model to predict the molecular effect of a non-coding variant in a cell-type specific manner

There has been much effort to prioritize genomic variants with respect to their impact on \"function\". However, function is often not precisely defined: Sometimes, it is the disease association of a variant; other times, it reflects a molecular effect on transcription or epigenetics. Here we coupled multiple genomic predictors to build GRAM, a generalized model, to predict a well-defined experimental target: the expression-modulating effect of a non-coding variant in a cell-specific manner. As a first step, we performed feature engineering: using a LASSO regularized linear model, we found transcription factor (TF) binding most predictive, especially for TFs that are hubs in the regulatory network; in contrast, evolutionary conservation, a popular feature in many other functional-impact predictors, has almost no contribution. Moreover, TF binding inferred from in vitro SELEX is as effective as that from in vivo ChIP-Seq. Second, we implemented GRAM integrating SELEX features and expression profiles. The program combines a universal regulatory score for a variant in a non-coding element with a modifier score reflecting the particular cell type. We benchmarked GRAM on a large-scale MPRA dataset in the GM12878 cell line, achieving a ROC score of [~]0.73; performance on the K562 cell line was similar. Finally, we evaluated the performance of GRAM on targeted regions using luciferase assays in MCF7 and K562 cell lines. We noted that changing the insertion position of the construct relative to the reporter gene gives very different results, highlighting the importance of carefully defining the functional target the model is predicting.\n\nAuthor SummaryNoncoding variants lie outside of protein-coding regions, and are found to have disease associations. However, knowledge on the molecular effect of these non-coding variants in a cell-specific context is very limited. Also, different output between multiple experiment platforms may introduce extra complexity in analyzing the molecular function of these variants. We developed GRAM, a generalized model to predict molecular effect of non-coding variants in multiple cell types for different experimental platforms. We first selected the most informative cell-independent SELEX transcription factor binding score on the variant locus as features and then combine cell-specific gene expression profile to build a multi-step prediction model. GRAM has been successfully tested on both MPRA and Luciferase assay, and on three different cell lines: GM12878, K562 and MCF7, shows high performance.

bioinformatics↗

bioRxiv2018

Bile canaliculi contract autonomously by releasing calcium into hepatocytes via mechanosensitive calcium channel

Bile canaliculi (BC) are the smallest vessels of the biliary tree. They are formed from the apical surfaces of adjoining hepatocytes, resulting in lumenal conduits for bile flow. Bile is propelled along the BC by hepatocyte contractions that arise from cyclic waves of apico-basal Ca2+, but the source and regulation of Ca2+ has been unclear. We report that BC contraction correlates with cyclic transfer of Ca2+ from BC lumen to apico-basal Ca2+ waves in adjacent hepatocytes, and does not correlate with endoplasmic reticulum Ca2+. BC contractility was triggered by ionophore A23187 and unaffected by Thapsigargin. The cycles of Ca2+ transfer could be blocked by the mechanosensitive calcium channel inhibitor GsMTx-4, resulting in cholestatic generation of BC-derived vesicles. The mechanosensitive calcium channel Piezo-1 is preferentially localized at BC membranes, and its hyper-activation by Yoda1 causes increased Ca2+ transfer and increased BC contractility. We propose that canaliculi achieve biomechanical homeostasis through the following feedback system: the pressure of accumulated bile is sensed by mechanosensitive channel, which transmit biliary calcium into adjacent hepatocytes for contraction of the BC lumen and propulsion of the bile.

cell biology↗

bioRxiv2018

Comparative genetic architectures of schizophrenia in East Asian and European populations

Author summarySchizophrenia is a severe psychiatric disorder with a lifetime risk of about 1% world-wide. Most large schizophrenia genetic studies have studied people of primarily European ancestry, potentially missing important biological insights. Here we present a study of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide significant schizophrenia associations in 19 genetic loci. Over the genome, the common genetic variants that confer risk for schizophrenia have highly similar effects in those of East Asian and European ancestry (rg=0.98), indicating for the first time that the genetic basis of schizophrenia and its biology are broadly shared across these world populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries revealed 208 genome-wide significant schizophrenia associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping more precisely isolated schizophrenia causal alleles in 70% of these loci. Despite consistent genetic effects across populations, polygenic risk models trained in one population have reduced performance in the other, highlighting the importance of including all major ancestral groups with sufficient sample size to ensure the findings have maximum relevance for all populations.

genetics↗

bioRxiv2018

Genomic Bayesian confirmatory factor analysis and Bayesian network to characterize a wide spectrum of rice phenotypes

Drawing biological inferences from large data generated to dissect the genetic basis of complex traits remains a challenge. Since multiple phenotypes likely share mutual relationships, elucidating the interdependencies among economically important traits can accelerate the genetic improvement of plants and animals. A Bayesian network depicts a probabilistic directed acyclic graph representing conditional dependencies among variables. This study aims to characterize various phenotypes in rice (Oryza sativa) via confirmatory factor analysis and Bayesian network. Confirmatory factor analysis under the Bayesian treatment hypothesized that 48 observed phenotypes resulted from six latent variables including grain morphology, morphology, flowering time, physiology (e.g., ion content), yield, and morphological salt response. This was followed by studying the genetics of each latent variable. Bayesian network structures involving the genomic component of six latent variables were established by fitting four different algorithms. Negative genomic correlations were obtained between salt response and yield, salt response and grain morphology, salt response and physiology, and morphology and yield, whereas a positive correlation was obtained between yield and grain morphology. There were four common directed edges across the different Bayesian networks. Physiological components influenced the flowering time and grain morphology, and morphology and 4 grain morphology influenced yield. This work suggests that the Bayesian network coupled with factor analysis can provide an effective approach to understand the interdependence patterns among phenotypes and to predict the potential influence of external interventions or selection related to target traits in the high-dimensional interrelated complex traits systems.

genetics↗

bioRxiv2018

PUMILIO hyperactivity drives premature aging of Norad-deficient mice

Although numerous long noncoding RNAs (lncRNAs) have been identified, our understanding of their roles in mammalian physiology remains limited. Here we investigated the physiologic function of the conserved lncRNA Norad in vivo. Deletion of Norad in mice results in genomic instability and mitochondrial dysfunction, leading to a dramatic multi-system degenerative phenotype resembling premature aging. Loss of tissue homeostasis in Norad-deficient animals is attributable to augmented activity of PUMILIO proteins, which act as post-transcriptional repressors of target mRNAs to which they bind. Norad is the preferred RNA target of PUMILIO2 (PUM2) in mouse tissues and, upon loss of Norad, PUM2 hyperactively represses key genes required for mitosis and mitochondrial function. Remarkably, enforced Pum2 expression fully phenocopies Norad deletion, resulting in rapid-onset aging-associated phenotypes. These findings provide new insights and open new lines of investigation into the roles of noncoding RNAs and RNA binding proteins in normal physiology and aging.

molecular biology↗

bioRxiv2018

Mitotic Regulators and the SHP2-MAPK Pathway Promote Insulin Receptor Endocytosis and Feedback Regulation of Insulin Signaling

Insulin controls glucose homeostasis and cell growth through bifurcated signaling pathways. Dysregulation of insulin signaling is linked to diabetes and cancer. The spindle checkpoint controls the fidelity of chromosome segregation during mitosis. Here, we show that insulin receptor substrate 1 and 2 (IRS1/2) cooperate with spindle checkpoint proteins to promote insulin receptor (IR) endocytosis through recruiting the clathrin adaptor complex AP2 to IR. A phosphorylation switch of IRS1/2 orchestrated by extracellularly regulated kinase 1 and 2 (ERK1/2) and Src homology phosphatase 2 (SHP2) ensures selective internalization of activated IR. SHP2 inhibition blocks this feedback regulation and growth-promoting IR signaling, prolongs insulin action on metabolism, and improves insulin sensitivity in mice. We propose that mitotic regulators and SHP2 promote feedback inhibition of IR, thereby limiting the duration of insulin signaling. Targeting this feedback inhibition can improve insulin sensitivity.

cell biology↗

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

Population based hospitalization burden of laboratory-confirmed hand, foot and mouth disease caused by multiple enterovirus serotypes in southern China

BackgroundHand, foot and mouth disease (HFMD) is spread widely across Asia, and the hospitalization burden is as yet not well understood. Here, we estimated serotype-specific and age-specific hospitalization rates of HFMD in Southern China.\n\nMethodsWe enrolled pediatric patients admitted to 3/3 county-level hospitals and 3/23 township level hospitals in Anhua county, Hunan (CN) with HFMD, and collected samples to identify enterovirus serotypes by RT-PCRs between October 2013 and September 2016. The information of other eligible but un-enrolled patients were retrospectively collected from the same six hospitals. Monthly number of hospitalizations for all causes was collected from each of 23 township level hospitals to extrapolate hospitalizations associated with HFMD among these.\n\nResultsDuring the three years, an estimated 3,236 pediatric patients were hospitalized with lab-confirmed HFMD, and among these only one patient was severe. The mean hospitalization rates were 660 (95% CI: 638-684) per 100,000 person-years for lab-confirmed HFMD, with higher rates among CV-A16 and CV-A6 associated HFMD (213 vs 209 per 100,000 person-years), and lower among EV-A71, CV-A10 and other enteroviruses associated HFMD (134, 39 and 66 per 100,000 person-years, p<0.001). Children aged 12-23 months had the highest hospitalization rates (3,594/100,000 person-years), followed by those aged 24-35 months (1,828/100,000 person-years) and 6-11 months (1,572/100,000 person-years). Compared with other serotypes, CV-A6-associated hospitalizations were evident at younger ages.\n\nConclusionsOur study indicates a substantial hospitalization burden associated with non-severe HFMD in a rural county in southern China. Future mitigation policies should take into account the disease burden identified, and optimize interventions for HFMD.

epidemiology↗

bioRxiv2018

LRRK2 kinase inhibitors induce a reversible effect in the lungs of non-human primates with no measurable pulmonary deficits

Putative gain-of-function mutations in leucine-rich repeat kinase 2 (LRRK2), resulting in increased kinase activity and cellular toxicity, are a leading genetic cause of Parkinsons disease (PD). Hence, there is strong interest in developing LRRK2 kinase inhibitors as a disease-modifying therapy. Published reports that repeat dosing with two LRRK2 kinase inhibitors (GNE-7915 and GNE-0877) induce histopathological changes in the lung of non-human primates Fuji et al. 2015 (1) raised concerns about potential safety liability of LRRK2 kinase inhibitors. In the present study, we sought to determine whether previously observed effects in the lung: (a) represent on-target pharmacology, but with the potential for margin of safety, (b) are reversible upon drug withdrawal, and (c) are associated with pulmonary function deficits. To this end, we evaluated the histopathological effects, toxicokinetics and target inhibition of three structurally diverse LRRK2 kinase inhibitors, GNE-7915 (30 mg/kg, BID, as a positive control), MLi-2 (15 and 50 mg/kg, QD) and PFE-360 (3 and 6 mg/kg, QD) following 2 weeks of dosing in non-human primates. Subsets of animals dosed with GNE-7915 or MLi-2 were evaluated after 2-week dose-free periods. All three LRRK2 kinase inhibitors induced mild cytoplasmic vacuolation of type II pneumocytes, as reported previously, confirming an on-target effect of these compounds. Interestingly, despite lower doses of both PFE-360 and MLi-2 producing nearly complete inhibition of LRRK2 kinase activity in the brain as assessed by levels of pS935-LRRK2, histopathological changes in lung were absent in animals treated with low-dose PFE-360 and observed only sporadically in the low-dose MLi-2 group. The lung effect was fully reversible at 2 weeks post-dosing of GNE-7915. In a second study of identical dosing with MLi-2 and GNE-7915, no deficits were observed in a battery of translational pulmonary functional tests. In aggregate, these results do not preclude the development of LRRK2 kinase inhibitors for clinical investigation in Parkinsons disease.

pharmacology and toxicology↗

bioRxiv2018

Using LASSO in gene co-expression network for genome-wide identification of gene interactions responding to salt stress in rice

In many applications, such as gene co-expression network analyses, data arises with a huge number of covariates while the size of sample is comparatively small. To improve the accuracy of prediction, variable selection is often used to get a sparse solution by forcing coefficients of variables contributing less to the observed response variable to zero. Various algorithms were developed for variable selection, but LASSO is well known for its statistical accuracy, computational feasibility and broad applicability to adaptation. In this project, we applied LASSO to the gene co-expression network of rice with salt stress to discover key gene interactions for salt-tolerance related phenotypes. The dataset we have is a high-dimensional one, having 50K genes from 100 samples, with the issue of multicollinearity for fitting linear regression - the expression level of genes in the same pathway tends to be highly correlated. The property of LASSO with sparse parameters is naturally suitable to identify gene interactions of interest in this dataset. After biologically functional modules in the co-expression network was identified, the major changed expression patterns were further selected by LASSO regression to establish a linear relationship between gene expression profiles and physiological responses, such as sodium/potassium condenses, with salt stress. Five modules of intensively co-expressed genes, from 45 to 291 genes, were identified by our method with significant P-values, which indicate these modules are significantly associated with physiological responses to stress. Genes in these modules have functions related to ion transport, osmotic adjustment, and oxidative tolerance. For example, LOC_Os7g47350 and LOC_Os07g37320 are co-expressed gene in the same module 15. Both are ion transporter genes and have higher gene expression levels for rice with low sodium levels with salt stress.

bioinformatics↗

bioRxiv2018

The functional genomic circuitry of human glioblastoma stem cells

SummarySuccessful glioblastoma (GBM) therapies have remained elusive due to limitations in understanding mechanisms of growth and survival of the tumorigenic population. Using CRISPR-Cas9 approaches in patient-derived GBM stem cells to interrogate function of the coding genome, we identify diverse actionable pathways responsible for growth that reveal the gene-essential circuitry of GBM stemness. In particular, we describe the Sox developmental transcription factor family; H3K79 methylation by DOT1L; and ufmylation stress responsiveness programs as essential for GBM stemness. Additionally, we find mechanisms of temozolomide resistance and sensitivity that could lead to combination strategies with this standard of care treatment. By reaching beyond static genome analysis of bulk tumors, with a genome wide functional approach, we dive deep into a broad range of biological processes to provide new understanding of GBM growth and treatment resistance.\n\nSignificanceGlioblastoma (GBM) remains an incurable disease despite an increasingly thorough depth of knowledge of the genomic and epigenomic alterations of bulk tumors. Evidence from multiple approaches support that GBM reflects an aberrant developmental hierarchy, with GBM stem cells (GSCs), fueling tumor growth and invasion. The properties of this tumor subpopulation may also in part explain treatment resistance and disease recurrence. Unfortunately, we still have a limited knowledge of the molecular circuitry of these cells and progress has been slow as we have not been able, until recently, to interrogate function at the genome-wide scale. Here, using parallel genome-wide CRISPR-Cas9 screens, we identify the essential genes for GSC growth. Further, by screening in the presence of low and high dose temozolomide, we identify mechanisms of drug resistance and sensitivity. These functional screens in patient derived cells reveal new aspects of GBM biology and identify a diversity of actionable targets such as genes governing stem cell traits, epigenome regulation and the response to stress stimuli.

cancer biology↗

bioRxiv2018

Base pair editing of goat embryos: nonsense codon introgression into FGF5 to improve cashmere yield

The ability to alter single bases without DNA double strand breaks provides a potential solution for multiplex editing of livestock genomes for quantitative traits. Here, we report using a single base editing system, Base Editor 3 (BE3), to induce nonsense codons (C-to-T transitions) at four target sites in caprine FGF5. All five progenies produced from microinjected single-cell embryos had alleles with a targeted nonsense mutation and yielded expected phenotypes. The effectiveness of BE3 to make single base changes varied considerably based on sgRNA design. Also, the rate of mosaicism differed between animals, target sites, and tissue type. PCR amplicon and whole genome resequencing analyses for off-target changes caused by BE3 were low at a genome-wide scale. This study provides first evidence of base editing in livestock, thus presenting a potentially better method to introgress complex human disease alleles into large animal models and provide genetic improvement of complex health and production traits in a single generation.

genetics↗

bioRxiv2018

Deciphering the rules which mRNA structures differs from vivo and vitro in Saccharomyces cerevisiae by deep neural networks

The structure of mRNA in vivo is influenced by various factors involved in the translation process, resulting in significant differentiation of mRNA structure from that in vitro. Because multiple factors cause the differentiation of in vivo and in vitro mRNA structures, it was difficult to perform a more accurate analysis of mRNA structures in previous studies. In this study, we have proposed a novel application of a deep neural network (DNN) model to predict the structural stability of mRNA in vivo by fitting six quantifiable features that may affect mRNA folding: ribosome density, minimum folding free energy, GC content, mRNA abundance, ribosomal initial density and position of mRNA structure. Simulated mutations of the mRNA structure were designed and then fed into the trained DNN model to compute their structural stability. We found unique effects of these six features on mRNA structural stability in vivo. Strikingly, the ribosome density of the structural region is the most important factor affecting the structural stability of mRNA in vivo, and the strength of the mRNA structure in vitro should have a relatively small effect on its structural stability in vivo. The recruitment of DNNs provides a new paradigm to decipher the differentiation of mRNA structure in vivo and in vitro. This improved knowledge on the mechanisms of factors influencing mRNA structural stability will facilitate the design and functional analysis of mRNA structure in vivo.

bioinformatics↗