Biology subjects

Yang, J.

Publications and source records attributed to Yang, J..

At least 991 records · Page 55Linked to original sources

bioRxiv2019

Bayesian analysis of GWAS summary data reveals differential signatures of natural selection across human complex traits and functional genomic categories

Understanding how natural selection has shaped the genetic architecture of complex traits and diseases is of importance in medical and evolutionary genetics. Bayesian methods have been developed using individual-level data to estimate multiple features of genetic architecture, including signatures of natural selection. Here, we present an enhanced method (SBayesS) that only requires GWAS summary statistics and incorporates functional genomic annotations. We analysed GWAS data with large sample sizes for 155 complex traits and detected pervasive signatures of negative selection with diverse estimates of SNP-based heritability and polygenicity. Projecting these estimates onto a map of genetic architecture obtained from evolutionary simulations revealed relatively strong natural selection on genetic variants associated with cardiorespiratory and cognitive traits and relatively small number of mutational targets for diseases. Averaging across traits, the joint distribution of SNP effect size and MAF varied across functional genomic regions (likely to be a consequence of natural selection), with enrichment in both the number of associated variants and the magnitude of effect sizes in regions such as transcriptional start sites, coding regions and 5- and 3-UTRs.

genetics↗

bioRxiv2019

A semi-automated technique for adenoma quantification in the ApcMin mouse using FeatureCounter

Colorectal cancer is a major contributor to death and disease worldwide. The ApcMin mouse is a widely used model of intestinal neoplasia, as it carries a mutation also found in human colorectal cancers. However, the method most commonly used to quantify tumour burden in these mice is manual adenoma counting, which is time consuming and poorly suited to standardization across different laboratories. We describe a method to produce suitable photographs of the small intestine, process them with an ImageJ macro, FeatureCounter, which automatically locates image features potentially corresponding to adenomas, and a machine learning pipeline to identify and quantify them. Compared to a manual method, the specificity (or True Negative Rate, TNR) and sensitivity (or True Positive Rate, TPR) of this method in detecting adenomas are similarly high at about 80% and 87%, respectively. Importantly, total adenoma area measures derived from the automatically-called tumours were just as capable of distinguishing high-burden from low-burden mice as those established manually. Overall, our strategy is quicker, helps control experimenter bias and yields a greater wealth of information about each tumour, thus providing a convenient route to getting consistent and reliable results from a study.

cancer biology↗

bioRxiv2019

Transcriptome analysis reveals the difference between \"healthy\" and \"common\" aging and their connection with age-related diseases

A key goal of aging research is to understand mechanisms underlying healthy aging and use them to develop methods to promote the human healthspan. One approach is to identify gene regulations differentiating healthy aging from aging in the general population (i.e., \"common\" aging). In this study, we leveraged GTEx (Genotype-Tissue Expression) project data to investigate \"healthy\" and \"common\" aging in humans and their interconnection with diseases.\n\nWe selected GTEx donors who were not annotated with diseases to approximate a \"healthy\" aging cohort. We then compared the age-associated genes derived from this cohort with age-associated genes from our \"common\" aging cohort which included all GTEx donors; we also compared the \"healthy\" and \"common\" aging gene expressions with various disease-associated gene expression to elucidate the relationships among \"healthy\", \"common\" aging and disease. Our analyses showed that 1. \"healthy\" and \"common\" aging shared a large number of gene regulations; 2. Despite the substantial commonality, \"healthy\" and \"common\" aging genes also showed distinct function enrichment, and \"common\" aging genes had a higher enrichment for disease genes; 3. Disease-associated gene regulations were overall different from aging gene regulations. However, for genes regulated by both, their regulation directions were largely consistent, implying some aging processes could increase the susceptibility to disease development; and 4. Possible protective mechanisms were associated with the \"healthy\" aging gene regulations.\n\nIn summary, our work highlights several unique features of human \"healthy\" aging program. This new knowledge can be used for the development of therapeutics to promote human healthspan.

genetics↗

bioRxiv2019

Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway

AO_SCPLOWBSTRACTC_SCPLOWOne of the most promising new compound classes in clinical development for the treatment of malaria is the imidazolopiperazines (IZPs) class. Human trials have demonstrated that members of the IZP series, which includes KAF156 (Ganaplacide) and GNF179, are potent and effective against Plasmodium symptomatic asexual blood-stage infections. Unlike other commonly used antimalarials, they also prevent transmission and block future infection in animal models. Despite the identification of several Plasmodium falciparum resistance mechanisms including mutations in ER-localized PfCARL (PfEMP65), Acetyl-coA transporter, and PfUGT transporter, IZPs mechanism of action remains unknown.\n\nTo investigate, we combined in vitro evolution and whole-genome analysis in the model organism Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods, in P. falciparum. S. cerevisiae clones that resist IZP activity carry multiple mutations in genes that encode endoplasmic reticulum(ER)-based lipid homeostasis and autophagy including elo2, elo3, sur2, atg15 and lcb4, as well as ER-based sec66. In Plasmodium, IZPs cause inhibition of protein trafficking, block the establishment of new permeation pathways and result in ER expansion. We also observe sensitization with other secretion inhibitors such as brefeldin A and golgicidin as well as synthetic lethality with PfSEC62. Our data show that IZPs target the secretory pathway and highlight a novel mechanism for blocking parasite growth and development that is distinct from those of standard compounds used to treat malaria. In addition, we provide physiological signatures and hallmarks for inhibitors that work through this mechanism of action and show that IZPs are tool compounds for studying ER-dependent protein processing in different species.

microbiology↗

bioRxiv2019

Unit quaternion description of spatial rotation in 3D electron cryo-microscopy

Electron cryo-microscopy (cryoEM) involves the estimation of orientations of projection images or three-dimensional (3D) volumes. However, the lack of statistical tools of rotations in cryoEM fails to answer the growing demands for adopting advanced statistical methods. In this study, we develop a comprehensive statistical tool specialized for cryoEM based on an unit quaternion description of spatial rotations. Some basic properties and definitions of the quaternion, as well as a way to use the unit quaternion to describe and perform rotations, are first recalled. Then, based on the unit quaternion, the distance and geodesic between rotations are designed for cryoEM to enable comparisons and interpolations between rotations, which are prerequisites of statistics of rotations in 3D cryoEM. Further, methods of directional statistics specialized for cryoEM are developed, including calculations of the average rotation, sampling, and inference with uniform and angular central Gaussian (ACG) distribution, as well as an estimation of the rotation precision. Finally, the method of handling molecular symmetry is introduced. Using the unit quaternion system for cryoEM, we provide comprehensive mathematical tools for the analysis of spatial rotations in cryoEM.

biophysics↗

bioRxiv2019

Dysfunction of Torr causes a Harlequin-type ichthyosis-like phenotype in Drosophila melanogaster

Prevention of desiccation is a constant challenge for terrestrial organisms. Land insects have an extracellular coat, the cuticle, that plays a major role in protection against exaggerated water loss. Here, we report that the ABC transporter Torr - a human ABCA12 paralog - contributes to the waterproof barrier function of the cuticle in the fruit fly Drosophila melanogaster. We show that the reduction or elimination of Torr function provokes rapid desiccation. Torr is also involved in defining the inward barrier against xenobiotics penetration. Consistently, the amounts of cuticular hydrocarbons that are involved in cuticle impermeability decrease markedly when Torr activity is reduced. GFP-tagged Torr localises to membrane nano-protrusions within the cuticle, likely pore canals. This suggests that Torr is mediating the transport of cuticular hydrocarbons (CHC) through the pore canals to the cuticle surface. The envelope, which is the outermost cuticle layer constituting the main barrier, is unaffected in torr mutant larvae. This contrasts with the function of Snu, another ABC transporter needed for the construction of the cuticular inward and outward barriers, that nevertheless is implicated in CHC deposition. Hence, Torr and Snu have overlapping and independent roles to establish cuticular resistance against transpiration and xenobiotic penetration. The torr deficient phenotype parallels the phenotype of Harlequin ichthyosis caused by mutations in the human abca12 gene. Thus, it seems that the cellular and molecular mechanisms of lipid barrier assembly in the skin are conserved in vertebrates in invertebrates.\n\nAuthor SummaryAs in humans, lipids on the surface of the skin of insects protect the organism against excessive water loss and penetration of potentially harmful substances. During evolution, a greasy surface was indeed an essential trait for adaptation to life outside a watery environment. Here, we show that the membrane-gate transporter Torr is needed for the deposition of barrier lipids on the skin surface in the fruit fly Drosophila melanogaster through extracellular nano-tubes, called pore canals. In principle, the involvement of Torr parallels the scenario in humans, where the membrane-gate transporter ABCA12 is implicated in the construction of the lipid-based stratum corneum of the skin. In both cases, mutations in the genes coding for the respective transporter cause rapid water-loss and are lethal soon after birth. We conclude that the interaction between the organism and the environment obviously implies an analogous mechanism of barrier formation and function in vertebrates and invertebrates.

cell biology↗

bioRxiv2019

Post-EMT: Cadherin-11 mediates cancer hijacking fibroblasts

Current prevailing knowledge on EMT (epithelial mesenchymal transition) deems epithelial cells acquire the characters of mesenchymal cells to be capable of invading and metastasizing on their own. One of the signature events of EMT is called "cadherin switch", e.g. the epithelial E-cadherin switching to the mesenchymal Cadherin-11. Here, we report the critical events after EMT that cancer cells utilize cadherin-11 to hijack the endogenous cadherin-11 positive fibroblasts. Numerous 3-D cell invasion assays with high-content live cell imaging methods reveal that cadherin-11 positive cancer cells adhere to and migrate back and forth dynamically on the cell bodies of fibroblasts. By adhering to fibroblasts for co-invasion through 3-D matrices, cancer cells acquire higher invasion speed and velocity, as well as significantly elevated invasion persistence, which are exclusive characteristics of fibroblast invasion. Silencing cadherin-11 in cancer cells or in fibroblasts, or in both, significantly decouples such physical co-invasion. Additional bioinformatics studies and PDX (patient derived xenograft) studies link such cadherin-11 mediated cancer hijacking fibroblasts to the clinical cancer progression in human such as triple-negative breast cancer patients. Further animal studies confirm cadherin-11 mediates cancer hijacking fibroblasts in vivo and promotes significant solid tumor progression and distant metastasis. Moreover, overexpression of cadherin-11 strikingly protects 4T1-luc cells from implant rejection against firefly luciferase in immunocompetent mice. Overall, our findings report and characterize the critical post-EMT event of cancer hijacking fibroblasts in cancer progression and suggest cadherin-11 can be a therapeutic target for solid tumors with stroma. Our studies hence provide significant updates on the "EMT" theory that EMT cancer cells can hijack fibroblasts to achieve full mesenchymal behaviors in vivo for efficient homing, growth, metastasis and evasion of immune surveillance. Our studies also reveal that cadherin-11 is the key molecule that helps link cancer cells to stromal fibroblasts in the "Seed & Soil" theory. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/729491v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@11317f1org.highwire.dtl.DTLVardef@88fffaorg.highwire.dtl.DTLVardef@5da692org.highwire.dtl.DTLVardef@62f6ed_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2019

Cas12a-based on-site and rapid nucleic acid detection of African swine fever

The mortality rate of hemorrhagic African swine fever (ASF), which targets domestic pigs and is caused by African swine fever virus (ASFV), can reach 100%. ASF has been reported in 25 Chinese provinces since August 2018. There is no effective treatment or vaccine for it and the present molecular diagnosis technologies have trade-offs in sensitivity, specificity, cost and speed, and none of them cater perfectly to ASF control. Thus, a technology that overcomes the need for laboratory facilities, is relatively low cost, and rapidly and sensitively detects ASFV would be highly valuable. Here, we describe an RAA-Cas12a-based system that combines recombinase-aided amplification (RAA) and CRISPR/Cas12a for ASFV detection. The fluorescence intensity readout of this system detected ASFV p72 gene levels as low as 10 aM. For on-site ASFV detection, lateral-flow strip readout was introduced for the first time in the RAA-Cas12a based system (named CORDS, Cas12a-based On-site and Rapid Detection System). We used CORDS to detect target DNA highly specifically using the lateral-flow strip readout. CORDS could identify the p72 gene at femtomolar sensitivity in an hour at 37{degrees}C, and only requires an incubator. For ease of use, the regents of CORDS was lyophilized to three tubes and remained the same sensitivity when stored at 4 {degrees}C for at least 7 days. Thus, CORDS provides a rapid, sensitive and easily operable method for ASFV on-site detection. Lyophilized CORDS can withstand long-term transportation and storage, and is ready for field applications.

molecular biology↗

bioRxiv2019

Trans-epithelial Fluid Pumping Performance of Renal Epithelial Cells and Mechanics of Cystic Expansion

Using a novel microfluidic platform to recapitulate fluid absorption activity of kidney cells, we report that renal epithelial cells can actively generate hydraulic pressure gradients across the epithelium. The fluidic flux declines with increasing hydraulic pressure until a stall pressure, at which the fluidic flux vanishes--in a manner similar to mechanical fluidic pumps. The developed pressure gradient translates to a force of 50-100 nanoNewtons per cell. For normal human kidney cells, the fluidic flux is from apical to basal, and the pressure is higher on the basal side. For human polycystic kidney disease (PKD) cells, the fluidic flux is reversed from basal to apical with a significantly higher stall pressure. Molecular studies and proteomic analysis reveal that renal epithelial cells are highly sensitive to hydraulic pressure gradients, developing different expression profiles and spatial arrangements of ion exchangers and the cytoskeleton in different pressure conditions. These results, together with data from osmotic and pharmacological perturbations of fluidic pumping, implicate mechanical force and hydraulic pressure as important variables during morphological changes in epithelial tubules, and provide further insights into pathophysiological mechanisms underlying the development of high luminal pressure within renal cysts.

biophysics↗

bioRxiv2019

Molecular signature of pruriceptive MrgprA3+ neurons

Itch, initiated by the activation of sensory neurons, is frequently associated with dermatological or systemic diseases and significantly affects patient quality of life. MrgprA3+ sensory neurons have been identified as one of the major itch-sensing neuronal populations. Mounting evidence has demonstrated that peripheral pathological conditions induce physiological regulations of sensory neurons, which is critical for the maintenance of chronic itch sensation. However, the underlying molecular mechanisms are not clear. Here we performed RNA sequencing of genetically labeled MrgprA3+ neurons under both naive and allergic contact dermatitis condition. Our results revealed the unique molecular signature of itch-sensing neurons and the distinct transcriptional profile changes that result in response to dermatitis. We found enrichment of nine Mrgpr family members and two histamine receptors in MrgprA3+ neurons, suggesting that MrgprA3+ neurons are the main, direct neuronal target for histamine and Mrgprs agonists. In addition, Ptpn6 and Pcdh12 were identified as novel and highly selective markers of MrgprA3+ neurons. We also discovered that MrgprA3+ neurons respond to skin dermatitis in a way that is unique from other sensory neurons by regulating a combination of transcriptional factors, ion channels, and key molecules involved in synaptic transmission. These results significantly increase our knowledge of itch transmission and uncover potentially novel targets for combating itch.

neuroscience↗

bioRxiv2019

SORBS2 is a susceptibility gene to arrhythmogenic right ventricular cardiomyopathy

BACKGROUNDArrhythogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by right ventricular remodeling and ventricular arrhythmia. To date, 16 ARVC causative genes have been identified from human genetic studies, accounting for about 60% of ARVC probands. Genetic basis for the remaining 40% ARVC probands remain elusive.\n\nMETHODSPrompted by a zebrafish mutagenesis screen that suggested the Sorbin and SH3 domain-containing 2 (SORBS2) ortholog as a candidate cardiomyopathy gene, we conducted detailed expressionl analysis of Sorbs2 in mice, as well as phenotypic characterization in the Sorbs2 knock-out (KO) mice. The intercalated disc (ICD) expression pattern and ARVC-like phenotypes further prompted us to conduct targeted sequencing of human patients with ARVC to search for rare variants in the SORBS2 gene.\n\nRESULTSSorbs2 is robustly expressed in the mouse heart, encoding an adhesion junction/desmosome protein that is mainly localized to the ICD. A mutation with near complete depletion of the Sorbs2 protein in mouse results in phenotypes characteristic of human ARVC, such as dilated right ventricle (RV), RV dysfunction, spontaneous ventricular tachycardia (VT), and premature death. Sorbs2 is required to maintain the structural integrity of ICD. Its absence resulted in profound cardiac electrical remodeling with impaired impulse conduction and action potential derangements. Five rare variants were identified from a cohort of 59 ARVC patients, among which two variants affect splicing.\n\nCONCLUSIONSSorbs2 KO mouse is an ARVC model and SORBS2 is a new ARVC susceptibility gene.

genetics↗

bioRxiv2019

Functional significance and therapeutic potential of miR-15a mimic in pancreatic ductal adenocarcinoma

Treatment of pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge. There is an urgent need to develop novel strategies to enhance survival and improve patient prognosis. microRNAs (miRNAs) play critical roles as oncogenes or tumor suppressors in the regulation of cancer development and progression. In this study, we demonstrate that low expression of miR-15a is associated with poor prognosis of PDAC patients. miR-15a expression is reduced in PDAC while closely related miR-16 expression remains relatively unchanged. miR-15a suppresses several important targets such as Wee1, Chk1, Yap-1, and BMI-1 causing cell cycle arrest and inhibiting cell proliferation. Ectopic expression of miR-15a sensitizes PDAC cells to gemcitabine reducing the IC50 over 6.5-fold. To investigate the therapeutic potential of miR-15a, we used a modified miR-15a (5-FU-miR-15a) with uracil (U) residues in the guide strand replaced with 5-fluorouracil (5-FU). We demonstrated enhanced inhibition of PDAC cell proliferation by 5-FU-miR-15a compared to native miR-15a. In vivo we showed the therapeutic power of 5-FU-miR-15a alone or in combination with gemcitabine with near complete elimination of PDAC lung metastatic tumor growth. These results support the future development of 5-FU-miR-15a as a novel therapeutic agent as well as a prognostic biomarker in the clinical management of PDAC.

cancer biology↗

bioRxiv2019

Identification of porcine RUNX1 as an LPS-dependent gene expression regulator in PBMCs by Super deepSAGE sequencing of multiple tissues

Genome-wide identification of gene expression regulators may facilitate our understanding of the transcriptome constructed by gene expression profiling experiment. These regulators may be selected as targets for genetic manipulations in farm animals. In this study, we developed a gene expression profile of 76,000+ unique transcripts for 224 porcine samples from 28 normal tissues collected from 32 animals using Super deepSAGE (serial analysis of gene expression by deep sequencing) technology. Excellent sequencing depth has been achieved for each multiplexed library, and principal component analysis showed that duplicated samples from the same tissues cluster together, demonstrating the high quality of the Super deepSAGE data. Comparison with previous research indicated that our results not only have excellent reproducibility but also have greatly extended the coverage of the sample types as well as the number of genes. Clustering analysis discovered ten groups of genes showing distinct expression patterns among those samples. Binding motif over representative analysis identified 41 regulators responsible for the regulation of these gene clusters. Finally, we demonstrate a potential application of this dataset to infectious and immune research by identifying an LPS-dependent transcription factor, runt-related transcription factor 1 (RUNX1), in peripheral blood mononuclear cells (PBMCs). The selected genes are specifically responsible for the transcription of toll-like receptor 2 (TLR2), lymphocyte-specific protein tyrosine kinase (LCK), vav1 oncogene (VAV1), and other 32 genes. These genes belong to the T and B cell signaling pathways, making them potential novel targets for the diagnostic and therapy of bacterial infections and other immune disorders.

genomics↗

bioRxiv2019

Simulated Plant Images Improve Maize Leaf Counting Accuracy

Automatically scoring plant traits using a combination of imaging and deep learning holds promise to accelerate data collection, scientific inquiry, and breeding progress. However, applications of this approach are currently held back by the availability of large and suitably annotated training datasets. Early training datasets targeted arabidopsis or tobacco. The morphology of these plants quite different from that of grass species like maize. Two sets of maize training data, one real-world and one synthetic were generated and annotated for late vegetative stage maize plants using leaf count as a model trait. Convolutional neural networks (CNNs) trained on entirely synthetic data provided predictive power for scoring leaf number in real-world images. This power was less than CNNs trained with equal numbers of real-world images, however, in some cases CNNs trained with larger numbers of synthetic images outperformed CNNs trained with smaller numbers of real-world images. When real-world training images were scarce, augmenting real-world training data with synthetic data provided improved prediction accuracy. Quantifying leaf number over time can provide insight into plant growth rates and stress responses, and can help to parameterize crop growth models. The approaches and annotated training data described here may help future efforts to develop accurate leaf counting algorithms for maize.

plant biology↗

bioRxiv2019

The methodological quality of animal studies: A cross-sectional study based on the SYRCLEs risk of bias tool

ObjectiveTo assess the methodological quality of animal studies published in China and abroad using the SYRCLEs risk of bias tool, and to provide references to improve the methodological quality of animal studies to encourage high quality preclinical studies.\n\nMethodsAn electronic search was performed in the Chinese Scientific Citation Database (CSCD) and Web of Science from 2014 to October 2018. Document screening and data extraction were performed independently by four researchers. The methodological quality of the included studies was assessed using the SYRCLEs risk of bias tool. Statistical analysis was performed using SPSS23.\n\nResultsA total of 2764 animal studies were included. Of the studies, 984 were published in English and 1780 were in Chinese. The citation frequency of more than 90% of the included studies was less than 5. The results of methodological quality assessment showed that 36.36% (8/22) of the sub-items were rated as \"low risk\" in more than 50% of the included studies, of which 75% (6/8) were rated as \"low risk\" in more than 80% of the included studies. A total of 59.09% (13/22) of the sub-items were rated as \"low risk\" in less than 30% of the included studies, of which 92.31% (12/13) were rated as \"low risk\" in less than 10% of the included studies. The incidence of \"low risk\" Chinese studies regarding performance bias, detection bias and reporting bias were lower than English studies. For foreign studies, more attention should be paid to selection bias, attrition bias, and reporting bias.\n\nConclusionWe identified limitations in the methodological quality of animal experiment studies published in China and abroad. We therefore suggest that it is necessary to take targeted measures to popularize the SYRCLEs risk of bias tool to effectively improve the design and implementation of animal experiments, and guide study development.

scientific communication and education↗

bioRxiv2019

Widespread associations between grey matter structure and the human phenome

The recent availability of large-scale neuroimaging cohorts (here the UK Biobank [UKB] and the Human Connectome Project [HCP]) facilitates deeper characterisation of the relationship between phenotypic and brain architecture variation in humans. We tested the association between 654,386 vertex-wise measures of cortical and subcortical morphology (from T1w and T2w MRI images) and behavioural, cognitive, psychiatric and lifestyle data. We found a significant association of grey-matter structure with 58 out of 167 UKB phenotypes spanning substance use, blood assay results, education or income level, diet, depression, being a twin as well as cognition domains (UKB discovery sample: N=9,888). Twenty-three of the 58 associations replicated (UKB replication sample: N=4,561; HCP, N=1,110). In addition, differences in body size (height, weight, BMI, waist and hip circumference, body fat percentage) could account for a substantial proportion of the association, providing possible insight into previous MRI case-control studies for psychiatric disorders where case status is associated with body mass index. Using the same linear mixed model, we showed that most of the associated characteristics (e.g. age, sex, body size, diabetes, being a twin, maternal smoking, body size) could be significantly predicted using all the brain measurements in out-of-sample prediction. Finally, we demonstrated other applications of our approach including a Region Of Interest (ROI) analysis that retain the vertex-wise complexity and ranking of the information contained across MRI processing options.\n\nHighlightsO_LIOur linear mixed model approach unifies association and prediction analyses for highly dimensional vertex-wise MRI data\nC_LIO_LIGrey-matter structure is associated with measures of substance use, blood assay results, education or income level, diet, depression, being a twin as well as cognition domains\nC_LIO_LIBody size (height, weight, BMI, waist and hip circumference) is an important source of covariation between the phenome and grey-matter structure\nC_LIO_LIGrey-matter scores quantify grey-matter based risk for the associated traits and allow to study phenotypes not collected\nC_LIO_LIThe most general cortical processing (\"fsaverage\" mesh with no smoothing) maximises the brain-morphometricity for all UKB phenotypes\nC_LI

neuroscience↗

bioRxiv2019

Domain-centric dissection and classification of prokaryotic poly(3-hydroxyalkanoate) synthases

Although many enzymes and multiple pathways involve in Polyhydroxyalkanoates (PHAs) synthesis, PHA synthases play a determinant role in the process, which include three subunits of PhaC, PhaE, and PhaR. Currently, PHA synthases are categorized into four classes according to its primary sequences, substrate specificity, and subunit composition. However, theoretical analysis of PHA synthases from the domain perspective has not been performed. In this study, we dissected PHA synthases thoroughly through analysis of domain organization. Both referenced bacterial and archaeal proteomes were then screened for the presence and absence of different PHA synthases along NCBI taxonomy ID-based phylogenetic tree. In addition, sequences annotated as bacterial and archaeal PhaCs in UniProt database were also analyzed for domain organizations and interactions. In sum, the in-silico study provided a better understanding of the domain features of PHA synthases in prokaryotes, which also assisted in the production of PHA polymers with optimized chemical properties.

genomics↗

bioRxiv2019

Evolutionary decomposition of genetic effects

Genic functions have long been confounded by pleiotropic mutational effects. To understand such genetic effects, we examine HAP4, a well-studied transcription factor in Saccharomyces cerevisiae that functions by forming a tetramer with HAP2, HAP3, and HAP5. Deletion of HAP4 results in highly pleiotropic gene expression responses, some of which are clustered in related cellular processes (clustered effects) while most are distributed randomly across diverse cellular processes (distributed effects). Strikingly, the distributed effects that account for much of HAP4 pleiotropy tend to be non-heritable in a population, suggesting they have little evolutionary consequences. Indeed, these effects are poorly conserved in closely related yeasts. We further show substantial overlaps of clustered effects, but not distributed effects, among the four genes encoding the HAP2/3/4/5 tetramer. This pattern holds for other biochemically characterized yeast protein complexes or metabolic pathways. Examination of a set of cell morphological traits of the deletion lines yields consistent results. Hence, only some gene deletion effects support related biochemical understandings with the rest being pleiotropic and evolutionarily decoupled from the genes normal functions.

genetics↗