Biology subjects

Yang, Y.

Publications and source records attributed to Yang, Y..

At least 1,315 records · Page 73Linked to original sources

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

Noninvasive Prenatal Diagnosis for Duchenne Muscular Dystrophy Based on the Direct Haplotype Phasing

ObjectiveWe aimed to investigate the validity of noninvasive prenatal diagnosis (NIPD) based on direct haplotype phasing without the proband and its feasibility for clinical application in the case of Duchenne Muscular Dystrophy (DMD).\n\nMethodsThirteen singleton-pregnancy families affected by DMD were recruited. Firstly, we resolved maternal haplotypes for each family by performing targeted linked-read sequencing of their high molecular weight DNA, respectively. Then, we identified SNPs of the DMD gene in all carrier mothers and inferred the DMD gene mutation status of all fetuses. Finally, the fetal genotypes were further validated by using chorionic villus sampling.\n\nResultsThe method of directly resolving maternal haplotype through targeted linked-read sequencing was smoothly performed in all participated families. The predicted mutational status of 13 fetuses was correct, which had been confirmed by invasive prenatal diagnosis.\n\nConclusionDirect haplotyping of NIPD based on linked-read sequencing for DMD is accurate.

genetics↗

bioRxiv2019

Chloroplast Genome Sequencing and Comparative Analysis for Five Species of the Turfgrass Fine Fescues (Festuca L., Poaceae)

Fine fescues (Festuca L., Poaceae) are turfgrass species that perform well in low-input environments. Based on morphological characteristics, the most commonly-utilized fine fescues are divided into five taxa: three are subspecies within F. rubra L. and the remaining two are treated as species within the F. ovina L. complex. Morphologically, these five taxa are very similar, both identification and classification of fine fescues remain challenging. In an effort to develop identification methods for fescues, we used flow cytometry to estimate genome size, ploidy level, and sequenced the chloroplast genome of all five taxa. Fine fescue chloroplast genome sizes ranged from 133,331 to 133,841 bp and contained 113 to 114 genes. Phylogenetic relationship reconstruction using whole chloroplast genome sequences agreed with previous work based on morphology. Comparative genomics suggested unique repeat signatures for each fine fescue taxon that could potentially be used for marker development for taxon identification.

plant biology↗

bioRxiv2019

Inhibiting Mycobacterium tuberculosis ClpP1P2 by addressing the equatorial handle domain of ClpP1 subunit

Unlike other bacterial ClpP systems, mycobacterial ClpP1P2 complex is essential for mycobacterial survival. The functional details of Mycobacterium tuberculosis (Mtb) ClpP1P2 remains largely elusive and selectively targeting ClpP of different species is a big challenge. In this work, cediranib was demonstrated to significantly decrease the activity of MtbClpP1P2. By solving the crystal structure of cediranib-bound MtbClpP1P2, we found that cediranib dysregulates MtbClpP1P2 by interfering with handle domain of the equatorial region of MtbClpP1, indicating that the inter-ring dynamics are crucial for its function. This finding provides direct evidence for the notion that a conformational switch in the equatorial handle domain is essential for ClpP activity. We also present biochemical data to interpret the distinct interaction pattern and inhibitory properties of cediranib toward MtbClpP1P2. These results suggest that the variable handle domain region is responsible for the species-selectivity of cediranib, which suggests the equatorial handle domain as a potential region for screening pathogen-specific ClpP inhibitors.

biochemistry↗

bioRxiv2019

HIV-1 Nef interacts with LMP7 to attenuate immunoproteasome formation and MHC-I antigen presentation

AbstractProteasome is major protein degradation machinery and plays essential roles in diverse biological functions. Upon cytokine inductions, proteasome subunits {beta}1, {beta}2, and {beta}5 are replaced by {beta}1i/LMP2, {beta}2i/MECL-1, and {beta}5i/LMP7, leading to the formation of immunoproteasome. Immunoproteasome-degraded products are loaded onto the major histocompatibility complex class I (MHC-I) to regulate immune responses and induce cytotoxic-T-lymphocytes (CTLs). Human immunodeficiency virus type 1 (HIV-1) is the causal agent of acquired immunodeficiency syndrome (AIDS). HIV-1-specific CTLs represent critical immune responses to limit viral replication. HIV-1 negative regulatory factor (Nef) counteracts host immunity, especially the MHC-I/CTL. This study reveals a distinct mechanism by which Nef facilitates immune evasion through attenuating the functions of immunoproteasome and MHC-I. Nef interacts with LMP7 on the endoplasmic reticulum (ER) to down-regulate the incorporation of LMP7 into immunoproteasome, and thereby attenuating immunoproteasome formation. Moreover, Nef represses immunoproteasome protein degradation function, MHC-I trafficking, and antigen presentation activity.\n\nImportanceUbiquitin-proteasome system (UPS) is essential for degradation of damaged proteins, which takes place in proteasome. Upon cytokine inductions, proteasome catalytic activities are replaced by distinct isoforms resulting in formation of immunoproteasome. Immunoproteasome generates peptides for MHC-I antigen presentation and plays important roles in immune responses. HIV-1 is the agent of AIDS, and HIV-1-specific CTLs represent immune responses to limit viral replication. This study reveals a distinct mechanism by which HIV-1 promotes immune evasion. Viral protein Nef interacts with immunoproteasome component LMP7 to attenuate immunoproteasome formation and protein degradation function, and repress MHC-I antigen presentation activity. Therefore, HIV-1 targets LMP7 to inhibit immunoproteasome activation and LMP7 may be used as a target for the development of anti-HIV-1/AIDS therapy.

microbiology↗

bioRxiv2019

The YdiU Domain Modulates Bacterial Stress Signaling through UMPylation

Sensing stressful conditions and adjusting cellular metabolism to adapt to the environment is essential for bacteria to survive in variable situations. Here, we describe a new stress-related protein YdiU, and characterize YdiU as an enzyme that catalyzes the covalent attachment of uridine 5-monophosphate to a protein tyrosine/histidine residue--a novel modification defined as UMPylation. Mn2+ serves as an essential co-factor for YdiU-mediated UMPylation. UTP and Mn2+-binding converts YdiU to an aggregate-prone state facilitating the recruitment of chaperones. The UMPylation of chaperones prevents them from binding co-factors or clients, thereby impairing their function. Consistent with the recent finding that YdiU acts as an AMPylator, we further demonstrate that the self-AMPylation of YdiU padlocks its chaperone-UMPylation activity. The detailed mechanism is proposed based on Apo-YdiU, YdiU-ATP, YdiU-AMP crystal structures and molecular dynamics simulation models of YdiU-UTP and YdiU-UTP-peptide. In vivo data demonstrate that YdiU effectively protects Salmonella from stress-induced ATP depletion through UMPylation. HighlightsO_LIYdiU involves in stress-resistance of Salmonella. C_LIO_LIYdiU mediates protein UMPylation in a Mn2+-dependent manner. C_LIO_LIStructural insights into YdiU-mediated UMPylation. C_LIO_LIUMPylation of chaperones by YdiU modulates their function. C_LI

biochemistry↗

bioRxiv2019

Long-read assembly of the Chinese rhesus macaque genome and identification of ape-specific structural variants

Rhesus macaque (Macaca mulatta) is a widely-studied nonhuman primate. Here we present a high-quality de novo genome assembly of the Chinese rhesus macaque (rheMacS) using long-read sequencing and multiplatform scaffolding approaches. Compared to the current Indian rhesus macaque reference genome (rheMac8), the rheMacS genome assembly improves sequence contiguity by 75-fold, closing 21,940 of the remaining assembly gaps (60.8 Mbp). To improve gene annotation, we generated more than two million full-length transcripts from ten different tissues by long-read RNA sequencing. We sequence resolve 53,916 structural variants (96% novel) and identify 17,000 ape-specific structural variants (ASSVs) based on comparison to the long-read assembly of ape genomes. We show that many ASSVs map within ChIP-seq predicted enhancer regions where apes and macaque show diverged enhancer activity and gene expression. We further characterize a set of candidate ASSVs that may contribute to ape- or great-ape-specific phenotypic traits, including taillessness, brain volume expansion, improved manual dexterity, and large body size. This improved rheMacS genome assembly serves as an ideal reference for future biomedical and evolutionary studies.

genomics↗

bioRxiv2019

Genome-wide Association study of facial morphology identifies novel genetic loci in Han Chinese

Human face is a heritable surface with many complex sensory organs. In recent years, many genetic loci associated with facial features have been reported in different populations, yet there is a lack for the Han Chinese population. We report a genome-wide association analysis of 3D normal human faces in 2659 Han Chinese with two groups of phenotypes, the partial and whole face phenotypes and the distance and angle phenotypes. We found significant signals in five genomic regions with traits related to nose or eyes, including rs970797 in 2q31.1 near HOXD1 and MTX2, rs16897517 in 8q22.2 at intron of VPS13B, rs9995821 in 4q31.3 near DCHS2 and SFRP2, rs12636297 in 3q23 near PISRT1, and rs12948076 in 17q24.3 near SOX9 and CASC17. We visualized changes in facial morphology by comparing the volume of local areas and observed that these nose-related loci were associated with different features of the nose, including nose prominence, nasion height, and nostril shape, suggesting that the nose underlies precise genetic regulation. These results provide a more comprehensive understanding of the relationship between genetic loci and human facial morphology.\n\nAuthor SummaryHuman face as a combination of delicate sensory organs has a strong genetic component, as evidenced by the identical appearance in twins and shared facial features in close relatives. Although facial genetics have been studied in different populations, our knowledge between genetic markers with facial features is still limited. In this paper, we found genetic variants associated with nose and eyes through a large-scale high-resolution 3D facial genetic study on the Han Chinese population. We observed that these nose-related loci were associated with different features of the nose, including nose prominence, nasion height, and nostril shape, which suggests the nose underlies precise genetic regulation. Intriguingly, we noted that genes (DCHS2 and SFRP2) related to one of these loci are differentially expressed in human and chimp cranial neural crest cells, which plays a crucial role in the early formation of facial morphology. The ongoing genetic studies of facial morphology will improve our understanding of human craniofacial development, and provide potential evolution evidence of human facial features.

genetics↗

bioRxiv2019

Druggable genome screen identifies new regulators of the abundance and toxicity of ATXN3, the Spinocerebellar Ataxia Type 3 disease protein

BackgroundSpinocerebellar Ataxia type 3 (SCA3, also known as Machado-Joseph disease) is a neurodegenerative disorder caused by a CAG repeat expansion encoding an abnormally long polyglutamine (polyQ) tract in the disease protein, ataxin-3 (ATXN3). No preventive treatment is yet available for SCA3. Because SCA3 is likely caused by a toxic gain of ATXN3 function, a rational therapeutic strategy is to reduce mutant ATXN3 levels by targeting pathways that control its production or stability. Here, we sought to identify genes that modulate ATXN3 levels as potential therapeutic targets in this fatal disorder.\n\nMethodsWe screened a collection of siRNAs targeting 2742 druggable human genes using a cell-based assay based on luminescence readout of polyQ-expanded ATXN3. From 317 candidate genes identified in the primary screen, 100 genes were selected for validation. Among the 33 genes confirmed in secondary assays, 15 were validated in an independent cell model as modulators of pathogenic ATXN3 protein levels. Ten of these genes were then assessed in a Drosophila model of SCA3, and one was confirmed as a key modulator of physiological ATXN3 abundance in SCA3 neuronal progenitor cells.\n\nResultsAmong the 15 genes shown to modulate ATXN3 in mammalian cells, orthologs of CHD4, FBXL3, HR and MC3R regulate mutant ATXN3-mediated toxicity in fly eyes. Further mechanistic studies of one of these genes, FBXL3, encoding a F-box protein that is a component of the SKP1-Cullin-F-box (SCF) ubiquitin ligase complex, showed that it reduces levels of normal and pathogenic ATXN3 in SCA3 neuronal progenitor cells, primarily via a SCF complex-dependent manner. Bioinformatic analysis of the 15 genes revealed a potential molecular network with connections to tumor necrosis factor-/nuclear factor-kappa B (TNF/NF-kB) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathways.\n\nConclusionsWe identified 15 druggable genes with diverse functions to be suppressors or enhancers of pathogenic ATXN3 abundance. Among identified pathways highlighted by this screen, the FBXL3/SCF axis represents a novel molecular pathway that regulates physiological levels of ATXN3 protein.

neuroscience↗

bioRxiv2019

MR-LDP: a two-sample Mendelian randomization for GWAS summary statistics accounting linkage disequilibrium and horizontal pleiotropy

The proliferation of genome-wide association studies (GWAS) has prompted the use of two-sample Mendelian randomization (MR) with genetic variants as instrumental variables (IV) for drawing reliable causal relationships between health risk factors and disease outcomes. However, the unique features of GWAS demand that MR methods account for both linkage disequilibrium (LD) and ubiquitously existing horizontal pleiotropy among complex traits, which is the phenomenon wherein a variant affects the outcome through mechanisms other than exclusively through the exposure. Therefore, statistical methods that fail to consider LD and horizontal pleiotropy can lead to biased estimates and false-positive causal relationships. To overcome these limitations, we propose a probabilistic model for MR analysis to identify the casual effects between risk factors and disease outcomes using GWAS summary statistics in the presence of LD and to properly account for horizontal pleiotropy among genetic variants (MR-LDP). MR-LDP utilizes a computationally efficient parameter-expanded variational Bayes expectation-maximization (PX-VBEM) algorithm to estimate the parameter of interest and further calibrates the evidence lower bound (ELBO) for a likelihood ratio test. We then conducted comprehensive simulation studies to demonstrate the advantages of MR-LDP over the existing methods in terms of both type-I error control and point estimates. Moreover, we used two real exposure-outcome pairs (CAD-CAD and Height-Height; CAD for coronary artery disease) to validate the results from MR-LDP compared with alternative methods, showing that our method is more efficient in using all instrumental variants in LD. By further applying MR-LDP to lipid traits and body mass index (BMI) as risk factors for complex diseases, we identified multiple pairs of significant causal relationships, including a protective effect of high-density lipoprotein cholesterol (HDL-C) on peripheral vascular disease (PVD), and a positive causal effect of body mass index (BMI) on hemorrhoids.

genetics↗

bioRxiv2019

SMNN: Batch Effect Correction for Single-cell RNA-seq data via Supervised Mutual Nearest Neighbor Detection

Batch effect correction has been recognized to be indispensable when integrating single-cell RNA sequencing (scRNA-seq) data from multiple batches. State-of-the-art methods ignore single-cell cluster label information, but such information can improve effectiveness of batch effect correction, particularly under realistic scenarios where biological differences are not orthogonal to batch effects. To address this issue, we propose SMNN for batch effect correction of scRNA-seq data via supervised mutual nearest neighbor detection. Our extensive evaluations in simulated and real datasets show that SMNN provides improved merging within the corresponding cell types across batches, leading to reduced differentiation across batches over MNN, Seurat v3, and LIGER. Furthermore, SMNN retains more cell type-specific features, partially manifested by differentially expressed genes identified between cell types after SMNN correction being biologically more relevant, with precision improving by up to 841%. Key PointsO_LIBatch effect correction has been recognized to be critical when integrating scRNA-seq data from multiple batches due to systematic differences in time points, generating laboratory and/or handling technician(s), experimental protocol, and/or sequencing platform. C_LIO_LIExisting batch effect correction methods that leverages information from mutual nearest neighbors across batches (for example, implemented in SC3 or Seurat) ignore cell type information and suffer from potentially mismatching single cells from different cell types across batches, which would lead to undesired correction results, especially under the scenario where variation from batch effects is non-negligible compared with biological effects. C_LIO_LITo address this critical issue, here we present SMNN, a supervised machine learning method that first takes cluster/cell-type label information from users or inferred from scRNA-seq clustering, and then searches mutual nearest neighbors within each cell type instead of global searching. C_LIO_LIOur SMNN method shows clear advantages over three state-of-the-art batch effect correction methods and can better mix cells of the same cell type across batches and more effectively recover cell-type specific features, in both simulations and real datasets. C_LI

bioinformatics↗

bioRxiv2019

The succession pattern of bacterial diversity in compost using pig manure mixed with wood chips analyzed by 16S rRNA gene analysis

The pig manure mixed with wood chips and formed compost by means of fermentation. We found that the protease activity, organic matter content and ammonium nitrogen concentration were higher in the early stage of composting. Meanwhile, the urease activity was highest in the high temperature period. The carbon to nitrogen ratio of the compost decreased continuously with fermentation. The dynamic change in the composition of bacterial overtime in the compost of a 180 kg piles were explored using microbial diversity analysis. The results showed that the microbial species increased with the compost fermentation. At the early stage of composting, the phyla of Firmicutes and Actinomycetes were dominant. The microbes in the high temperature period were mainly composed of Firmicutes and Proteobacteria while the proportion of Bacteroides was increased during the cooling period. In the compost of maturity stage, the proportion of Chloroflexi increased, becoming dominant species with other microorganisms including Firmicutes, Proteobacteria, Bacteroides, Chloroflexi but not Actinomycetes. Bacteria involved in lignocellulose degradation, such as those of the Thermobifida, Cellvibrio, Mycobacterium, Streptomyces and Rhodococcus, were concentrated in the maturity stages of composting. Through correlation analysis, the environmental factors including organic matter, ammonium nitrogen and temperature were consistent with the succession of microbial including Rhodocyclaceae, Anaerolineaceae, Thiopseudomonas, Sinibacillus and Tepidimicrobium. The change of urease activity and carbon to nitrogen ratio corresponded to microbial communities, mainly containing Anaerolineaceae, Rhodocyclaceae, Luteimoas, Bacillaceae, Corynebacterium, Bacillus, Anaerococcus, Lactobacillus, Ignatzschineria, and Bacillaceae.

microbiology↗

bioRxiv2019

Study of the AMP-activated protein kinase role in energy metabolism changes during the postmortem aging of yak longissimus lumborum

To explore the postmortem physiological mechanism of muscle, activity of adenosine monophosphate activated protein kinase (AMPK) as well as its role in energy metabolism of postmortem yaks were studied. In this experiment, we injected 5-amino-1-beta-d-furanonyl imidazole-4-formamide (AICAR), a specific activator of AMPK, and the specific AMPK inhibitor STO-609, to observe the changes in glycolysis, energy metabolism, AMPK activity and AMPK gene expression (PRKA1 and PRKA2) in postmortem yaks during maturation. The results showed that AICAR could increase the expression of the PRKKA1 and PRKAA2 genes, activate AMPK and increase its activity. The effects of AICAR include a lower concentration of ATP, an increase in AMP production, an acceleration of glycolysis, an increase in the lactic acid concentration, and a decrease in the pH value. In contrast, STO-609 had the opposite effect. Under hypoxic adaptation, the activity of the meat AMPK increased, which accelerated glycolysis and metabolism, and more effectively regulated energy production.

biochemistry↗

bioRxiv2019

The small noncoding RNA sr8384 determines solvent synthesis and cell growth in industrial solventogenic clostridia

Small noncoding RNAs (sncRNAs) are crucial regulatory molecules in organisms and are well known not only for their roles in the control of diverse essential biological processes but also for their value in genetic modification. However, to date, in gram-positive anaerobic solventogenic clostridia (which are a group of important industrial bacteria with exceptional substrate and product diversity), sncRNAs remain minimally explored, leading to a lack of detailed understanding regarding these important molecules and their use as targets for genetic improvement. Here, we performed large-scale phenotypic screens of a transposon-mediated mutant library of Clostridium acetobutylicum, a typical solventogenic clostridial species, and discovered a novel sncRNA (sr8384) that functions as a determinant positive regulator of growth and solvent synthesis. Comparative transcriptomic data combined with genetic and biochemical analyses revealed that sr8384 acts as a pleiotropic regulator and controls multiple targets that are associated with crucial biological processes, through direct or indirect interactions. Notably, modulation of the expression level of either sr8384 or its core target genes significantly increased the growth rate, solvent titer and productivity of the cells, indicating the importance of sr8384-mediated regulatory network in C. acetobutylicum. Furthermore, a homolog of sr8384 was discovered and proven to be functional in another important Clostridium species, C. beijerinckii, suggesting the potential broad role of this sncRNA in clostridia. Our work showcases a previously unknown potent and complex role of sncRNAs in clostridia, providing new opportunities for understanding and engineering these anaerobes, including pathogenic Clostridium species.\n\nIMPORTANCEThe discovery of sncRNAs as new resources for functional studies and strain modifications are promising strategies in microorganisms. However, these crucial regulatory molecules have hardly been explored in industrially important solventogenic clostridia. Here, we identified sr8384 as a novel determinant sncRNA controlling cellular performance of solventogenic Clostridium acetobutylicum and performed detailed functional analysis, which is the most in-depth study of sncRNAs in clostridia to date. We reveal the pleiotropic function of sr8384 and its multiple direct and indirect crucial targets, which represents a valuable source for understanding and optimizing this anaerobe. Of note, manipulation of these targets leads to improved cell growth and solvent synthesis. Our findings provide a new perspective for future studies on regulatory sncRNAs in clostridia.

microbiology↗

bioRxiv2019

Microstructural plasticity in the bilingual brain

The human brain has been uniquely equipped with the remarkable ability to acquire more than one language, as in bilingual individuals. Previous neuroimaging studies have indicated that learning a second language (L2) induced neuroplasticity at the macrostructural level. In this study, using the quantitative MRI (qMRI) combined with functional MRI (fMRI) techniques, we quantified the microstructural properties and tested whether second language learning modulates the microstructure in the bilingual brain. We found significant microstructural variations related to age of acquisition of second language in the left inferior frontal region and the left fusiform gyrus that are crucial for resolving lexical competition of bilinguals two languages. Early second language acquisition contributes to enhance cortical development at the microstructural level.\n\nSignificant statementThe ability to communicate in two languages is becoming more and more important in the increasingly global community. Does learning a second language (L2) affect the human brain development? At the macrostructural level, there has been neuroimaging evidence revealing neuroplasticity induced by the acquisition of L2. Here, we employed the quantitative MRI technique to investigate the microstructural variations related to L2 learning, and found that age of acquisition of L2, but not its proficiency, is associated with cortical proliferation. Early second language acquisition seems to enhance cortical development at the microstructural level.

neuroscience↗

bioRxiv2019

CoMM-S2: a collaborative mixed model using summary statistics in transcriptome-wide association studies

MotivationAlthough genome-wide association studies (GWAS) have deepened our understanding of the genetic architecture of complex traits, the mechanistic links that underlie how genetic variants cause complex traits remains elusive. To advance our understanding of the underlying mechanistic links, various consortia have collected a vast volume of genomic data that enable us to investigate the role that genetic variants play in gene expression regulation. Recently, a collaborative mixed model (CoMM) [42] was proposed to jointly interrogate genome on complex traits by integrating both the GWAS dataset and the expression quantitative trait loci (eQTL) dataset. Although CoMM is a powerful approach that leverages regulatory information while accounting for the uncertainty in using an eQTL dataset, it requires individual-level GWAS data and cannot fully make use of widely available GWAS summary statistics. Therefore, statistically efficient methods that leverages transcriptome information using only summary statistics information from GWAS data are required.\n\nResultsIn this study, we propose a novel probabilistic model, CoMM-S2, to examine the mechanistic role that genetic variants play, by using only GWAS summary statistics instead of individual-level GWAS data. Similar to CoMM which uses individual-level GWAS data, CoMM-S2 combines two models: the first model examines the relationship between gene expression and genotype, while the second model examines the relationship between the phenotype and the predicted gene expression from the first model. Distinct from CoMM, CoMM-S2 requires only GWAS summary statistics. Using both simulation studies and real data analysis, we demonstrate that even though CoMM-S2 utilizes GWAS summary statistics, it has comparable performance as CoMM, which uses individual-level GWAS data.\n\nContactjin.liu@duke-nus.edu.sg\n\nAvailability and implementationThe implement of CoMM-S2 is included in the CoMM package that can be downloaded from https://github.com/gordonliu810822/CoMM.\n\nSupplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2019

SAME-clustering: Single-cell Aggregated Clustering via Mixture Model Ensemble

Clustering is an essential step in the analysis of single cell RNA-seq (scRNA-seq) data to shed light on tissue complexity including the number of cell types and transcriptomic signatures of each cell type. Due to its importance, novel methods have been developed recently for this purpose. However, different approaches generate varying estimates regarding the number of clusters and the single-cell level cluster assignments. This type of unsupervised clustering is challenging and it is often times hard to gauge which method to use because none of the existing methods outperform others across all scenarios. We present SAME-clustering, a mixture model-based approach that takes clustering solutions from multiple methods and selects a maximally diverse subset to produce an improved ensemble solution. We tested SAME-clustering across 15 scRNA-seq datasets generated by different platforms, with number of clusters varying from 3 to 15, and number of single cells from 49 to 32,695. Results show that our SAME-clustering ensemble method yields enhanced clustering, in terms of both cluster assignments and number of clusters. The mixture model ensemble clustering is not limited to clustering scRNA-seq data and may be useful to a wide range of clustering applications.

bioinformatics↗

bioRxiv2019

Transgenerational inheritance of betaine-induced epigenetic alterations in estrogen-responsive IGF-2/IGFBP2 genes in rat hippocampus

Betaine as a methyl donor participates in DNA methylation. Here, we sought to investigate the effects of betaine on hippocampal expression of neurogenesis genes and their DNA methylation status across three generations. Pregnant rats (F0) were fed control and betaine-supplemented diets throughout gestation and lactation; and female F1 and F2 offspring at weaning, together with the F0 dams, were used in the study. Hippocampal expression of aromatase, estrogen receptor and estrogen related receptor {beta} was down-regulated in F1, together with the estrogen-responsive IGF-2/IGFBP2 genes. However, all these genes were up-regulated in F2, which follows the same pattern of F0. In agreement with changes in mRNA expression, the imprinting control region (ICR) of IGF-2 gene was hypomethylated in F1 but hypermethylated in F2 and F0. In contrast, the promoter DNA methylation status of all the affected genes was hypermethylated in F1 but hypomethylated in F2 and F0. Betaine homocysteine methyltransferase followed same pattern of transgenerational inheritance. These results indicate that betaine exerts a transgenerational effect on hippocampal expression of estrogen-responsive genes in rat offspring, which is associated with corresponding alterations in DNA methylation on ICR of IGF-2 gene and the promoter of affected genes.\n\nAuthor SummaryEpigenetic transgenerational inheritance is defined as the phenotypic change across generations and germline transmission of epigenetic information without direct genetic manipulation or environmental exposure. Maternal and paternal diet has been shown to have transgenerational behavioral and physiological effects. Maternal intake of methyl donors, including folate, betaine, and choline during different gestation period alters epigenetic modifications of many imprinted genes in the genomic DNA isolated from cord blood. Betaine as a methyl donor nutrition plays an important role in brain development. However, the effect of maternal betaine supplementation on transgenerational inheritance of imprinted gene IGF-2 in offspring hippocampus is still unknown. Here, we sought to investigate the effects of betaine on rat hippocampal expression of neurogenesis genes and their DNA methylation status across three generations. We found that betaine significantly decreased estrogen-responsive genes IGF-2/IGFBP2 expression in rat F1 offspring, yet increased in F2 offspring, which is associated with corresponding alterations in DNA methylation on ICR of IGF-2 gene and the promoter of affected genes. Our results suggesting that maternal methyl donor nutrition supplementation may be exert an epigenetic transgenerational effect on female offspring.

genetics↗