Biology subjects

Wang, W.

Publications and source records attributed to Wang, W..

At least 55 records · Page 3Linked to original sources

bioRxiv2018

Fusing Mobile Phone Sensing and Brain Imaging to Assess Depression in College Students: A Proof-of-Concept study

As smartphone usage has become increasingly prevalent in our society, so have rates of depression, particularly among young adults. Individual differences in smartphone usage patterns have been shown to reflect individual differences in underlying affective processes such as depression (Wang et al., 2018). In the current study, we identified a positive relationship between smartphone screen time (e.g. phone unlock duration) and resting-state functional connectivity (RSFC) between the subgenual cingulate cortex (sgCC), a brain region implicated in depression and antidepressant treatment response, and regions of the ventromedial/orbitofrontal cortex, such that increased phone usage was related to stronger connectivity between these regions. We then used this cluster to constrain subsequent analyses looking at depressive symptoms in the same cohort and observed partial replication in a separate cohort. We believe the data and analyses presented here provide relatively simplistic initial analyses which replicate and provide a first step in combining functional brain activity and smartphone usage patterns to better understand issues related to mental health. Smartphones are a prevalent part of modern life and the usage of mobile sensing data from smartphones promises to be an important tool for mental health diagnostics and neuroscience research.

neuroscience↗

bioRxiv2018

Identifying tissues implicated in Anorexia Nervosa using Transcriptomic Imputation

Anorexia nervosa (AN) is a complex and serious eating disorder, occurring in ~1% of individuals. Despite having the highest mortality rate of any psychiatric disorder, little is known about the aetiology of AN, and few effective treatments exist.\n\nGlobal efforts to collect large sample sizes of individuals with AN have been highly successful, and a recent study consequently identified the first genome-wide significant locus involved in AN. This result, coupled with other recent studies and epidemiological evidence, suggest that previous characterizations of AN as a purely psychiatric disorder are over-simplified. Rather, both neurological and metabolic pathways may also be involved.\n\nIn order to elucidate more of the system-specific aetiology of AN, we applied transcriptomic imputation methods to 3,495 cases and 10,982 controls, collected by the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED). Transcriptomic Imputation (TI) methods approaches use machine-learning methods to impute tissue-specific gene expression from large genotype data using curated eQTL reference panels. These offer an exciting opportunity to compare gene associations across neurological and metabolic tissues. Here, we applied CommonMind Consortium (CMC) and GTEx-derived gene expression prediction models for 13 brain tissues and 12 tissues with potential metabolic involvement (adipose, adrenal gland, 2 colon, 3 esophagus, liver, pancreas, small intestine, spleen, stomach).\n\nWe identified 35 significant gene-tissue associations within the large chromosome 12 region described in the recent PGC-ED GWAS. We applied forward stepwise conditional analyses and FINEMAP to associations within this locus to identify putatively causal signals. We identified four independently associated genes; RPS26, C12orf49, SUOX, and RDH16. We also identified two further genome-wide significant gene-tissue associations, both in brain tissues; REEP5, in the dorso-lateral pre-frontal cortex (DLPFC; p=8.52x10-07), and CUL3, in the caudate basal ganglia (p=1.8x10-06). These genes are significantly enriched for associations with anthropometric phenotypes in the UK BioBank, as well as multiple psychiatric, addiction, and appetite/satiety pathways. Our results support a model of AN risk influenced by both metabolic and psychiatric factors.

genetics↗

bioRxiv2018

Xist Intron 1 Repression by TALE Transcriptional Factor Improves Somatic Cell Reprogamming in Mice

Xist is the master regulator of X chromosome inactivation (XCI). In order to further understand the Xist locus in reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) and in somatic cell nuclear transfer (SCNT), we tested transcription-factor-like effectors (TALE)-based designer transcriptional factors (dTFs), which were specific to numerous regions at the Xist locus. We report that the selected dTF repressor 6 (R6) binding the intron 1 of Xist, which did not affect Xist expression in mouse embryonic fibroblasts (MEFs), substantially improved the iPSC generation and the SCNT preimplantation embryo development. Conversely, the dTF activator targeting the same genomic region of R6 decreased iPSC formation, and blocked SCNT-embryo development. These results thus uncover the critical requirement for the Xist locus in epigenetic resetting, which is not directly related to Xist transcription. This may provide a unique route to improving the reprogramming.

developmental biology↗

bioRxiv2018

A MinION-based pipeline for fast and cost-effective DNA barcoding

DNA barcodes are useful for species discovery and species identification, but obtaining barcodes currently requires a well-equipped molecular laboratory, is time-consuming, and/or expensive. We here address these issues by developing a barcoding pipeline for Oxford Nanopore MinION and demonstrate that one flowcell can generate barcodes for [~]500 specimens despite high base-call error rates of MinION. The pipeline overcomes the errors by first summarizing all reads for the same tagged amplicon as a consensus barcode. These barcodes are overall mismatch-free but retain indel errors that are concentrated in homopolymeric regions. We thus complement the barcode caller with an optional error correction pipeline that uses conserved amino-acid motifs from publicly available barcodes to correct the indel errors. The effectiveness of this pipeline is documented by analysing reads from three MinION runs that represent three different stages of MinION development. They generated data for (1) 511 specimens of a mixed Diptera sample, (2) 575 specimens of ants, and (3) 50 specimens of Chironomidae. The run based on the latest chemistry yielded MinION barcodes for 490 specimens which were assessed against reference Sanger barcodes (N=471). Overall, the MinION barcodes have an accuracy of 99.3%-100% and the number of ambiguities ranges from <0.01-1.5% depending on which correction pipeline is used. We demonstrate that it requires only 2 hours of sequencing to gather all information that is needed for obtaining reliable barcodes for most specimens (>90%). We estimate that up to 1000 barcodes can be generated in one flowcell and that the cost of a MinION barcode can be <USD 2.

bioinformatics↗

bioRxiv2017

Spontaneous dormancy protects Trypanosoma cruzi during extended drug exposure

The ability of the Chagas disease agent Trypanosoma cruzi to resist extended in vivo exposure to highly effective trypanocidal compounds prompted us to explore the potential for dormancy and its contribution to failed drug treatments in this infection. We document the development of non-proliferating intracellular amastigotes in vivo and in vitro in the absence of drug treatment. Non-proliferative amastigotes ultimately converted to trypomastigotes and established infections in new host cells. Most significantly, dormant amastigotes were uniquely resistant to extended drug treatment in vivo and in vitro and could re-establish a flourishing infection after as many as 30 days of drug exposure. These results demonstrate a dormancy pathway in T. cruzi that accounts for the failure of highly cytotoxic compounds to completely resolve the infection. The ability of T. cruzi to establish dormancy throws into question current methods for identifying curative drugs but also suggests alternative therapeutic approaches.

microbiology↗

bioRxiv2017

Adult-specific trimethylation of histone H3 lysine 4 is prone to dynamic changes with aging in C. elegans somatic cells

Tri-methylation on histone H3 lysine 4 (H3K4me3) is associated with active gene expression but its regulatory role in transcriptional activation is unclear. Here we used Caenorhabditis elegans to investigate the connection between H3K4me3 and gene expression regulation during aging. We uncovered around 30% of H3K4me3 enriched regions to show significant and reproducible changes with age. We further showed that these age-dynamic H3K4me3 regions largely mark gene-bodies and are acquired during adult stages. We found that these adult-specific age-dynamic H3K4me3 regions are correlated with gene expression changes with age. In contrast, H3K4me3 marking established during developmental stages remained largely stable with age, even when the H3K4me3 associated genes exhibited RNA expression changes during aging. Moreover, we found that global reduction of H3K4me3 levels results in significantly decreased RNA expression of genes that acquire H3K4me3 marking in their gene-bodies during adult stage, suggesting that altered H3K4me3 levels with age could result in age-dependent gene expression changes. Interestingly, the genes with dynamic changes in H3K4me3 and RNA levels with age are enriched for those involved in fatty acid metabolism, oxidation-reduction, and stress response. Therefore, our findings revealed divergent roles of H3K4me3 in gene expression regulation during aging, with important implications on physiological relevance.

molecular biology↗

bioRxiv2017

TahcoRoll: An Efficient Approach for Signature Profiling in Genomic Data through Variable-Length k-mers

k-mer profiling has been one of the trending approaches to analyze read data generated by high-throughput sequencing technologies. The tasks of k-mer profiling include, but are not limited to, counting the frequencies and determining the occurrences of short sequences in a dataset. The notion of k-mer has been extensively used to build de Bruijn graphs in genome or transcriptome assembly, which requires examining all possible k-mers presented in the dataset. Recently, an alternative way of profiling has been proposed, which constructs a set of representative k-mers as genomic markers and profiles their occurrences in the sequencing data. This technique has been applied in both transcript quantification through RNA-Seq and taxonomic classification of metagenomic reads. Most of these applications use a set of fixed-size k-mers since the majority of existing k-mer counters are inadequate to process genomic sequences with variable-length k-mers. However, choosing the appropriate k is challenging, as it varies for different applications. As a pioneer work to profile a set of variable-length k-mers, we propose TahcoRoll in order to enhance the Aho-Corasick algorithm. More specifically, we use one bit to represent each nucleotide, and integrate the rolling hash technique to construct an efficient in-memory data structure for this task. Using both synthetic and real datasets, results show that TahcoRoll outperforms existing approaches in either or both time and memory efficiency without using any disk space. In addition, compared to the most efficient state-of-the-art k-mer counters, such as KMC and MSBWT, TahcoRoll is the only approach that can process long read data from both PacBio and Oxford Nanopore on a commodity desktop computer. The source code of TahcoRoll is implemented in C++14, and available at https://github.com/chelseaju/TahcoRoll.git.

bioinformatics↗

bioRxiv2017

Natural Variation of OsLG3 Controls Drought Stress Tolerance in Rice by Inducing ROS Scavenging

BackgroundImproving performance of rice under drought stress has potential to significant impact on rice productivity. Previously we reported that OsLG3 positively control rice grain length and yield.\n\nResultsIn this study, we found that OsLG3 was more strongly expressed in upland rice compared to lowland rice under drought stress condition. Candidate gene association analysis showed that the natural variation in OsLG3 was associated with tolerance to water deficit stress in germinating rice seeds. Transgenic rice with enhanced OsLG3 expression exhibited improved tolerance to drought and that is most likely due to enhanced ROS scavenging efficiency. Phylogenetic analysis and pedigree records indicated that the tolerant allele of OsLG3 has potential to improve drought tolerance of japonica rice.\n\nConclusionsCollectively, our work revealed that the natural variation of OsLG3 contributes to rice drought tolerance and the elite allele of OsLG3 is a promising genetic resource for the development of drought-tolerant and high-yield rice varieties.

plant biology↗

bioRxiv2017

Gene expression imputation across multiple brain regions reveals schizophrenia risk throughout development.

Transcriptomic imputation approaches offer an opportunity to test associations between disease and gene expression in otherwise inaccessible tissues, such as brain, by combining eQTL reference panels with large-scale genotype data. These genic associations could elucidate signals in complex GWAS loci and may disentangle the role of different tissues in disease development. Here, we use the largest eQTL reference panel for the dorso-lateral pre-frontal cortex (DLPFC), collected by the CommonMind Consortium, to create a set of gene expression predictors and demonstrate their utility. We applied these predictors to 40,299 schizophrenia cases and 65,264 matched controls, constituting the largest transcriptomic imputation study of schizophrenia to date. We also computed predicted gene expression levels for 12 additional brain regions, using publicly available predictor models from GTEx. We identified 413 genic associations across 13 brain regions. Stepwise conditioning across the genes and tissues identified 71 associated genes (67 outside the MHC), with the majority of associations found in the DLPFC, and of which 14/67 genes did not fall within previously genome-wide significant loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple pathways associated with porphyric disorders. We investigated developmental expression patterns for all 67 non-MHC associated genes using BRAINSPAN, and identified groups of genes expressed specifically pre-natally or post-natally.

genetics↗

bioRxiv2017

Transcriptomic Imputation of Bipolar Disorder and Bipolar subtypes reveals 29 novel associated genes

Bipolar disorder is a complex neuropsychiatric disorder presenting with episodic mood disturbances. In this study we use a transcriptomic imputation approach to identify novel genes and pathways associated with bipolar disorder, as well as three diagnostically and genetically distinct subtypes. Transcriptomic imputation approaches leverage well-curated and publicly available eQTL reference panels to create gene-expression prediction models, which may then be applied to \"impute\" genetically regulated gene expression (GREX) in large GWAS datasets. By testing for association between phenotype and GREX, rather than genotype, we hope to identify more biologically interpretable associations, and thus elucidate more of the genetic architecture of bipolar disorder.\n\nWe applied GREX prediction models for 13 brain regions (derived from CommonMind Consortium and GTEx eQTL reference panels) to 21,488 bipolar cases and 54,303 matched controls, constituting the largest transcriptomic imputation study of bipolar disorder (BPD) to date. Additionally, we analyzed three specific BPD subtypes, including 14,938 individuals with subtype 1 (BD-I), 3,543 individuals with subtype 2 (BD-II), and 1,500 individuals with schizoaffective subtype (SAB).\n\nWe identified 125 gene-tissue associations with BPD, of which 53 represent independent associations after FINEMAP analysis. 29/53 associations were novel; i.e., did not lie within 1Mb of a locus identified in the recent PGC-BD GWAS. We identified 37 independent BD-I gene-tissue associations (10 novel), 2 BD-II associations, and 2 SAB associations. Our BPD, BD-I and BD-II associations were significantly more likely to be differentially expressed in post-mortem brain tissue of BPD, BD-I and BD-II cases than we might expect by chance. Together with our pathway analysis, our results support long-standing hypotheses about bipolar disorder risk, including a role for oxidative stress and mitochondrial dysfunction, the post-synaptic density, and an enrichment of circadian rhythm and clock genes within our results.

genetics↗

bioRxiv2017

Rapid, modular, and cost-effective generation of donor DNA constructs for CRISPR-based gene knock-in

CRISPR-based gene knock-in at endogenous sites is desirable in multiple fields such as quantitative studies of signal transduction pathways and gene regulation, synthetic biology, and disease modeling. Contrasting the knock-out procedure, a key step of CRISPR knock-in procedure relies on the homology-directed repairing (HDR) process that requires a donor construct as repair template. Therefore, it is desirable to generate a series of donor DNA constructs efficiently and cost-effectively. In this study, we developed a general Gibson assembly procedure that combines strengths of a Modular Overlap-Directed Assembly with Linkers (MODAL) strategy and a restriction enzyme based hierarchical framework. This procedure also allows fusing sgRNAs to the constructs for enhanced homology-directed repairing efficiency. Experimental tests on multiple constructs achieved from 3-8 folds of increase in assembly efficiency to high yield of constructs that failed to make with conventional Gibson assembly. The modularized procedure is simple, fast and cost-effective while making multiple constructs, and a computer package is provided for customized design.

molecular biology↗

bioRxiv2017

Genome-Wide Identification of Early-Firing Human Replication Origins by Optical Replication Mapping

The timing of DNA replication is largely regulated by the location and timing of replication origin firing. Therefore, much effort has been invested in identifying and analyzing human replication origins. However, the heterogeneous nature of eukaryotic replication kinetics and the low efficiency of individual origins in metazoans has made mapping the location and timing of replication initiation in human cells difficult. We have mapped early-firing origins in HeLa cells using Optical Replication Mapping, a high-throughput single-molecule approach based on Bionano Genomics genomic mapping technology. The single-molecule nature and 290-fold coverage of our dataset allowed us to identify origins that fire with as little as 1% efficiency. We find sites of human replication initiation in early S phase are not confined to well-defined efficient replication origins, but are instead distributed across broad initiation zones consisting of many inefficient origins. These early-firing initiation zones co-localize with initiation zones inferred from Okazaki-fragment-mapping analysis and are enriched in ORC1 binding sites. Although most early-firing origins fire in early-replication regions of the genome, a significant number fire in late-replicating regions, suggesting that the major difference between origins in early and late replicating regions is their probability of firing in early S-phase, as opposed to qualitative differences in their firing-time distributions. This observation is consistent with stochastic models of origin timing regulation, which explain the regulation of replication timing in yeast.

genomics↗

bioRxiv2017

Contextual Regression: An Accurate and Conveniently Interpretable Nonlinear Model for Mining Discovery from Scientific Data

Machine learning algorithms such as linear regression, SVM and neural network have played an increasingly important role in the process of scientific discovery. However, none of them is both interpretable and accurate on nonlinear datasets. Here we present contextual regression, a method that joins these two desirable properties together using a hybrid architecture of neural network embedding and dot product layer. We demonstrate its high prediction accuracy and sensitivity through the task of predictive feature selection on a simulated dataset and the application of predicting open chromatin sites in the human genome. On the simulated data, our method achieved high fidelity recovery of feature contributions under random noise levels up to {+/-}200%. On the open chromatin dataset, the application of our method not only outperformed the state of the art method in terms of accuracy, but also unveiled two previously unfound open chromatin related histone marks. Our method fills in the gap of accurate and interpretable nonlinear modeling in scientific data mining tasks.

bioinformatics↗

bioRxiv2017

Diffusional conductance to CO2 is the key limitation to photosynthesis in salt-stressed leaves of rice (Oryza sativa)

Salinity significantly limits leaf photosynthesis but the photosynthetic limiting factors in salt- stressed leaves remain unclear. In the present work, photosynthetic and biochemical traits were investigated in four rice genotypes under two NaCl (0 and 150 mM) concentration to assess the stomatal, mesophyll and biochemical contributions to reduced photosynthetic rate (A) in salt stressed leaves. Our results indicated that salinity led to a decrease in A, leaf osmotic potential, electron transport rate and CO2 concentrations in the chloroplasts (Cc) of rice leaves. Decreased A in salt-stressed leaves was mainly attributable to low Cc, which was determined by stomatal and mesophyll conductance. The increased stomatal limitation was mainly related to the low leaf osmotic potential caused by soil salinity. However, the increased mesophyll limitation in salt stressed leaves was related to both osmotic stress and ion stress. These findings highlight the importance of considering mesophyll conductance when developing salinity-tolerant rice cultivars.\n\nAbbreviations

plant biology↗

bioRxiv2017

Restoration longevity among geriatric and adult special needs patients

This study aimed to describe the survival trajectory of dental restorations placed in an outpatient population of geriatric and adult special needs patients over a 15-year span, with particular interest in longevity of subsequent restorations in teeth that received multiple restorations over time. Dental restorations of different types and sizes in patients age [≥]65 years treated between 2000-14 at the University of Iowa, College of Dentistry were followed until they incurred an event (i.e., restoration replacement, extraction of the tooth, or endodontic treatment of the tooth). Survival analysis and extended Cox regression models were used to generate hazards ratios for selected predictor variables. A total of 9184 restorations were followed in 1551 unique patients. During the follow-up period, 28.7% of these restorations incurred an event; and overall the restorations had a median lifespan of 6.25 years. In multivariable regression models, after controlling for gender and age, composite restorations and greater number of restoration surfaces were associated with higher risks of failure; and the initial restoration recorded in the database for each subject tended to have lower risk of failure than restorations placed later that included any of those same surfaces. This information potentially could be helpful to elderly patients considering various restorative treatment options during the dental treatment planning and informed consent process.

bioengineering↗

bioRxiv2017

Sulforaphane modulates microRNA expression in colon cancer cells to implicate the regulation of oncogenes CDC25A, HMGA2 and MYC

Colorectal cancer is an increasingly important cause of morbidity and mortality, whose incidence is associated with dietary and lifestyle factors, particularly inversely so with the consumption of cruciferous vegetables. These vegetables contain glucosinolates, from the breakdown of which are derived isothiocyanates, such as sulforaphane. Sulforaphane is well-characterised for wide-ranging tumour-suppressive and chemoprotective activities in vitro, yet deeper elucidation of its biological interactions would aid in better realising its potential in chemoprevention and/or chemotherapy. There is evidence to suggest that sulforaphane modulates microRNA expression in the colon, thus implying the potential for microRNA modulation to play a role in the anti-cancer effects of sulforaphane. Therefore, the effects of sulforaphane on microRNA expression profiles in the colonic adenocarcinoma Caco-2 and non-cancerous colonic CCD-841 cell lines were investigated by small RNA cloning and deep sequencing, followed by Northern Blot validation experiments. Sulforaphane upregulated let-7f-5p and let-7g-5p expression at 24 h in Caco-2 cells, but not in CCD-841. Such treatment also downregulated miR-29b-3p in Caco-2. Dual luciferase assays with a let-7f-5p mimic and inhibitor confirmed the binding of the miRNA to predicted binding sites in the mRNA transcript 3-UTRs of cell division cycle 25A (CDC25A), high-mobility group AT-hook-2 (HMGA2) and MYC. Therefore, we hypothesize that let-7f-5p translationally represses CDC25A, HMGA2 and MYC, thereby playing a role in the tumour-suppressive effects of sulforaphane. The apparent selectivity of let-7f-5p induction towards tumour cells would be therapeutically desirable if applicable in vivo. MiR-29b-3p is predicted to target a number of tumour-suppressing genes, further investigation of which could be informative regarding the potential of sulforaphane to suppress tumour progression.

cancer biology↗

bioRxiv2017

Discovering genetic interactions bridging pathways in genome-wide association studies

Genetic interactions have been reported to underlie phenotypes in a variety of systems, but the extent to which they contribute to complex disease in humans remains unclear. In principle, genome-wide association studies (GWAS) provide a platform for detecting genetic interactions, but existing methods for identifying them from GWAS data tend to focus on testing individual locus pairs, which undermines statistical power. Importantly, the global genetic networks mapped for a model eukaryotic organism revealed that genetic interactions often connect genes between compensatory functional modules in a highly coherent manner. Taking advantage of this expected structure, we developed a computational approach called BridGE that identifies pathways connected by genetic interactions from GWAS data. Applying BridGE broadly, we discovered significant interactions in Parkinsons disease, schizophrenia, hypertension, prostate cancer, breast cancer, and type 2 diabetes. Our novel approach provides a general framework for mapping complex genetic networks underlying human disease from genome-wide genotype data.

genetics↗

bioRxiv2017

A Caenorhabditis elegans model of adenylosuccinate lyase deficiency reveals neuromuscular and reproductive phenotypes of distinct etiology

Inborn errors of purine metabolism are rare syndromes with an array of complex phenotypes in humans. One such disorder, adenylosuccinate lyase deficiency (ASLD), is caused by a decrease in the activity of the bi-functional purine biosynthetic enzyme, adenylosuccinate lyase (ADSL). Mutations in human ADSL cause epilepsy, muscle ataxia, and autistic-like symptoms. Although the genetic basis of ASLD syndrome is known, the molecular mechanisms driving phenotypic outcome are not. Here, we characterize neuromuscular and reproductive phenotypes associated with a deficiency of adsl-1 in Caenorhabditis elegans. Characterization of the neuromuscular phenotype reveals a disruption of cholinergic transmission affecting muscular contraction. Using genetics, pharmacological supplementation, and metabolite measurements, we correlate phenotypes with distinct metabolic perturbations. The neuromuscular defect is associated with a toxic accumulation of a purine biosynthetic intermediate whereas the reproductive defect can be ameliorated by purine supplementation, indicating differing molecular mechanisms behind the phenotypes of ASLD. Because purine metabolism is highly conserved in metazoans, we suggest that similar separable metabolic perturbations result in the varied symptoms in the human disorder and that a dual-approach therapeutic strategy may be beneficial.

genetics↗