Biology subjects

Gao, Z.

Publications and source records attributed to Gao, Z..

At least 235 records · Page 13Linked to original sources

bioRxiv2019

U-PASS: unified power analysis and forensics for qualitative traits in genetic association studies

SummaryDespite the availability of existing calculators for statistical power analysis in genetic association studies, there has not been a model-invariant and test-independent tool that allows for both planning of prospective studies and systematic review of reported findings. In this work, we develop a web-based application U-PASS (Unified Power analysis of ASsociation Studies), implementing a unified framework for the analysis of common association tests for binary qualitative traits. The application quantifies the shared asymptotic power limits of the common association tests, and visualizes the fundamental statistical trade-off between risk allele frequency (RAF) and odds ratio (OR). The application also addresses the applicability of asymptotics-based power calculations in finite samples, and provides guidelines for single- SNP-based association tests. In addition to designing prospective studies, U-PASS enables researchers to retrospectively assess the statistical validity of previously reported associations.\n\nAvailability and implementationU-PASS is available as a web-based R Shiny application at https://power.stat.lsa.umich.edu. Source code is available at https://github.com/Pill-GZ/U-PASS.\n\nContactgaozheng@umich.edu\n\nSupplementary informationSupplementary data are available in the application.

genetics↗

bioRxiv2019

Complete genome sequence and evolution analysis of Psychrobacter sp. YP14 from Gammaridea Gastrointestinal Microbiota of Yap Trench

Psychrobacter sp. YP14, a moderately psychrophilic bacterium belonging to the class Gammaproteobacteria, was isolated from Gammaridea Gastrointestinal Microbiota of Yap Trench. The strain has one circular chromosome of 2,895,311 bp with a 44.66% GC content, consisting of 2333 protein-coding genes, 53 tRNA genes and 9 rRNA genes. Four plasmids were completely assembled and their sizes were 13,712 bp, 19711 bp, 36270 bp, 8194 bp, respectively. In particular, a putative open reading frame (ORF) for dienelactone hydrolase (DLH) related to degradation of chlorinated aromatic hydrocarbons. To get an better understanding of the evolution of Psychrobacter sp. YP14 in this genus, six Psychrobacter strains (G, PRwf-1, DAB_AL43B, AntiMn-1,P11G5, P2G3), with publicly available complete genome, were selected and comparative genomics analysis were performed among them. The closest phylogenetic relationship was identified between strains G and K5 based on 16s gene and ANI (average nucleotide identity) values. Analysis of the pan-genome structure found that YP14 has fewer COG clusters associated with transposons and prophage which indicates fewer sequence rearrangements compared with PRwf-1. Besides, stress response-related genes of strain YP14 demonstrates that it has less strategies to cope with extreme environment, which is consistent with its intestinal habitat. The difference of metabolism and strategies coped with stress response of YP14 are more conducive to the study of microbial survival and metabolic mechanisms in deep sea environment.

genomics↗

bioRxiv2019

Large, three-generation CEPH families reveal post-zygotic mosaicism and variability in germline mutation accumulation

The number of de novo mutations (DNMs) found in an offsprings genome is known to increase with both paternal and maternal age. But does the rate of mutation accumulation in parental gametes differ across families? To answer this question, we analyzed DNMs in 33 large, three-generation families collected in Utah by the Centre dEtude du Polymorphisme Humain (CEPH) consortium. We observed significant variability in parental age effects on DNM counts across families, ranging from 0.24 to 3.33 additional DNMs per year. Using up to 14 grandchildren in these families, we find that 3% of DNMs originated following primordial germ cell specification (PGCS) in a parent, and differ from non-mosaic germline DNMs in their mutational spectra. We also identify a median of 3 gonosomal mutations per sample in the F1 generation, which, along with post-PGCS DNMs, occur at equivalent frequencies on the paternal and maternal haplotypes. These results demonstrate that the rate of germline mutation accumulation varies among families with similar ancestry, and confirm that parental mosaicism is a substantial source of de novo mutations in children. Data and code availabilityCode used for statistical analysis and figure generation has been deposited on GitHub as a collection of annotated Jupyter Notebooks: https://github.com/quinlan-lab/ceph-dnm-manuscript. Data files containing germline de novo mutations, as well as the gonosomal and post-primordial germ cell specification (PGCS) mosaic mutations, are included with these Notebooks. To mitigate compatibility/version issues, we have also made all notebooks available in a Binder environment, accessible at the above GitHub repository.

genetics↗

bioRxiv2019

Discovery of a redox-thiol switch regulating cellular energy metabolism

Previously, we reported that increased synthesis of the gas hydrogen sulfide (H2S) during the Integrated Stress Response (ISR) induced proteome-wide cysteine-sulfhydration with the predominant modified pathway being enzymes of cellular energy metabolism (Gao, et al. 2015). Using pancreatic beta cells and quantitative proteomics in this study, we identified a Redox Thiol Switch from S-glutathionylation to S-sulfhydration and we named it, RTSGS. About half of the identified proteins are involved in energy metabolism, and one novel target was the mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2) whose catalytic Cys306was targeted by both modifications. The enzymatic activity of PCK2 was inhibited by S-glutathionylation, and this inhibition was largely reversed by S-sulfhydration. S-sulfhydration also reversed the S-glutathionylation-mediated inhibition of glucose flux, indicating a broad metabolic significance. We propose that a Redox Thiol Switch from S-glutathionylation to S-sulfhydration is a key mechanism to fine tune cellular energy metabolism in response to different levels of oxidative stress.

biochemistry↗

bioRxiv2018

Whole-tree heartwood inducing technique for Dalbergia odorifera

The dried heartwood of Dalbergia odorifera is a very important traditional Chinese medicine. In nature, D. odorifera heartwood forms slowly over several decades, and excessive harvesting has caused large-scale reductions of its wild populations. To date, there have been no studies on artificial methods to induce heartwood formation in trees that have not already begun producing heartwood. We have published a patent for a whole-tree heartwood inducing technique for D. odorifera (the \"Dodor-Wit\" method); here, we describe and analyze its efficacy. Trees in four plantations in China were treated using this method. After two years, in 2016 and 2017, they were harvested and analyzed. Average heartwood yield per tree was 3,161.95 g. Heartwood induction rate (dry heartwood weight to total dry trunk weight after peeling) was 21.60%. Average volatile oil content per tree was 1.42%. Alcohol-soluble extract of the induced heartwood was 15.77%, exceeding the Chinese Pharmacopoeia standard. This is the first report on the Dodor-Wit method and heartwood induction in D. odorifera trees aged 5-8 years. The heartwood induced by Dodor-Wit satisfies the requirements of the Chinese Pharmacopoeia. The Dodor-Wit method has an important role in solving the extreme scarcity of Chinese medicinal herbs.

plant biology↗

bioRxiv2018

Romantic jealousy is positively associated with fronto-striatal, insula and limbic responses to angry faces

Romantic jealousy is a complex social emotion combining the different primary emotions of anger, fear and sadness. Previous evidence has suggested the involvement of fronto-striatal dopaminergic circuitry in clinical pathological jealousy, although little is known about overlaps with the neural representation of primary emotions involved in non-morbid jealousy. In the current study, 85 healthy subjects underwent fMRI during resting state and an emotional face recognition paradigm. A total of 150 faces (happy, angry, fearful, sad, neutral) were presented and subjects were required to identify the expression and rate its intensity. Trait romantic jealousy was assessed using the Multidimensional Jealousy Scale. Behavioral results showed that only intensity ratings of angry faces were positively associated with subjects jealousy scores. During processing of angry versus neutral expression faces, subjects with higher jealousy scores exhibited greater activation in the right thalamus, insula, fusiform gyrus and hippocampus, left dorsal striatum and superior parietal lobule and bilateral cerebellum and inferior frontal gyrus after controlling for trait aggression and sex. Functional connectivity between the inferior frontal gyrus and caudate was also increased. No associations with resting state functional connectivity were found. Overall, the present study demonstrates an association between romantic jealousy and increased intensity ratings of angry faces as well as in activity and functional connectivity of dorsal striatal-inferior frontal circuitry. Thus, increased emotional responsivity to social threat and enhanced activity in limbic regions and dopaminergic fronto-striatal circuitry may be features of both non-morbid and pathological jealousy.

neuroscience↗

bioRxiv2018

Oxytocin facilitates self-serving rather than altruistic tendencies in competitive social interactions via orbitofrontal cortex

While the neuropeptide oxytocin can facilitate empathy and altruistic behavior it may also promote self-serving tendencies in some contexts, and it remains unclear if it would increase altruistic or self-interest behaviors when they compete within a social situation. The current between-subject, double-blind, placebo-controlled fMRI study investigated the effect of intranasal oxytocin on empathy for social exclusion using a modified online ball-tossing game which incorporated monetary rewards and both the potential to display altruistic and self-interest behaviors. Results showed that when subjects in both oxytocin and placebo groups were observing a player being excluded (victim) by other players in the game there was activation in the mentalizing network. When subjects then played both with the victim and the players who had excluded them they threw more balls to the victim player, indicative of an altruistic response. However, subjects in the oxytocin group threw more balls to the excluder players indicative of greater self-interest, since the latter would be perceived as more likely to reciprocate to maximize financial gain. This behavioral effect of oxytocin was associated with greater medial orbitofrontal cortex activation when playing with the excluders and negatively correlated with trait-altruism scores. Overall, our findings suggest that in the context of competing motivations for exhibiting altruistic or self-interest behavior oxytocin enhanced self-interest and this was associated with greater activation in frontal reward areas.

neuroscience↗

bioRxiv2018

Anterior insular cortex plays a critical role in interoceptive attention

Although accumulating evidence indicates that the anterior insular cortex (AIC) mediates interoceptive attention, which refers the attention towards physiological signals arising from the body, the necessity of the AIC in this process has not been demonstrated. Using a novel task that directs attention toward breathing rhythm, we assessed the involvement of the AIC in interoceptive attention in healthy participants using functional magnetic resonance imaging and examined the necessity of the AIC in interoceptive attention in patients with AIC lesions. We found that interoceptive attention was associated with greater AIC activation, as well as enhanced coupling between the AIC and somatosensory area along with reduced coupling between AIC and visual sensory areas. AIC activation and connectivity were predictive of individual differences in interoceptive accuracy. Importantly, AIC lesion patients showed disrupted interoceptive discrimination accuracy and sensitivity. Together, these results provide compelling evidence that AIC plays a critical role in interoceptive attention.

neuroscience↗

bioRxiv2018

Landscape of stimulation-responsive chromatin across diverse human immune cells

The immune system is controlled by a balanced interplay among specialized cell types transitioning between resting and stimulated states. Despite its importance, the regulatory landscape of this system has not yet been fully characterized. To address this gap, we collected ATAC-seq and RNA-seq data under resting and stimulated conditions for 25 immune cell types from peripheral blood of four healthy individuals, and seven cell types from three fetal thymus samples. We found that stimulation caused widespread chromatin remodeling, including a large class of response elements shared between stimulated B and T cells. Furthermore, several autoimmune traits showed significant heritability in stimulation-responsive elements from distinct cell types, highlighting the critical importance of these cell states in autoimmunity. Use of allele-specific read-mapping identified thousands of variants that alter chromatin accessibility in particular conditions. Notably, variants associated with changes in stimulation-specific chromatin accessibility were not enriched for associations with gene expression regulation in whole blood - a tissue commonly used in eQTL studies. Thus, large-scale maps of variants associated with gene regulation lack a condition important for understanding autoimmunity. As a proof-of-principle we identified variant rs6927172, which links stimulated T cell-specific chromatin dysregulation in the TNFAIP3 locus to ulcerative colitis and rheumatoid arthritis. Overall, our results provide a broad resource of chromatin landscape dynamics and highlight the need for large-scale characterization of effects of genetic variation in stimulated cells.

genomics↗

bioRxiv2018

Integrated modeling of peptide digestion and detection for the prediction of proteotypic peptides in targeted proteomics

MotivationThe selection of proteotypic peptides, i.e., detectable unique representatives of proteins of interest, is a key step in targeted shotgun proteomics. To date, much effort has been made to predict proteotypic peptides in the absence of mass spectrometry data. However, the performance of existing tools is still unsatisfactory. One crucial reason is their neglect of the close relationship between protein proteolytic digestion and peptide detection.\n\nResultsWe present an algorithm (named AP3) that firstly considers peptide digestion probability as a feature for proteotypic peptide prediction and demonstrated peptide digestion probability is the most important feature for accurate prediction of proteotypic peptides. AP3 showed higher accuracy than existing tools and accurately predicted the proteotypic peptides for a targeted proteomics assay, showing its great potential for assisting the design of targeted proteomics experiments.\n\nAvailability and ImplementationFreely available at http://fugroup.amss.ac.cn/software/AP3/AP3.html.\n\nContactyfu@amss.ac.cn or zhuyunping@gmail.com\n\nSupplementary InformationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2018

Single-cell RNA-seq reveals dynamic transcriptome profiling in human early neural differentiation

BackgroundInvestigating cell fate decision and subpopulation specification in the context of the neural lineage is fundamental to understanding neurogenesis and neurodegenerative diseases. The differentiation process of neural-tube-like rosettes in vitro is representative of neural tube structures, which are composed of radially organized, columnar epithelial cells and give rise to functional neural cells. However, the underlying regulatory network of cell fate commitment during early neural differentiation remains elusive.\n\nResultsIn this study, we investigated the genome-wide transcriptome profile of single cells from six consecutive reprogramming and neural differentiation time points and identified cellular subpopulations present at each differentiation stage. Based on the inferred reconstructed trajectory and the characteristics of subpopulations contributing the most towards commitment to the central nervous system (CNS) lineage at each stage during differentiation, we identified putative novel transcription factors in regulating neural differentiation. In addition, we dissected the dynamics of chromatin accessibility at the neural differentiation stages and revealed active c/s-regulatory elements for transcription factors known to have a key role in neural differentiation as well as for those that we suggest are also involved. Further, communication network analysis demonstrated that cellular interactions most frequently occurred among embryoid body (EB) stage and each cell subpopulation possessed a distinctive spectrum of ligands and receptors associated with neural differentiation which could reflect the identity of each subpopulation.\n\nConclusionsOur study provides a comprehensive and integrative study of the transcriptomics and epigenetics of human early neural differentiation, which paves the way for a deeper understanding of the regulatory mechanisms driving the differentiation of the neural lineage.

developmental biology↗

bioRxiv2018

Measurement of selective constraint on human gene expression

Gene expression variation is a major contributor to phenotypic variation in human complex traits. Selection on complex traits may therefore be reflected in constraint on gene expression levels. Here, we explore the effects of stabilizing selection on cis-regulatory genetic variation in humans. We analyze patterns of expression variation at copy number variants and find evidence for selection against large increases in gene expression. Using allele-specific expression (ASE) data, we further show evidence of selection against smaller-effect variants. We estimate that, across all genes, singletons in a sample of 122 individuals have approximately 2.5 x greater effects on expression variance than common variants. Despite their increased effect sizes relative to common variants, we estimate that singletons in the sample studied explain, on average, only 5% of the heritability of gene expression from cis-regulatory variants. Finally, we show that genes depleted for loss-of-function variants are also depleted for cis-eQTLs and have low levels of allelic imbalance, confirming tighter constraint on the expression levels of these genes. We conclude that constraint on gene expression is present, but has relatively weak effects on most cis-regulatory variants, thus permitting high levels of gene-regulatory genetic variation.

genomics↗

bioRxiv2018

LFAQ: towards unbiased label-free absolute protein quantification by predicting peptide quantitative factors

Mass spectrometry (MS) has become a prominent choice for large-scale absolute protein quantification, but its quantification accuracy still has substantial room for improvement. A crucial issue is the bias between the peptide MS intensity and the actual peptide abundance, i.e., the fact that peptides with equal abundance may have different MS intensities. This bias is mainly caused by the diverse physicochemical properties of peptides. Here, we propose a novel algorithm for label-free absolute protein quantification, LFAQ, which can correct the biased MS intensities by using the predicted peptide quantitative factors for all identified peptides. When validated on datasets produced by different MS instruments and data acquisition modes, LFAQ presented accuracy and precision superior to those of existing methods. In particular, it reduced the quantification error by an average of 46% for low-abundance proteins.

bioinformatics↗

bioRxiv2018

Overlooked roles of DNA damage and maternal age in generating human germline mutations

Although the textbook view is that most germline mutations arise from replication errors, when analyzing large de novo mutation datasets in humans, we find multiple lines of evidence that call that understanding into question. Notably, despite the drastic increase in the ratio of male to female germ cell divisions after the onset of spermatogenesis, even young fathers contribute three times more mutations than young mothers, and this ratio barely increases with parental ages. This surprising finding points to a substantial contribution of damage-induced mutations. Indeed, C to G transversions and CpG transitions, which together constitute one third of all mutations, show genomic distributions and sex-specific age dependencies indicative of doublestrand break repair and methylation-associated damage, respectively. Moreover, the data indicate that maternal age at conception influences the mutation rate both because of the accumulation of damage in oocytes and potentially through an influence on the number of postzygotic mutations.

genetics↗

bioRxiv2018

Deconvolution of single-cell multi-omics layers reveals regulatory heterogeneity

Integrative analysis of multi-omics layers at single cell level is critical for accurate dissection of cell-to-cell variation within certain cell populations. Here we report scCAT-seq, a technique for simultaneously assaying chromatin accessibility and the transcriptome within the same single cell. We show that the combined single cell signatures enable accurate construction of regulatory relationships between cis-regulatory elements and the target genes at single-cell resolution, providing a new dimension of features that helps direct discovery of regulatory patterns specific to distinct cell identities. Moreover, we generated the first single cell integrated maps of chromatin accessibility and transcriptome in human pre-implantation embryos and demonstrated the robustness of scCAT-seq in the precise dissection of master transcription factors in cells of distinct states during embryo development. The ability to obtain these two layers of omics data will help provide more accurate definitions of \"single cell state\" and enable the deconvolution of regulatory heterogeneity from complex cell populations.

genomics↗

bioRxiv2018

Sex- and Context-dependent Effects of Oxytocin on Social Reward Processing

We interact socially and form bonds with others because such experiences are rewarding. However, an insecure attachment style or social anxiety can reduce these rewarding effects. The neuropeptide oxytocin (OXT) may facilitate social interactions either by increasing their rewarding experience or by attenuating anxiety, although effects can be sex- and attachment-style dependent. In this study, 64 pairs of same-sex friends completed a social sharing paradigm in a double-blind, placebo-controlled, between-subject design with one friend inside an MRI scanner and the other in a remote behavioral testing room. In this way we could examine whether intranasal-OXT differentially modulated the emotional impact of social sharing and associated neural processing. Additionally, we investigated if OXT effects were modulated by sex and attachment style. Results showed that in women, but not men, OXT increased ratings for sharing stimuli with their friend but not with a stranger, particularly in the friend in the scanner. Corresponding neuroimaging results showed that OXT decreased both amygdala and insula activity as well as their functional connectivity in women when they shared with friends but had the opposite effect in men. On the other hand, OXT did not enhance responses in brain reward circuitry. In the PLC treated group amygdala responses in women when they shared pictures with their friend were positively associated with attachment anxiety and OXT uncoupled this. Our findings demonstrate that OXT facilitates the impact of sharing positive experiences with others in women, but not men, and that this is associated with differential effects on the amygdala and insula and their functional connections. Furthermore, OXT particularly reduced increased amygdala responses during sharing in individuals with higher attachment anxiety. Thus, OXT effects in this context may be due more to reduced anxiety when sharing with a friend than to enhanced social reward.

neuroscience↗

bioRxiv2018

HDL-AuNPs-BMS nanoparticle conjugates as molecularly targeted therapy for leukemia

In previous work, gold nanoparticles (AuNPs) with adsorbed high-density lipoprotein (HDL) nanoparticles have been utilized to deliver oligonucleotides, yet HDL-AuNPs functionalized with small molecule inhibitors have not been systematically explored. Here, we report an AuNP-based therapeutic system (HDL-AuNPs-BMS) for acute myeloid leukemia (AML) by delivering BMS309403 (BMS), a small molecule that selectively inhibits AML-promoting factor fatty acid binding protein 4 (FABP4). HDL-AuNPs-BMS are synthesized using a gold nanoparticle as template to control conjugate size and ensure a spherical shape to engineer HDL-like nanoparticle containing BMS. The zeta potential and size of the HDL-AuNPs obtained from transmission electron microscopy (TEM) show that the nanoparticles are electrostatically stable and 25 nm in diameter. Functionally, compared to free drug, HDL-AuNPs-BMS conjugates are more readily internalized by AML cells and have more pronounced effect on downregulation of DNA methyltransferase 1 (DNMT1), reduction of global DNA methylation, and restoration of epigenetically-silenced tumor suppressor p15INK4b coupled with AML growth arrest. Importantly, systemic administration of HDL-AuNPs-BMS conjugates into AML-bearing mice inhibits DNMT1-dependent DNA methylation, induces AML cell differentiation and diminishes AML disease progression without obvious side effects. In summary, these data, for the first time, demonstrate HDL-AuNPs as an effective delivery platform with great potential to attach distinct inhibitors, and HDL-AuNPs-BMS conjugates as a promising therapeutic platform to treat leukemia.

cancer biology↗

bioRxiv2017

Frequent Non-Allelic Gene Conversion On The Human Lineage And Its Effect On The Divergence Of Gene Duplicates

Gene conversion is the copying of genetic sequence from a \"donor\" region to an \"acceptor\". In non-allelic gene conversion (NAGC), the donor and the acceptor are at distinct genetic loci. Despite the role NAGC plays in various genetic diseases and the concerted evolution of gene families, the parameters that govern NAGC are not well-characterized. Here, we survey duplicate gene families and identify converted tracts in 46% of them. These conversions reflect a large GC-bias of NAGC. We develop a sequence evolution model that leverages substantially more information in duplicate sequences than used by previous methods and use it to estimate the parameters that govern NAGC in humans: a mean converted tract length of 250bp and a probability of 2.5x10-7 per generation for a nucleotide to be converted (an order of magnitude higher than the point mutation rate). Despite this high baseline rate, we show that NAGC slows down as duplicate sequences diverge--until an eventual \"escape\" of the sequences from its influence. As a result, NAGC has a small average effect on the sequence divergence of duplicates. This work improves our understanding of the NAGC mechanism and the role that it plays in the evolution of gene duplicates.

genomics↗