Biology subjects

He, Y.

Publications and source records attributed to He, Y..

640 records · Page 36Linked to original sources

bioRxiv2017

Pan-cancer study of heterogeneous RNA aberrations

We present the most comprehensive catalogue of cancer-associated gene alterations through characterization of tumor transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes project. Using matched whole-genome sequencing data, we attributed RNA alterations to germline and somatic DNA alterations, revealing likely genetic mechanisms. We identified 444 associations of gene expression with somatic non-coding single-nucleotide variants. We found 1,872 splicing alterations associated with somatic mutation in intronic regions, including novel exonization events associated with Alu elements. Somatic copy number alterations were the major driver of total gene and allele-specific expression (ASE) variation. Additionally, 82% of gene fusions had structural variant support, including 75 of a novel class called \"bridged\" fusions, in which a third genomic location bridged two different genes. Globally, we observe transcriptomic alteration signatures that differ between cancer types and have associations with DNA mutational signatures. Given this unique dataset of RNA alterations, we also identified 1,012 genes significantly altered through both DNA and RNA mechanisms. Our study represents an extensive catalog of RNA alterations and reveals new insights into the heterogeneous molecular mechanisms of cancer gene alterations.

genomics↗

bioRxiv2017

Systematic mapping of chromatin state landscapes during mouse development

Embryogenesis requires epigenetic information that allows each cell to respond appropriately to developmental cues. Histone modifications are core components of a cells epigenome, giving rise to chromatin states that modulate genome function. Here, we systematically profile histone modifications in a diverse panel of mouse tissues at 8 developmental stages from 10.5 days post conception until birth, performing a total of 1,128 ChIP-seq assays across 72 distinct tissue-stages. We combine these histone modification profiles into a unified set of chromatin state annotations, and track their activity across developmental time and space. Through integrative analysis we identify dynamic enhancers, reveal key transcriptional regulators, and characterize the role of chromatin-based repression in developmental gene regulation. We also leverage these data to link enhancers to putative target genes, revealing connections between coding and non-coding sequence variation in disease etiology. Our study provides a compendium of resources for biomedical researchers, and achieves the most comprehensive view of embryonic chromatin states to date.

genomics↗

bioRxiv2017

Spatiotemporal DNA Methylome Dynamics of the Developing Mammalian Fetus

Genetic studies have revealed an essential role for cytosine DNA methylation in mammalian development. However, its spatiotemporal distribution in the developing embryo remains obscure. Here, we profiled the methylome landscapes of 12 mouse tissues/organs at 8 developmental stages spanning from early embryogenesis to birth. Indepth analysis of these spatiotemporal epigenome maps systematically delineated ~2 million methylation variant regions and uncovered widespread methylation dynamics at nearly one-half million tissue-specific enhancers, whose human counterparts were enriched for variants involved in genetic diseases. Strikingly, these predicted regulatory elements predominantly lose CG methylation during fetal development, whereas the trend is reversed after birth. Accumulation of non-CG methylation within gene bodies of key developmental transcription factors coincided with their transcriptional repression during later stages of fetal development. These spatiotemporal epigenomic maps provide a valuable resource for studying gene regulation during mammalian tissue/organ progression and for pinpointing regulatory elements involved in human developmental diseases.

genomics↗

bioRxiv2017

Comprehensive genome and transcriptome analysis reveals genetic basis for gene fusions in cancer

Gene fusions are an important class of cancer-driving events with therapeutic and diagnostic values, yet their underlying genetic mechanisms have not been systematically characterized. Here by combining RNA and whole genome DNA sequencing data from 1188 donors across 27 cancer types we obtained a list of 3297 high-confidence tumour-specific gene fusions, 82% of which had structural variant (SV) support and 2372 of which were novel. Such a large collection of RNA and DNA alterations provides the first opportunity to systematically classify the gene fusions at a mechanistic level. While many could be explained by single SVs, numerous fusions involved series of structural rearrangements and thus are composite fusions. We discovered 75 fusions of a novel class of inter-chromosomal composite fusions, termed bridged fusions, in which a third genomic location bridged two different genes. In addition, we identified 522 fusions involving non-coding genes and 157 ORF-retaining fusions, in which the complete open reading frame of one gene was fused to the UTR region of another. Although only a small proportion (5%) of the discovered fusions were recurrent, we found a set of highly recurrent fusion partner genes, which exhibited strong 5 or 3 bias and were significantly enriched for cancer genes. Our findings broaden the view of the gene fusion landscape and reveal the general properties of genetic alterations underlying gene fusions for the first time.

genetics↗

bioRxiv2017

Demoralization among cancer patients in mainland China: validity of the Demoralization Scale (DS)

Demoralization, characterized by hopelessness, helplessness, and loss of meaning and purpose, reflects existential distress. The objectives is To assess the validity of a Mainland Chinese versions of the demoralization scale (MC-DS) for using with Mainland Chinese cancer patients. In-patients sequentially recruited from a specialist tertiary-level cancer hospital in Beijing between January 2016-April 2016 completed Demoralization Scale, (DS) Patient Health Questionnaire-9 (PHQ-9), Revised Life Orientation Test (CLOT-R), Beck Hopelessness Scale (BHS), and provided sociodemographic and clinical information. We determined DS factor structure and convergent and divergent validity. 296/424 (70.0%) participants reported mean DS score=30.42(SD=13.00). EFA identified 3-factors explaining 21.4%, 17.8%, and 10.6% respectively of observed variance. Respective Cronbach Alphas were 0.88, 0.84, and 0.64 (0.90 full-scale). Convergent was shown by PHQ-9 scores correlating with Factor 2 (r=0.606), and BHS and C-LOT-R scores correlating (r=0.632,r=0.407 respectively) with Factor 1. Dichotomizing demoralization (high >30, low[less double equals]30) cross-tabulated against PHQ-9 score (mood) scores revealed 47% of patients exceeded demoralization cut-off, 60% of whom were not depressed. Using mean value{+/-}SD indicated demoralization cutoffs at <17.4 (low), 17.4-43.4 (medium) and >43.4 (high). Overall 71% met criteria for medium demoralization, and 15% for high demoralization. Sixty percent of all medium demoralization patients were not depressed, but only 5% of high demoralization patients were not depressed. The conclusion is that the Mainland Chinese Demoralization Scale is useful for detecting mild-to-moderate demoralization in cancer patients but at higher scores has poor specificity against depression.

epidemiology↗

bioRxiv2017

Changing geographic patterns and risk factors for avian influenza A(H7N9) infection in China

The 5th epidemic wave in 2016-2017 of avian influenza A(H7N9) virus in China caused more human cases than any previous waves but the factors that may explain the recent range expansion and surge in incidence remain unknown. We investigated the effect of anthropogenic, poultry and wetland information and of market closures on all epidemic waves (1-5). Poultry predictor variables recently became much more important than before, supporting the assumption of much wider H7N9 transmission in the chicken reservoir, that could be linked to increases in pathogenicity. We show that the future range expansion of H7N9 to northern China may translate into a higher risk of coinciding peaks with those of seasonal influenza, leading to a higher risk of reassortments. Live-poultry market closures are showed to be effective in reducing the local incidence rates of H7N9 human cases, but should be paired with other prevention and control measures to prevent transmission.

epidemiology↗

bioRxiv2017

Stem cell intrinsic, Seven-up-triggered temporal factor gradients diversify intermediate neural progenitors

Drosophila type II neuroblasts produce numerous neurons and glia due to transiently amplifying, intermediate neural progenitors (INP). Consecutively born INPs produce morphologically distinct progeny, presumably due to temporal patterning in type II neuroblasts. We therefore profiled type II neuroblasts transcriptome across time. Our results reveal opposing temporal gradients of Imp and Syp RNA-binding proteins (descending and ascending, respectively). Maintaining Imp expression throughout brain development expands the number of neurons/glia with early temporal fate at the expense of cells with late fate. Conversely, precocious upregulation of Syp reduces the number of cells with early fate. Further, we reveal that the transcription factor, Seven-up initiates progression of the Imp/Syp gradients. Interestingly, genetic manipulations that fix Imp or Syp levels still yield progeny with a small range of early fates. We propose that the Seven-up-initiated Imp/Syp gradients create coarse temporal windows within type II neuroblasts to pattern INPs, which subsequently undergo fine-tuned subtemporal patterning.

neuroscience↗

bioRxiv2017

Precise insertion and guided editing of higher plant genomes using Cpf1 CRISPR nucleases

Introduction Paragraph Introduction Paragraph Main Body Online Methods References Precise genome editing of plants has the potential to reshape global agriculture through the targeted engineering of endogenous pathways or the introduction of new traits. To develop a CRISPR nuclease-based platform that would enable higher efficiencies of precise gene insertion or replacement, we screened the Cpf1 nucleases from Francisella novicida and Lachnospiraceae bacterium ND2006 for their capacity to induce targeted gene insertions via homology directed repair. Both nucleases, in the presence of guide RNA and repairing DNA template, were demonstrated to generate precise gene insertions as well as indel mutations at the target site in the rice genome. The frequency of targeted insertions for these Cpf1 nucleases, up to 8%, is higher than most other genome editi ...

plant biology↗

bioRxiv2017

JDINAC: joint density-based non-parametric differential interaction network analysis and classification using high-dimensional sparse omics data

MotivationA complex disease is usually driven by a number of genes interwoven into networks, rather than a single gene product. Network comparison or differential network analysis has become an important means of revealing the underlying mechanism of pathogenesis and identifying clinical biomarkers for disease classification. Most studies, however, are limited to network correlations that mainly capture the linear relationship among genes, or rely on the assumption of a parametric probability distribution of gene measurements. They are restrictive in real application.\n\nResultsWe propose a new Joint density based non-parametric Differential Interaction Network Analysis and Classification (JDINAC) method to identify differential interaction patterns of network activation between two groups. At the same time, JDINAC uses the network biomarkers to build a classification model. The novelty of JDINAC lies in its potential to capture non-linear relations between molecular interactions using high-dimensional sparse data as well as to adjust confounding factors, without the need of the assumption of a parametric probability distribution of gene measurements. Simulation studies demonstrate that JDINAC provides more accurate differential network estimation and lower classification error than that achieved by other state-of-the-art methods. We apply JDINAC to a Breast Invasive Carcinoma dataset, which includes 114 patients who have both tumor and matched normal samples. The hub genes and differential interaction patterns identified were consistent with existing experimental studies. Furthermore, JDINAC discriminated the tumor and normal sample with high accuracy by virtue of the identified biomarkers. JDINAC provides a general framework for feature selection and classification using high-dimensional sparse omics data.\n\nAvailabilityR scripts available at https://github.com/jijiadong/JDINAC\n\nContactlxie@iscb.org\n\nSupplementary informationSupplementary data are available at bioRxiv online.

systems biology↗

bioRxiv2017

Stability and function of a putative microtubule organizing center in the human parasite Toxoplasma gondii

The organization of the microtubule cytoskeleton is dictated by microtubule nucleators or organizing centers. Toxoplasma gondii, an important human parasite, has an array of 22 regularly spaced cortical microtubules stemming from a hypothesized organizing center, the apical polar ring. Here, we examine the functions of the apical polar ring by characterizing two of its components, KinesinA and APR1, and discovered that its putative role in templating can be separated from its mechanical stability. Parasites that lack both KinesinA and APR1 ({Delta}kinesinA{Delta}apr1) are capable of generating 22 cortical microtubules. However, the apical polar ring is fragmented in live{Delta} kinesinA{Delta}apr1 parasites, and is undetectable by electron microscopy after detergent extraction. Disintegration of the apical polar ring results in the detachment of groups of microtubules from the apical end of the parasite. These structural defects are linked to a diminished ability of the parasite to move and to invade host cells, as well as decreased secretion of effectors important for these processes. Together, the findings demonstrate the importance of the structural integrity of the apical polar ring and the microtubule array in the Toxoplasma lytic cycle, which is responsible for massive tissue destruction in acute toxoplasmosis.

cell biology↗