Biology subjects

Su, Z.

Publications and source records attributed to Su, Z..

140 records · Page 8Linked to original sources

bioRxiv2019

Source of additive genetic variance of important traits

Fishers fundamental theorem of natural selection predicts no additive variance of fitness in a natural population. Consistently, observations in a variety of wild populations show virtually no narrow-sense heritability (h2) for traits important to fitness. However, counterexamples are occasionally reported, calling for a deeper understanding on the evolution of additive variance. In this study we propose adaptive divergence followed by population admixture as a source of the additive genetic variance of evolutionarily important traits. We experimentally tested the hypothesis by examining a panel of ~1,000 yeast segregants produced by a hybrid of two yeast strains that experienced adaptive divergence. We measured over 400 yeast cell morphological traits and found a strong positive correlation between h2 and evolutionary importance. Because adaptive divergence followed by population admixture could happen constantly, particularly in some species such as humans, the finding reconciles the observation of abundant additive variances in evolutionarily important traits with Fishers fundamental theorem of natural selection. It also suggests natural selection may effectively promote rather than suppress additive genetic variance in species with wide geographic distribution and strong migratory capacity.

evolutionary biology↗

bioRxiv2019

The role of ANGIOGENIN, or lack thereof, in the generation of stress-induced tRNA halves and of smaller tRNA fragments that enter Argonaute complexes

Overexpressed Angiogenin (ANG) cleaves tRNA anticodons to produce tRNA halves similar to those produced in response to stress, but it is not clear whether endogenous ANG is essential for producing the stress-induced tRNA halves. It is also not clear whether smaller tRNA fragments (tRFs) are generated from the tRNA halves. Global short RNAseq experiments reveal that ANG over-expression selectively cleaves a subset of tRNAs (tRNAGlu, tRNAGly, tRNALys, tRNAVal, tRNAHis, tRNAAsp and tRNASeC) to produce tRNA halves and 26-30 bases long tRF-5s. Surprisingly, knockout of ANG reveals that the majority of stress-induced tRNA halves except 5 half from tRNAHisGTG and 3 half from tRNAAspGTC are ANG-independent, suggesting there are other RNases that can produce tRNA halves. The 17-25 bases long tRF-3s and tRF-5s that could enter into Argonaute complexes are not induced by ANG overexpression, suggesting that they are generated independently from tRNA halves. Consistent with this, knockout of ANG did not decrease tRF-3 levels or gene-silencing activity. Therefore ANG cleaves specific tRNAs, is not the only RNAse that creates tRNA halves and the shorter tRFs are not generated from the tRNA halves or from independent tRNA cleavage by ANG.

molecular biology↗

bioRxiv2019

Measurement of Atom Resolvability in CryoEM Maps with Q-scores

CryoEM density maps are now at the point where resolvability of individual atoms can be achieved. However, resolvability is not necessarily uniform throughout the map. We introduce a quantitative parameter to characterize the resolvability of individual atoms in cryoEM maps, the map Q-score. Q-scores can be calculated for atoms in proteins, nucleic acids, water, ligands, and other solvent atoms, using models fitted to or derived from cryoEM maps. Q-scores can also be averaged to represent larger features such as entire residues and nucleotides. Averaged over entire models, Q-scores correlate very well with the estimated resolution of cryoEM maps for both protein and RNA. Assuming the models they are calculated from are well-fitted to the map, Q-scores can thus be used as another measure to indicate resolvability of features in cryoEM maps at various scales, from entire complexes down to individual atoms. Q-score analysis of multiple cryoEM maps of the same proteins derived from different labs confirms reproducibility of structural features down to water and ion atoms.

biochemistry↗

bioRxiv2019

Ribosolve: Rapid determination of three-dimensional RNA-only structures

The discovery and design of biologically important RNA molecules is dramatically outpacing three-dimensional structural characterization. To address this challenge, we present Ribosolve, a hybrid method integrating moderate-resolution cryo-EM maps, chemical mapping, and Rosetta computational modeling, and demonstrate its application to thirteen previously unknown 119-to 338-nucleotide protein-free RNA-only structures: full-length Tetrahymena ribozyme, hc16 ligase with and without substrate, full-length V. cholerae and F. nucleatum glycine riboswitch aptamers with and without glycine, Mycobacterium SAM-IV riboswitch with and without S-adenosylmethionine, and computer-designed spinach-TTR-3, eterna3D-JR_1, and ATP-TTR-3 with and without AMP. Blind challenges, prospective compensatory mutagenesis, internal controls, and simulation benchmarks validate the Ribosolve models and establish that modeling convergence is quantitatively predictive of model accuracy. These results demonstrate that RNA-only 3D structure determination can be rapid and routine.

biophysics↗

bioRxiv2019

Normal development and fertility of Fut1, Fut2, and Sec1 triple knockout mice

The fucose alpha(1,2) galactose structure (H antigen) is synthesized by 1,2 fucosyltransferases Fut1, Fut2 and Sec1. H antigen has been reported to be involved in cancer progression, neurite migration, synaptic plasticity, host-microbe interaction, blastocyst implantation, and the maintenance of gut microbiome. Genetic depletion of Fut1 or Fut2 only cause defects of alpha1,2 fucosylation in limited tissues because of enzyme redundancy. In this study, we generated mice with deficiencies in Fut1, Fut2, and Sec1 genes to deplete H antigen through BAC Engineering for the generation of ES Cell-Targeting construct. The homogenous triple knockout mice showed no significant decrease of viability or development. Mass spectrometry and Western blot analysis confirmed the absence of H blood group antigen in multiple organs. These results indicate normal development and fertility of mice devoid of blood group H. The fine pathophysiological alterations in these mice remain to be carefully studied, and they may serve as valuable tools to study gut microbiome and host-microbe interactions.

biochemistry↗

bioRxiv2019

Tissue-specific changes in the RNA structurome mediate salinity response in Arabidopsis

RNA structures are influenced by their physico-chemical environment. Few studies have assessed genome-wide impacts of abiotic stresses on in vivo RNA structure, however, and none have investigated tissue-specificity. We applied our Structure-seq method to assess in vivo mRNA secondary structure in Arabidopsis shoots and roots under control and salt stress conditions. Structure-seq utilizes dimethyl sulfate (DMS) for in vivo transcriptome-wide covalent modification of accessible As and Cs, i.e. those lacking base pairing and protection. Tissue type was a strong determinant of DMS reactivity, indicating tissue-specificity of RNA structuromes. Both tissues exhibited a significant inverse correlation between salt stress-induced changes in transcript reactivity and changes in transcript abundance, implicating changes in RNA structure and accessibility in transcriptome regulation. In mRNAs wherein the 5UTR, CDS and 3UTR concertedly increased or decreased in mean reactivity under salinity, this inverse correlation was more pronounced, suggesting that concordant structural changes across the mRNA have the greatest impact on abundance. Transcripts with the greatest and least salt stress-induced changes in DMS reactivity were enriched in genes encoding stress-related functions and included housekeeping functions, respectively. We conclude that secondary structure regulates mRNA abundance, thereby contributing to tissue specificity of the transcriptome and its dynamic adjustment under stress.\n\nOne Sentence Summary: Transcriptome-wide methods reveal dynamic tissue-specific and salt stress-dependent modulation of mRNA accessibility and structure, and correlated mRNA abundance changes.

plant biology↗

bioRxiv2019

Serial femtosecond X-ray diffraction of HIV-1 Gag MA-IP6 microcrystals at ambient temperature

The Human immunodeficiency virus-1 (HIV-1) matrix (MA) domain is involved in the highly regulated assembly process of the virus particles that occur at the host cells plasma membrane. High-resolution structures of the MA domain determined using cryo X- ray crystallography have provided initial insights into the possible steps in the viral assembly process. However, these structural studies have relied on large and frozen crystals in order to reduce radiation damage caused by the intense X-rays. Here, we report the first XFEL study of the HIV-1 MA domains interaction with inositol hexaphosphate (IP6), a phospholipid headgroup mimic. We also describe the purification, characterization and microcrystallization of two MA crystal forms obtained in the presence of IP6. In addition, we describe the capabilities of serial femtosecond X-ray crystallography (SFX) using X-ray free-electron laser (XFEL) to elucidate the diffraction data of MA-IP6 complex microcrystals in liquid suspension at ambient temperature. Two different microcrystal forms of MA-IP6 complex both diffracted to beyond 3.5 [A] resolution, demonstrating the feasibility of using SFX to study the complexes of MA domain of HIV-1 Gag polyprotein with IP6 at near-physiological temperatures. Further optimization of the experimental and data analysis procedures will lead to better understanding of the MA domain of HIV-1 Gag and IP6 interaction at high resolution and provide basis for optimization of the lead compounds for efficient inhibition of the Gag protein recruitment to the plasma membrane prior to virion formation.

biophysics↗

bioRxiv2018

Deciphering epigenomic code for cell differentiation using deep learning

Epigenomic markers, such as histone modifications, play important roles in cell fate determination and type maintenance during cell differentiation. Although genomic sequence plays a crucial role in establishing the unique epigenome in each cell type produced during cell differentiation, little is known about the sequence determinants that lead to the unique epigenomes of the cells. Here, using a dataset of six histone markers measured in four human CD4+ T cell types produced at different stages of T cell development, we showed that two types of highly accurate deep convolutional neural networks (CNNs) constructed for each cell type and for each histone marker are a powerful strategy to uncover the sequence determinants of the various histone modification patterns in difference cell types. We found that sequence motifs learned by the CNN models are highly similar to known binding motifs of transcription factors known to play important roles in CD4+ T cell differentiation. Our results suggest that both the unique histone modification patterns in each cell type and the different patterns of the same histone marker in different cell types are determined by a set of motifs with unique combinations. Interestingly, the level of shared few motifs learned in the different cell models reflect the lineage relationships of the cells, while the level of few shared motifs learned in different histone marker models reflect their functional relationships. Furthermore, using these models, we can predict the importance of the learned motifs and their interactions in determining specific histone marker patterns in the cell types.

bioinformatics↗

bioRxiv2018

New genetic variants associated with major adverse cardiovascular events in patients with acute coronary syndromes and treated with clopidogrel and aspirin

ImportanceAlthough a few studies have reported the effects of several polymorphisms on major adverse cardiovascular events (MACE) in patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI), these genotypes account for only a small fraction of the variation and evidence is insufficient. This study aims to identify new genetic variants associated with MACE by large-scale sequencing data.\n\nObjectiveTo identify the genetic variants that caused MACE.\n\nDesignAll patients in this study were allocated to dual antiplatelet therapy for up to 12 months and have the follow-up duration of 18 months.\n\nSettingA two-stage association study was performed.\n\nParticipantsWe evaluated the associations of genetic variants and MACE in 1961 patients with ACS undergoing PCI (2009-2012), including high-depth whole exome sequencing of 168 patients in the discovery cohort and high-depth targeted sequencing of 1793 patients in the replication cohort.\n\nMain Outcomes and MeasureThe primary clinical efficacy endpoint was the major adverse cardiovascular events (MACE) composite endpoint, including cardiovascular death, myocardial infarction (MI), stroke (CT or MR scan confirmed) and repeated revascularization (RR).\n\nResultsWe discovered and confirmed six new genotypes associated with MACE in patients with ACS. Of which, rs17064642 at MYOM2 increased the risk of MACE (hazard ratio [HR] 2.76; P = 2.95 x 10-9) and reached genome-wide significance. The other five suggestive variants were KRTAP10-4 (rs201441480), WDR24 (rs11640115), ECHS1 (rs140410716), AGAP3 (rs75750968) and NECAB1 (rs74569896). Notably, the expressions of MYOM2 and ECHS1 are down-regulated in both animal models and patients with phenotypes related to MACE. Importantly, we developed the first superior classifier for predicting MACE and achieved high predictive accuracy (0.809).\n\nConclusions and RelevanceWe identified six new genotypes associated with MACE and developed a superior classifier for predicting MACE. Our findings shed light on the pathogenesis of cardiovascular outcomes and may help clinician to make decision on the therapeutic intervention for ACS patients.\n\nTrial RegistrationThis study has been registered in the Chinese Clinical Trial Registry (http://www.chictr.org.cn, Registration number: ChiCTR-OCH-11001198).

genetics↗

bioRxiv2018

BicGO: a new biclustering algorithm based on global optimization

Recognizing complicated biclusters submerged in large scale datasets (matrix) has been being a highly challenging problem. We introduce a biclustering algorithm BicGO consisting of two separate strategies which can be selectively used by users. The BicGO which was developed based on global optimization can be implemented by iteratively answering if a real number belongs to a given interval. Tested on various simulated datasets in which most complicated and most general trend-preserved biclusters were submerged, BicGO almost always extracted all the actual bicluters with accuracy close to 100%, while on real datasets, it also achieved an incredible superiority over all the salient tools compared in this article. As far as we know, the BicGO is the first tool capable of identifying any complicated (e.g., constant, shift, scale, shift-scale, order-preserved, trend-preserved, etc), any shapes (narrow or broad) of biclusters with overlaps allowed. In addition, it is also highly parsimonious in the usage of computing resources. The BicGO is available at https://www.dropbox.com/s/hsj3j96rekoks5n/BicGO.zip?dl=0 for free download.

bioinformatics↗

bioRxiv2018

Ultra-fast and accurate motif finding in large ChIP-seq datasets reveals transcription factor binding patterns

The availability of a large volume of chromatin immunoprecipitation followed by sequencing (ChIP-seq) datasets for various transcription factors (TF) has provided an unprecedented opportunity to identify all functional TF binding motifs clustered in the enhancers in genomes. However, the progress has been largely hindered by the lack of a highly efficient and accurate tool that is fast enough to find not only the target motifs, but also cooperative motifs contained in very large ChIP-seq datasets with a binding peak length of typical enhancers ([~] 1,000 bp). To circumvent this hurdle, we herein present an ultra-fast and highly accurate motif-finding algorithm, ProSampler, with automatic motif length detection. ProSampler first identifies significant k-mers in the dataset and combines highly similar significant k-mers to form preliminary motifs. ProSampler then merges preliminary motifs with subtle similarity using a novel graph-based Gibbs sampler to find core motifs. Finally, ProSampler extends the core motifs by applying a two-proportion z-test to the flanking positions to identify motifs longer than k. As the number of preliminary motifs is much smaller than that of k-mers in a dataset, we greatly reduce the search space of the Gibbs sampler compared with conventional ones. By storing flanking sequences in a hash table, we avoid extensive IO and the necessity of examining all lengths of motifs in an interval. When evaluated on both synthetic and real ChIP-seq datasets, ProSampler runs orders of magnitude faster than the fastest existing tools while more accurately discovering primary motifs as well as cooperative motifs than do the best existing tools. Using ProSampler, we revealed previously unknown complex motif occurrence patterns in large ChIP-seq datasets, thereby providing insights into the mechanisms of cooperative TF binding for gene transcriptional regulation. Therefore, by allowing fast and accurate mining of the entire ChIP-seq datasets, ProSampler can greatly facilitate the efforts to identify the entire cis-regulatory code in genomes.

bioinformatics↗

bioRxiv2018

Myricetin Attenuates LPS-induced Inflammation in RAW 264.7 Macrophages and Mouse Models

BackgroundMyricetin has been demonstrated to inhibit inflammation in a variety of diseases, but little is known about its characters in acute lung injury (ALI). In this study, we aimed to investigate the protective effects of myricetin on inflammation in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and a LPS-induced lung injury model.\n\nMethodsSpecifically, we investigated its effects on lung edema and histological damage by lung W/D weight ratio, HE staining and Evans Blue dye. Then macrophage activation was detected by evaluating the TNF-, IL-6 and IL-1{beta} mRNA and protein iNOS and COX-2. Myricetin was used to detect the impact on the inflammatory responses in LPS-induced RAW264.7 cells with the same manners in mouse model. Finally, NF-{kappa}B and MAPK signaling pathways were investigated with Western blot assay in LPS-induced RAW264.7 cells.\n\nResultsMyricetin significantly inhibited the production of the pro-inflammatory cytokines in vitro and in vivo. The in vivo experiments showed that pretreatment with Myricetin markedly attenuated the development of pulmonary edema, histological severities and macrophage activation in mice with ALI. The underlying mechanisms were further demonstrated in vitro that myricetin exerted an anti-inflammatory effect through suppressing the NF-{kappa}B p65 and AKT activation in NF-{kappa}B pathway and JNK, p-ERK and p38 in mitogen-activated protein kinases signaling pathway.\n\nConclusionMyricetin alleviated ALI by inhibiting macrophage activation, and inhibited inflammation in vitro and in vivo. It may be a potential therapeutic candidate for the prevention of inflammatory diseases.

cell biology↗

bioRxiv2017

Unexpected CRISPR off-target mutation pattern in vivo are not typicallygermline-like

To the EditorSchaefer et al.1 (referred to as Study_1) recently presented the provocative conclusion that CRISPR-Cas9 nuclease can induce many unexpected off-target mutations across the genome that arise from the sites with poor homology to the gRNA. As Wilson et al.2 pointed out, however, the selection of a co-housed mouse as the control is insufficient to attribute the observed mutation differences between the CRISPR-treated mice and control mice. Therefore, the causes of these mutations need to be further investigated. In 2015, Iyer et al.3 (referred to as Study_2) used Cas9 and a pair of sgRNAs to mutate the Ar gene in vivo and off-target mutations were investigated by comparison the control mice and the offspring of the modified mice. After analyzing the whole genome sequencing (WGS) of the offspring and the control mice, they claimed that off-target mutations are rare from CRISPR-Cas9 engineering. Notably, their study only focused on indel off-target mutations. We re-analyzed the WGS data of these two studies and detected both single nucleotide variants (SNVs) and indel mutations.

genetics↗

bioRxiv2017

Global Gene Repression By Dicer-Independent tRNA Fragments

tRNA derived RNA fragments (tRFs) is an emerging group of small RNAs as abundant as miRNAs, and yet their roles are not well understood. Here, we focus on endogenous tRFs (18-22 bases) derived from 3 end of human mature tRNAs (tRF-3) and their functions in gene repression. tRF-3 levels increase upon parental tRNA over-expression or tRNA induction by c-Myc oncogene activation. Elevated tRF-3 levels lead to repression of target genes with a sequence complementary to the tRF-3 in the 3 UTR. The tRF-3-mediated repression is Dicer-independent, Argonaute-dependent and the targets are recognized by 5 seed sequence rules similar to miRNAs. Furthermore, tRF-3s associate with GW proteins in P-bodies. RNA-seq identifies the endogenous target genes of tRF-3s that are specifically repressed upon tRF-3 induction. Overall, our analysis shows Dicer-independent tRF-3s, generated upon tRNA upregulation such as c-Myc overexpression, regulate gene expression globally through Argounate via seed sequence matches.

molecular biology↗