ScDesign2: a transparent simulator that generates high-fidelity single-cell gene expression count data with gene correlations captured.
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ABSTRACT:
SUBMITTER: Sun T
PROVIDER: S-EPMC8147071 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Single-cell Hi-C technology provides an unprecedented opportunity to reveal chromatin structure in individual cells. However, high sequencing cost impedes the generation of biological Hi-C data with high sequencing depths and multiple replicates for downstream analysis. Here, we developed a single-cell Hi-C simulator (scHi-CSim) that generates high-fidelity data for benchmarking. scHi-CSim merges neighboring cells to overcome the sparseness of data, samples interactions in distance-stratified chromosomes to maintain the heterogeneity of single cells, and estimates the empirical distribution of restriction fragments to generate simulated data. We demonstrated that scHi-CSim can generate high-fidelity data by comparing the performance of single-cell clustering and detection of chromosomal high-order structures with raw data. Furthermore, scHi-CSim is flexible to change sequencing depth and the number of simulated replicates. We showed that increasing sequencing depth could improve the accuracy of detecting topologically associating domains. We also used scHi-CSim to generate a series of simulated datasets with different sequencing depths to benchmark scHi-C clustering methods.
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Project description:BackgroundIn the last few years, 16S rRNA gene sequencing (16S rDNA-seq) has seen a surprisingly rapid increase in election rate as a methodology to perform microbial community studies. Despite the considerable popularity of this technique, an exiguous number of specific tools are currently available for proper 16S rDNA-seq count data preprocessing and simulation. Indeed, the great majority of tools have been developed adapting methodologies previously used for bulk RNA-seq data, with poor assessment of their applicability in the metagenomics field. For such tools and the few ones specifically developed for 16S rDNA-seq data, performance assessment is challenging, mainly due to the complex nature of the data and the lack of realistic simulation models. In fact, to the best of our knowledge, no software thought for data simulation are available to directly obtain synthetic 16S rDNA-seq count tables that properly model heavy sparsity and compositionality typical of these data.ResultsIn this paper we present metaSPARSim, a sparse count matrix simulator intended for usage in development of 16S rDNA-seq metagenomic data processing pipelines. metaSPARSim implements a new generative process that models the sequencing process with a Multivariate Hypergeometric distribution in order to realistically simulate 16S rDNA-seq count table, resembling real experimental data compositionality and sparsity. It provides ready-to-use count matrices and comes with the possibility to reproduce different pre-coded scenarios and to estimate simulation parameters from real experimental data. The tool is made available at http://sysbiobig.dei.unipd.it/?q=Software#metaSPARSimand https://gitlab.com/sysbiobig/metasparsim.ConclusionmetaSPARSim is able to generate count matrices resembling real 16S rDNA-seq data. The availability of count data simulators is extremely valuable both for methods developers, for which a ground truth for tools validation is needed, and for users who want to assess state of the art analysis tools for choosing the most accurate one. Thus, we believe that metaSPARSim is a valuable tool for researchers involved in developing, testing and using robust and reliable data analysis methods in the context of 16S rRNA gene sequencing.
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Project description:BackgroundMany approaches have been developed to overcome technical noise in single cell RNA-sequencing (scRNAseq). As researchers dig deeper into data-looking for rare cell types, subtleties of cell states, and details of gene regulatory networks-there is a growing need for algorithms with controllable accuracy and fewer ad hoc parameters and thresholds. Impeding this goal is the fact that an appropriate null distribution for scRNAseq cannot simply be extracted from data when ground truth about biological variation is unknown (i.e., usually).ResultsWe approach this problem analytically, assuming that scRNAseq data reflect only cell heterogeneity (what we seek to characterize), transcriptional noise (temporal fluctuations randomly distributed across cells), and sampling error (i.e., Poisson noise). We analyze scRNAseq data without normalization-a step that skews distributions, particularly for sparse data-and calculate p-values associated with key statistics. We develop an improved method for selecting features for cell clustering and identifying gene-gene correlations, both positive and negative. Using simulated data, we show that this method, which we call BigSur (Basic Informatics and Gene Statistics from Unnormalized Reads), captures even weak yet significant correlation structures in scRNAseq data. Applying BigSur to data from a clonal human melanoma cell line, we identify thousands of correlations that, when clustered without supervision into gene communities, align with known cellular components and biological processes, and highlight potentially novel cell biological relationships.ConclusionsNew insights into functionally relevant gene regulatory networks can be obtained using a statistically grounded approach to the identification of gene-gene correlations.
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Project description:We proposed and fabricated multiscale transparent arteriole and capillary vessel models with circular cross sections of 10-500 μm using photolithography. The circularities of the fabricated 10, 50, and 500 μm diameter microchannels were 84.0%, 61.5%, and 82.3%, respectively. Next, we connected these different models to realize a circulation type blood vessel model simulating arteriole networks. We proposed a novel connection method using an intermediate connector made of wax, which we used to connect these models to make a circulation model. In flow experiments, the fabricated models showed no leakage and circulation models with seamless connections were achieved.
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Project description:BackgroundExperimental studies of gene expression have identified some of the individual molecular components and elementary reactions that comprise and control cellular behavior. Given our current understanding of gene expression, and the goals of biotechnology research, both scientists and engineers would benefit from detailed simulators that can explicitly compute genome-wide expression levels as a function of individual molecular events, including the activities and interactions of molecules on DNA at single base pair resolution. However, for practical reasons including computational tractability, available simulators have not been able to represent genome-scale models of gene expression at this level of detail.ResultsHere we develop a simulator, TABASCO http://openwetware.org/wiki/TABASCO, which enables the precise representation of individual molecules and events in gene expression for genome-scale systems. We use a single molecule computational engine to track individual molecules interacting with and along nucleic acid polymers at single base resolution. Tabasco uses logical rules to automatically update and delimit the set of species and reactions that comprise a system during simulation, thereby avoiding the need for a priori specification of all possible combinations of molecules and reaction events. We confirm that single molecule, base-pair resolved simulation using TABASCO (Tabasco) can accurately compute gene expression dynamics and, moving beyond previous simulators, provide for the direct representation of intermolecular events such as polymerase collisions and promoter occlusion. We demonstrate the computational capacity of Tabasco by simulating the entirety of gene expression during bacteriophage T7 infection; for reference, the 39,937 base pair T7 genome encodes 56 genes that are transcribed by two types of RNA polymerases active across 22 promoters.ConclusionTabasco enables genome-scale simulation of transcription and translation at individual molecule and single base-pair resolution. By directly representing the position and activity of individual molecules on DNA, Tabasco can directly test the effects of detailed molecular processes on system-wide gene expression. Tabasco would also be useful for studying the complex regulatory mechanisms controlling eukaryotic gene expression. The computational engine underlying Tabasco could also be adapted to represent other types of processive systems in which individual reaction events are organized across a single spatial dimension (e.g., polysaccharide synthesis).
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Project description:A common approach to benchmarking of single-cell transcriptomics tools is to generate synthetic datasets that statistically resemble experimental data. However, most existing single-cell simulators do not incorporate transcription factor-gene regulatory interactions that underlie expression dynamics. Here, we present SERGIO, a simulator of single-cell gene expression data that models the stochastic nature of transcription as well as regulation of genes by multiple transcription factors according to a user-provided gene regulatory network. SERGIO can simulate any number of cell types in steady state or cells differentiating to multiple fates. We show that datasets generated by SERGIO are statistically comparable to experimental data generated by Illumina HiSeq2000, Drop-seq, Illumina 10X chromium, and Smart-seq. We use SERGIO to benchmark several single-cell analysis tools, including GRN inference methods, and identify Tcf7, Gata3, and Bcl11b as key drivers of T cell differentiation by performing in silico knockout experiments. SERGIO is freely available for download here: https://github.com/PayamDiba/SERGIO.
| S-EPMC7530147 | biostudies-literature
Project description:Score-based motif enrichment analysis (MEA) is typically applied to regulatory DNA to infer transcription factors (TFs) that may modulate transcription and chromatin state in different conditions. Most MEA methods determine motif enrichment independent of motif position within a sequence, even when those sequences harbor anchor points that motifs and their bound TFs may functionally interact with in a distance-dependent fashion, such as other TF binding motifs, transcription start sites (TSS), sequencing assay cleavage sites, or other biologically meaningful features. We developed motif enrichment positional profiling (MEPP), a novel MEA method that outputs a positional enrichment profile of a given TF's binding motif relative to key anchor points (e.g. transcription start sites, or other motifs) within the analyzed sequences while accounting for lower-order nucleotide bias. Using transcription initiation and TF binding as test cases, we demonstrate MEPP's utility in determining the sequence positions where motif presence correlates with measures of biological activity, inferring positional dependencies of binding site function. We demonstrate how MEPP can be applied to interpretation and hypothesis generation from experiments that quantify transcription initiation, chromatin structure, or TF binding measurements. MEPP is available for download from https://github.com/npdeloss/mepp.
| S-EPMC9575187 | biostudies-literature
Project description:Computation in the nervous system often relies on the integration of signals from parallel circuits with different functional properties. Correlated noise in these inputs can, in principle, have diverse and dramatic effects on the reliability of the resulting computations. Such theoretical predictions have rarely been tested experimentally because of a scarcity of preparations that permit measurement of both the covariation of a neuron's input signals and the effect on a cell's output of manipulating such covariation. Here we introduce a method to measure covariation of the excitatory and inhibitory inputs a cell receives. This method revealed strong correlated noise in the inputs to two types of retinal ganglion cell. Eliminating correlated noise without changing other input properties substantially decreased the accuracy with which a cell's spike outputs encoded light inputs. Thus, covariation of excitatory and inhibitory inputs can be a critical determinant of the reliability of neural coding and computation.
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Project description:Objectives:To evaluate the effect of simulator fidelity on procedure skill training through a review of existing studies. Methods:MEDLINE, OVID and EMBASE databases were searched between January 1990 and January 2019. Search terms included "simulator fidelity and comparison" and "low fidelity" and "high fidelity" and "comparison" and "simulator". Author classification of low- and high-fidelity was used for non-laparoscopic procedures. Laparoscopic simulators are classified using a proposed schema. All included studies used a randomized methodology with two or more groups and were written in English. Data was abstracted to a standard data sheet and critically appraised from 17 eligible full papers. Results:Of 17 studies, eight were for laparoscopic and nine for other skill training. Studies employed evaluation methodologies, including subjective and objective measures. The evaluation was conducted once in 13/17 studies and before-after in 4/17. Didactic training only or control groups were used in 5/17 studies, while 10/17 studies included two groups only. Skill acquisition and simulator fidelity were different for the level of training in 1/17 studies. Simulation training was followed by clinical evaluation or a live animal evaluation in 3/17 studies. Low-fidelity training was not inferior to training with a high-fidelity simulator in 15/17 studies. Conclusions:Procedure skill after training with low fidelity simulators was not inferior to skill after training with high fidelity simulators in 15/17 studies. Some data suggest that the effectiveness of different fidelity simulators depends on the level of training of participants and requires further study.
| S-EPMC7246118 | biostudies-literature
Project description:High-throughput single-cell RNA-seq (scRNA-seq) is a powerful tool for studying gene expression in single cells. Most current scRNA-seq bioinformatics tools focus on analysing overall expression levels, largely ignoring alternative mRNA isoform expression. We present a computational pipeline, Sierra, that readily detects differential transcript usage from data generated by commonly used polyA-captured scRNA-seq technology. We validate Sierra by comparing cardiac scRNA-seq cell types to bulk RNA-seq of matched populations, finding significant overlap in differential transcripts. Sierra detects differential transcript usage across human peripheral blood mononuclear cells and the Tabula Muris, and 3 'UTR shortening in cardiac fibroblasts. Sierra is available at https://github.com/VCCRI/Sierra .
| S-EPMC7341584 | biostudies-literature