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Register a new userModeling and analysis of RNA-seq data: a review from a statistical perspective
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Background: Since the invention of next-generation RNA sequencing (RNA-seq) technologies, they have become a powerful tool to study the presence and quantity of RNA molecules in biological samples and have revolutionized transcriptomic studies. The analysis of RNA-seq data at four different levels (samples, genes, transcripts, and exons) involve multiple statistical and computational questions, some of which remain challenging up to date. Results: We review RNA-seq analysis tools at the sample, gene, transcript, and exon levels from a statistical perspective. We also highlight the biological and statistical questions of most practical considerations. Conclusion: The development of statistical and computational methods for analyzing RNA- seq data has made significant advances in the past decade. However, methods developed to answer the same biological question often rely on diverse statical models and exhibit different performance under different scenarios. This review discusses and compares multiple commonly used statistical models regarding their assumptions, in the hope of helping users select appropriate methods as needed, as well as assisting developers for future method development.
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RNA-Seq technology allows for studying the transcriptional state of the cell at an unprecedented level of detail. Beyond quantification of whole-gene expression, it is now possible to disentangle the abundance of individual alternatively spliced transcript isoforms of a gene. A central question is to understand the regulatory processes that lead to differences in relative abundance variation due to external and genetic factors. Here, we present a mixed model approach that allows for (i) joint analysis and genetic mapping of multiple transcript isoforms and (ii) mapping of isoform-specific effects. Central to our approach is to comprehensively model the causes of variation and correlation between transcript isoforms, including the genomic background and technical quantification uncertainty. As a result, our method allows to accurately test for shared as well as transcript-specific genetic regulation of transcript isoforms and achieves substantially improved calibration of these statistical tests. Experiments on genotype and RNA-Seq data from 126 human HapMap individuals demonstrate that our model can help to obtain a more fine-grained picture of the genetic basis of gene expression variation.
The analysis of differential gene expression from RNA-Seq data has become a standard for several research areas mainly involving bioinformatics. The steps for the computational analysis of these data include many data types and file formats, and a wide variety of computational tools that can be applied alone or together as pipelines. This paper presents a review of differential expression analysis pipeline, addressing its steps and the respective objectives, the principal methods available in each step and their properties, bringing an overview in an organized way in this context. In particular, this review aims to address mainly the aspects involved in the differentially expressed gene (DEG) analysis from RNA sequencing data (RNA-Seq), considering the computational methods and its properties. In addition, a timeline of the evolution of computational methods for DEG is presented and discussed, as well as the relationships existing between the main computational tools are presented by an interaction network. A discussion on the challenges and gaps in DEG analysis is also highlighted in this review.
RNA-seq has rapidly become the de facto technique to measure gene expression. However, the time required for analysis has not kept up with the pace of data generation. Here we introduce Sailfish, a novel computational method for quantifying the abundance of previously annotated RNA isoforms from RNA-seq data. Sailfish entirely avoids mapping reads, which is a time-consuming step in all current methods. Sailfish provides quantification estimates much faster than existing approaches (typically 20-times faster) without loss of accuracy.
Background: High-throughput techniques bring novel tools but also statistical challenges to genomic research. Identifying genes with differential expression between different species is an effective way to discover evolutionarily conserved transcriptional responses. To remove systematic variation between different species for a fair comparison, the normalization procedure serves as a crucial pre-processing step that adjusts for the varying sample sequencing depths and other confounding technical effects. Results: In this paper, we propose a scale based normalization (SCBN) method by taking into account the available knowledge of conserved orthologous genes and hypothesis testing framework. Considering the different gene lengths and unmapped genes between different species, we formulate the problem from the perspective of hypothesis testing and search for the optimal scaling factor that minimizes the deviation between the empirical and nominal type I errors. Conclusions: Simulation studies show that the proposed method performs significantly better than the existing competitor in a wide range of settings. An RNA-seq dataset of different species is also analyzed and it coincides with the conclusion that the proposed method outperforms the existing method. For practical applications, we have also developed an R package named SCBN and the software is available at http://www.bioconductor.org/packages/devel/bioc/html/SCBN.html.
Microbes are essentially yet convolutedly linked with human lives on the earth. They critically interfere in different physiological processes and thus influence overall health status. Studying microbial species is used to be constrained to those that can be cultured in the lab. But it excluded a huge portion of the microbiome that could not survive on lab conditions. In the past few years, the culture-independent metagenomic sequencing enabled us to explore the complex microbial community coexisting within and on us. Metagenomics has equipped us with new avenues of investigating the microbiome, from studying a single species to a complex community in a dynamic ecosystem. Thus, identifying the involved microbes and their genomes becomes one of the core tasks in metagenomic sequencing. Metagenome-assembled genomes are groups of contigs with similar sequence characteristics from de novo assembly and could represent the microbial genomes from metagenomic sequencing. In this paper, we reviewed a spectrum of tools for producing and annotating metagenome-assembled genomes from metagenomic sequencing data and discussed their technical and biological perspectives.
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