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The Expanding Landscape of Alternative Splicing Variation in Human Populations.
Alternative splicing is a tightly regulated biological process by which the number of gene products for any given gene can be greatly expanded. Genomic variants in splicing regulatory sequences can disrupt splicing and cause disease. Recent developments in sequencing technologies and computational biology have allowed researchers to investigate alternative splicing at an unprecedented scale and resolution. Population-scale transcriptome studies have revealed many naturally occurring genetic variants that modulate alternative splicing and consequently influence phenotypic variability and disease susceptibility in human populations. Innovations in experimental and computational tools such as massively parallel reporter assays and deep learning have enabled the rapid screening of genomic variants for their causal impacts on splicing. In this review, we describe technological advances that have greatly increased the speed and scale at which discoveries are made about the genetic variation of alternative splicing. We summarize major findings from population transcriptomic studies of alternative splicing and discuss the implications of these findings for human genetics and medicine
What I talk about when I talk about integration of single-cell data
Over the past decade, single-cell technologies evolved from profiling hundreds of cells to millions of cells, and emerged from a single modality of data to cover multiple views at single-cell resolution, including genome, epigenome, transcriptome, and so on. With advance of these single-cell technologies, the booming of multimodal single-cell data creates a valuable resource for us to understand cellular heterogeneity and molecular mechanism at a comprehensive level. However, the large-scale multimodal single-cell data also presents a huge computational challenge for insightful integrative analysis. Here, I will lay out problems in data integration that single-cell research community is interested in and introduce computational principles for solving these integration problems. In the following chapters, I will present four computational methods for data integration under different scenarios. Finally, I will discuss some future directions and potential applications of single-cell data integration
Progress and Opportunities of Foundation Models in Bioinformatics
Bioinformatics has witnessed a paradigm shift with the increasing integration
of artificial intelligence (AI), particularly through the adoption of
foundation models (FMs). These AI techniques have rapidly advanced, addressing
historical challenges in bioinformatics such as the scarcity of annotated data
and the presence of data noise. FMs are particularly adept at handling
large-scale, unlabeled data, a common scenario in biological contexts due to
the time-consuming and costly nature of experimentally determining labeled
data. This characteristic has allowed FMs to excel and achieve notable results
in various downstream validation tasks, demonstrating their ability to
represent diverse biological entities effectively. Undoubtedly, FMs have
ushered in a new era in computational biology, especially in the realm of deep
learning. The primary goal of this survey is to conduct a systematic
investigation and summary of FMs in bioinformatics, tracing their evolution,
current research status, and the methodologies employed. Central to our focus
is the application of FMs to specific biological problems, aiming to guide the
research community in choosing appropriate FMs for their research needs. We
delve into the specifics of the problem at hand including sequence analysis,
structure prediction, function annotation, and multimodal integration,
comparing the structures and advancements against traditional methods.
Furthermore, the review analyses challenges and limitations faced by FMs in
biology, such as data noise, model explainability, and potential biases.
Finally, we outline potential development paths and strategies for FMs in
future biological research, setting the stage for continued innovation and
application in this rapidly evolving field. This comprehensive review serves
not only as an academic resource but also as a roadmap for future explorations
and applications of FMs in biology.Comment: 27 pages, 3 figures, 2 table
Deep Learning in Single-Cell Analysis
Single-cell technologies are revolutionizing the entire field of biology. The
large volumes of data generated by single-cell technologies are
high-dimensional, sparse, heterogeneous, and have complicated dependency
structures, making analyses using conventional machine learning approaches
challenging and impractical. In tackling these challenges, deep learning often
demonstrates superior performance compared to traditional machine learning
methods. In this work, we give a comprehensive survey on deep learning in
single-cell analysis. We first introduce background on single-cell technologies
and their development, as well as fundamental concepts of deep learning
including the most popular deep architectures. We present an overview of the
single-cell analytic pipeline pursued in research applications while noting
divergences due to data sources or specific applications. We then review seven
popular tasks spanning through different stages of the single-cell analysis
pipeline, including multimodal integration, imputation, clustering, spatial
domain identification, cell-type deconvolution, cell segmentation, and
cell-type annotation. Under each task, we describe the most recent developments
in classical and deep learning methods and discuss their advantages and
disadvantages. Deep learning tools and benchmark datasets are also summarized
for each task. Finally, we discuss the future directions and the most recent
challenges. This survey will serve as a reference for biologists and computer
scientists, encouraging collaborations.Comment: 77 pages, 11 figures, 15 tables, deep learning, single-cell analysi
Machine Learning for Uncovering Biological Insights in Spatial Transcriptomics Data
Development and homeostasis in multicellular systems both require exquisite
control over spatial molecular pattern formation and maintenance. Advances in
spatially-resolved and high-throughput molecular imaging methods such as
multiplexed immunofluorescence and spatial transcriptomics (ST) provide
exciting new opportunities to augment our fundamental understanding of these
processes in health and disease. The large and complex datasets resulting from
these techniques, particularly ST, have led to rapid development of innovative
machine learning (ML) tools primarily based on deep learning techniques. These
ML tools are now increasingly featured in integrated experimental and
computational workflows to disentangle signals from noise in complex biological
systems. However, it can be difficult to understand and balance the different
implicit assumptions and methodologies of a rapidly expanding toolbox of
analytical tools in ST. To address this, we summarize major ST analysis goals
that ML can help address and current analysis trends. We also describe four
major data science concepts and related heuristics that can help guide
practitioners in their choices of the right tools for the right biological
questions
Essential guidelines for computational method benchmarking
In computational biology and other sciences, researchers are frequently faced
with a choice between several computational methods for performing data
analyses. Benchmarking studies aim to rigorously compare the performance of
different methods using well-characterized benchmark datasets, to determine the
strengths of each method or to provide recommendations regarding suitable
choices of methods for an analysis. However, benchmarking studies must be
carefully designed and implemented to provide accurate, unbiased, and
informative results. Here, we summarize key practical guidelines and
recommendations for performing high-quality benchmarking analyses, based on our
experiences in computational biology.Comment: Minor update
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