Whole-genome sequencing (WGS) data has facilitated genome-wide identification of rare noncoding variants. However, elucidating these variants’ associations with complex diseases remains challenging. A previous study utilized a deep-learning-based framework and reported a significant brain-related association signal of autism spectrum disorder (ASD) detected from de novo noncoding variants in the Simons

Enhancer elements interact with target genes at a distance to modulate their expression, but the molecular details of enhancer–promoter interaction are incompletely understood. G-quadruplex DNA secondary structures (G4s) have recently been shown to co-occur with 3D chromatin interactions; however, the functional importance of G4s within enhancers remains unclear. In this study, we identify novel G4

Metastatic hormone-naïve prostate cancer (mHNPC) is an infrequent form of this tumor type that is characterized by metastasis at the time of diagnosis and accounts for up to 50% of prostate cancer-related deaths. Despite the extensive characterization of localized and metastatic castration-resistant prostate cancer, the molecular characteristics of mHNPC remain largely unexplored. Here, we provide

The rapid advancements in spatially resolved transcriptomics (SRT) enable the characterization of gene expressions while preserving spatial information. However, high dropout rates and noise hinder accurate spatial domain identification for understanding tissue architecture. We present DeepGFT, a method that simultaneously models spot-wise and gene-wise relationships by integrating deep learning with

New technologies enable single-cell transcriptome analysis, mapping genome-wide expression across the human body. Here, we present an extended analysis of protein-coding genes in all major human tissues and organs, combining single-cell and bulk transcriptomics. To enhance transcriptome depth, 31 tissues were analyzed using a pooling method, identifying 557 unique cell clusters, manually annotated

Publisher Correction: Genome Biol 26, 140 (2025) https://doi.org/10.1186/s13059-025-03617-3 Following publication of the original article [1], the authors identified typesetting error, whereby the Jaccard index has a subset 1 in the numerator, however the absolute value bars were missing in the denominator. Incorrect index: Jaccard index = \(\frac{\left|{G}_{1}\bigcap {G}_{j}\right|}{{G}_{i}\bigcup

There is a Chinese proverb that good tea comes from high mountains with clouds and mists, suggesting the important impact of environmental factors on the development and secondary metabolism in tea plants. However, the epigenetic mechanism involved is still unclear. High altitude results in light enhancement with a higher retention of short-wavelength light in cloudy conditions, suggesting the key

Analyzing multi-sample spatial transcriptomics data requires accounting for biological variation. We present multi-sample non-negative spatial factorization (mNSF), an alignment-free framework extending single-sample spatial factorization to multi-sample datasets. mNSF incorporates sample-specific spatial correlation modeling and extracts low-dimensional data representations. Through simulations and

Field inoculation of crops with beneficial microbes is a promising sustainable strategy to enhance plant fitness and nutrient acquisition. However, effectiveness can vary due to environmental factors, microbial competition, and methodological challenges, while their precise modes of action remain uncertain. This underscores the need for further research to optimize inoculation strategies for consistent

Differences in the relative level of expression of homoeologs, known as homoeolog expression bias, are widely observed in allopolyploids. While the evolution of homoeolog expression bias through hybridization has been characterized, on shorter timescales such as those found in crop breeding programs, the extent to which homoeolog expression bias is preserved or altered between generations remains elusive

Non-cyanobacteria diazotrophs (NCDs) are shown to dominate in surface waters shifting the long-held paradigm of cyanobacteria dominance. This raises fundamental questions on how these putative heterotrophic bacteria thrive in sunlit oceans. The absence of laboratory cultures of these bacteria significantly limits our ability to understand their behavior in natural environments and, consequently, their

Transcriptome sequencing (RNA-seq) is a powerful technology for gene expression profiling. Selection of optimal parameters for cDNA library generation is crucial for acquisition of high-quality data. In this study, we investigate the impact of the amount of RNA and the number of PCR cycles used for sample amplification on the rate of PCR duplication and, in consequence, on the RNA-seq data quality

Egg-laying mammals (monotremes) evolved multiple sex chromosomes independently of therian mammals and lack the sex-determining gene SRY. The Y-localized anti-Müllerian hormone gene (AMHY) is the candidate sex-determination gene in monotremes. Here, we describe the evolution of monotreme AMHX and AMHY gametologues and for the first time, investigate their expression during gonad sexual differentiation

Author Correction: Genome Biol 18, 35 (2017) https://doi.org/10.1186/s13059-017-1164-8 Following publication of the original article [1], the authors identified an error in Figure 2: the last two flowcharts in Figure 2b were inadvertently duplicated. This error does not affect the main results and conclusions of the paper. The incorrect Fig. 2 is given below The correct Fig. 2 is given below Zhang

Genome-wide CRISPR-Cas9 screens have untangled regulatory networks driving diverse biological processes. Their success relies on interrogating specific molecular phenotypes and distinguishing key regulators from background effects. Here, we realize these goals by optimizing CRISPR interference with barcoded expression reporter sequencing (CiBER-seq) to dramatically improve the sensitivity and scope

Fragmentomics features of cell-free DNA represent promising non-invasive biomarkers for cancer diagnosis. A lack of systematic evaluation of biases in feature quantification hinders the adoption of such applications. We compare features derived from whole-genome sequencing of ten healthy donors using nine library kits and ten data-processing routes and validated in 1182 plasma samples from published

DNA 5-methylcytosine (5mC) and RNA N6-methyladenosine (m6A) methylation are prevalent modifications in eukaryotes, both playing crucial roles in gene regulation. Recent studies have explored their crosstalk and impact on transcription. However, the intricate relationships among 5mC, m6A, and gene expression remain incompletely elucidated. We collect data on 5mC, m6A, and gene expression from samples

Statistical normalizations are used in differential analyses to address sample-to-sample variation in sequencing depth. Yet normalizations make strong, implicit assumptions about the scale of biological systems, such as microbial load, leading to false positives and negatives. We introduce scale models as a generalization of normalizations, which allows researchers to model potential errors in these

A pangenome can reveal the genetic diversity across different individuals simultaneously. It offers a more comprehensive reference for genome analysis compared to a single linear genome that may introduce allele bias. Pangenomes are often represented as genome graphs, making sequence-to-graph mapping a fundamental task for pangenome construction and analysis. Numerous sequence-to-graph mapping algorithms

The H2A.Z histone variant is highly enriched over gene bodies, playing an essential role in several genome-templated processes, including transcriptional regulation and epigenetic patterning across eukaryotes. Deposition of H2A.Z is mediated by the SWR1 remodeling complex. How SWR1 is directed to gene bodies is largely unknown. Here, we show that ALFIN-LIKE (AL) proteins are responsible for H2A.Z gene

Enabled by long-read sequencing technologies, particularly Single Molecule, Real-Time sequencing, N6-methyladenine (6mA) footprinting is a transformative methodology for revealing the heterogenous and dynamic distribution of nucleosomes and other DNA-binding proteins. Here, we present ipdTrimming, a novel 6mA-calling pipeline that outperforms existing tools in both computational efficiency and accuracy

Technological advances have enabled us to profile multiple omics layers with spatial information, significantly enhancing spatial domain detection and advancing a variety of biomedical research fields. Despite these advancements, there is a notable lack of effective methods for modeling spatial multi-omics data. We introduce SMOPCA, a Spatial Multi-Omics Principal Component Analysis method designed

The mutations found in a cancer genome are shaped by diverse processes, each displaying a characteristic mutational signature that may be influenced by the genome’s architecture. While prior analyses have evaluated the effect of topographical genomic features on mutational signatures, there has been no computational tool that can comprehensively examine this interplay. Here, we present SigProfilerTopography

The large-scale application of the mammalian methylation array has substantially expanded the availability of DNA methylation data in mammalian species. However, this data captures only a small portion of species-tissue combinations. To address this, we develop CMImpute (Cross-species Methylation Imputation), a method based on a conditional variational autoencoder, to impute DNA methylation representing

Ploidy determination across the genome has been challenging for low-pass-WGS tumor-only samples. We present BACDAC, a method that calculates tumor ploidy down to 1.2X effective tumor coverage. Allele fraction patterns displayed in the Constellation Plot verify tumor ploidy and reveal subclonal populations. BACDAC outputs a metric, 2N+LOH, that when combined with ploidy better distinguishes near-diploid

Despite tremendous advances in long-read sequencing, some structurally complex and repeat-rich genomic regions remain challenging to assemble. Furthermore, we lack tools to assess local assembly quality, making it hard to identify problems and assess progress. Here we develop a new approach “CloseRead” for visualizing local assembly quality and diagnosing errors using multiple metrics. We apply CloseRead

Processes shaping the formation of the present-day population structure in highly urbanized Northern Europe are still poorly understood. Gaps remain in our understanding of when and how currently observable regional differences emerged and what impact city growth, migration, and disease pandemics during and after the Middle Ages had on these processes. We perform low-coverage sequencing of the genomes

Venoms and their associated glands and delivery structures have evolved numerous times among animals. Within these venom systems, the molecular, cellular, and morphological components interact and co-evolve to generate distinct, venom phenotypes that are increasingly recognized as models for studying adaptive evolution. However, toxins are often unevenly distributed across venom-producing tissues in

Topologically associating domains (TADs) are fundamental units of 3D genomes and play essential roles in gene regulation. Hi-C data suggests a hierarchical organization of TADs. Accurately annotating nested TADs from Hi-C data remains challenging, both in terms of the precise identification of boundaries and the correct inference of hierarchies. While domain boundary is relatively well conserved across

Switchgrass (Panicum virgatum L.) is a bioenergy and forage crop. Upland switchgrass exhibits superior cold tolerance compared to the lowland ecotype, but the underlying molecular mechanisms remain unclear. Here, we present a high-quality haplotype-resolved genome of the upland ecotype “Jingji31.” We then conduct multi-omics analysis to explore the mechanism underlying its cold tolerance. By comparative

CTCF, a highly studied transcription factor, is essential for chromatin interaction maintenance. Several independent studies report that CTCF interacts with RNAs in vitro and in cells. Yet continuous debates about the authenticity of the RNA-binding affinity of CTCF and its biological role remain in large part due to limited research techniques available, such as CLIP-seq. Here, we investigate RNA’s

Parental experience can influence progeny behavior through gamete-mediated non-genetic inheritance, that is, mechanisms that do not involve changes in inherited DNA sequence. However, underlying mechanisms remain poorly understood in vertebrates, especially for maternal effects. Here, we use the medaka, a model fish species, to investigate the role of auts2a, the ortholog of human AUTS2, a gene repressed

The incidence and mortality of endometrial cancer (EC) is on the rise. Eighty-five percent of ECs depend on estrogen receptor alpha (ERα) for proliferation, but little is known about its transcriptional regulation in these tumors. We generate epigenomics, transcriptomics, and Hi-C datastreams in healthy and tumor endometrial tissues, identifying robust ERα reprogramming and profound alterations in

We introduce ChromActivity, a computational framework for predicting and annotating regulatory activity across the genome through integration of multiple epigenomic maps and various functional characterization datasets. ChromActivity generates genomewide predictions of regulatory activity associated with each functional characterization dataset across many cell types based on available epigenomic data

The identification of sites of DNA replication initiation in mammalian cells has been challenging. Here, we present unbiased detection of replication initiation events in human cells using BrdU incorporation and single-molecule nanopore sequencing. Increases in BrdU incorporation allow us to measure DNA replication dynamics, including identification of replication initiation, fork direction, and termination

Pepper (Capsicum annuum) is one of the earliest and most widely cultivated vegetable crops worldwide. While the large and complex genome of pepper severely hampered the understanding of its functional genome, it also indicates a rich yet unexplored reservoir of regulatory elements (REs). In fact, variations in the REs represent a major driving force in evolution and domestication in both plants and

During meiosis, the oocyte genome keeps dormant for a long time until zygotic genome activation. The dynamics and homeostasis of the maternal transcriptome are essential for maternal-to-zygotic transition. Zygotic arrest 1 (ZAR1) and its homolog, ZAR2, are RNA-binding proteins that are important for the regulation of maternal mRNA stability. Smart-seq2 analysis reveals drastically downregulated maternal

Cell-free RNAs (cfRNAs) can be detected in biofluids and have emerged as valuable disease biomarkers. Accurate identification of the fragmented cfRNA signals, especially those originating from pathological cells, is crucial for understanding their biological functions and clinical value. However, many challenges still need to be addressed for their application, including developing specific analysis

It is important for porcine models to replicate gene mutations present in human diseases to improve the translatability of animal studies. In this study, the high efficacy of a whole exome sequencing kit was demonstrated for the improved pig reference genome (Sus scrofa 11.1) to profile biomedically relevant swine breeds and enable high-depth sequencing required for intratumor heterogeneity profiling

Recent technological advances enable mapping of tissue spatial organization at single-cell resolution, but methods for analyzing spatially continuous microenvironments are still lacking. We introduce ONTraC, a graph neural network-based framework for constructing spatial trajectories at niche-level. Through benchmarking analyses using multiple simulated and real datasets, we show that ONTraC outperforms

The tight correlation between topologically associating domains (TADs) and epigenetic domains in Drosophila suggests that the epigenome contributes to define TADs. However, it is still unknown whether histone modifications are essential for TAD formation and structure. By either deleting or shifting key regulatory elements needed to establish the epigenetic signature of Polycomb TADs, we show that

Adenine base editors (ABEs) enable the conversion of A•T to G•C base pairs. Since the sequence of the target locus influences base editing efficiency, efforts have been made to develop computational models that can predict base editing outcomes based on the targeted sequence. However, these models were trained on base editing datasets generated in cell lines and their predictive power for base editing

Genetic variations linked to changes in gene expression are known as expression quantitative loci (eQTLs). The identification of eQTLs helps to understand the mechanisms governing gene expression. However, prior studies have primarily utilized short-read sequencing techniques, and the analysis of eQTLs on isoforms has been relatively limited. In this study, we employ long-read sequencing technology

The design of regulatory elements is pivotal in gene and cell therapy, where DNA sequences are engineered to drive elevated and cell-type specific expression. However, the systematic assessment of synthetic DNA sequences without robust metrics and easy-to-use software remains challenging. Here, we introduce Polygraph, a Python framework that evaluates synthetic DNA elements, based on features like

Predicting the functional impact of point mutations is a critical challenge in genomics. PRESCOTT reconstructs complete mutational landscapes, identifies mutation-sensitive regions, and categorizes missense variants as benign, pathogenic, or variants of uncertain significance. Leveraging protein sequences, structural models, and population-specific allele frequencies, PRESCOTT surpasses existing methods

Solid tumors are spatially heterogeneous in their genetic, molecular, and cellular composition, but recent spatial profiling studies have mostly charted genetic and RNA variation in tumors separately. To leverage the potential of RNA to identify copy number alterations (CNAs), we develop SlideCNA, a computational tool to extract CNA signals from sparse spatial transcriptomics data with near single

Centromeres play a crucial role in maintaining genomic stability during cell division. They are typically composed of large arrays of tandem satellite repeats, which hinder high-quality assembly and complicate our efforts to understand their evolution across species. Here, we use long-read sequencing to generate near-complete genome assemblies for two Populus and two Salix species belonging to the

Normalization of spatial transcriptomics data is challenging due to spatial association between region-specific library size and biology. We develop SpaNorm, the first spatially-aware normalization method that concurrently models library size effects and the underlying biology, segregates these effects, and thereby removes library size effects without removing biological information. Using 27 tissue

The Islamic influence on the Iberian Peninsula left an enduring cultural and linguistic legacy. However, the demographic impact is less well understood. This study aims to explore the dynamics of gene flow and population structure in eastern Iberia from the early to late medieval period through ancient DNA. Our comprehensive genomic analysis uncovers gene flow from various Mediterranean regions into

The interplay between 3D genomic structure and transposable elements (TE) in regulating cell state-specific gene expression program is largely unknown. Here, we explore the utilization of TE-derived enhancers in naïve and expanded pluripotent states by integrative analysis of genome-wide Hi-C-defined enhancer interactions, H3K27ac HiChIP profiling and CRISPR-guided TE proteomics landscape. We find

Lean body mass is a crucial physiological component of body composition. Although lean body mass has a high heritability, studies evaluating the genetic determinants of lean mass (LM) have to date been limited largely to genome-wide association studies (GWAS) and common variants. Using whole genome sequencing (WGS)-based studies, we aimed to discover novel genetic variants associated with LM in population-based

In spatial transcriptomics data, spatially correlated genes promise to reveal high-interest phenomena like cell–cell interactions and latent variables. But in practice, most spatial correlations arise from the spatial arrangement of cell types, obscuring the more interesting relationships we hope to discover. We introduce InSituCor, a toolkit for discovering modules of spatially correlated genes. InSituCor

Understanding the relationship between protein sequence and function is crucial for accurate classification of missense variants. Variant effect predictors (VEPs) play a vital role in deciphering this complex relationship, yet evaluating their performance remains challenging for several reasons, including data circularity, where the same or related data is used for training and assessment. High-throughput

Epigenetic aging signatures provide insights into human aging, but traditional clocks rely on linear regression of DNA methylation levels, assuming linear trajectories. This study explores a non-parametric approach using 2D-kernel density estimation to determine epigenetic age. Our weighted model achieves similar predictive accuracy as conventional clocks and provides a variation score reflecting the

MicroRNA-seq data is produced by aligning small RNA sequencing reads of different microRNA transcript isoforms, called isomiRs, to known microRNAs. Aggregation to microRNA-level counts discards information and violates core assumptions of differential expression methods developed for mRNA-seq data. We establish miRglmm, a differential expression method for microRNA-seq data, that uses a generalized

Foundation models such as scGPT and Geneformer have not been rigorously evaluated in a setting where they are used without any further training (i.e., zero-shot). Understanding the performance of models in zero-shot settings is critical to applications that exclude the ability to fine-tune, such as discovery settings where labels are unknown. Our evaluation of the zero-shot performance of Geneformer

Direct conversion of reactive glial cells to neurons is a promising avenue for neuronal replacement therapies after brain injury or neurodegeneration. The overexpression of neurogenic fate determinants in glial cells results in conversion to neurons. For repair purposes, the conversion should ideally be induced in the pathology-induced neuroinflammatory environment. However, very little is known regarding

Monocots possess a fibrous root system comprising an embryonic root, crown roots, and lateral roots. The distinct cellular origins highlight the diversity of the initiation mechanism. To date, the distinct initiation mechanisms have been poorly studied. In this study, we conduct a comprehensive transcriptome and DNA methylome assay of these root types during their initiation. Our findings indicate

Mutational signatures are typically identified from tumor genome sequencing data using non-negative matrix factorization (NMF). However, existing NMF techniques only decompose a single dataset, limiting rigorous comparisons of signatures across conditions. We propose a Bayesian NMF method that jointly decomposes multiple datasets to identify signatures and their sharing pattern across conditions. We

Computational methods for assessing the likely impacts of mutations, known as variant effect predictors (VEPs), are widely used in the assessment and interpretation of human genetic variation, as well as in other applications like protein engineering. Many different VEPs have been released, and there is tremendous variability in their underlying algorithms, outputs, and the ways in which the methodologies