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

Ro60 is a conserved RNA-binding protein essential for RNA quality control and implicated in autoimmune responses. In this study, we present the structural and functional characterization of φRo60, an Ro60 homolog from Thermus phage phiLo, with its crystal structure determined at 1.99 Å. Despite limited sequence identity with bacterial and amphibian homologs, φRo60 maintains the canonical doughnut-shaped

Efficient DNA repair is essential for maintaining genome integrity and ensuring cell survival. In Escherichia coli, RecBCD plays a crucial role in processing DNA ends, following a DNA double-strand break (DSB), to initiate repair. While RecBCD has been extensively studied in vitro, less is known about how it contributes to rapid and efficient repair in living bacteria. Here, we use single-molecule

Recently long-read sequencing technologies and bioinformatics have enabled the construction of haplotype-resolved genome assemblies. Here, we present the complete and accurate de novo characterization of two challenging genomic regions, the major histocompatibility complex (MHC) and Killer-cell immunoglobulin-like receptors (KIRs), in phased haplotypic form, using the Oxford Nanopore Technology (ONT)

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

People with disabilities are under-represented in general (non-disability-specific) precision medicine research (PMR), limiting access to its benefits. We examine key reasons for this, focusing on the role of (dis)trust, and identify areas for further inquiry to guide researchers and enhance PMR’s trustworthiness for people with disabilities.

Stress erythropoiesis elevates the rate of red blood cell (RBC) production as a physiological response to stressors such as anemia or hypoxia. In acute anemia, RBC progenitors and precursors temporarily rewire their transcriptome, up- and downregulating hundreds of genes to accelerate the production of mature RBCs. Effective regeneration requires communication between critical cytokine signals (e.g

High-throughput massive parallel sequencing has significantly improved bacterial pathogen genomics, diagnostics, and epidemiology. Despite its high accuracy, short-read sequencing struggles with complete genome reconstruction and assembly of extrachromosomal elements such as plasmids. Long-read sequencing with Oxford Nanopore Technologies (ONT) presents an alternative that offers benefits including

Steroid receptors are involved in a wide array of crosstalk mechanisms that regulate diverse biological processes, with significant implications in diseases, particularly in cancers. In prostate cancer, indirect crosstalk between androgen receptor (AR) and glucocorticoid receptor NR3C1 (also known as GR) is well-documented, wherein AR suppression by antiandrogen therapy leads to elevated GR levels

Generating high-quality variant callsets across diverse species remains challenging as most bioinformatics tools default to assumptions based on human genomes. DeepVariant (DV) excels without joint genotyping while offering fewer implementation barriers. However, the growing appeal of a "universal" algorithm has magnified the unknown impacts when used with non-human species. We use bovine genomes to

The interaction between genetic variants and environmental stressors is key to understanding the mechanisms underlying neurological diseases. In this study, we used human brain organoids to explore how varying oxygen levels expose context-dependent gene regulatory effects. By subjecting a genetically diverse panel of 21 brain organoids to hypoxic and hyperoxic conditions, we identified hundreds of

Genome Research 27: 2061–2071 (2017)

Genome Research 34: 2229–2243 (2024)

The relationship between TP53 and transposable elements (TEs) has been obscure. Given the important role of TEs in oncogenesis, a comprehensive profiling of TE expression dynamics under the regulation of TP53 provides valuable resources for more clarity in TP53's roles in cancer. In this study, we characterized the TE transcriptomic landscape using long-read RNA-seq and short-read RNA-seq in three

Isoform diversity is known to enhance a gene's functional repertoire by producing protein variants with distinct functional implications. Despite numerous studies on transcriptome diversifying processes (alternative splicing/transcription), understanding their extent and correlated impact on proteome diversity remains limited owing to dearth of subsequent proteogenomic consequences. To coalesce the

Reprogramming cell state transitions provides the potential for cell engineering and regenerative therapy. Finding the reprogramming transcription factors (TFs) and their combinations that can direct the desired state transition is crucial for the task. Computational methods have been developed to identify such reprogramming TFs. However, most of them can only generate a ranked list of individual TFs

The rapid advance of spatially resolved transcriptomics technologies has yielded substantial spatial transcriptomics data. Deriving biological insights from these data poses nontrivial computational and analysis challenges, of which the most fundamental step is spatial domain detection (or spatial clustering). Although a number of tools for spatial domain detection have been proposed in recent years

The emergence of spatial transcriptomics (ST) provides unprecedented opportunities to better decipher cell–cell communication (CCC). How to integrate spatial information and complex signaling mechanisms to infer functional CCC, however, remains a major challenge. Here, we present stMLnet, a method that takes into account spatial information and multilayer signaling regulation to identify signaling

Long-read sequencing has the capacity to interrogate difficult genomic regions and phase variants; however, short-read sequencing is more commonly implemented for clinical testing. Given the advances in long-read HiFi sequencing chemistry and variant calling, we analytically validated this technology for small variant detection (single nucleotide variants, insertions/deletions; SNVs/indels; <50 bp)

Blastocystis, an obligate host-associated protist, is the most common microbial eukaryote in the human gut, and is widely distributed across vertebrate hosts. The evolutionary transition of Blastocystis from its free-living stramenopile ancestors to a radiation of host-associated organisms is poorly understood. To explore this, we cultured and sequenced eight strains representing the significant phylogenetic

Phased telomere-to-telomere (T2T) genome assemblies are revolutionizing our understanding of long-hidden genome biology “dark matter” such as centromeres, rDNA repeats, inter-haplotype variation, and allele-specific expression (ASE), yet insights into dikaryotic fungi that separate their haploid genomes into distinct nuclei are limited. Here, we explore the impact of dikaryotism on the genome biology

Transfer of chloroplast or mitochondrial DNA into the nuclear genome is a common phenomenon in many species. However, little is known about the evolutionary fate and mechanism of transfer of organellar DNA sequences in higher plants. We observe abundant insertions of organelle DNA into the nuclear genomes of 22 genome assemblies across seven Oryza species and further categorize nuclear organelle DNA

Premature stop codon–containing mRNAs can produce truncated and dominantly acting proteins that harm cells. Eukaryotic cells protect themselves by degrading such mRNAs via the nonsense-mediated mRNA decay (NMD) pathway. The precise reactions by which cells attack NMD-target mRNAs remain obscure, precluding a biochemical understanding of NMD and hampering therapeutic efforts to control NMD. Here, we

Unlike the highly degenerated sex chromosomes in birds and mammals, many amphibians possess homomorphic sex chromosomes, which may result from high rates of sex chromosome turnover and/or occasional recombination between the X and Y (or Z and W) Chromosomes. Yet, the molecular basis for maintaining homomorphy remains elusive, particularly the power of rare recombination events to arrest sex chromosome

Sporadically, genetic material that originates from an organelle genome integrates into the nuclear genome. However, it is unclear what processes maintain such integrations over evolutionary time. Recently, it was shown that nuclear DNA of mitochondrial origin (NUMT) may harbor genes with intact mitochondrial reading frames despite the fact that they are highly divergent from the host's mitochondrial

Activity-dependent gene expression in neurons is well established, yet few studies have examined activity-dependent alternative splicing. Alternative splicing regulates >95% of genes and is essential to diverse neuronal functions, including synapse development and calcium channel diversity. Alternative splicing is regulated by the expression and activity of RNA-binding proteins and through changes

Transposons, occasionally domesticated as novel host protein-coding genes, are responsible for the lineage-specific functions in vertebrates. LINE-1 (L1) is one of the most active transposons in the vertebrate genomes. Despite its abundance, few examples of L1 co-option for vertebrate proteins have been reported. Here, we describe protein isoforms, in which the L1 retrotransposons are incorporated

Enhancer–promoter communication is fundamental to gene regulation in metazoans, yet the mechanisms underlying these interactions remain debated. Two primary models have been proposed: the structural bridge model, in which enhancers and promoters come into close proximity through stable, protein-mediated interactions, and the hub model, in which dynamic clusters of transcription-associated proteins

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

Genes & Development 23: 1207–1220 (2009)

Genes & Development 29: 2475–2489 (2015)

Despite the general detriment of aneuploidy to cellular fitness, >90% of solid tumors carry an imbalanced karyotype. This existing paradox and the molecular responses to aneuploidy remain poorly understood. Here, we explore these cellular stresses and unique vulnerabilities of aneuploidy in human mammary epithelial cells (HMECs) enriched for breast cancer-associated copy number alterations (CNAs).

During early transcription, RNA polymerase II (RNAPII) undergoes a series of structural transitions controlled by cyclin-dependent kinases. How protein ubiquitylation and proteasomal degradation control the function of RNAPII is less well understood. Here we show that the deubiquitinating enzyme USP11 forms a complex with TCEAL1, a member of the TFIIS (TCEA)-like protein family. TCEAL1 shares sequence

Mutations in the microRNA processing genes DROSHA and DICER1 drive several cancers that resemble embryonic progenitors. To understand how microRNAs regulate tumorigenesis, we ablated Drosha or Dicer1 in the developing pineal gland to emulate the pathogenesis of pineoblastoma, a brain tumor that resembles undifferentiated precursors of the pineal gland. Accordingly, these mice develop pineal tumors

Regulatory elements, such as enhancers and silencers, control transcription by establishing physical proximity to target gene promoters. Neurons in flies and mammals exhibit long-range three-dimensional genome contacts, proposed to connect genes with distal regulatory elements. However, the relevance of these contacts for neuronal gene transcription and the mechanisms underlying their specificity necessitate

Cohesin contributes to genome spatial organization and sister chromatid cohesion. In this way, it not only supports accurate chromosome segregation and efficient DNA repair but also regulates gene expression. These functions are essential during embryonic development, the process that converts the fertilized egg into a complex organism with billions of specialized cells organized into tissues and organs

The two major genomic alterations in pediatric pilocytic astrocytoma (PA) are NF1 loss and KIAA1549:BRAF rearrangement. Although these molecular changes result in increased MEK activity and tumor growth, it is not clear exactly how MEK controls human neuroglial cell proliferation. Leveraging human-induced pluripotent stem cells harboring these PA-associated alterations, we used a combination of genetic

To investigate the pathogenesis and target the vulnerability of human pineoblastoma, researchers have developed multiple genetically engineered mouse models that represent distinct molecular subtypes of the disease. In this issue of Genes & Development, Fraire and colleagues (doi:10.1101/gad.352485.124) examined the roles of key microRNA (miRNA) processing components Drosha and Dicer1. Loss of either

The emergence of numerous variants of SARS-CoV-2 still presents the major challenges in the fight against this disease by reducing the efficacy of vaccines and drugs. RNA G-quadruplexes (G4s) in the SARS-CoV-2 genome are highly conserved and have thus been spotlighted as a promising therapeutic target to combat a wider range of variants. However, very few RNA G4 specific compounds have been reported

The segmentation clock is a molecular oscillator that regulates the timing of somite formation in the developing vertebrate embryo. NOTCH signaling is one of the key pathways required for proper functioning of the segmentation clock. Aberrant NOTCH signaling results in developmental abnormalities such as congenital scoliosis as well as diseases such as T-cell acute lymphoblastic lymphoma (T-ALL). In

Porphyromonas gingivalis, an anaerobic pathogen in chronic periodontitis, belongs to the Bacteroidota phylum and is associated with various virulence factors. Its antibiotic-resistant strains and its propensity to form biofilms pose a challenge to effective treatment. To explore therapeutic avenues, we studied the high-resolution cryogenic electron microscope structures of ribosomes from the wild-type

DNA methylation plays a fundamental role in regulating transcription during development and differentiation. However, its functional role in the regulation of endothelial cell (EC) transcription during state transition, meaning the switch from an angiogenic to a quiescent cell state, has not been systematically studied. Here, we report the longitudinal changes of the DNA methylome over the lifetime

Telomeres ensure genome stability and the levels of telomeric RNA reflect the integrity of telomeric chromatin. The highly conserved RNA-binding protein Ars2 (Arsenite-resistance protein 2) plays an essential role in the RNA nuclear metabolism and negatively regulates the expression of telomeric transcripts in human cells and in Drosophila. We found that germline knockdown of Drosophila Ars2 does not

The A-loop of the 23S ribosomal RNA is a critical region of the ribosome involved in stabilizing the CCA-end of A-site-bound transfer RNA. Within this loop, nucleotide U2552 is frequently 2′-O-methylated (Um2552) in various organisms belonging to the three domains of life. Until now, two enzymatic systems are known to modify this position, relying on either a Rossmann fold-like methyltransferase (RFM)

Bacteria take up environmental DNA using dynamic appendages called type IV pili (T4P) to elicit horizontal gene transfer in a process called natural transformation. Natural transformation is widespread amongst bacteria yet the parameters that enhance or limit this process across species are poorly understood. We show that the most naturally transformable species known, Acinetobacter baylyi, owes this

Mammalian enhancers can regulate genes over large genomic distances, often skipping over other genes. Despite this, precise developmental regulation suggests that mechanisms exist to ensure enhancers only activate their correct targets. Sculpting of three-dimensional chromosome organization through cohesin-dependent loop extrusion is thought to be important for facilitating and constraining enhancer