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Somatic small variants in cancer genomes are identified in both short-read and long-read data.

A new version of nanorate DNA sequencing, with an error rate lower than five errors per billion base pairs and compatible with whole-exome and targeted capture, enables epidemiological-scale studies of somatic mutation and selection and the generation of high-resolution selection maps across coding and non-coding sites for many genes.

Given rising diabetes prevalence globally, access to diabetes treatments is gaining urgency. Here, the authors show patterns of glucose-lowering medication use for diabetes across 62 low- and middle-income countries.

A combined sequencing technique assesses 18 patients with high-grade serous ovarian cancer over a multi-year period from diagnosis to recurrence and shows drug resistance typically arises from selective expansion of one or a few clones present at diagnosis.

Acetyl-CoA synthetases have been proposed as targets for development of new antimicrobial drugs. Here, Jezewski et al. identify isoxazole-based compounds with activity against the pathogenic fungus Cryptococcus neoformans, and describe their mechanism of action as inhibitors of fungal acetyl-CoA synthetases.

cfDNA fragmentomics is a potential clinically applicable method for identifying cancer. Here, the authors assess fragmentomics analysis methods and their application to commercial targeted sequencing panels.

The authors report that an AS03-adjuvanted chimeric hemagglutinin-based influenza vaccine induces persistent stalk-specific serum antibody and bone marrow plasma cell responses in nonhuman primates, offering promise for broader and durable flu protection.

Phaeocystales are ecologically significant nanoplankton whose evolutionary history and functional diversity remain incompletely characterized. Here, the authors integrate genomic and transcriptomic data to reveal their lineage diversification, metabolic plasticity, and adaptation to polar and temperate regimes.

Transposable elements are genetic parasites that have colonised genomes and they express as parts of coding and noncoding RNAs. Here, the authors explore how they are expressed in transcripts in normal human development, and how they alter transcript dynamics.

Klein and colleagues characterize 04_A06, a new V_H1-2-encoded broadly neutralizing antibody that has marked breadth and potency against extended multiclade HIV-1 pseudovirus panels and can maintain full viral suppression in HIV-1-infected humanized mice.

This work introduces a pedigree-derived benchmark for single-nucleotide variants, indels, structural variants and tandem repeats, offering a variant map to validate sequencing workflows or to support the development and evaluation of new variant callers.

Two-qubit operations exceeding 99% fidelity have been demonstrated by silicon devices made with standard semiconductor tooling in a 300-mm foundry environment.

Cell state plasticity of neuroblastoma cells is linked to therapy resistance. Here, the authors develop a transcriptomic and epigenetic map of indisulam (RBM39 degrader) resistant neuroblastoma, demonstrating bidirectional cell state switching accompanied by increased NK cell activity, which they therapeutically enhance by the addition of an anti-GD2 antibody.

McCreery, Stubb et al. show that mechano-osmotic changes in the nucleus induce general transcriptional repression and prime chromatin for cell fate transitions by relieving repression of specific differentiation genes.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Here the authors perform a trans expression quantitative trait locus meta-analysis study of over 3,700 people and link a USP18 variant to expression of 50 inflammation genes and lupus risk, highlighting how genetic regulation of immune responses drives autoimmune disease and informs new therapies.

Neural mechanisms underlying flexible learning and decision-making are not fully understood. Using single-cell calcium imaging, authors here found that neurons in orbitofrontal and secondary motor cortex exhibit complementary roles in reward learning, with neurons in the former exerting a sustained role in conditions of uncertainty.

A combination of whole-genome NanoSeq with deep whole-exome and targeted NanoSeq is used to accurately characterize mutation rates and genes under positive selection in sperm cells.

LRP8, an apolipoprotein E and reelin receptor with high expression in the brain, is a receptor for tick-borne encephalitis virus.

In vivo loss-of-function CRISPR screens were performed to identify genes influencing CAR T cell persistence and function in human multiple myeloma, highlighting CDKN1B as a promising target.

Gene isoforms are quantified with a machine learning method that optimally integrates long and short sequencing reads.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Complex structural variations and rearrangements in cancer are identified using long-read sequencing.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Gut bacteria digest dietary fiber and release molecules as energy for the host. Here, Yu et al. find that the ability of certain gut bacteria to digest different fibers influences host consumption of food containing these fibers.

The majority of human genes can produce multiple isoforms, but studying their functional relevance requires tools to target specific isoforms. Here, the authors develop a CRISPR-based exon-exon junction-targeting strategy to achieve isoform-specific RNA knockdown.

In a phase 3 trial for Huntington’s disease, pridopidine did not meet its primary endpoints but was safe and favored in some prespecified subgroup analyses.

Available wheat genomes are annotated by projecting Chinese Spring gene models across the new assemblies. Here, the authors generate de novo gene annotations for the 9 wheat genomes, identify core and dispensable transcriptome, and reveal conservation and divergence of gene expression balance across homoeologous subgenomes.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

In a randomized, placebo-controlled, stepwise dose-escalation phase 1 trial evaluating a conjugate vaccine against both typhoid and invasive non-typhoidal Salmonella infections, the vaccine was found to be safe and immunogenic in healthy adults.

In this study, the authors assess the global response to the toxic aldehyde glyoxal (GO) in Pseudomonas aeruginosa, suggesting that GO controls quorum sensing during infection through a mechanism involving a novel protein, ArqI.

In the CheckMate 142 study, nivolumab (anti-PD-1) alone and in combination with ipilimumab (anti-CTLA-4) was shown to induce durable clinical benefit in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer. Here, the authors perform exploratory biomarker analysis of the CheckMate 142 study.

In a post-hoc analysis of circulating tumor DNA (ctDNA) features from patients with metastatic prostate cancer treated with [¹⁷⁷Lu]Lu–PSMA-617 or cabazitaxel in the randomized phase 2 TheraP trial, low ctDNA levels at baseline were predictive of clinical benefit from [¹⁷⁷Lu]Lu–PSMA-617, and PTEN or ATM alterations were identified as potential biomarkers of response.

HTLV-1 type-C causes more severe disease than type-A, but the underlying reason is unclear. Here the authors show in a macaque model how type-C orf-I affects lung pathogenesis and the immune response to HTLV-1, providing a model to test viral targets for disease prevention.

Integrated multi-omic analyses using samples from the TRACERx study highlight cross-talk between DNA hypermethylation and genomic lesions in non-small cell lung cancer.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

This analysis provides a collection of sequencing datasets generated from long-read and short-read RNA sequencing, serving as a valuable resource for transcriptome profiling.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

DNA variant calling methods based on deep neural networks can use local haplotyping information with long-reads to improve genotyping accuracy, however this increases computational complexity. Here the authors develop an approximate haplotagging method that simplifies the process and enables state-of-the-art variant calling performance with multiple sequencing platforms.

Perineural invasion and cancer-induced nerve injury of tumour-associated nerves are associated with poor response to anti-PD-1 therapy, which can be reversed by combining anti-PD-1 therapy with anti-inflammatory interventions.

Here the authors show that MRAP2 tunes the melanocortin-4 receptor by boosting its G-protein signaling while limiting β-arrestin2 interaction and destabilizing receptor oligomers, shaping appetite regulation.

How genetic predisposition drives late-onset disease risk remains unclear. Here, the authors show that epigenetic predisposition via NR3C1-dependent early postnatal 3D gene regulation primes astrocytes for lifelong immune vulnerability.

The ability to sequence oligonucleotides which consist entirely of artificial bases will facilitate their ongoing development and use. Here authors demonstrate de novo nanopore sequencing of DNA oligomers composed of “P” “Z” “S” and “B” bases with high sequencing accuracy.

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

PBK is a mitotic kinase implicated in cancer. This study reveals how PBK evicts key C2H2-zinc finger transcription factors such as Ikaros, Aiolos and CTCF from DNA as cells divide, regulating mitotic chromatin accessibility and chromosome compaction.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

A study presents ALPACA, a computational method for inferring clone- and allele-specific copy numbers of individual clones from multi-sample bulk DNA-sequencing data, and demonstrates its use to study metastasis trajectories.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

β-cell dysfunction and dedifferentiation towards an α-cell-like phenotype are hallmarks of type 2 diabetes. Her,e the authors detect five α-cell subpopulations, find differences between healthy and diabetic donors, and identify SMOC1 as an inducer of human β-cell dysfunction and dedifferentiation.