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Analyses of genome and exome sequencing data identify rare coding and structural variants associated with atrial fibrillation and highlight genetic links between atrial fibrillation and cardiomyopathies.

Allele-preferential transcription factor binding can influence pancreatic ductal adenocarcinoma risk loci function. Here, the authors show allele-specific JunB and JunD binding at chr1p36.33 and propose a role for KLHL17 in protein homeostasis by mitigating inflammation.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

The signaling mechanisms regulating adipose thermogenesis have not been fully elucidated. Here, the authors show that a brown fat-enriched adipokine ADISSP promotes adipose thermogenesis and improves metabolic health independently of b-adrenergic receptor.

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

Genome-wide association studies (GWAS) have improved our understanding of the genetic basis of lung adenocarcinoma but known susceptibility variants explain only a small fraction of the familial risk. Here, the authors perform a two-stage GWAS and report 12 novel genetic loci associated with lung adenocarcinoma in East Asians.

The activity of the tumour-suppressor protein p53 is repressed in the thymus to augment fluctuations in background chromatin accessibility as a means of mediating ectopic gene expression and immune tolerance.

Genome-wide analyses identify 30 independent loci associated with obsessive–compulsive disorder, highlighting genetic overlap with other psychiatric disorders and implicating putative effector genes and cell types contributing to its etiology.

FAM72A differentially controls mutation rates by regulating uracil processing at different stages of the cell cycle, thereby regulating somatic hypermutation and class-switch recombination in B cells.

Sequencing data from two large-scale studies show that most of the genetic variation influencing the risk of type 2 diabetes involves common alleles and is found in regions previously identified by genome-wide association studies, clarifying the genetic architecture of this disease.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

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.

In this work, authors show that the nucleoside prodrug obeldesivir has potent antiviral activity across respiratory syncytial virus (RSV) clinical isolates with a high resistance barrier. Once-daily obeldesivir treatment was efficacious against RSV in a non-human primate model.

Computationally designed genetically encoded proteins can be used to target surface proteins, thereby triggering endocytosis and subsequent intracellular degradation, activating signalling or increasing cellular uptake in specific tissues.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

Nature Biotechnology asks a selection of leaders from across biotech to look at the future of the sector and make some predictions for the coming years.

Metagenomic and metatranscriptomic analyses of stool samples from 308 individuals over time indicate that longitudinal sampling is important for detecting dynamic functional features of the gut microbiome.

Different functional variants in ADH1B (and elsewhere) in Europeans and Africans strongly affect risk for alcohol dependence. Dependence only partly genetically correlates with consumption, with strong correlations to other psychiatric disorders.

A combination of mass spectrometry, pooled genome screens and STRING analysis identifies key uptake mediating interactions between nanoparticle-adsorbed proteins and cells via the low-density lipoprotein receptor.

‘Protein arginine methyltransferase 5 (PRMT5) is known to regulate the expression of genes involved in metastasis. Here, the authors show that PRMT5 methylates Akt and methylation is required for phosphorylation and activation of Akt; ultimately leading to the increase in expression of pro-metastatic transcription factors.

Chan et al. report that 3′ UTR splicing is widespread and enhanced across different cancer types and is associated with more advanced tumour progression.

The causative agent of sea star wasting disease has been elusive. This study used genetic datasets and experimental exposures to demonstrate that a strain of the bacterium Vibrio pectenicida caused disease and mortality in sea stars.

Centromeric satellite repeats on Arabidopsis chromosome 5 are interrupted by ATHILA5 retrotransposons, and cohesion is compromised in ddm1 chromatin remodelling mutants that have also lost RNAi. Mis-segregation is epigenetically inherited but can be rescued by ATHILA5 small RNA.

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.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Hagenbeek et al. identify a small-molecule pan-TEAD inhibitor that blocks the interaction between YAP/TAZ and TEAD proteins. They demonstrate that treatment with the inhibitor leads to antitumor activity and can synergize with KRAS G12C inhibition.

Tumour endothelial cell macropinocytosis is the dominant mechanism for nanoparticle entry into the tumour. Enhanced nanoparticle tumour accumulation may be due to upregulated macropinocytosis membrane ruffling compared with most healthy tissues.

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.

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.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

A genome-wide association study meta-analysis combined with multiomics data of osteoarthritis identifies 700 effector genes as well as biological processes with a convergent involvement of multiple effector genes; 10% of these genes express the target of approved drugs.

The pathogenic bacterium Vibrio cholerae typically has two circular chromosomes. Here, Cuénod et al. analyse 467 clinical isolates and identify several independent chromosome fusion events that are likely transmissible within a household, can be stable for 200 generations under laboratory conditions, and do not substantively affect bacterial growth, virulence factor expression, or biofilm formation.

The human endoderm-derived organoid cell atlas (HEOCA) presents an integrative analysis of single-cell transcriptomes across different conditions, sources and protocols. It compares cell types and states between models, and harmonizes cell annotations through mapping to primary tissues.

A brain-imaging study in humans demonstrates that older age brain network decline varies in relation to an individual’s education and predicts future dementia severity beyond other markers of Alzheimer’s disease-related genetic risk and pathology.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

In chemical-genetic and lipidomics analyses, the clinical candidate oncology drug tegavivint induced an unconventional form of nonapoptotic cell death that required the lipid metabolic enzyme trans-2,3-enoyl-CoA reductase.

The success of HER2-targeted cancer therapy is limited by treatment resistance. Here, the authors engineer an anti-HER2 biparatopic antibody with multiple mechanisms of action including induction of HER2 clustering to trigger complement dependent cytotoxicity, signal inhibition, antibody dependent cellular cytotoxicity and phagocytosis.

Thermostable antibodies called SPEARs enable rapid immunostaining with improved tissue penetration.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.

A CRISPR knock-in strategy that uses endogenous gene regulatory mechanisms can engineer ‘armoured’ CAR T cells that secrete proinflammatory cytokines directly within a tumour without causing toxicity, leading to prolonged survival in mice.

Stereotactic needle biopsies are currently performed for diagnosis only in glioblastoma; this study highlights the depth of information available through multi-omics analysis.

Analysis of human faecal metatranscriptomes and metagenomes reveals core and variable metatranscriptomes across time and individuals, and similar strain-level variation within and between subjects, providing further insights into human microbial ecology.

A diverse collection of potent neutralizing antibodies against the SARS-CoV-2 spike protein have been isolated from five patients with severe COVID-19 and high serum neutralization titres.

KDM4C regulates cathepsin L-mediated histone H3 N-terminal tail clipping through grainyhead-like 2 (GRHL2) methylation in breast cancer. This link between the cellular redox state and chromatin remodeling might represent a therapeutic target in KDM4C-amplified tumors.

Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

Of 12 serology assays tested, four detect antibodies in more than 80% of patients with COVID-19.

Nanoparticle-based ‘microgauges’ are developed for in vivo force sensing and deployed in C. elegans to investigate how mechanical force correlates with electrical signalling in neuromuscular organs.