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Genome-wide libraries for CRISPR knockout, interference, and activation have allowed the systemic interrogation of gene function. Here, the authors evaluate the Brunello CRISPRko library and introduce Dolcetto and Calabrese for CRISPRi and CRISPRa, respectively.

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.

BamA is the catalytic core of the BAM complex, which inserts proteins into bacterial outer membranes. Here, the authors show that hinge flexibility between BamA’s β-barrel and POTRA domains is vital, demonstrating how evolution has fine-tuned the BamA sequence and structure for function.

Platelets are known to have functions beyond those in thrombosis and haemostasis. Here the authors use multi-colour flow cytometry and proteomics to analyse platelet phenotypes in psoriatic disease and proteins that are potentially involved in the interaction of platelets with immune cells.

Federated learning (FL) algorithms have emerged as a promising solution to train models for healthcare imaging across institutions while preserving privacy. Here, the authors describe the Federated Tumor Segmentation (FeTS) challenge for the decentralised benchmarking of FL algorithms and evaluation of Healthcare AI algorithm generalizability in real-world cancer imaging datasets.

Trumpp and colleagues develop a method to obtain long-term circulating tumor cell-derived organoids from individuals with metastatic breast cancer and identify the neuregulin 1–HER3 axis as important for organoid growth and a promising therapeutic target.

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.

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.

Mitochondrial oxidative phosphorylation produces ATP and is an important source for cellular energy equivalents. Here the authors perform a cell-based screen to identify genes that alleviate perturbed mitochondrial complex I function and identify malic enzyme (ME-1), which promotes survival by production of NADPH and glutathione.

Federated ML (FL) provides an alternative to train accurate and generalizable ML models, by only sharing numerical model updates. Here, the authors present the largest FL study to-date to generate an automatic tumor boundary detector for glioblastoma.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Detlef Weigel and colleagues report results from the first phase of the Arabidopsis 1001 Genomes Project, based on short-read sequencing of 80 geographically diverse strains. This collection of strains has been made available to the scientific community, and the authors show that the identified polymorphisms in these strains can be useful for imputation and genome-wide association studies.

The BRCC36 isopeptidase complex (BRISC) is a deubiquitylase that stabilizes interferon receptors, driving inflammation. We discovered ‘BRISC molecular glue’ inhibitors (BLUEs) that selectively inactivate BRISC, promoting interferon receptor ubiquitylation and degradation to dampen immune responses.

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

Magnetic resonance imaging (MRI) is widely used to study the rat brain. Here, the authors provide standardized MRI brain templates and descriptive atlases for the rat, incorporating both structural and functional MRI data, along with associated resources.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

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.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

The RING protein RBX-1 is implicated in both NEDDylation and ubiquitylation reactions. In this issue, new structural analysis reveals how conformational flexibility of the RBX-1 linker allows for a marked reorientation of the CUL1–RBX1 complex to facilitate transfer of NEDD8 or ubiquitin by closing the gap between the E2 catalytic site and the substrate.

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.

Bridging covalent ligand discovery with chimeric degrader design has emerged as a mechanism to target proteins that lack enzymatic activity or are intractable. Here, the authors use biochemical and cellular tools to deconvolute the role of covalent modification in targeted protein degradation using Bruton’s tyrosine kinase.

The LHCb experiment at CERN has observed significant asymmetries between the decay rates of the beauty baryon and its CP-conjugated antibaryon, thus demonstrating CP violation in baryon decays.

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.

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.

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.

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.

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.

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 characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

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.

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.

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.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

Study shows PTSD predisposition shares distinct genes and genomic regions with several cardiovascular conditions. Here the findings reveal neuronal, immune, and metabolic pathways, and repurposed drug targets that further the understanding of the comorbidity.

Small molecule antagonists of CCR6 are potential drugs for autoimmune disorders. Here the authors present inactive structures of CCR6 bound by different allosteric antagonists from two series simultaneously, offering multiple approaches to inhibit CCR6.

Petrels are wide-ranging, highly threatened seabirds that often ingest plastic. This study used tracking data for 7,137 petrels of 77 species to map global exposure risk and compare regions, species, and populations. The results show higher exposure risk for threatened species and stress the need for international cooperation to tackle marine litter.

Multi-ancestry genome-wide analyses identify 95 loci associated with post-traumatic stress disorder and implicate candidate genes, pathways and neurobiological systems underlying its pathophysiology.

The authors report PROTAC ternary complex structures involving the E3 ligase cIAP1 and target protein BTK, showing that cooperativity is not always correlated with degradation efficiency.

Analysis of HbA1c and FPG levels across 117 population-based studies demonstrates regional variation in prevalence of previously undiagnosed screen-detected diabetes using one or both measures and suggests that use of elevated FPG alone could underestimate diabetes prevalence in low- and middle-income countries.