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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.

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.

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.

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.

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.

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.

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.

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

The engineering of 5′ UTRs that modulate protein expression remains a great challenge. Here we leverage synthetic biology and computational design to develop a high-throughput strategy to design, screen, and optimize 5′ UTRs that enhance protein expression for non-viral gene therapies.

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.

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.

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.

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 this work, Yang et al. provide evidence of triclosan exposure resulting in increased evolvability of K. pneumoniae in experimental evolution studies. They utilize sequencing and transcriptomics to explore the chromosomally and horizontally acquired antimicrobial resistance mechanisms.

Curli are bacterial functional amyloids that have gained interest as self-assembling biomaterial for biotechnology applications. Here, the authors show that DNA origami decorated with CsgB nucleator proteins induced the site-specific nucleation and subsequent fibrillization of CsgA proteins.

Park et al. redesigned the abscisic acid-induced dimerization module to respond to diverse ligands and function orthogonally to the natural modules, enabling synthetic biological circuit design in plants and yeast.

Kumar et al. show that under glucose-depleted conditions, neurons can use fatty acids as an alternative source of energy to support synaptic function.

This study uncovers a highly conserved jumbo phage protein, Imp1, that possesses multiple interfaces to license protein import into a proteinaceous nucleus-like compartment, using a genetic selection that forces the phage to decrease or abolish the import of specific proteins.

Gonzalez et al. use a viral evolutionary approach to generate cross-species compatible AAV (ccAAVs) vectors. They describe a highly potent new variant, AAV.cc47, with enhanced transduction efficiency over AAV serotype 9 and show its efficacy in different mouse models, pigs and non-human primates.

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).

This study reveals how the pathogen Staphylococcus aureus adapts to the lung microenvironment, rich in host metabolites fumarate and itaconate, by using a key enzyme, FumC, to support its metabolic fitness, survival, and persistence.

This study provides a structural and functional characterisation of the phage resistance system, BREX. Went et. al. provide structures of the methyltransferase component, PglX, and rationally mutate PglX to retarget BREX defence against new phages.

Long-read sequencing allows the detection of RNA isoforms, but is hampered by low throughput and potential artefacts. Here, the authors develop the scTaILoR-seq hybridisation capture method for long-read RNA sequencing to improve transcript detection, and use this method to detect isoforms at the single-cell level in ovarian cancer.

Co-opting the amyloid machinery from Bacillus subtilis, engineering of TasA fusion proteins enables the assembly of functionalized biofilms with tunable physicochemical properties that are amenable to 3D printing and microencapsulation techniques.

Knock-in mice conditionally or constitutively expressing Cas12 variants enable a wide range of ex vivo and in vivo applications requiring multiplexed genome engineering.

An undetected, phenotypically colistin-resistant subpopulation of Enterobacter cloacae mediates antibiotic treatment failure

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

Using integrative multi-omics and CRISPR knock-out of all ~1,900 transcription factors, the authors identify essential transcription factors required for Neurogenin-driven differentiation of human cortical neurons.

Hexanucleotide repeat expansion in the C9ORF72 gene produces toxic dipeptide repeat (DPR) in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here the authors apply single-molecule methods to study the translation dynamics of C9ORF72 expanded repeat in different frames showing that multiple translation steps contribute to the final toxic dipeptide production.

Crossing the blood–brain barrier in primates is a major obstacle to gene delivery in the brain. Here an adeno-associated virus variant (AAV.CAP-Mac) is identified and demonstrated for crossing the blood–brain barrier and delivering gene sequences to the brain of different non-human primates species.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Cellular stressors can impact clonal hematopoiesis. Here, the authors explore the impact of cytotoxic therapy and hematopoietic transplantation on clonal expansion, suggesting different stressors can promote expansion of distinct long-lived clones.

Precisely tuning the genetic response to environmental stimuli is a key step in engineering synthetic biology systems. Here, the authors profile 8269 IPTG-induced promoters to deconstruct the relationship between sequence architecture and gene expression.

A structural, biochemical and metabolomic analysis reveals the mechanistic basis for transport of extracellular choline and ethanolamine into cells by the human transport protein FLVCR1.

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.

There are few robust circuit architectures for sequential gene perturbations. Here, the authors use a modular recombinase-based design that sequentially edits loci, synchronizes cells, and deletes itself.

Efficient, large-scale genomic analysis is facilitated on the cloud by a computational tool with error-diagnosing and self-healing capabilities.

Engineered biosensing bacteria can potentially probe the human gut microbiome to prevent, diagnose, or treat disease. Here the authors present a robust biocontainment assisted by Cas9 and an engineered gene expression control combined in a genetically engineered human commensal bacterium that successfully functioned in a mouse intestinal tract as well as cell culture condition.

Pol δ bound to the proliferating cell nuclear antigen (PCNA) replicates the lagging strand in eukaryotes and cooperates with flap endonuclease 1 (FEN1) to process the Okazaki fragments for their ligation. Here, the authors present a Cryo-EM structure of the human 4-subunit Pol δ bound to DNA and PCNA in a replicating state with an incoming nucleotide in the active site.

Gram-positive bacteria contain a transcription factor HelD that is able to remove and recycle stalled transcription complexes. Here the authors provide mechanistic insights into this process by determining the cryo-EM structures of the Bacillus subtilis RNA polymerase (RNAP) elongation complex and the RNAP-HelD transcription recycling complex and propose a model of HelD catalysed transcription recycling.

Whole-genome sequencing and phenotype data sharing are introduced in a national health system to streamline diagnosis and to discover coding and non-coding variants that cause rare diseases.

Zebrafish can regenerate after paralyzing spine injuries and regain locomotor ability, unlike mammals. Here authors show that the neurogenic factor Hb-egf promotes spinal cord regeneration in zebrafish and is regulated by an enhancer that can similarly direct expression in the pro-regenerative setting of neonatal mice.

Digital and analogue gene circuits each have distinct advantages in natural and engineered cells. Here, Rubens et al. engineer synthetic gene circuits that implement mixed-signal digital and analogue computations in living cells.

A global multi-taxon extinction risk assessment of freshwater fauna for The IUCN Red List of Threatened Species finds one-quarter of species to be at high risk of extinction.

Cancer cells have altered lipid metabolism. Here the authors show that DAXX promotes lipogenesis and tumorigenesis through interaction with SREBP1/2.