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Engineered DNA recombinases efficiently and specifically insert genetic cargos without the use of landing pads.

Current yeast extracellular secretion measuring tools lack the sensitivity, throughput, and speed required for large-scale metabolic analysis. Here, the authors introduce molecular sensors on mother yeast cell membranes to screen for single-cell secretions and rapidly isolate productive strains.

Genome-scale genetic screens identify the small RNA-binding protein La as a strong mediator of prime editing.

Intravenous delivery of an adenine base editor and a single-guide RNA for the Fah gene can correct an A>G splice-site mutation in an adult mouse model of tyrosinaemia.

Barrett et al. identify a key Rubisco phase-separating protein in the CO₂-fixing pyrenoid of Chlorella algae. This protein’s broad promiscuity for green lineage Rubiscos may aid in engineering CO₂-supercharging pyrenoids in plants to boost yields.

A chromosome-level genome assembly for the Ninu (greater bilby) and genome sequences for the extinct Yallara (lesser bilby), together with resequenced genomes, shed light on the demographic history of Ninu and inform conservation plans for this culturally and ecologically important marsupial.

Efforts to rationally engineer nonribosomal peptide synthetase (NRPS) enzymes have focused on making individual modifications. Here the authors describe a targeted random engineering approach that uses thousands of NRPS domains amplified from the soil metagenome for mass substitution experiments.

CRISPR-Cas9 has been widely used to manipulate genomes, however control over activity is necessary to explore transcriptional or epigenetic regulation. Here the authors use a split Cas9 fused to nuclear receptor ligand-binding domains to achieve tuneable Cas9 activity.

Polyamines are essential metabolites linked to aging, cancer, and Parkinson’s disease. Here, authors develop a live-cell polyamine reporter and use a genome-wide CRISPR screen to uncover a link between mitochondrial respiration and polyamine import.

In a mouse model of progeria, an adenine base editor delivered with adeno-associated virus corrects the pathogenic mutation in LMNA, rescues vascular pathology and markedly extends the lifespan of the mice.

TALEs are programmable DNA-binding proteins with practical use in genome engineering and synthetic biology. Here the authors use single-molecule fluorescence microscopy to establish that TALE proteins function using two distinct DNA-interaction modes during sequence-specific target search.

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).

An engineered Cas12a enables higher-order combinatorial functional genomic screens using CRISPR interference.

Reporter gene expression history in cells is recorded with engineered fluorescent protein fibers.

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.

Culex mosquitoes are carriers of major diseases like West Nile virus and are a public health concern. Here the authors present a CRISPR-Cas9 gene drive as a control technology in the Culex quinquefasciatus mosquito species.

The development of site-specific recombinases as genome editing tools is limited by the difficulty of altering their DNA sequence specificity. Here the authors present Rec-seq, a method for identifying specificity determinants and off-target substrates of recombinases in an unbiased manner.

Body size and composition are complex traits that are challenging to characterize due to environmental and genetic influences. Here, Arehart et al. disentangle shared and distinct genetic signals underlying body size and composition.

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.

Neural mechanisms mediating information flow and processing in dendrites are not fully understood. Here the authors developed techniques to map bioelectrical excitations in the dendrites of neurons in acute slices of mouse brain tissue. They developed a holistic picture of the roles of dendritic excitations in spike back-propagation.

Early positioning of the embryo nuclei is not well understood. Now, experiments show that the orientation of the mitotic spindle is controlled by topological interactions, which determine whether the nucleus remains inside the Drosophila embryo.

A novel multi-omics workflow, combining gut microbiome metagenomics, metatranscriptomics and metabolomics, enabled the identification of the microbial pathways responsible for the degradation of the immunomodulatory drug 5-ASA in the gut of patients with inflammatory bowel disease.

Lipid production in the oleaginous microalga Nannocholoropsis gaditana is doubled by decreasing the expression of a transcriptional regulator identified through a CRISPR–Cas9 reverse-genetics approach.

A single-molecule approach demonstrates that TALEs scan DNA using a unique ‘zip-line’ mechanism wherein the TALEs move without rotating along the DNA helix, yet the DNA remains threaded through the loosely wrapped TALE.

A new DNA-editing technique called prime editing offers improved versatility and efficiency with reduced byproducts compared with existing techniques, and shows potential for correcting disease-associated mutations.

Optimized adeno-associated viruses delivering split cytosine base editors and adenine base editors with trans-splicing inteins can edit brain, liver, retina, heart and skeletal-muscle tissues at therapeutically relevant efficiencies.

The bacterial periplasmic predator Bdellovibrio bacteriovorus deacetylates the peptidoglycan of the prey bacterium early upon invasion. Here, the authors identify and characterize a Bdellovibrio lysozyme that acts specifically on deacetylated peptidoglycan and is important for periplasmic exit.

Structural and biochemical studies of the RAD51B–RAD51C–RAD51D–XRCC2 complex reveal that it uses coupled RAD51B and RAD51C ATPase activities to promote the nucleation and extension of RAD51 nucleoprotein filaments.

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.

Kim and coworkers describe a technique, EPSILON, to map AMPA receptor exocytosis, a proxy for synaptic plasticity, in mice. The authors demonstrated a correlation between AMPA receptor exocytosis and cFos expression during a fear conditioning experiment.

Efficiency of transversion base editing is increased by matching a set of base editors to target sequences.

In this study, Yang et al. show that the mitochondrial-stress-induced cleavage product of DELE1 oligomerizes to generate a signaling platform that activates a cascade of kinases, triggering the integrated stress response.

Programmable and reversible CRISPRi-based genetic circuits function in a variety of plants.

Single-stranded DNA annealing is driven by RAD52 open rings in association with RPA.

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.

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.

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.

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.

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.

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.

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.