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Two individuals with KCNT1-related epileptic encephalopathy were treated with a KCNT1-targeting antisense oligonucleotide, leading to significant reductions in seizure frequency and intensity, but also the development of hydrocephalus.

Genetic analyses in more than 15,000 individuals from across the Americas, including individuals with autism and family members, define the genetic landscape of autism in Latin American populations and identify significant overlap with other ancestries.

Livestock play a role in maintaining antibiotic resistance reservoirs. Here, Liu et al. use metagenomics to study the dynamics of antibiotic resistance genes (ARGs) in the gut of dairy cattle during early life, showing that colostrum is a potential source of ARGs and ARG abundance declines during nursing covarying with dietary transition.

Jonaitis et al demonstrate that serotonin differentially modulates feedforward inhibitory neurons in the olfactory system of Drosophila which likely reflects odor categorization in higher order brain regions.

Lynch and colleagues characterize γδ T cells in colorectal and endometrial cancer and identify distinct subsets with opposing cytotoxic and wound healing functions, leading them to develop an expansion method that enhances cytotoxic functions.

Universities and those who work there must reimagine spaces, behaviour and processes to promote a sense of belonging for everyone, say Danielle McCullough and Ruth Gotian.

Vaccines against the WA1 SARS-CoV2 strain confer protection against other variants. However, the mechanisms underlying cross-protection are not fully understood. Here, the authors develop a method for rapid analysis of single B cells from patient samples and show that infection with a variant elicits convergent, public B cell responses to other variants.

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.

Typhoidal Salmonella is a major pathogen, but there is still a lack of knowledge about suitable vaccine antigens. Cerundolo and colleagues deep-phenotype bacteria-specific CD4⁺ T cells of Salmonella-infected volunteers to define cross-reactive and serovar-specific responses.

Disparities in risk and outcomes of pediatric acute lymphoblastic leukemia (ALL) are apparent between different ancestries. Here the authors identify genetic variants with African ancestry-specific risks for developing pediatric B-cell ALL that are also linked to greater 5-year mortality risk.

Whilst the ChAdOx1 nCoV-19 (AZD1222) vaccine has demonstrated efficacy against symptomatic disease, variants of concern (VOCs) with spike protein substitutions have led researchers to explore updating vaccines from ancestral spike protein. Authors use a Syrian hamster model to evaluate a vaccine encoding the spike protein of Beta VOC and assess efficacy against VOCs.

The ability to visualise stochastic invasion events is limited in murine models of metastatic cancers. Here the authors use a transparent zebrafish epidermis model to follow the invasion events of K-Ras transformed epithelial cells and show that these cells invade through basal cell extrusion.

Caloric restriction (CR) can extend the organism life- and health-span. Here, the authors show that mild caloric restriction enhances insulin sensititivy to promote beta cell health and longevity, through an optimization of energy metabolism and homeostasis pathways.

It has been hypothesized that domestication can occur through the ‘commensal pathway’ in which the domesticate takes advantage of a niche created as a byproduct by the domesticator. Here, Brooker et al. provide evidence for a commensal domestication process between longfin damselfish and mysid shrimps.

This study examines the history of North Atlantic deep-water masses, as recorded in marine sediments. Major lithological changes and increased rate of deposition reveal that stronger deep-ocean circulation initiated 3.6 million years ago.

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.

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.

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.

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

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.

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.

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.

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.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

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.

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.

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.

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.

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.

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.

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.

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.

Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient ‘biotypes’ characterized by partially distinct disease mechanisms.

A well-preserved 319-million-year-old brain of the extinct vertebrate Coccocephalus wildi provides insights into neural anatomy deep within the phylogeny of ray-finned fish.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

The CNV analysis group of the Psychiatric Genomic Consortium analyzes a large schizophrenia cohort to examine genomic copy number variants (CNVs) and disease risk. They find an enrichment of CNV burden in cases versus controls and identify 8 genome-wide significant loci as well as novel suggestive loci conferring either risk or protection to schizophrenia.

Whole-genome sequencing analyses in a cohort of individuals with ataxia-telangiectasia are used to identify genetic variants that might be amenable to treatment with splice-switching antisense oligonucleotides (ASOs), and develop ASOs with therapeutic potential.

Addressing nutrition and climate resilience together requires transdisciplinary participatory action research with clear impact pathways for systems change that starts from the ground up. The concept of ‘crops that nourish’ is proposed here to offer a new mode of pursuing agricultural development. It involves iterative co-creation between farmers and researchers that prioritizes local needs and agency, human health, resilience and sustainability through a focus on opportunity crops.

Walsh and colleagues use prospective sequencing in a large cohort of pediatric patients with solid tumors to detect mutations in cancer predisposition genes and guide downstream clinical care.

Kazachstania pintolopesii is a highly prevalent fungal symbiont that can trigger type 2 immunity and influence the composition of the gut mycobiome, as well as immune and disease phenotypes.