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Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

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.

Osteosarcomas (OS) are aggressive bone tumors which have no actionable recurrent driver mutations. Here the authors identify aberrant expression of EZHIP in a subset of OS patients as an oncogenic driver, which exhibits vulnerability to epigenetic therapies.

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.

Non-small cell lung cancers with inactivating SMARCA4 mutations are currently undruggable. Here, the authors show that the absence of SMARCA4/2 reduces chromatin accessibility at the CCND1 locus, leading to a subsequent reduction in cyclin D1 expression, which promotes vulnerability of these cancers to CDK4/6 inhibition.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

Researchers in Canada prepare for turbulence in the wake of US funding changes — but there’s a silver lining.

SMARCA4/2 loss in ovarian and lung cancers is associated with chemotherapy resistance. Here, the authors show that SMARCA4/2 deficiency in cancer cells reduces the expression of the ER-Ca²⁺ channel IP3R3 and subsequently calcium transfer to the mitochondria, which inhibits apoptotic cell death.

Glioma stem-like cells (GSCs) exhibit plasticity during proneural-to-mesenchymal transition. Here the authors show that extracellular vesicles from endothelial cells can promote this transition of GSCs through activation of MMPs and NFkB, and inactivation of NOTCH.

Single-cell multiome and spatial transcriptomic analysis reveals new disease markers in the hippocampus implicated in both early and late stage of a tauopathy model of Alzheimer’s Disease.

Vasectasia is a newly described, non-angiogenic form of blood vessel formation induced by mesenchymal glioblastoma cells, and driven by endothelial cell responses to extracellular vesicles containing oncogenic EGFR.

Alzheimer’s disease has been associated with increased structural brain aging. Here the authors describe a model that predicts brain aging from resting state functional connectivity data, and demonstrate this is accelerated in individuals with pre-clinical familial Alzheimer’s disease.

The variability in clinical outcomes of SARS-CoV-2 infection is partly due to deficiencies in production or response to type I interferons (IFN). Here, the authors describe a FIP200-dependent lysosomal degradation pathway, independent of canonical autophagy and type I IFN, that restricts SARS-CoV-2 replication, offering insights into critical COVID-19 pneumonia mechanisms.

Comprehensive genomic profiling of human H3K27M mutant diffuse midline gliomas, combining single-cell RNA sequencing and ATAC sequencing with bulk ChIP sequencing and other data, proposes distinct oligodendrocyte populations as potential cells of origin.

The amygdala is known to be engaged in emotional and autonomic function, yet the detailed functional connectivity of the human amygdala remains unclear. Here, the authors examine effective connectivity in the amygdala of patients with epilepsy using direct focal electrical stimulation.

Histone H3-mutant gliomas are deadly brain tumours and the tumour microenvironment is not fully understood. Here the authors profile the immune microenvironment from human samples and mouse models and implicate myeloid cells in immune suppression and show inhibition of myeloid cells and checkpoint blockade demonstrates therapeutic benefits in mice.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is driven by SMARCA4 loss. Here the authors demonstrate that SCCOHT cells are highly sensitive to CDK4/6 inhibition and provide mechanistic insights, whereby this druggable vulnerability is driven by cyclin D1 deficiency induced by SMARCA4 loss.

A single-cell transcriptomic atlas from embryonal pons and forebrain provides insights into the developmental origins of pediatric brain tumors. The study identifies impaired differentiation of specific neural progenitors as a common mechanism underlying these cancers.

Creative experiences such as dance, music, drawing, and strategy video games might preserve brain health. The authors show that regular practice or short training in these activities is linked to brains that look younger and work more efficiently.

A genome-wide study by the Long COVID Host Genetics Initiative identifies an association between the FOXP4 locus and long COVID, implicating altered lung function in its pathophysiology.

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.

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 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.

Here, the authors show that PRMT1 targeting inhibits clear cell renal cell carcinoma cells through perturbation of RNA metabolism and down-regulation of DNA repair pathways, resulting in the accumulation of unresolved R-loops and DNA damage.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

This study reveals near-atomic interfacial details of an Alzheimer’s Positron Emission Tomography (PET) molecule MK-6240 with its target disease marker, tau amyloid, showing MK-6240 mostly interacts with itself, like a pancake stack, which stabilizes an otherwise small interface with the amyloid.

A large international panel of experts reach consensus on a new standard for reporting settings in psychedelic trials, identifying 30 key non-pharmacological factors to strengthen the rigor of psychedelic research.

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.

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.

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.

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 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.

In the geographically and taxonomically divided systems of vertebrates in the Living Planet Index, a small percentage of clusters showed extreme declines or increases, whereas most vertebrate populations across all systems showed no mean global trend.

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.

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.