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This flagship study from the European Solve-Rare Diseases Consortium presents a diagnostic framework including bioinformatic analysis of clinical, pedigree and genomic data coupled with expert panel review, leading to 500 new diagnoses in a cohort of 6,000 families with suspected rare diseases.

Harasimov, Gorry, Welp, Penir, Horokhovskyi et al. analyse proteostasis in mammalian oocytes and ovaries: the maintenance of oocytes involves exceptional protein longevity, and many of the extremely long-lived proteins decline as the ovary ages.

Elephant endotheliotropic herpesvirus (EEHV) haemorrhagic disease is a major threat for juvenile Asian elephants. This study reports a proof-of-concept trial that evaluates the safety and immunogenicity of a vaccine against EEHV.

DNA methylation plays an important role in silencing transposable elements. Here the authors find that loss of DNMT1 and DNA methylation leads to transcriptional activation and chromatin remodelling of evolutionarily young—hominoid-specific —LINE-1 elements which then act as alternative promoters for neuronal genes.

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.

Myelin formation is regulated by epigenetic mechanisms and ensures proper neuronal function during development and after demyelination. Here, the authors show that TET1, a DNA hydroxymethylase, regulates myelin repair in adult mice, but is defective with aging.

Stress resilience is the maintenance of mental health despite adversity. Here, the authors show that how we typically evaluate adverse events is a key resilience factor and that improving it goes along with improved resilience.

Long-distance migration and dispersion is a common characteristic of nearly all classes of telencephalic GABAergic neurons, which diversify extensively after birth in the cortex and striatum, but show limited postnatal changes in the septum, preoptic area and pallidum.

There is currently no approved influenza vaccine for newborns, so development of such a vaccine is warranted. Here the authors show, using a African green monkey newborn model, that an adjuvanted nanoparticle vaccine containing the stem region of influenza hemagglutinin can induce robust IgG responses, with the functionality of the antibodies linked to viral clearance.

An implementation trial conducted across 60 schools in Rwanda found that CyberRwanda, a digital, school-based intervention, did not affect the primary outcomes of modern contraceptive use, childbearing and HIV testing among adolescents but was associated with higher contraceptive use among sexually active participants.

A phase 1/2 trial of dual-vector rAAVrh8 gene therapy for GM2 gangliosidosis, administered by bilateral intrathalamic, cisterna magna and intrathecal delivery found a dose-dependent biochemical correction of the disease.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

McCreery, Stubb et al. show that mechano-osmotic changes in the nucleus induce general transcriptional repression and prime chromatin for cell fate transitions by relieving repression of specific differentiation genes.

Knee osteoarthritis has a sex-specific phenotype with post-menopausal persons experiencing the highest incidence. Here the authors investigate the underlying mechanisms in a mouse model of menopause and find that the loss of 17β-estradiol and progesterone enhanced susceptibility to senescence, extracellular matrix disassembly and cartilage degradation.

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 planum temporale is a key structure in the human language network. Here the authors show that planum temporale asymmetry at birth in baboons predicts the development of communicative right-hand use, which suggests some common features in the wiring of communicative properties between species.

The Global Flourishing Study provides a comprehensive view of the distribution and determinants of well-being by assessing domains such as health, happiness, meaning, character, relationships and financial security. Initial findings reveal significant variations in flourishing across countries and demographic groups, with factors such as age, marital status and religious service attendance showing strong associations with well-being.

In this study, Aggarwal and colleagues perform prospective sequencing of SARS-CoV-2 isolates derived from asymptomatic student screening and symptomatic testing of students and staff at the University of Cambridge. They identify important factors that contributed to within university transmission and onward spread into the wider community.

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.

Using single-cell imaging of a fluorescent chaperone-mediated autophagy (CMA) reporter and RNA sequencing data, the authors present a resource on basal CMA activity across organs, cell types and sexes in young and old mice, offering a comprehensive overview of changes in this proteostatic mechanism in the context of aging.

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.

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.

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.

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.

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.

It is reported that measles epidemics in Niger are unexpectedly episodic, and it is shown through modelling that powerful seasonality in transmission generates high amplitude, chaotic epidemics, with potentially important consequences for vaccine-based control strategies.

T-cell acute lymphoblastic leukemia is a highly aggressive disease with varying recurrence rates. Here, the authors build a single cell transcriptomic atlas of childhood T-cell acute lymphoblastic leukaemia (T-ALL). They identified a distinctive cancer cell state that correlates with high risk, treatment refractory T-ALL.

Chemically induced protein degradation is a powerful alternative to classical inhibition, but some proteins have deeply masked binding pockets that make the development of degrader molecules difficult. Here, the authors discover an alternate site on nuclear receptors that can be targeted by degraders.

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 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.

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

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.

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.

UBA1-mutant macrophages exposed to inflammatory stimuli undergo aberrant apoptotic and necroptotic cell death mediated by CASP8 and RIPK3–MLKL, offering insights into the mechanisms underlying VEXAS syndrome.

The assembly of the genome of the koala provides insights into its adaptive biology and identifies gene expansions that contribute to its ability to detoxify eucalyptus-derived compounds and perceive plant secondary metabolites.

Pancreatic cancer progression is driven by a switch from HNF4G-driven transcriptional activity in primary disease to FOXA1-mediated transcription in the metastatic setting.

Wang et al. show that intestinal sphingosine-1-phosphate is transferred to oocytes and influences sphingolipid metabolism in the next generations. In the offspring, sphingosine-1-phosphate protects Caenorhabditis elegans neurons against axon fragility.

Khetarpal et al. show that the metabolic regulator PGC-1α is essential in heart muscle cells for exercise-driven cardiac growth, and that suppression of the stress-induced myokine GDF15 is required to enable cardiomyocyte adaptations to training.

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.

White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.

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.

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 transfer of nuclear chromatin to the cytoplasm drives the pro-aging inflammatory phenotype of senescent cells. Here, Miller et al. show that this process is suppressed by p53 and that activation of p53 reverses some features of aging in vivo.

The hunt for a quantum spin liquid has involved many different material families and models. Now, Zn-barlowite has been found to have similar behaviour to another candidate material, herbertsmithite, hinting there may be universal physical behaviour.