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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.

Annunziato, Quan and Donckele et al. identify G3BP2 (Ras–GAP SH3 domain-binding protein 2) as a molecular glue-induced neosubstrate of the CRL4^CRBN E3 ubiquitin ligase. The CRBN–glue neosurface uses a molecular surface mimicry mechanism to recruit and degrade G3BP2 in a compound-dependent manner.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Spin-enhanced lateral flow tests use nanodiamonds for the sensitive, robust detection of disease biomarkers. Here, authors report a clinical evaluation of a test for SARS-CoV-2 antigen, finding 95.1% sensitivity (Ct ≤ 30) and 100% specificity, with detection 2.0 days earlier than conventional tests.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Pathogenic variants in UNC13A underlie a novel neurodevelopmental syndrome, with three subtypes defined by distinct genotypes with varying clinical and functional impacts characterized in cellular and animal models.

Here the authors develop a novel statistical method for quantifying mutation burden from whole genome sequencing data and use it to discover the genetic, genomic, and phenotypic correlates of clonal hematopoiesis without known driver genetic lesions.

A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

An investigation using various methods reports an association between adeno-associated virus 2 and paediatric hepatitis of unknown aetiology.

In this Stage 2 Registered Report, Buchanan et al. show evidence confirming the phenomenon of semantic priming across speakers of 19 diverse languages.

Using multi-ancestry genome-wide association study and fine-mapping, 298 loci and 36 credible genes are identified in the aetiology of bipolar disorder.

Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

A high-resolution, global atlas of mortality of children under five years of age between 2000 and 2017 highlights subnational geographical inequalities in the distribution, rates and absolute counts of child deaths by age.

From 1980 to 2018, the levels of total and non-high-density lipoprotein cholesterol increased in low- and middle-income countries, especially in east and southeast Asia, and decreased in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe.

Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.

Bernhard et al. reveal the architecture of the tetrameric Trypanosoma brucei nuclear cap-binding complex. Using cryo-electron microscopy and biochemical assays, the researchers characterize its binding to the 5’-cap of the spliced-leader RNA.

This study used fine-mapping to analyze genetic regions associated with bipolar disorder, identifying specific risk genes and providing new insights into the biology of the condition that may guide future research and treatment approaches.

A case–control study investigating the causes of recent cases of acute hepatitis of unknown aetiology in 32 children identifies an association between adeno-associated virus infection and host genetics in disease susceptibility.

What is the state of trust in scientists around the world? To answer this question, the authors surveyed 71,922 respondents in 68 countries and found that trust in scientists is moderately high.

Pathology-oriented multiplexing (PathoPlex) represents a framework for widespread access to multiplexed imaging and computational image analysis of clinical specimens at a relatively high throughput and subcellular resolution.

In this largest whole-exome sequencing study of epilepsies to date, the Epi25 Collaborative identified extremely rare variants that confer risk for diverse epilepsy subtypes, highlighting roles in synaptic transmission and neuronal excitability.

Trans-ancestry meta-analysis of estimated glomerular filtration rate (eGFR) from 1,046,070 individuals identifies 264 associated loci, providing a resource of molecular targets for translational research of chronic kidney disease.

Oxidative stress is known to play a role in lung cancer carcinogenesis with protein cysteines residues being key in redox signaling. Here, the authors discover in lung cancer patients through redox proteomics that there is a higher oxidation of the cysteines of glycolytic and methylglyoxal metabolism enzymes.

Anna Köttgen and colleagues report genome-wide association studies for serum urate in over 140,000 individuals from the Global Urate Genetics Consortium (GUGC). They identify 18 loci newly associated with serum urate concentrations and confirm 10 known loci, characterize their associations with gout and include a network analysis suggesting a role for inhibins-activins pathways in regulating urate homeostasis.

STAARpipeline is a comprehensive framework for flexible and scalable rare-variant association analysis using whole-genome sequencing data and annotation information.

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.

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.

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.

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.