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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.

An integrated analysis of de novo and inherited coding variants in 42,607 individuals with autism spectrum disorder identifies 60 risk genes of which five have not previously been associated with neurodevelopmental disorders.

Morphological subtypes of autism spectrum disorder (ASD) may differ in their genetic bases. Chan et al. develop a method for calculating a patient-level, genome-wide rare variant score and find significant differences in rare and common variant associations between dysmorphic and nondysmorphic ASD groups.

Lv et al. discover that homologous disordered regions of proteins linked to ALS/FTD and Parkinson’s, CHCHD10 and CHCHD2, form amyloid fibrils in vitro and that the structures of these fibrils are consistent with potential roles for them in disease.

Environmental micro-compartment genomics provides efficient and high-throughput single-particle DNA sequencing that captures overlooked members of microbial communities.

The non-coding RNA RNU4-2, which is highly expressed in the developing human brain, is identified as a syndromic neurodevelopmental disorder gene, and, using RNA sequencing, 5′ splice-site use is shown to be systematically disrupted in individuals with RNU4-2 variants.

Evan Eichler and colleagues report an expanded copy number variation (CNV) morbidity map of developmental delay, with additional resequencing of candidate genes in regions implicated by large CNVs. They identify several new disease-associated CNVs and show how their combined approach facilitates discovery of new developmental syndromes and disease genes.

Alterations in the tumour microenvironment (TME) can contribute to prostate cancer progression, but it is unclear how tumours mediate those changes. Here, analysis of human prostate cancer tissues and key stages of prostate cancer progression in a genetically engineered mouse model using single-cell RNA-sequencing reveals the central role of MYC signalling in reprogramming the TME.

Multisystem inflammatory syndrome in children (MIS-C) onsets in COVID-19 patients with manifestations similar to Kawasaki disease (KD). Here the author probe the peripheral blood transcriptome of MIS-C patients to find signatures related to natural killer (NK) cell activation and CD8+ T cell exhaustion that are shared with KD patients.

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

The authors use a computational model of word recognition to show that adults’ interpretation of young children’s speech depends heavily on beliefs about what children are likely to say.

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.

Neuron-specific DNA methylation and intragenic enhancers target the Rett syndrome protein methyl-CpG-binding protein 2 to regulate genes that delineate closely related neuron types, suggesting breakdown of fine-scale neuronal specification in developmental disorders.

How Indigenous populations in the southern tip of South America have changed over time has been unclear. Here the authors generate genome-wide data for 20 ancient individuals and examine how past migrations and admixture events correlate to geography and shifts in the archaeological record.

The impact of structural variation on the evolution of the amylase genes is explored using human pangenome resources and ancient DNA data.

The SPECULOOS project detected an Earth-sized planet in a short orbit around a nearby Jupiter-sized star. This planet, SPECULOOS-3 b, is one of the most promising rocky exoplanets for detailed emission spectroscopy characterization with JWST.

Oby, Degenhart, Grigsby and colleagues used a brain–computer interface to challenge monkeys to override their natural time courses of neural activity. They found the time courses to be highly robust, suggestive of network-level computational mechanisms.

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.

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

Rare de novo single nucleotide variants in brain-expressed genes are found to be associated with autism spectrum disorders and to carry large effects.

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.

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 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.

Familial Mediterranean fever is an autoinflammatory disease caused by gain-of-function mutations in the pyrin inflammasome. Kastner and colleagues show that mutant pyrin better resists suppression by the plague bacterium Yersinia pestis and may have been positively selected in human Middle Eastern populations.

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.

For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Some RNA polymerase (POLR) 3-related leukodystrophy cases do not have the causal mutations in POLR3A and POLR3B. Here, by exome sequencing, the authors identify recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, impairing assembly and nuclear import of POLR3, but not POLR1.

Transcriptomic analyses of acute phase whole blood from a large cohort of patients with COVID-19 identify molecular determinants of post-infection long-term sequelae.

Senescent melanocytes of skin nevi drive hyperactivation of hair growth through the signalling factor SPP1.

microbeMASST is a tool to associate known and unknown metabolites to microbial producers leveraging untargeted metabolomics data.

Myelodysplastic syndromes are a broad group of haematopoietic malignancies that often progress to acute myeloid leukaemia. Here, the authors show that linear and branched evolution occurs within myelodysplastic syndrome and these patterns can be impacted by treatment.

Markov, Ren, Senkow and colleagues report that in patients with severe SARS-CoV-2 pneumonia, alveolar T cell interferon responses targeting structural SARS-CoV-2 proteins characterized patients who recovered, whereas responses against nonstructural proteins and activation of NF-κB were associated with poor outcomes.

An alternative HIV vaccine design facilitates generation of HIV-1-antibodies, with promising neutralization breadth in rodents and nonhuman primates.

During a photoinduced phase transition, electronic rearrangements are usually faster than lattice ones. Time-resolved measurements now show that the insulator-to-metal transition in a thin-film Mott insulator is preceded by lattice reconfiguration.

A report from the Australian Acute Care Genomics programme shows that the integration of rapid whole-genome sequencing and multi-omic analyses informs diagnoses and treatment decisions in a prospective cohort of 290 critically ill infants and children.