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The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

Functional and structural characterization of PtmA2 reveals that it is an unusual non-adenylating acyl-CoA ligase and part of a system wherein the canonical acyl-CoA ligase reaction is separated into two half-reactions performed by distinct enzymes.

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.

Semi-metallic single crystals of antimony can be deposited using molecular beam epitaxy on molybdenum disulfide to create ohmic contacts with resistance of under 100 Ω µm at a contact length of 18 nm.

The backbones of all natural peptides and proteins are composed of amide bonds. In the laboratory, the construction of such bonds generally relies on dehydrative approaches, although there are alternatives. It is now shown that the activation of amines and nitroalkanes with an electrophilic iodine source can lead directly to amide products.

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

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.

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.

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.

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.

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.

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.

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.

The Longmen Shan Mountains rise up 6,000 m over a distance of just 100 km, but the mechanisms driving formation of this striking topography are debated. Analyses of crustal movements during the 2008 Wenchuan earthquake suggest that fault-induced uplift plays a role in building the high topography.

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.

The Galleri MCED cfDNA test is designed to screen for cancer signal in asymptomatic individuals. Here, the authors analyse the real-world performance of the test in over 100,000 individuals. In agreement with clinical validation studies, they observe a 49.4% empirical positive predictive value, with 87% accuracy for cancer signal localization in the body.

Understanding the growth pathway of faceted alloy nanoparticles at the atomic level is crucial to morphology control and property tuning, but remains a challenge. Here, the authors reveal the particle growth and facet formation mechanisms of octahedral Pt₃Ni nanoparticles using multiple cutting-edge in situ techniques.

Typical quantum error correcting codes assign fixed roles to the underlying physical qubits. Now the performance benefits of alternative, dynamic error correction schemes have been demonstrated on a superconducting quantum processor.

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.

Long-term consequences of COVID-19 can be identified by patient reported symptoms (long COVID) or clinical diagnosis (post-acute complications of SARS-CoV-2). Here, the authors perform two case control studies using data from UK Biobank to investigate risk factors for both outcomes.

The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease.

Alterations in DNA methylation patterns are known as predictors of cancer diagnosis. Here, the authors develop a method to analyze both symmetric- and hemi-methylated regions in plasma cell free DNA and show its utility in detecting both liver and brain cancer.

Experimental measurements of high-order out-of-time-order correlators on a superconducting quantum processor show that these correlators remain highly sensitive to the quantum many-body dynamics in quantum computers at long timescales.

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.

A subcortical circuit that regulates food consumption in mice is described, involving neurons in the ventromedial hypothalamus that are directly linked to motor centres that regulate feeding and jaw movements.

A multi-cohort genome-wide association study of tau PET, a brain imaging-based marker of Alzheimer’s disease, identifies a CYP1B1-RMDN2 locus as associated with higher tau and faster cognitive decline. These results suggest a new genetic contribution to cerebral tau and target for Alzheimer’s disease research.

A high-bandwidth neuromotor interface offers performant out-of-the-box generalization across people.

Mutations in histone acetyltransferases (HATs) CREBBP and EP300 are generally thought to lead to decreased function or absence of protein product. Here the authors describe a gain of function of several CREBBP mutations leading to baseline hyper-acetylation, increased homologous recombination and potential synergy between radiation and HAT inhibition in CREBBP/EP300 mutant tumors.

Shi et al. report a sulfonation-dependent vulnerability of liver tumors expressing the sulfotransferase SULT1A1 by showing their sensitivity to the small molecule YC-1 and identifying structurally related compounds that can be modified by SULT1A1.