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

A redox reaction network, comprising concurrent oxidation and reduction pathways, is described that can drive autonomous unidirectional motion about a C–C bond in a structurally simple synthetic molecular motor based on an achiral biphenyl.

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.

Integrated multi-omic analyses using samples from the TRACERx study highlight cross-talk between DNA hypermethylation and genomic lesions in non-small cell lung cancer.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

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.

New field measurements and modeling show meltwater refreezing in Greenland’s bare ice may reduce runoff to surrounding oceans, highlighting a process climate models can incorporate for improved predictions of future sea-level rise.

R2 retrotransposons are natural RNA guided gene insertion systems. Here, Edmonds et al. characterize the structure and biochemistry of an avian R2 and engineer a compact, all-RNA system to integrate DNA in mammalian cells, aiding the development of future retrotransposon-based gene editors.

A study reports whole-genome sequences for 490,640 participants from the UK Biobank and combines these data with phenotypic data to provide new insights into the relationship between human variation and sequence variation.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

Here Iliev et al. review the interactions between the microbiota and the mucosal immune system from infancy to adulthood, highlighting the impact on health and disease.

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 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.

Protein complexes consisting of a cyclin-dependent kinase (CDK4 or CDK6) and cyclin D control passage through the G1 checkpoint of the cell cycle by phosphorylating the retinoblastoma (RB) protein¹. The ability of these complexes to phosphorylate RB is inhibited by a family of low molecular weight proteins including p16^INK4a (refs 2,3), p15^iNK4B (ref 4)? and p18 (ref 5) Germline mutations in the p16^INK4a gene have been identified in approximately half of families with hereditary melanoma^6–12. In this report, we describe an Arg24Cys mutation in CDK4 in two unrelated melanoma families which do not carry germline p16^INK4a mutations6. This mutation was detected in 11/11 melanoma patients, 2/17 unaffecteds and 0/5 spouses. The CDK4-Arg24Cys substitution has previously been identified as a somatic mutation in a melanoma that gives rise to a tumour-specific antigen recognized by autologous cytolytic T lymphocytes¹³. This mutation has a specific effect on the p16^INK4a binding domain of CDK4, but has no effect on its ability to bind cyclin D and form a functional kinase¹³. Therefore, the germline Arg24Cys mutation in CDK4 generates a dominant oncogene that is resistant to normal physiological inhibition by p16^INK4a. The only previous example of a dominant oncogene transmitted in the human germline is the RET gene that gives rise to MEN2A^14,15 and MEN2B¹⁶.

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.

Cosmic rays flying through superconducting quantum devices create bursts of excitations that destroy qubit coherence. Rapid, spatially resolved measurements of qubit error rates make it possible to observe the evolution of the bursts across a chip.

Comparing anatomy and life habits for fossil echinoderms spanning the Cambrian to Ordovician periods, the authors show that anatomical form and functional diversity are decoupled, and ecological innovation is constrained.

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.

Retromer complex cooperates with Vps5 and Vps17 in yeast to traffic transmembrane proteins. Here, the authors present structural and functional studies that reveal the mechanism of Retromer and Vps5 interaction.

A meta-analysis of genome-wide association studies of type 2 diabetes (T2D) identifies more than 600 T2D-associated loci; integrating physiological trait and single-cell chromatin accessibility data at these loci sheds light on heterogeneity within the T2D phenotype.

The CAPItello-291 phase 3 study reported that capivasertib (an AKT inhibitor) and fulvestrant (a selective estrogen receptor degrader) improved progression free survival in patients with HR-positive/HER2-negative advanced breast cancer. Here, the authors report the results of an extended Chinese cohort recruited as part of the original global CAPItello-291 study.

The use of functional genomics in primary immune cells has been limited by inefficient vector delivery and risk of perturbing cell states. Here the authors present CHimeric IMmune Editing (CHIME) for in vivo evaluation of gene function and pooled screening approaches.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

Shallow moonquakes detected at four Apollo landing sites between 1969 and 1977 occurred during maximum stress and in close proximity to young faults, suggesting that the Moon is tectonically active, according to reanalyses of the seismic data and tidal force modelling.

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.

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.

Timothy Frayling, Joel Hirschhorn, Peter Visscher and colleagues report a meta-analysis of genome-wide association studies for adult height in 253,288 individuals. They identify 697 variants in 423 loci significantly associated with adult height and find that these variants cluster in pathways involved in growth and together explain one-fifth of the heritability for this trait.

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.

Patients with metastatic cancers of unknown primary (CUP) are currently unable to gain access to drugs through standard of care or clinical trials. Here, the authors perform whole-genome and transcriptome sequencing (WGTS) on 72 patients with CUP and demonstrate the feasibility of using WGTS to determine the specific cancer types of CUP, thereby clinically benefiting patients with CUP.

Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.

Impact-induced acoustic and seismic wave events on Mars recorded by the InSight lander’s seismometer have been traced to fresh craters observed in spacecraft imagery.

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.

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.