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Insect venom can cause severe allergic reactions including anaphylaxis. Here, the authors report structural and functional evidence that nanobody-based inhibitors can limit the allergenic and toxic activity of the major honeybee venom allergen and that passive administration prevents anaphylaxis in vivo.

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.

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.

Here, the authors characterize the gut virome of 647 one-year-old children in the COPSAC2010 cohort, finding that anelloviruses are highly prevalent and associated with daycare attendance, gestational age, and FUT2 secretor status.

Damgaard et al. analyze Bacteroides fragilis genomes isolated from people with and without colorectal cancer, identifying prophages. Screening 877 faecal metagenomes, they find that these specific prophages are significantly enriched in colorectal cancer patients.

Using reactivity-based metabolomics, methylglyoxal and its main metabolite lactoylglutathione were found to react rapidly with cysteines to generate l-lactoylated and d-lactoylated thioesters, suggesting additional pathways to enable protein lactoylation.

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.

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.

The cellular origin of soft-tissue cancers, such as synovial sarcoma (SyS), is unknown. Here, expression of the oncoprotein, SS18::SSX, in fibroblasts was sufficient to produce human-like SyS tumours, thereby identifying a cell of origin for SyS.

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.

An analysis of rare genetic variants identifies three genes—MAP1A, ANO8 and ANK2—that have a role in attention deficit hyperactivity disorder (ADHD) and investigates the potential underlying biological mechanisms.

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 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.

Large-scale genome-wide analyses identify hundreds of genetic loci associated with hypothyroidism and thyroid hormone levels, demonstrating the potential of using polygenic risk scores to predict disease onset and progression.

The chlorosome of the photosynthetic bacterium C. tepidumharvests light and transfers the energy to the photosynthetic reaction centre. Here the authors determine the structure of the baseplate, a scaffolding super-structure, to show that the baseplate consists of rods of repeated CsmA dimers containing pigment molecules.

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.

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.

The arthropod head is complex and its evolution has been difficult to reconstruct. Here, Park et al. describe new specimens of the Cambrian stem-group euarthropod Kerygmachela that preserve evidence of primitive compound eyes and a unipartite brain, providing insight into the structure of the early arthropod head.

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.

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.

Taxonomic classification of DNA sequences is typically performed on each sequence individually. Here the authors present a deep learning-based method that utilizes information across a dataset to enhance taxonomic annotations of any microbiome.

Dietary protein restriction in healthy, lean men elicits an increased energy intake to maintain body weight, which is driven, at least in part, by FGF21-mediated alterations to adipose tissue mitochondria.

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

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 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.

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.

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.

Catch certificates and eco-labels are used to control illegal fishing worldwide, however, independent control methods are needed. Here, gene-associated SNPs are used to assign individual marine fish back to their population of origin with high precision, with potential application for illegal fishing control.

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.

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.

Here, Johansen et al. develop an approach, Phages from Metagenomics Binning (PHAMB), that allows the binning of thousands of viral genomes directly from bulk metagenomics data, while simultaneously enabling clustering of viral genomes into accurate taxonomic viral populations, unveiling viral-microbial host interactions in the gut.

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.

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.

DNA from tumour cells can be detected in the blood of cancer patients. Here, the authors show that cell free DNA fragmentation patterns can identify lung cancer patients and when this information is further interrogated it can be used to predict lung cancer histological subtype.

De novo assembly of 23 Aspergillus section Nigri and 6 Aspergillus niger genome sequences allows for inter- and intraspecies comparisons and prediction of secondary metabolite gene clusters.

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.

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 mouse and nonhuman primate models, treatment with selective, long-acting neurokinin 2 receptor agonists aids weight loss by suppressing appetite and increasing energy expenditure, as well as by increasing insulin sensitivity.

The first genome sequence of an ancient human is reported. It comes from an approximately 4,000-year-old permafrost-preserved hair from a male from the first known culture to settle in Greenland. Functional single-nucleotide polymorphism (SNP) assessment is used to assign possible phenotypic characteristics and high-confidence SNPs are compared to those of contemporary populations to find those most closely related to the individual.

Genome-wide analyses using fetal and parental genotypes identify 40 independent associations influencing placental weight and highlight the role of the fetus in preeclampsia risk and placental growth regulation via insulin signaling.

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.

The authors uncover the roles and regulations of DNA polymerase κ (Polκ) during DNA damage bypass. In addition to a catalytic function across minor groove DNA lesions, Polκ stimulates Polζ-mediated extension past various DNA lesions.

DNA mismatch repair (MMR)-deficient cancers with microsatellite-instability are characterized by a high load of frameshift mutation-derived neoantigens. Here, by mapping the frameshift mutation landscape and predicting the immunogenicity of the resulting peptides, the authors show evidence of immunoediting in MMR-deficient colorectal and endometrial cancers.

InstaNovo, a transformer-based model, and InstaNovo+, a multinomial diffusion model, enhance de novo peptide sequencing, enabling discovery of novel peptides, improved therapeutics sequencing coverage and detection of unreported organisms in proteomics studies

Ramachandran plots are a convenient means of describing protein backbone conformation by depicting the distribution of Ca bond rotations. Here, the authors devise an alternative descriptor based on hydrogen bond rotations, and apply it to describe protein structures using a vocabulary of 30 hydrogen-bonding motifs.