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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.

He and colleagues develop a METTL3-based RNA base-editing screening strategy to identify functional N⁶-methyladenosine (m⁶A) sites that are important for prostate cancer cells and validate the role of a top m⁶A target, CHD9, in this context.

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.

Whether weak brain rhythms carry information about ongoing behavior remains unclear. Here, the authors develop a neural network that finds subtle motifs in irregular brain rhythms arising from neural populations to read out where a rat is in its environment.

Stable and cell-specific transgene expression can be achieved through in vivo site-specific integration of large DNA payloads using a two-vector system of enveloped delivery vehicles and adeno-associated viruses.

The roles of orbitofrontal and cingulate cortex in emotional decisions remain unclear. Here the authors show distinct timing between caudal orbitofrontal and cingulate signals, that orbitofrontal stimulation increases avoidance, and that physiological responses mirror behavior.

A multiancestry phenome-wide analysis of copy number variants in the UK Biobank genomes increases power to detect genetic associations with complex traits across human populations.

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.

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.

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 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.

Exai-1, a cell-free RNA foundation model that integrates sequence, structure and expression features, advances liquid biopsy diagnostics by denoising noisy data, augmenting limited datasets and improving the generalizability of cancer detection models.

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 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.

The role of oxytocin in modulating astrocytes during stress behaviour is not fully understood. Here the authors show that in the amygdala, oxytocin modulates stress related behaviour by transient Gαi-dependent retraction of astrocytic processes, followed by enhanced neuronal sensitivity to extracellular potassium.

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.

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.

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 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.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

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.

Single-cell RNA sequencing and assay for transposase-accessible chromatin using sequencing profiling of human retinal samples from diverse ancestries create an epitranscriptomic atlas characterizing over 130 cell types. Integration with genome-wide association study and expression quantitative trait loci data provides further insights into gene regulation and disease etiology.

The lipid transporter FATP2 reprograms neutrophils to polymorphonuclear myeloid-derived suppressor cells by mediating the uptake of arachidonic acid and promoting the synthesis of prostaglandin E₂.

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.

Transcriptome-wide m⁶A RNA methylation profile in 162 primary prostate tumors identifies m⁶A association with prognostic clinical features and disease aggression.

While therapies targeting type I BRAF mutations have been developed, there are limited options for those with type II and III mutations. Here, the authors identify a subset of BRAF-mutant non-small cell lung cancer patients and characterise the pan-RAF inhibitor exarafenib, demonstrating efficacy in preclinical models and investigating subsequent resistance mechanisms.

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.

The combination of the brain-permeable mTOR inhibitor RapaLink-1 and the brain-impermeable FKBP12 ligand RapaBlock enable brain-specific inhibition of mTOR.

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

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.

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.

Results of the phase 1/2 TACTOPS trial show that autologous T cell therapy targeting PRAME, SSX2, MAGEA4, Survivin and NY-ESO-1 in patients with pancreatic ductal adenocarcinoma is feasible and safe, and leads to encouraging clinical responses and evidence of antigen spreading in responders.

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.

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.

Individuals with SYK gain-of-function variants develop immunodeficiency and systemic inflammation, which are recapitulated in a knock-in mouse model. Treatment of these mice with bone marrow transplantation or with a SYK inhibitor ameliorates disease symptoms, highlighting potential therapeutic strategies for patients with SYK mutations.

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.

This work advances multimodal structural refinements to generate 3D polarization maps for relaxor ferroelectrics, revealing continuous textures with vortex meron features tied to chemical disorder and deepening understanding of relaxor phenomena.

The authors report a large-scale spin-locking effect of light within a Brownian medium arising from the intrinsic spin–orbit interactions of scattering from multiple individual nanoparticles in a complex disordered system.