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Exportin-1 (XPO-1) inhibitor selinexor has been reported as a therapeutic option in solid cancer. Here, the authors present a phase 1 clinical trial combining selinexor with chemotherapy by gemcitabine in patients with advanced sarcoma.

The impact of transcription on germline mutagenesis remains poorly understood. Here, the authors identify a mutational hotspot at transcription start sites in the human germline that is significantly enriched with early mosaic variants; they also analyse the molecular mechanisms that could cause it and explore its potential consequences for disease.

Wastewater-based surveillance tends to focus on specific pathogens. Here, the authors mapped the wastewater virome from 62 cities worldwide to identify over 2,500 viruses, revealing city-specific virome fingerprints and showing that wastewater metagenomics enables early detection of emerging viruses.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

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).

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.

Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

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 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.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.

An analysis of viral genomes and epidemiological data from the 2022 mpox outbreak in Portugal sheds light on the heterogeneity of early transmission events, with national and international linkages.

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.

The authors analyze rare coding variants in 1990 individuals with congenital kidney anomalies, finding diagnostic variants in 14.1% of cases. They identify two new causal genes, ARID3A and NR6A1, along with 38 candidate genes, providing evidence for shared genetics with other developmental disorders.

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.

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.

Here the authors apply machine learning approaches to Alzheimer’s genetics, confirm known associations and suggest novel risk loci. These methods demonstrate predictive power comparable to traditional approaches, while also offering potential new insights beyond standard genetic analyses.

The social exposome—lifelong social and economic adversity—can shape brain health and dementia risk. Here, the authors show that an adverse social exposome is linked to poorer clinical, cognitive, and brain changes in Latin American older adults.

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.

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.

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.

Inventory data from more than 1 million trees across African, Amazonian and Southeast Asian tropical forests suggests that, despite their high diversity, just 1,053 species, representing a consistent ~2.2% of tropical tree species in each region, constitute half of Earth’s 800 billion tropical trees.

Polygenic risk scores for Alzheimer’s disease derived from individuals of European ancestry can show improved performance in multiancestry settings after incorporating genome-wide association summary statistics from diverse populations.

Analysing >1,700 inventory plots from the Amazon Tree Diversity Network, the authors show that the majority of Amazon tree species can occupy floodplains and that patterns of species turnover are closely linked to regional flood patterns.

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.

What happens to correlated electronic phases—superconductivity and charge density wave ordering—as a material is thinned? Experiments show that both can remain intact in just a single layer of niobium diselenide.

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.

Three-dimensional nanofabrication allows for the precise tailoring of curvature of magnetic nanowires, and therefore the local symmetry breaking. Here, Ruiz-Gomez et al use this control to study the interaction of domain walls with local curvature, engineering potential wells and shift registers.

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.

Genotype and exome sequencing of 150,000 participants and whole-genome sequencing of 9,950 selected individuals recruited into the Mexico City Prospective Study constitute a valuable, publicly available resource of non-European sequencing data.

Analysis of HbA1c and FPG levels across 117 population-based studies demonstrates regional variation in prevalence of previously undiagnosed screen-detected diabetes using one or both measures and suggests that use of elevated FPG alone could underestimate diabetes prevalence in low- and middle-income countries.

Genome-wide association analyses of intracranial and nine subcortical brain volumes in 74,898 participants of European ancestry identify 254 independent loci and yield polygenic scores accounting for brain variation across ancestries.

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

The study introduces NXT2 as a candidate gene for male infertility and shows that the encoded protein is involved in RNA nucleocytoplasmic transport in human testis by interacting with the RNA export factor NXF1 and proteins of the nuclear pore complex. NXT2 also interacts with the human testis-specific NXF1 paralogues NXF2 and NXF3. Mutations in NXT2 and NXF3 are linked to a disruption of nuclear export, leading to defective germ cell development and human male infertility.

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.

The bacterium Helicobacter pylori, often found in the human stomach, can be classified into distinct subpopulations associated with the geographic origin of the host. Here, the authors provide insights into H. pylori population structure by collecting over 1,000 clinical strains from 50 countries and generating and analyzing high-quality bacterial genome sequences.

Genome-wide association studies have uncovered several loci associated with diabetes risk. Here, the authors reanalyse public type 2 diabetes GWAS data to fine map 50 known loci and identify seven new ones, including one near ATGR2 on the X-chromosome that doubles the risk of diabetes in men.

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.

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 tumor microenvironment influences the metabolic behavior of cancer cells. Here, using Dual Ribosome Profiling, the authors uncover a cancer-stromal cell interaction under glucose starvation that increases nutrient availability, in response to type I interferon. In addition, in vivo, immune checkpoint blockade triggers metabolic constraints in T cells, reducing their proliferation and cytotoxicity.

The GREGoR consortium provides foundational resources and substrates for the future of rare disease genomics.