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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.

Here the authors use a range of approaches to examine the interplay between genetic variants linked to risk for polygenic skin diseases and transcription factors (TFs) important for skin homeostasis. The findings implicate dysregulated binding of specific TF families in risk for diverse skin diseases.

UCHL5 is a deubiquitinating enzyme that cleaves Lys-48-linked polyubiquitin chains. Here, the authors discover through in-vivo CRISPR-Cas9 screens that Uchl5 is involved in immune evasion and modulation of extracellular matrix deposition in head and neck squamous cell carcinoma.

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.

African ancestry is a known risk factor for prostate cancer development, but the genetic determinants of this are incompletely understood. Here, the authors identify 172 potentially pathogenic variants which are enriched in an African population.

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.

Machine learning analyses and playback experiments in wild African elephants suggest that individuals address conspecifics with name-like calls that do not rely on imitation of the receiver.

An analog optical computer that combines analog electronics, three-dimensional optics, and an iterative architecture accelerates artificial intelligence inference and combinatorial optimization in a single platform, paving a promising path for faster and sustainable computing.

The tumor environment is nutrient deficient. Here the authors show that early availability of methionine is critical for optimal T cell activation and prevents T cell dysfunction, and that dietary methionine can improve the efficacy of cancer immunotherapy in mice.

Researchers mapped the protein structure landscape, revealing structural complementarity across databases and functional clustering in specific regions. Their web tool helps explore this space, unlocking new insights into protein roles, evolution, and diversity.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

Deep learning enables large-scale protein structure prediction, yet linking structure to function remains a challenge. Here, the authors use topology to reveal fundamental organising features of the protein universe, providing insights into domain architecture, binding sites, evolution, and disease.

Analysis of soundscape data from 139 globally distributed sites reveals that sounds of biological origin exhibit predictable rhythms depending on location and season, whereas sounds of anthropogenic origin are less predictable. Comparisons between paired urban–rural sites show that urban green spaces are noisier and dominated by sounds of technological origin.

Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient ‘biotypes’ characterized by partially distinct disease mechanisms.

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.

A comprehensive analysis of the cell-specific molecular regulatory mechanisms underlying post-traumatic stress disorder in the human prefrontal cortex.

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

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.

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.

Together with a companion paper, the generation of a transcriptomic atlas for the mouse lemur and analyses of example cell types establish this animal as a molecularly tractable primate model organism.

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.

Douglas Easton, Per Hall and colleagues report meta-analyses of genome-wide association studies for breast cancer, including 10,052 cases and 12,575 controls, followed by genotyping using the iCOGS array in an additional 52,675 cases and 49,436 controls from studies within the Breast Cancer Association Consortium (BCAC). They identify 41 loci newly associated with susceptibility to breast cancer.

The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

Together with an accompanying paper presenting a transcriptomic atlas of the mouse lemur, interrogation of the atlas provides a rich body of data to support the use of the organism as a model for primate biology and health.

An in vivo screen of small-molecule compounds to inhibit the mosquito-stage development of Plasmodium identified hits that can be incorporated into bed nets and led to effective parasite killing in the insect host.

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 CNV analysis group of the Psychiatric Genomic Consortium analyzes a large schizophrenia cohort to examine genomic copy number variants (CNVs) and disease risk. They find an enrichment of CNV burden in cases versus controls and identify 8 genome-wide significant loci as well as novel suggestive loci conferring either risk or protection to schizophrenia.

Multi-ancestry genome-wide analyses identify 95 loci associated with post-traumatic stress disorder and implicate candidate genes, pathways and neurobiological systems underlying its pathophysiology.

Post-traumatic stress disorder (PTSD) is a common mental health problem. Here, the authors report a GWAS from the Psychiatric Genomics Consortium in which they identify two risk loci in European ancestry and one locus in African ancestry individuals and find that PTSD is genetically correlated with several other psychiatric traits.

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.

The three-dimensional structure of all cloud complexes in the solar neighbourhood is revealed, showing a narrow and coherent 2.7-kpc arrangement of dense gas, in disagreement with the Gould Belt model.

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.

Paul Pharoah and colleagues report the results of a large genome-wide association study of ovarian cancer. They identify new susceptibility loci for different epithelial ovarian cancer histotypes and use integrated analyses of genes and regulatory features at each locus to predict candidate susceptibility genes, including OBFC1.

This genome-wide association study identifies four novel risk loci for testicular germ cell tumour, and provides functional correlation between a disease-associated variant and gene expression in patient samples for one of the identified loci.

Gebhardt and colleagues developed a computational method using a naïve Bayes classifier to identify optimal protein labelling sites. Their analysis of 100+ proteins revealed four predictive parameters, leading to a Python package and a web-tool for protein structure analysis and labelling score calculations.

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.

Genome-wide association analyses based on whole-genome sequencing and imputation identify 40 new risk variants for colorectal cancer, including a strongly protective low-frequency variant at CHD1 and loci implicating signaling and immune function in disease etiology.

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).

Radiotherapy induces expression of the EGFR ligand amphiregulin, which promotes metastasis growth at remote sites in mouse models and human patients by shifting myeloid cells towards an immunosuppressive state.

Hourglasses measure time because the discharge rate of dry sand is constant. Here Koivistoet al. show that when such a system contains water there is a surge in discharge because the fluid drains faster than the grains, which might help us understand the transport of grains in silos.

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.