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This study applies generalized linear mixed models (GLMM) and advanced transcriptome wide association study (TWAS) methods to improve the discovery of colorectal cancer risk transcription factors and genes, including potential druggable targets.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

Convergent mutations in hot spots of the spike proteins of currently circulating SARS-CoV-2 Omicron variants increase the binding affinity for the host receptor and promote more efficient fusion with host cell membranes.

Risk associated with genetically defined forms of autism spectrum disorder (ASD) can propagate by means of transcriptional regulation to affect convergently dysregulated pathways, providing insight into the convergent impact of ASD genetic risk on human neurodevelopment.

cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

Here, the authors sample air and surfaces in hospital rooms of COVID-19 patients, detect SARS-CoV-2 RNA in air samples of two of three tested airborne infection isolation rooms, and find surface contamination in 66.7% of tested rooms during the first week of illness and 20% beyond the first week of illness.

The hypothalamic neuropeptide oxytocin exerts analgesic effects, but the underlying pathways remain largely elusive. Here, the authors describe an analgesic pathway formed by oxytocin neurons projecting to the periaqueductal grey, where axonally released oxytocin activates oxytocin-receptor expressing GABA neurons and subsequently reduces pain-like behaviors in both female and male rats.

The 4D Nucleome Project demonstrates the use of genomic assays and computational methods to measure genome folding and then predict genomic structure from DNA sequence, facilitating the discovery of potential effects of genetic variants, including variants associated with disease, on genome structure and function.

Here, the authors perform large trans-ancestry fine-mapping analyses identifying large numbers of association signals and putative target genes for colorectal cancer risk, advancing our understanding of the genetic and biological basis of this cancer.

Many premalignant colorectal polyps in familial adenomatous polyposis arise polyclonally rather than from a single mutated cell, showing diverse early evolutionary trajectories that frequently occur without clonal APC or KRAS driver events.

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).

Analyses of single-cell transcriptomic data from patients with VEXAS syndrome combined with xenotransplantation experiments in a mouse model of the disease provide insights on the mechanisms of clonal dominance of mutated cells leading to bone marrow failure

Increasing evidence suggests that activation of oncogenic pathways contributes to an unfavorable tumor microenvironment. Here, the authors show that wild-type KRAS plays a key role in immune evasion in hepatocellular carcinoma by impairing interferon-mediated immunity and promoting resistance to immunotherapy via the EGFR/MEK/ERK pathway.

Chemically induced protein degradation is a powerful alternative to classical inhibition, but some proteins have deeply masked binding pockets that make the development of degrader molecules difficult. Here, the authors discover an alternate site on nuclear receptors that can be targeted by degraders.

Florfenicol amine hijacks intrinsic resistance in Mycobacterium abscessus, highlighting that antimicrobial resistance mechanisms can be harnessed for antibiotic activation.

Multimodal results (iEEG, fMRI and MEG) of predictions from integrated information theory and global neuronal workspace theory align with some predictions of both theories on visual consciousness, but also critically challenge key tenets of both theories.

mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.

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.

MultiSTAAR provides a general and flexible statistical framework for functionally informed multi-trait rare variant analysis of biobank-scale sequencing studies by jointly analyzing multiple traits and incorporating annotation information.

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

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.

Wastewater treatment plants are important reservoirs of antibiotic resistance genes (ARGs). Here, the authors analyze ARGs in a global collection of samples from wastewater treatment plants across six continents, providing insights into biotic and abiotic mechanisms that appear to control ARG diversity and distribution.

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.

Dominant coactivation patterns are primarily studied in resting-state fMRI. Here, the authors study the rest of the signal, which reveals ‘caricatured’ connectomes with improved behavioral prediction.

WNT-activating mutations in CTNNB1 are common in hepatoblastoma, but downstream molecular phenotypes are heterogenous. Using multiomic approaches, the authors identify distinct subgroups of hepatoblastoma cells based on WNT-signaling patterns and create a biobank of patient-derived hepatoblastoma organoids representing these subtypes.

Learning to balance work, family, optimism and setbacks is a process for all early-career investigators. Stephanie Correa and Leng Han share their stories in this instalment of Career pathways.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

A multi-ancestry genome-wide association study meta-analysis, combined with transcriptome- and methylome-wide association analyses, identifies risk loci associated with colorectal cancer. Credible effector genes and their target tissues are also highlighted, showing that over a third probably act outside the colonic mucosa.

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.

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 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.

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.

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.

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.

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.

Peng et al. show that DLL1-expressing muscle myoblasts not only regulate NOTCH signaling in neighbor cells but also send a retrograde signal to themselves via the DLL1 intracellular domain.

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.

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.

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.

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.

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.

The authors report a computational framework for determining the meiotic/mitotic origin of nondisjunction (NDJ) in trisomies without parental data. Applying this to Down syndrome, they uncover links between NDJ error stage and leukemia genomics.

This study maps the connections of layer 5 pyramidal neurons in the mouse cortex, revealing distinct local and intercortical wiring patterns, and provides an open framework for exploring the connectivity of cell types.

Deadenylation leads to mRNA decay, with PABPC1 protecting the poly(A) tail, while tristetraprolin and CCR4–NOT promote deadenylation. Here, the authors describe how these three proteins interact to regulate mRNA stability.

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.

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.