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A genome-wide association study meta-analysis combined with multiomics data of osteoarthritis identifies 700 effector genes as well as biological processes with a convergent involvement of multiple effector genes; 10% of these genes express the target of approved drugs.

Available wheat genomes are annotated by projecting Chinese Spring gene models across the new assemblies. Here, the authors generate de novo gene annotations for the 9 wheat genomes, identify core and dispensable transcriptome, and reveal conservation and divergence of gene expression balance across homoeologous subgenomes.

A global dataset of the satellite-tracked movements of pelagic sharks and fishing fleets show that sharks—and, in particular, commercially important species—have limited spatial refuge from fishing effort.

The role of long non-coding RNAs (lncRNAs) in metastatic colorectal cancer (mCRC) and treatment resistance is unclear. Here, the authors use transcriptome sequencing of matched normal, primary, and metastatic CRC tissues to discover and validate that lncRNA RAMS11 promotes metastasis and resistance to topoisomerase inhibitors in mCRC.

Using high-fidelity imaging of pHluorin-tagged vesicular monoamine transporter 2, the authors report differences in coupling of calcium entry and exocytosis between different populations of dopamine neurons. In ventral tegmental area neurons, exocytosis is controlled by calbindin-D28k, and this maintains a lower vesicular release probability as compared with substantia nigra neurons.

A large empirical assessment of sequence-resolved structural variants from 14,891 genomes across diverse global populations in the Genome Aggregation Database (gnomAD) provides a reference map for disease-association studies, population genetics, and diagnostic screening.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

Bladder cancer can often exhibit genomic and morphological heterogeneity. Here, the authors use genomics analysis to show lineage plasticity of bladder cancers with squamous differentiation, and identify key transcription factors related to this morphological and immune heterogeneity.

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.

A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.

The human brain is a distributed system composed of highly interconnected hubs. Here, patients undergoing a rare operation reveal the immediate impact and compensatory brain network changes that occur when a key hub is removed.

Most studies of the genetics of the metabolome have been done in individuals of European descent. Here, the authors integrate genomics and metabolomics in Black individuals, highlighting the value of whole genome sequencing in diverse populations and linking circulating metabolites to human disease.

Analysis of 97,691 high-coverage human blood DNA-derived whole-genome sequences enabled simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells, indicating that both inherited and acquired mutations are linked to age-related cancers and coronary heart disease.

The authors took a multimodal approach to characterize the differential transcriptome and epigenetic landscape between distinct regions of the embryonic mouse forebrain, revealing many unexplored presumptive promoter-enhancer interactions.

Genome-wide analyses identify common variants associated with 11 distinct neuropathology endophenotypes, providing insights into the mechanisms underlying the genetic risk of Alzheimer’s disease and related dementias.

Iron-laden microglia assume a disease-relevant, ferroptosis-associated signature and cause neurotoxicity. CRISPR screen uncovered regulators of ferroptosis in microglia. This ferroptosis–microglia–neurodegeneration axis could be targeted therapeutically.

Knock-in mice conditionally or constitutively expressing Cas12 variants enable a wide range of ex vivo and in vivo applications requiring multiplexed genome engineering.

IFNy can polarize macrophages in the tumour microenvironment to an inflammatory state and thereby contributes to their anti-tumour function. Here the authors show an underlying mechanism in this process is IFNy-driven STAT1 occupancy and activation of NRE1, a regulatory region within the NAMPT gene, thereby implicating inducible NAD salvage synthesis in TAM functions.

Here the authors find that the kinetics of synaptic vesicle endocytosis are widely variable across different neurons and is stochastic regardless of neuronal firing histories or number of presynaptic boutons.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

The receptor binding mode of recent human H3N2 hemagglutinin has evolved due to mutations G186D and D190N, which epistatically interact and co-emerged in clades 3C.2a1b.1a and 3C.2a1b.2a2.

COVID-19 can be associated with neurological complications. Here the authors show that markers of brain injury, but not immune markers, are elevated in the blood of patients with COVID-19 both early and months after SARS-CoV-2 infection, particularly in those with brain dysfunction or neurological diagnoses.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

A catalogue of predicted loss-of-function variants in 125,748 whole-exome and 15,708 whole-genome sequencing datasets from the Genome Aggregation Database (gnomAD) reveals the spectrum of mutational constraints that affect these human protein-coding genes.

Federated ML (FL) provides an alternative to train accurate and generalizable ML models, by only sharing numerical model updates. Here, the authors present the largest FL study to-date to generate an automatic tumor boundary detector for glioblastoma.

Calcium signalling downstream of VEGF is essential for VEGF-induced angiogenesis. Here Savage et al. show that Transmembrane Protein 33 (TMEM33) is required for angiogenesis and the endothelial calcium response to VEGF, revealing a function for TMEM33 in multicellular organisms.

The tumour microenvironment is low in glucose and high in the alternative metabolite lactate, which regulatory T cells are shown here to use, maintaining their ability to suppress effector immune cells.

 A transcriptomic cell-type atlas of the whole adult mouse brain with ~5,300 clusters built from single-cell and spatial transcriptomic datasets with more than eight million cells reveals remarkable cell type diversity across the brain and unique cell type characteristics of different brain regions. 

Cell type labelling in single-cell datasets remains a major bottleneck. Here, the authors present AnnDictionary, an open-source toolkit that enables atlas-scale analysis and provides the first benchmark of LLMs for de novo cell type annotation from marker genes, showing high accuracy at low cost.

Ticks transmit a large number of pathogens that cause human diseases. Here, the authors sequence the genome of the tick Ixodes scapularisand uncover expansion of genes associated with parasitic processes unique to ticks and tick-host interactions.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.

The burden of asthma varies between ancestries, but GWAS have so far focused on mainly European ancestry populations. Here, Daya et al. perform GWAS for asthma in 14,654 individuals of African ancestry and, besides confirming previously known loci, identify two potentially African ancestry-specific loci.

MetaSTAAR enables functionally informed rare variant association analysis in biobank-scale cohorts using an efficient, sparse matrix approach for summary statistic storage.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

Stephanie London, Martin Tobin and colleagues report meta-analyses of genome-wide association studies for forced vital capacity (FVC), a spirometric measure of pulmonary function that reflects lung volume. They identify six regions newly associated with FVC and demonstrate that candidate genes at these loci are expressed in lung tissue and primary lung cells.

Understanding the immune response to SARS-CoV-2 is dependent on being able to distinguish COVID-19 immune responses from cross-reactive immune responses to other coronaviruses. Here the authors show that choice of antigens and whether an ICS, ELISPOT or T cell proliferation assay is used has a major effect on this discriminatory ability.

Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

Literature produced inconsistent findings regarding the links between extreme weather events and climate policy support across regions, populations and events. This global study offers a holistic assessment of these relationships and highlights the role of subjective attribution.

Analysis of copy number alterations in 1,451 patient-derived xenografts (PDXs) and matched patient tumor samples shows strong conservation from patient tumors through late-passage PDXs and a lack of systematic copy number evolution driven by the mouse host.

There is currently no disease-modifying treatment for Parkinson’s disease, a common neurodegenerative disorder. Here, the authors use genetic variation associated with gene and protein expression to find putative drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

Chronic lymphocytic leukaemia has a hereditary component, much of which remains to be identified. Here, the authors perform a genome-wide association study and find new risk loci for the disease, which are associated with genes involved in immune function.

The developing pelvis in birds revisits its dinosaurian state before transitioning to the characteristic avian form, providing evidence of terminal addition during evolution.

Chronic lymphocytic leukemia is a highly inheritable cancer. Here the authors conduct a metaanalysis of four genome-wide association studies and identify three novel loci located near EOMES, SERPINB6 and LPPassociated with risk of this disease.

This study describes the integrative analysis of 111 reference human epigenomes, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression; the results annotate candidate regulatory elements in diverse tissues and cell types, their candidate regulators, and the set of human traits for which they show genetic variant enrichment, providing a resource for interpreting the molecular basis of human disease.