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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.

Pilcher et al. present a single-cell transcriptomics-based immune atlas of participants with newly diagnosed multiple myeloma, reporting on the association of cell types, gene expression and intercellular interactions with disease progression phenotypes.

Transcriptomic and proteomic analyses of cells and matrix along the fibrotic trajectory in mouse lung identified PI16 as an anti-fibrotic factor with potential for therapeutic application in humans.

The catalytic subunit of DNA-PK autophosphorylates and contributes to ribosome biogenesis and haematopoiesis by binding to the U3 small nucleolar RNA.

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.

Dnmt3a mutations in mouse haematopoietic stem and progenitor cells equivalent to R882 mutations in human cause increased mitochondrial respiration, suggesting that this is a mechanism of clonal haematopoiesis and a potential therapeutic target.

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.

Mouse models of severe congenital neutropenia using patient-derived mutations in the GFI1 locus are used to determine the mechanisms by which the disease progresses.

A genome-wide association study identifies 17 genetic loci that are associated with the risk of myeloproliferative neoplasms (MPNs), and shows that the modulation of haematopoietic stem cell function drives MPN risk.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

Myeloid cells contribute to the etiology of multiple sclerosis (MS), but the dynamics of myelopoiesis during disease progression is still unclear. Here the authors show, in both mouse models and clinical data, that myelopoiesis is differentially regulated via M-CSF modulation in different organs at distinct stages of MS, with diet and lifestyle being potential modifiers.

Innate lymphoid cells (ILCs) contribute to lymphoid tissue development and influence immune responses. Locksley and colleagues identify arginase 1–expressing fetal ILC precursors that give rise to multiple ILC subsets and lymphoid tissue–inducer cells.

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.

NKp46⁺ innate lymphoid cells are important for the control of gut microbes, but their development is unclear. Belz and colleagues show that they develop from lymphoid tissue–inducer cells in a Notch- and T-bet-dependent manner.

Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

Here, the authors report recent updates to the ENCODE data portal including a redesigned home page, an improved search interface, custom-designed pages highlighting biologically related datasets and an enhanced cart interface for data visualisation plus user-friendly data download options.

Group 1 and 3 innate lymphoid cells can be functionally plastic. Humbles and colleagues find that group 2 innate lymphoid cells in the lungs also exhibit phenotypic plasticity after exposure to infectious or noxious agents.

Ants evolved a transcriptional-interference-based mechanism to express a single odorant receptor from an array of Or genes with functionally similar promoters.

AIRES (algorithmic iterative reticular synthesis) is an integrated cycle combining automated synthesis, image recognition, single-crystal X-ray diffraction and algorithmic decision-making to maximize the discovery of distinct crystal structures. Demonstrated on zeolitic imidazolate frameworks, AIRES offers a systematic and efficient blueprint for reticular synthesis, with broad implications for accelerating materials discovery.

Type-2 innate lymphoid cells (ILC2) affect adipose tissue metabolism and function. Here the authors show that the ILC2 are present in para-aortic adipose tissue and represent a major source of IL-5 and IL-13 required for mounting atheroprotective immunity, which can be altered by high fat diet.

Small proteins (<50 kDa) are difficult to resolve by cryo-EM due to low signal-to-noise ratios and alignment challenges. Here, authors engineered conformationally rigid antibody fragments (Rigid Fabs) enabling high-resolution cryo-EM structures of small (~20 kDa) proteins like KRAS.

SRPK1, a kinase involved in splicing regulation, is a potential therapeutic target for AML patients. Here, the authors show that SRPK1 inhibition changes isoform levels of key epigenetic regulators, including BRD4, and it has anti-tumor effects specifically against MLL-rearranged AML cells.

Targeting resistant stem cells in leukaemia, Perry et al. show that doxorubicin at low doses decreases Akt-mediated β-catenin activity, downregulates expression of multiple immune-checkpoint genes and dampens tumorigenesis of leukaemia stem cells.

Cancer metabolism adapts the metabolic network of its cell of origin. Mahendralingam et al. find that lineage-rooted metabolic identities of normal mammary cells reflect breast cancer subtype metabolism.

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.

Technical challenges have previously hindered the detailed study of in vivo senescent cells. Here, the authors deeply characterize senescent skeletal cells across murine aging, establishing CD24 as a marker of osteolineage cells cleared by senolytics.

STAAR is a powerful rare variant association test that incorporates variant functional categories and complementary functional annotations using a dynamic weighting scheme based on annotation principal components. STAAR accounts for population structure and relatedness and is scalable for analyzing large whole-genome sequencing studies.

Molecular ferroelectrics contain stimuli-responsive structure and ionic building blocks, promising for ionically tailored multifunctionality. Here, the authors report molecular ionic ferroelectrics exhibiting the coexistence of room-temperature ionic conductivity and ferroelectricity.

Fat-associated lymphoid clusters are lymphoid tissues that support B-1 cells. Caamaño and colleagues show that inflammation that elicits the cytokine TNF and activates natural killer cells contributes to the formation of these clusters in visceral fat.

A study shows that clonal haematopoiesis of indeterminate potential is associated with an increased risk of chronic liver disease specifically through the promotion of liver inflammation and injury.

Proteins in the fungal plasma membrane are key antifungal targets but their native structure and spatial distribution are poorly understood. Here, Jiang et al. use proteomics and cryo-electron tomography to investigate the organisation of membrane proteins in the fungal plasma membrane and how this is affected by antifungal drugs.

Data from over 700,000 individuals reveal the identity of 83 sequence variants that affect human height, implicating new candidate genes and pathways as being involved in growth.

Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.

Analysis of whole-genome sequences of 25,465 individuals of European ancestry shows that rare variants contribute substantially to the heritability of height and body mass index.

The extracellular matrix (ECM) is critical for animal development and intricately patterned at multiple scales. Here Adams and Pooranachithra et al. show how specific collagens are precisely localized to struts, highly patterned sub-micron structures in the nematode cuticle ECM.

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.

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.

An engineered clustered regularly interspaced short palindromic repeat ribonucleoprotein delivered in lipid nanoparticles efficiently edits cells in vivo.

Trans-ethnic analyses of exome array data identify new risk loci for type 2 diabetes. Fine-mapping analyses using genome-wide association data show that the index coding variants represent the likely causal variants at only a subset of these loci.

Here, the authors find that relative abundances of stress-sensitive gastrointestinal microbes at age 2 years predicts internalizing symptoms in middle childhood through altered emotion-related brain network connectivity.

Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1Rsignificantly associated with these traits.

Boyd et al. monitored the effects of patient-derived acute myeloid leukaemia (AML) cells on human HSPCs in vivo and found that AML impairs bone marrow adipocyte differentiation, and this in turn impedes healthy endogenous haematopoiesis.

Pooling participant-level genetic data into a single analysis can result in variance stratification, reducing statistical performance. Here, the authors develop variant-specific inflation factors to assess variance stratification and apply this to pooled individual-level data from whole genome sequencing.

Polygenic risk scores can help identify individuals at higher risk of type 2 diabetes. Here, the authors characterise a multi-ancestry score across nearly 900,000 people, showing that its predictive value depends on demographic and clinical context and extends to related traits and complications.

Reduced fitness of the tumor microenvironment is mediated by a long non-coding RNA expressed in tumors.

Responses to immune checkpoint inhibitors in patients with pancreatic ductal adenocarcinoma (PDA) remain low and alternative combinatorial approaches are warranted. Here the authors report the results of a phase 2 clinical trial of entinostat (histone deacetylases inhibitor) and nivolumab (anti-PD-1 inhibitor) in patients with metastatic PDA.

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

Extracellular matrices are viscoelastic, yet how matrix viscoelasticity regulates the epigenome remains unclear. Here, the authors show that cells cultured on viscoelastic matrices exhibit changes in the nucleoskeleton and in chromatin that enhance cell reprogramming.