The organization of the genome in three-dimensional space is highly dynamic, yet how these dynamics are regulated and the role they play in genome function is poorly understood. Here we utilized acute depletion of NIPBL...The organization of the genome in three-dimensional space is highly dynamic, yet how these dynamics are regulated and the role they play in genome function is poorly understood. Here we utilized acute depletion of NIPBL to characterize cohesin-mediated loop extrusion in vivo. We find that many chromatin loops are rapidly diminished upon loss of NIBPL, but some cohesin-dependent chromatin loops persist for multiple hours. These persistent loops required NIPBL for their establishment during mitotic exit, were associated with distinct chromatin states and were preferentially dependent on STAG1 for their persistence. Furthermore, by depleting NIPBL from multiple cell types, we find that NIPBL specifically regulates cell identity genes by supporting a unique local genome conformation defined by greater spatial proximity to nearby super-enhancers and weaker transcription start site insulation of genomic contacts. Overall, we show that NIPBL-mediated loop extrusion is critical to genome organization and transcription regulation in vivo.
Everall A, Tapinos A, Hawari A
… +12 more, Cornish AJ, Sud A, Chubb D, Kinnersley B, Frangou A, Barquin M, Jung J, Church DN, Alexandrov LB, Houlston RS, Gruber AJ, Wedge DC
Whole-genome sequencing (WGS) enables exploration of the full spectrum of oncogenic processes that generate characteristic patterns of mutations. Mutational signatures provide clues to tumor etiology and highlight potent...Whole-genome sequencing (WGS) enables exploration of the full spectrum of oncogenic processes that generate characteristic patterns of mutations. Mutational signatures provide clues to tumor etiology and highlight potentially targetable pathway defects. Here alongside single-base substitution, doublet-base substitution, small insertion and deletion and copy number aberration signatures previously covered by the Catalogue of Somatic Mutations in Cancer (COSMIC), we report signatures from an additional mutation type, structural variations (SVs), extracted de novo from WGS in 10,983 patients across 16 tumor types recruited to the 100,000 Genomes Project. Across the five mutation classes, we report 134 signatures, 26 of which are new to COSMIC, including an SV signature reference set. By relating signatures to genomic features and clinical phenotypes, we provide further insights into mutagenic processes and the application of signature analysis to precision oncology.
Dekkers KF, Pertiwi K, Baldanzi G
… +32 more, Lundmark P, Hammar U, Moksnes MR, Coward E, Nethander M, Salih GA, Miari M, Nguyen D, Sayols-Baixeras S, Eklund AC, Holm JB, Nielsen HB, Volpiano CG, Méric G, Thangam M, Hakaste L, Tuomi T, Ahlqvist E, Smith CA, Allen M, Reimann F, Gribble FM, Ohlsson C, Hveem K, Melander O, Nilsson PM, Engström G, Smith JG, Michaëlsson K, Ärnlöv J, Orho-Melander M, Fall T
Despite the importance of the gut microbiome to health, the role of human genetic variation in shaping its composition remains poorly understood. Here we report genome-wide association analyses of harmonized metagenomic...Despite the importance of the gut microbiome to health, the role of human genetic variation in shaping its composition remains poorly understood. Here we report genome-wide association analyses of harmonized metagenomic data from 16,017 adults in four Swedish population-based studies, with replication in 12,652 people from the Norwegian HUNT study. We identified variants in the OR51E1-OR51E2 locus, encoding sensors for microbiome-derived fatty acids, associated with microbial richness. We further identified 15 study-wide significant genetic associations (P < 5.4 × 10) involving eight loci and 14 common bacterial species, of which 11 associations at six loci were replicated. The results confirm previously reported associations at LCT, ABO and FUT2, and provide evidence for new loci MUC12, CORO7-HMOX2, SLC5A11, FOXP1 and FUT3-FUT6, with supporting data from metabolomics and gene expression analyses. Our findings link gut microbial variation genetically to gastrointestinal functions, including enteroendocrine fatty acid sensing, bile composition and mucosal layer composition.
The gut microbiota is associated with human health and disease. Here we conducted a genome-wide association study of host genetic factors influencing gut microbiota composition in 12,652 individuals from the Trøndelag He...The gut microbiota is associated with human health and disease. Here we conducted a genome-wide association study of host genetic factors influencing gut microbiota composition in 12,652 individuals from the Trøndelag Health Study (HUNT), with replication in Nordic cohorts (n = 16,017-21,976). We identified 12 reproducible SNP-species associations across six genomic loci, including known (LCT, ABO) and novel (HLA-DQB1, MUC12, SLC37A2, FUT2) regions. Additionally, we detected genetic signals associated with gut microbiota functional modules at three loci (LCT, ABO, FUT2). Follow-up analyses suggest that these host-microbiota associations are linked to the pathogenesis of celiac disease and hemorrhoidal disease. Mendelian randomization analyses provided evidence supporting a causal effect of body mass index on gut microbiota composition. These findings highlight the interplay between host genetics and gut microbiota for human health and disease.
Ofori-Acquah SF, Nuno M, Osae-Larbi JA
… +13 more, Tavares K, Osei-Tutu A, Barkers Ansah DA, Brobbey EY, Akuffo F, Honny J, Buertey I, Dei-Adomakoh Y, Renner L, Paemka L, Benneh-Akwasi Kuma A, Kudzi W, Anie KA
Although the functional effects of many recurrent cancer mutations have been characterized, The Cancer Genome Atlas contains more than 10 million functionally uncharacterized, nonrecurrent events. It is proposed that the...Although the functional effects of many recurrent cancer mutations have been characterized, The Cancer Genome Atlas contains more than 10 million functionally uncharacterized, nonrecurrent events. It is proposed that the context-specific activity of transcription factors assessed through the expression of their transcriptional targets serves as a sensitive and accurate reporter assay for evaluating the functional roles of oncogene mutations. Analysis of transcription factor activity in samples with mutations of unknown significance, compared to established gain-of-function (hypermorph) or loss-of-function (hypomorph) mutations in the same gene, enabled functional characterization of 583,089 individual mutational events across TCGA. This approach facilitated the identification of neomorphic mutations (gain of new function) or mutations that phenocopy mutations in other genes (mutational mimicry). Validation using exogenous mutation expression assays confirmed the majority of predicted loss-of-function, gain-of-function, neomorphic and neutral (no predicted functional effect) mutations in PIK3CA and FGFR2. These findings may inform targeted therapy decisions for patients with mutations of unknown significance in established oncogenes.
Structural variants (SVs) represent an important yet underexplored component of plant genome diversity. Here we present a graph-based cucumber pangenome constructed from 39 reference-quality genomes, including 27 newly a...Structural variants (SVs) represent an important yet underexplored component of plant genome diversity. Here we present a graph-based cucumber pangenome constructed from 39 reference-quality genomes, including 27 newly assembled and 12 previously published. The pangenome captures 171,892 high-confidence SVs, which were genotyped across 447 wild and cultivated accessions. Our analyses reveal that, during cucumber domestication, a substantial portion of mildly deleterious SNPs were retained, whereas SVs were consistently purged, highlighting their highly deleterious nature. During geographical expansion, a reduced SV burden and a younger age of SVs compared to SNPs were observed, suggesting stronger purifying selection acting on SVs. Introgressions from wild populations increased SV burden, potentially due to hitchhiking. Notably, incorporating SV burden into genomic prediction models improved prediction accuracy for several agronomically important traits. This study illuminates SV dynamics during cucumber domestication and range expansion and underscores the implications of SVs for future cucumber breeding.
Alfares A, Imtiaz F, Maddirevula S
… +12 more, Moghrabi N, Alhamdoosh M, Alazami AM, Alowain M, Alsuwaidan A, Alsedairy S, Meyer BF, Abouelhoda M, Bindayel I, Alkuraya FS, Baz SM, Mallawi Y
Wang G, Lunardi A, Zhang J
… +16 more, Chen Z, Ala U, Webster KA, Tay Y, Gonzalez-Billalabeitia E, Egia A, Shaffer DR, Carver B, Liu XS, Taulli R, Kuo WP, Nardella C, Signoretti S, Cordon-Cardo C, Gerald WL, Pandolfi PP
Maas SLN, Tang Y, Stutheit-Zhao E
… +66 more, Rahmanzade R, Blume C, Hielscher T, Zettl F, Benfatto S, Calafato D, Sill M, Benotmane JK, Yabo YA, Behling F, Suwala A, Kardo H, Ritter M, Peyre M, Sankowski R, Okonechnikov K, Sievers P, Patel A, Reuss D, Friedrich MJ, Stichel D, Schrimpf D, Van den Bosch TPP, Beck K, Wirsching HG, Jungwirth G, Hanemann CO, Lamszus K, Etminan N, Unterberg A, Mawrin C, Remke M, Ayrault O, Lichter P, Reifenberger G, Platten M, Kacprowski T, List M, Pauling JK, Baumbach J, Milde T, Grossmann R, Ram Z, Ratliff M, Mallm JP, Neidert MC, Bos EM, Prinz M, Weller M, Acker T, Hartmann FJ, Preusser M, Tabatabai G, Herold-Mende C, Krieg SM, Jones DTW, Pfister SM, Wick W, Kalamarides M, von Deimling A, Heiland DH, Hovestadt V, Gerstung M, Schlesner M, German “Aggressive Meningiomas” Consortium (KAM), Sahm F
Classification of tumors in neuro-oncology today relies on molecular patterns (mostly DNA methylation) and their machine learning-supported interpretation. Understanding the process of algorithmic interpretation is essen...Classification of tumors in neuro-oncology today relies on molecular patterns (mostly DNA methylation) and their machine learning-supported interpretation. Understanding the process of algorithmic interpretation is essential for safe application in clinical routine. This is paradigmatically true for the most common primary intracranial tumor in adults, meningioma. Here, by applying multiomic profiling and multiple lines of orthogonal computational evaluation in multiple independent datasets, we found that not only tumor cell characteristics but also incremental changes in the tumor microenvironment (TME) have impact on epigenetic meningioma classification and clinical outcome. Besides revealing the decisive role of non-neoplastic cells in the CNS methylation classifier, this challenges the model of distinct meningioma subgroups toward a TME-determined risk continuum. This refines current controversies in molecular meningioma subtyping. In addition, we apply these learnings to devise and validate a simple diagnostic approach for increased clinical prediction accuracy based on immunohistochemistry, which is also applicable in resource-limited settings.
Thyroid diseases are common and highly heritable. We performed a meta-analysis of genome-wide association studies from 19 biobanks for five thyroid diseases: thyroid cancer (ThC), benign nodular goiter, Graves' disease,...Thyroid diseases are common and highly heritable. We performed a meta-analysis of genome-wide association studies from 19 biobanks for five thyroid diseases: thyroid cancer (ThC), benign nodular goiter, Graves' disease, lymphocytic thyroiditis and primary hypothyroidism. We analyzed genetic association data from ~2.9 million genomes and identified 313 known and 570 new independent loci linked to thyroid diseases. We discovered genetic correlations between ThC, benign nodular goiter and autoimmune thyroid diseases (rg = 0.16-0.97). Telomere maintenance genes contributed to benign and malignant thyroid nodular disease risk, whereas cell cycle, DNA repair and damage response genes were associated with ThC. We propose a paradigm that explains genetic predisposition to benign and malignant thyroid nodules. We found polygenic risk score associations with ThC risk of structural disease recurrence, tumor size, multifocality, lymph node metastases and extranodal extension. Polygenic risk scores identified individuals with aggressive ThC in a biobank, creating an opportunity for genetically informed population screening.
Genomic prediction has become central to human, animal and plant biology, enabling quantitative inference of how genetic variation shapes complex traits. Although these domains share statistical foundations, such as line...Genomic prediction has become central to human, animal and plant biology, enabling quantitative inference of how genetic variation shapes complex traits. Although these domains share statistical foundations, such as linear mixed models, Bayesian regression and deep-learning frameworks, they have advanced largely in parallel. Here we synthesize their methodological evolution and highlight opportunities for integration and deeper collaborations. Agricultural genetics contributed to the mixed-model and Bayesian frameworks underlying modern polygenic scores, while human genomics has driven advances in nonlinear modeling, federated learning and biology-informed artificial intelligence. We propose a roadmap centered on interoperable data standards, shared benchmarks and cross-disciplinary training to unify predictive genomics across species. Together, these efforts establish genomic prediction as a comparative science capable of explaining how genetic information drives form and function across the diversity of life. We emphasize that shared biological architectures and knowledge transfer across species can directly improve the robustness, interpretability and generalizability of predictive models.