Koyama S, Yu Z, Choi SH
… +27 more, Jurgens SJ, Selvaraj MS, Klarin D, Huffman JE, Clarke SL, Zhang SK, Trinh MN, Ravi A, Dron JS, Spinks C, Surakka I, Bhatnagar A, Lannery K, Hornsby W, Damrauer SM, Chang KM, Lynch JA, Assimes TL, Tsao PS, Rader DJ, Cho K, Peloso GM, Ellinor PT, Sun YV, Wilson PWF, VA Million Veteran Program, Natarajan P
Rare coding alleles have crucial roles in the molecular diagnosis of genetic diseases. However, the systematic identification of these alleles has been challenging due to their scarcity in the general population. Here we...Rare coding alleles have crucial roles in the molecular diagnosis of genetic diseases. However, the systematic identification of these alleles has been challenging due to their scarcity in the general population. Here we discovered and characterized rare coding alleles contributing to genetic dyslipidemia, a principal risk for coronary artery disease (CAD), among 1,158,017 multi-ancestral individuals. Testing 2,997,401 rare coding variants, we identified 800 exome-wide significant associations (176 predicted loss of function (pLoF) and 624 missense variants). Associated alleles are enriched in functional variant classes, show significant additive and recessive associations, exhibit similar effects across populations and resolve pathogenicity for variants of unknown significance. Furthermore, we identified five lipid-associated genes associated with CAD. Among them, silencing RORC represents a potential therapeutic target for lowering low-density lipoprotein cholesterol. This study provides resources and insights for understanding causal mechanisms, quantifying the expressivity of rare coding alleles and identifying new drug targets for dyslipidemia across diverse populations.
Epigenetic mechanisms such as genomic imprinting demonstrate that molecular inheritance can deviate from typical Mendelian patterns. Despite this, the intergenerational inheritance of DNA methylation remains poorly under...Epigenetic mechanisms such as genomic imprinting demonstrate that molecular inheritance can deviate from typical Mendelian patterns. Despite this, the intergenerational inheritance of DNA methylation remains poorly understood. Here we developed a genome-wide approach to study epigenetic inheritance in mice using long-read nanopore sequencing. Using this approach in both liver and muscle, we found that ~93% of autosomal epigenetic inheritance patterns followed Mendel's laws, primarily driven by cis-acting methylation quantitative trait loci. However, we also identified extensive non-Mendelian inheritance, including emergent epigenetic inheritance patterns, widespread sex-specific DNA methylation patterns localized to the liver, and five seemingly new autosomal and X-linked imprinted genes. Notably, we also report an example of naturally occurring intergenerational paramutation, confirmed over strain-specific transposable elements within Capn11 and highly likely at Vps37c. Overall, an unexpectedly high ~7% of autosomal epigenetic inheritance patterns identified were non-Mendelian, highlighting the importance of epigenetic information in the analysis of inherited traits and disorders.
Recent advances in spatial transcriptomics (ST) have brought unprecedented insights into cellular diversity and cell-cell interactions within their spatial context. High-resolution ST techniques, including barcoding-base...Recent advances in spatial transcriptomics (ST) have brought unprecedented insights into cellular diversity and cell-cell interactions within their spatial context. High-resolution ST techniques, including barcoding-based and imaging-based platforms, have achieved remarkable subcellular resolution. However, precise cell segmentation remains a major challenge, hampering effective single-cell spatial analysis. Existing methods are often platform specific and lack scalability for datasets with large fields of view. Here we introduce Cellist, a new, multi-modal, cell-segmentation method that combines image and expression information, enabling comprehensive cell-level analyses. Applied to mouse brain Stereo-seq data, Cellist improves within-cell transcriptomic coherence compared to existing approaches. It further enhances spatial domain identification and cell-type annotation. Importantly, Cellist is compatible with various ST techniques including Seq-Scope, seqFISH+, STARmap and 10x Xenium, exhibiting robust performance and high computational efficiency across diverse ST platforms and biological systems. Finally, application to post-neoadjuvant immunotherapy, nonsmall cell lung-cancer samples reveals the spatial heterogeneity of tumor clones and identifies therapy response-related myeloid subtypes and structures. These findings highlight the potential of Cellist in enhancing the power of high-resolution ST techniques for characterizing intricate tissue architectures. Cellist is publicly available at https://github.com/wanglabtongji/Cellist .
Structural variants (SVs) are a major type of genetic variation, yet their role in human traits remains largely uncharacterized, primarily due to challenges in genotyping them on a genome-wide scale in large cohorts. Her...Structural variants (SVs) are a major type of genetic variation, yet their role in human traits remains largely uncharacterized, primarily due to challenges in genotyping them on a genome-wide scale in large cohorts. Here we identified 171,233 high-quality, genome-wide SVs from 482 haplotype-resolved genome assemblies derived from PacBio HiFi long-read sequencing of 241 individuals. We developed a reference panel and a web application (ImputeSV) to impute these SVs from single-nucleotide polymorphism (SNP) data and demonstrated high imputation accuracy at both the individual and cohort levels. Using this tool, we imputed 54,578 common SVs (minor allele frequencies (MAFs) ≥1%) in 456,643 UK Biobank (UKB) participants of European ancestry. Through analysis of UKB data and simulations, we estimated that SVs contributed to at least 4.7% of the common genetic variation for complex traits. Genome-wide association analyses of SVs for 2,624 UKB traits identified 17,335 SV-trait associations, including 958 unlikely to be driven by small genetic variants. Our study demonstrates the power of using long-read assemblies for imputing SVs from SNPs, unveils the role of SVs in complex trait variation and provides a catalog of SV associations in the UKB.
Clonal expansions of hematopoietic cells carrying mosaic chromosomal alterations (mCAs) are commonly detectable in elderly individuals. Here we studied 43,617 autosomal mCAs ascertained in 484,081 UK Biobank participants...Clonal expansions of hematopoietic cells carrying mosaic chromosomal alterations (mCAs) are commonly detectable in elderly individuals. Here we studied 43,617 autosomal mCAs ascertained in 484,081 UK Biobank participants using new, high-resolution computational methods to analyze blood-derived, whole-genome sequencing data. Shorter mCAs (≤1 Mb) clustered at 53 genomic hotspots (46 previously undetected), several of which implicated chromosomal fragile sites as a recurrent source of somatic deletions. Chronic lymphocytic leukemia (CLL)-associated deletions at 13q14 were detectable in 1% of individuals aged 65-70 years, suggesting opportunities for incorporating this mosaic mutation into clinical screening and in genetic association studies of CLL. Rare protein-coding variants in 38 genes associated (P < 1.2 × 10; false recovery rate <0.01) with clonal expansions of copy-neutral loss-of-heterozygosity (CN-LOH) mutations that modified the allelic dosages of these variants, identifying likely targets of clonal selection via CN-LOH-induced allelic substitution. These results show that our blood genomes often accrue mCAs in predictable ways as they evolve with age.
Lin J, Zhang C, Liu Z
… +17 more, Li J, Yang Q, Chu W, Liu D, Zhang L, Zhao D, Peng X, Jia W, An H, Xin M, Yao Y, Guo W, Peng H, Xie C, Ni Z, Sun Q, Hu Z
Global climate change intensifies drought threats to wheat productivity, necessitating genetic enhancement of drought resistance. We present a high-quality genome assembly of drought-resistant wheat genotype Jin50LP82 (J...Global climate change intensifies drought threats to wheat productivity, necessitating genetic enhancement of drought resistance. We present a high-quality genome assembly of drought-resistant wheat genotype Jin50LP82 (JIN50; contig N50 = 50.24 Mb) and conduct genomic analyses across 31 wheat genomes and 196 germplasm samples, revealing 430,739 structural variants. Integrated structural variant-, single-nucleotide polymorphism- and InDel-based genome-wide association study identified 46 drought-resistance loci enriched in JIN50. Notably, the structural variation in the promoter of the root development regulator TaLBD1 and functional haplotypes of the methylglyoxal detoxification enzyme TaGLYI7 contribute to drought adaptation through distinct mechanisms. The JIN50 genome and genetic resources provide valuable tools for elucidating drought-resistance networks and for facilitating molecular breeding. These findings contribute to a better understanding of the multigenic drought response system in wheat and support the development of genomic strategies to enhance food security amid climate challenges.
Boesch M, Anak S, El Abyad D
… +45 more, Ostyn T, Antoranz A, My Van T, Newhouse D, Myers C, Van Melkebeke L, Palmer J, Saffarzadeh N, Chui JS, Feio-Azevedo R, Smets L, Shankar G, Dubroja Lakić N, Calvo PL, Voet T, Clark J, Cockell S, Lannoo M, Deleus E, Jaekers J, Topal H, Topal B, Schneider KM, Vacca M, Allison M, Ekstedt M, Boursier J, Bugianesi E, Ratziu V, De Smet F, Boeckx B, Daly AK, Schattenberg JM, Verbeek J, Bosisio F, Lambrechts D, Roskams T, Schneider CV, Francque S, Korf H, Härtlova A, Tiniakos D, Anstee QM, van der Merwe S, Govaere O
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic condition impacting over 30% population, yet the dynamic changes in macrophage composition from steatosis to steatohepatitis (metabolic dysfun...Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic condition impacting over 30% population, yet the dynamic changes in macrophage composition from steatosis to steatohepatitis (metabolic dysfunction-associated steatohepatitis, MASH) remain unclear. Here, by integrating single-nucleus transcriptomics, spatial multi-omics and proteomics on human samples, we delineate the evolving landscape of hepatic macrophages across the MASLD spectrum. Our analysis reveals a progressive depletion of Kupffer cells accompanied by the emergence of diverse, phenotypically distinct macrophage subsets. Spatial multi-omics further demonstrates that disease progression toward MASH is marked by an accumulation of antigen-presenting, phagocytic GPNMB macrophages, supported by IL32-producing hepatocytes. These macrophages showed an adaptive metabolic and pro-inflammatory phenotype that is tightly regulated by both spatial context and disease stage. Identified macrophage markers enable patient stratification by disease activity and its stage across independent clinical cohorts. Our study sheds light on the diversity of macrophage identities and metabolic-adaptive phenotypes during the progression of MASLD.
Krug B, Hu B, Chen H
… +34 more, Negrón-Lomas C, Chen X, El Mouatani A, Gretarsson KH, Ptack A, Deshmukh S, Kabir N, Jawhar W, Andrade AF, Jabbour E, Harutyunyan AS, Wang X, Taylor R, Lee JJY, Hulswit M, Faury D, Russo C, Xu X, Yang J, Baguette A, Dahl NA, Weil AG, Ellezam B, Dali R, Blanchette M, Wilson K, Garcia BA, Soni RK, Gallo M, Taylor MD, Kleinman CL, Majewski J, Jabado N, Lu C
Polycomb repressive complex 2 (PRC2)-mediated histone H3 K27 trimethylation (H3K27me3) recruits canonical PRC1 (cPRC1) to maintain heterochromatin. In early development, Polycomb-regulated genes can display long-range th...Polycomb repressive complex 2 (PRC2)-mediated histone H3 K27 trimethylation (H3K27me3) recruits canonical PRC1 (cPRC1) to maintain heterochromatin. In early development, Polycomb-regulated genes can display long-range three-dimensional interactions, many of which resolve during lineage differentiation. Here we report that Polycomb-anchored looping is controlled by H3K27me3 spreading and regulates target gene silencing to influence cell fate specification. Using glioma-derived H3 Lys27-to-Met (H3K27M) mutations as tools to restrict H3K27me3 spreading, we show that H3K27me3 confinement concentrates the chromatin pool of cPRC1, resulting in heightened three-dimensional interactions that mirror the chromatin architecture of pluripotency. Conversely, H3K27me3 spread in pluripotent stem cells dilutes local cPRC1 chromatin concentration, weakening Polycomb loop contact frequencies. Disruption of cPRC1 binding or aggregation compromises stringent repression of Polycomb genes and induces differentiation and tumor regression of H3K27M-mutant glioma. These results identify the regulatory principles and disease implications of Polycomb looping and show that histone-modification-guided distribution of reader complexes is an important mechanism for nuclear compartment organization.
Rare-variant association studies typically perform gene-level tests in which coding variants are filtered (or 'masked') and aggregated based on functional annotation and allele frequency. Through a systematic literature...Rare-variant association studies typically perform gene-level tests in which coding variants are filtered (or 'masked') and aggregated based on functional annotation and allele frequency. Through a systematic literature review, we cataloged 664 masks used across 234 studies and found that masking strategies (that is, sets of masks) rarely repeat across studies and are rarely justified. To quantify their impact on association results, we applied all previously employed strategies to 54 traits within 189,947 UK Biobank exomes. Here we find that the number of significant associations greatly depends on the masking strategy (ranging from 58 to 2,523 associations), which is a key reason for the modest overlap (<30%) of associations between separate published analyses of this dataset. We empirically determine masking strategies with high discovery power for low-frequency and rare variant gene-level associations across numerous datasets and traits, and we use these to explore the impact of other factors on burden test results. These findings offer a baseline strategy in burden tests to increase study power and replicability, addressing one source of inconsistency in previous studies.
Rojas-Hidalgo A, Arias-Carrasco R, Silva JK
… +23 more, Armingol E, Urquiza-Zurich S, Vinagre B, Prada-Medina CA, Triana S, Russo DD, Pérez-Stuardo D, Vicencio E, Muñoz G, de Lanna CA, Santos L, Rapozo G, Tavares N, Moreno-Estrada A, Randell J, Severino P, Khouri R, Ashenberg O, Shalek AK, Boroni M, Cuesta-Astroz Y, Carvalho BS, Maracaja-Coutinho V