Genome-wide association studies in complex polyploids are hindered by genotyping ambiguity and allele dosage complexity. Here we present KMERIA, a k-mer-based framework specifically designed to address these challenges,...Genome-wide association studies in complex polyploids are hindered by genotyping ambiguity and allele dosage complexity. Here we present KMERIA, a k-mer-based framework specifically designed to address these challenges, enabling efficient genotyping and robust association mapping in complex polyploid genomes. Rigorous benchmarking with simulated and empirical datasets demonstrates that KMERIA surpasses existing methods in accuracy and statistical power. By applying KMERIA to 290 wild sugarcane (Saccharum spontaneum) accessions and integrating a 15-accession graph pangenome to capture structural variations, we identified new genes regulating sucrose biosynthesis (SsMGT) and tillering (for example, SsERF14, SsNGA5, SsNAC, SsARF8, SsLOG and SsSCR). These findings elucidate the genetic architecture of yield-related traits and provide actionable targets for sugarcane breeding. Collectively, KMERIA bridges a critical methodological gap in polyploid genomics, while our graph-pangenome integration provides a powerful framework for deciphering genotype-phenotype relationships in crops with complex architectures.
Sarni D, Neary G, Carroll PL
… +69 more, Vink CS, Billard CV, Isobe T, Weng X, Portman JR, McCartney DL, Heyn P, van 't Hof RJ, Morrison LR, Martin CA, Stok C, Harley ME, Leitch A, van den Ancker M, Robertson N, Kitto L, Clark R, Rennie M, Popravko A, McClure JJ, Parry DA, Camiolo G, Leah T, Jakobczyk H, Megaw R, McKie L, Marshall GF, Balkic N, Amiel J, Barragán Arévalo T, Bronken McCarthy G, Buchanan CA, Buffet A, Cascón A, Cogne B, Conrad S, Cueto-González AM, Currás-Freixes M, Houge GD, Fong CT, George-Abraham JK, Gibson K, Ibáñez L, Longo N, Lussey-Lepoutre C, Miller BS, Moles-Fernandez A, Pillai NR, Tvrdik T, Vincent M, Yokoyama E, Abbott CM, Sanchez-Luque FJ, Ottersbach K, De Bari C, Roelofs AJ, Tillotson R, Kranc KR, Brown SJ, Marioni RE, Crisan M, Göttgens B, Henderson NC, Semple RK, Myant KB, Dzierzak E, Reijns MAM, Sproul D, Jackson AP
Declining tissue function and regenerative capacity underlie many chronic diseases. Experimentally establishing the mechanistic basis for such tissue aging presents substantial challenges, given decades-long timescales a...Declining tissue function and regenerative capacity underlie many chronic diseases. Experimentally establishing the mechanistic basis for such tissue aging presents substantial challenges, given decades-long timescales and multifactorial origins. Epigenetic alterations have been proposed to have a key etiological role, but whether they are correlative or causal remains a key unanswered question, as does their contribution to specific age-related pathologies. Here we describe an epigenetically driven accelerated aging syndrome. We demonstrate that DNMT3A gain-of-function mutations in Heyn-Sproul-Jackson syndrome recapitulate age-related gains in DNA methylation (DNAme), cause multilineage stem cell dysfunction, and phenocopy aspects of aging in humans and mice. We also show that region-specific DNA hypermethylation at lineage-specific genes can explain reduced stem cell output and lineage skewing. Hence, starting from a Mendelian disorder, we implicate DNAme-mediated stem cell dysfunction in the etiology of medically important age-related hematological, bone and metabolic pathologies, which might be targetable by future therapies.
Jie Z, Liang W, Ding Q
… +30 more, Liu X, Zhang Y, Chen N, Li S, Tong X, Gao H, Lu R, Huang X, Guo R, Chen J, Zhu J, Zhang Z, Liu N, Xie Z, Wang X, Qi L, Li Y, Xiao L, Zhang S, Jin X, Xu X, Yang H, Wang J, Zhao F, Jia H, Kristiansen K, Zhang T, Hao L, Zhu L, Chen C
The vaginal microbiome is essential for women's health, yet its genomic diversity and interaction with the host remain incompletely characterized. Here we present the Global Vaginal Metagenome-assembled Genomes catalog,...The vaginal microbiome is essential for women's health, yet its genomic diversity and interaction with the host remain incompletely characterized. Here we present the Global Vaginal Metagenome-assembled Genomes catalog, an extensive repository of vaginal microbial genomes generated by integrating 10,665 in-house Chinese metagenomes, with 2,967 publicly available metagenomes and 1,433 bacterial isolates. The catalog comprises 65,055 genomes from 890 prokaryotes, 11 eukaryotes and 6,590 viral taxonomic units, many not represented in public reference databases. We investigate virus-bacteria interactions, revealing conserved phages-host associations. We then identify substantial intraspecies genomic and functional variations displaying population-specific patterns. A metagenome-genome-wide association study identifies seven host genetic loci associated with vaginal species at study-wide significance and replicated in at least one independent cohort, notably connecting the gene OPRK1 with the potential pathogen Ureaplasma urealyticum. In summary, our research provides a comprehensive reference for future studies on genotype-phenotype interplay within the human vaginal microbiome.
Moore AR, Biehs B, Kljavin N
… +20 more, Nguyen TTT, Shah A, Burton J, Jiang H, Tan J, Chakroborty D, Wang L, Chaudhary N, He D, Lin W, Mesh K, Ye X, Bhat KP, Tai L, Xie S, Ye W, McGinnis L, Malek S, Melo SP, de Sauvage FJ
Colorectal cancer (CRC) frequently harbors activating mutations in the WNT and MAPK pathways. While KRAS mutations alone can drive tumor initiation in many tissues, they are insufficient in the intestine. Leveraging alle...Colorectal cancer (CRC) frequently harbors activating mutations in the WNT and MAPK pathways. While KRAS mutations alone can drive tumor initiation in many tissues, they are insufficient in the intestine. Leveraging allele-specific properties of RAS, we developed a mouse model to investigate MAPK hyperactivation. Here we show that KRAS mutations drive a regenerative state while antagonizing the Lgr5 intestinal stem cell state; however, this regenerative state cannot initiate tumorigenesis. Instead, tumor initiation requires a stem-like state dependent on mutational activation of the WNT pathway. We identify two aberrant states-a WNT-driven stem-like state for tumor initiation and MAPK-driven transit-amplifying-like state for tumor growth. These plastic states, essential for tumorigenesis, also impact drug response, potentially explaining lower response rates and shorter duration of response to KRAS-G12C inhibitors in CRC compared to non-small cell lung cancer. These findings highlight the need to target both pathways and their associated cell states for effective CRC treatment.
Cells communicate through ligand-receptor (LR) signaling interactions, but identifying when and where these interactions are active remains challenging. We developed CytoSignal to infer the locations and dynamics of cell...Cells communicate through ligand-receptor (LR) signaling interactions, but identifying when and where these interactions are active remains challenging. We developed CytoSignal to infer the locations and dynamics of cell-cell communication at cellular resolution from spatial transcriptomic data. Here we show that our cellular resolution, spatially resolved signaling scores enable several important analyses-identifying spatial gradients in signaling strength, quantifying the locations of contact-dependent and diffusible interactions, detecting signaling-associated genes and identifying differential signaling across multisample data. Additionally, we can predict the temporal dynamics of a signaling interaction at each spatial location. We experimentally validate our results in situ by proximity ligation assay, confirming that CytoSignal predicts the locations of LR interactions more accurately than previous approaches. This study addresses the field's current need for a robust and scalable tool to detect cell-cell signaling interactions and their dynamics at cellular resolution from spatial transcriptomic data.
Zhang L, Kong X, Ma Q
… +17 more, Hu X, Cai S, Wang B, Zou W, Bai T, Zhang M, Fan L, Tan R, Dai Z, Jia Z, Li T, Liu X, Xu H, Wu J, Zheng Y, Xu Z, Zhou H
Major depressive disorder (MDD) is a complex disorder with numerous risk genes identified through genome-wide association studies, but their in vivo functions remain unclear. Here we built an in vivo adeno-associated vir...Major depressive disorder (MDD) is a complex disorder with numerous risk genes identified through genome-wide association studies, but their in vivo functions remain unclear. Here we built an in vivo adeno-associated virus (AAV)-Perturb-seq system to perform parallel loss-of-function screening of MDD risk genes in the mouse brain and to define their transcriptional effects and functional relationships. By comparing perturbation profiles with transcriptomic data from patients with MDD, we identified a cluster of risk genes whose loss led to neuronal downregulation of oxytocin signaling, a feature shared with patients with MDD. Mechanistic studies using Dennd1a as an example revealed that its neuron-specific downregulation impaired the oxytocin receptor-extracellular signal-regulated kinase pathway and induced depressive-like behaviors in mice. Pharmacological enhancement of this pathway alleviated depressive-like phenotypes in Dennd1a-deficient mice and restored oxytocin signaling in DENND1A-deficient human neurons, highlighting the importance of patient stratification for targeted treatment in complex diseases such as psychiatric disorders.
Landry AP, Yefet LS, Wang JZ
… +15 more, Ajisebutu A, Gui C, Ellenbogen Y, Liu J, Patil V, Ding CQ, Wei Q, Mansouri S, Singh O, Cohen-Gadol AA, Tsang DS, Gao A, Aldape K, Nassiri F, Zadeh G
Recent advances in our understanding of the molecular landscape of meningioma have generated new insights into the biology and heterogeneity of this disease, with demonstrated clinical value. However, there remains a nee...Recent advances in our understanding of the molecular landscape of meningioma have generated new insights into the biology and heterogeneity of this disease, with demonstrated clinical value. However, there remains a need to understand tumor-intrinsic heterogeneity at single-cell resolution to inform potential therapeutic avenues. In this study, we examined the breadth of cell types and states in meningioma using a large cohort profiled with single-nuclear RNA sequencing and high-resolution spatial transcriptomics, as well as bulk DNA methylation and RNA sequencing (n = 712), bulk proteomics (n = 88) and plasma methylation (n = 59). We demonstrated that myeloid cell states differ across molecular groups of meningiomas and evolve meaningfully from dura to tumor. Myeloid cell states were also associated with unique myeloid-neoplastic interactions and neoplastic gene programs, suggesting a role in shaping the microenvironment. Finally, multiple non-neoplastic cell states refined outcome prediction beyond molecular group, suggesting a role in meningioma progression.
Many multi-population polygenic risk score (PRS) methods have been proposed to improve prediction in underrepresented populations; however, no single method performs best across all scenarios. Although integrating PRSs a...Many multi-population polygenic risk score (PRS) methods have been proposed to improve prediction in underrepresented populations; however, no single method performs best across all scenarios. Although integrating PRSs across multiple methods and populations may improve prediction, this approach is often limited by the need for individual-level tuning data. Here we introduce MIXPRS, a robust framework based on the data fission paradigm for combining multiple multi-population PRS methods using only genome-wide association study summary statistics. MIXPRS uses single nucleotide polymorphism pruning to mitigate linkage disequilibrium mismatch and non-negative least squares regression to estimate combination weights. Across simulations and real-data analyses spanning up to 26 traits, MIXPRS consistently improves prediction accuracy over existing methods. We further extend this framework to MIXPRS+, incorporating functional annotations and clinical PRSs, yielding additional gains in non-European populations. MIXPRS relies only on summary statistics, thus offering broad accessibility and robustness for underrepresented populations.
The overall contribution of pleiotropy to disease architectures is unknown, as most studies estimate genetic correlations with each auxiliary disease in turn. Here we propose a method-pleiotropic shared heritability with...The overall contribution of pleiotropy to disease architectures is unknown, as most studies estimate genetic correlations with each auxiliary disease in turn. Here we propose a method-pleiotropic shared heritability with bias correction (PHBC)-to estimate the liability-scale genetic variance of a target disease that is shared with a specific set of auxiliary diseases ( ). PHBC estimates from a genetic correlation matrix using a Monte Carlo bias correction procedure to account for sampling noise. The average ratio of to total single-nucleotide polymorphism heritability ( ) across 15 UK Biobank diseases (spanning seven disease categories) was 27 ± 3%, increasing to 48 ± 5% when expanding to 62 auxiliary diseases/traits. was broadly distributed across disease categories, decreasing only modestly when removing the most informative auxiliary disease categories. The average was 1.51 ± 0.16-times larger than the proportion of total phenotypic variance explained by auxiliary diseases, implying higher pleiotropy for genetic effects. In summary, roughly half of common disease heritability is pleiotropic with a broad range of diseases.
Tumor cells respond and adapt to environmental stresses that facilitate growth in hostile environments, including cytokine-mediated inflammation elicited by antitumor immunity and enhanced by immune checkpoint blockade (...Tumor cells respond and adapt to environmental stresses that facilitate growth in hostile environments, including cytokine-mediated inflammation elicited by antitumor immunity and enhanced by immune checkpoint blockade (ICB). However, cytokine responses also induce transcriptional and cell-state changes that may predispose tumor cells to new vulnerabilities, which remain poorly explored. Here we performed in vitro genome-scale CRISPR loss-of-function screens in eight cancer models exposed to interferon-γ (IFNγ), interferon-β or tumor necrosis factor to map inflammation-induced genetic vulnerabilities. We identified members of the glycosylphosphatidylinositol (GPI) transamidase complex and the lipid phosphatase FITM2 as interferon-specific cancer dependencies. Tumor-specific deletion of GPI transamidase subunits or FITM2 markedly enhanced response to ICB in vivo. By integrating functional genomics, metabolomics and pharmacologic perturbation of downstream stress pathways, we found that loss of FITM2 predisposed cancer cells to IFNγ-driven endoplasmic reticulum and oxidative stress, culminating in paraptosis-like cell death. Collectively, these findings identify tumor-intrinsic dependencies governing responses to inflammatory cytokines.
Brassica rapa has been a key oilseed and vegetable crop since the Neolithic era, yet its obscure evolutionary history has hindered understanding of its domestication and the speciation of its allotetraploid descendants,...Brassica rapa has been a key oilseed and vegetable crop since the Neolithic era, yet its obscure evolutionary history has hindered understanding of its domestication and the speciation of its allotetraploid descendants, Brassica napus and Brassica juncea. Here we defined pan-blocks comprising all syntenic regions from 21 B. rapa genome assemblies and analyzed 3,330 accessions spanning the three species to reconstruct the evolutionary trajectory of the Brassica A genome. Our findings reveal its origin in Central and West Asia and subsequent spread across Eurasia by means of three routes. An ancient inversion was identified that supports the divergent origins of the A subgenomes in B. napus and B. juncea. Furthermore, the S-locus exhibited exceptional haplotype diversity, with each variant characterized by a unique transposable element barcode pattern essential for the self-incompatibility system. These findings emphasize the significant value of pan-block-integrated 3,330 A genome variants for the Brassica research community.
To better characterize the genetic architecture underlying Alzheimer's disease (AD) and related dementias (ADRD), we performed a meta-analysis of European-ancestry genome-wide association studies in 128,681 cases or prox...To better characterize the genetic architecture underlying Alzheimer's disease (AD) and related dementias (ADRD), we performed a meta-analysis of European-ancestry genome-wide association studies in 128,681 cases or proxy cases of ADRD and 849,833 (proxy) controls. We identified 91 genetic loci associated with ADRD risk, of which 16 are new and 56 are specifically detected in clinically diagnosed AD cases. We also provide a list of 18 loci (15 new) requiring further external validation. A polygenic score combining the effects of ADRD loci other than APOE was primarily associated with AD rather than non-AD pathology. Individuals in the tenth decile of the score exhibited a twofold increased risk of presenting with Braak neurofibrillary tangles stage of >4 and moderate-to-severe neuritic amyloid plaque pathology at death compared to individuals in the median score group. In conclusion, our study validated a large number of loci associated with the risk of clinically diagnosed AD, while further investigations are required to confirm the impact of the other loci on AD clinical diagnosis and of each locus on AD pathology.
Zhu B, He N, Xiao Y
… +15 more, Chen B, Li C, Mandla R, Liu Y, Zhang J, Chang X, Yu F, Vujkovic M, Lynch JA, Chang KM, VA Million Veteran Program, Pasaniuc B, Rader DJ, Lazar MA, Hu W
Genome-wide association studies have identified >100 loci associated with metabolic dysfunction-associated steatotic liver disease (MASLD), yet the mechanisms by which noncoding variants alter disease risk remain unclear...Genome-wide association studies have identified >100 loci associated with metabolic dysfunction-associated steatotic liver disease (MASLD), yet the mechanisms by which noncoding variants alter disease risk remain unclear. Here we map chromatin accessibility in human MASLD liver nuclei, revealing enrichment of risk variants within cell-type-specific regulatory elements bound by lineage-determining transcription factors. Using a massively parallel reporter assay, we identified hundreds of differential activity variants (DAVs) that act in a cell-type-dependent and stimulus-dependent manner and perturb transcriptional regulatory networks linked to liver pathology. Integration of liver expression quantitative trait loci, chromatin looping and single-cell CRISPR interference screening assigns target genes to these DAVs. Importantly, DAVs at numerous loci, including SLC22A3 and key triglyceride metabolism regulators (APOA5, ANGPTL3 and LPL), modulate gene expression, lipid metabolism and hepatic stellate cell activation. Moreover, these DAVs allow improved prediction of MASLD risk. These results define a regulatory framework linking noncoding genetic variation to MASLD pathogenesis.
We have proposed PGS-TRI, a framework for analyzing polygenic scores (PGSs) in case-parent trio studies that estimate the risk of an index condition associated with direct PGS effects, gene-environment interactions and a...We have proposed PGS-TRI, a framework for analyzing polygenic scores (PGSs) in case-parent trio studies that estimate the risk of an index condition associated with direct PGS effects, gene-environment interactions and asymmetrical maternal and paternal indirect effects. Simulations confirm its robustness in the presence of complex population structure and assortative mating. Applied to multi-ancestry autism spectrum disorders (ASD) trios (n = 18,383), PGS-TRI yielded transmission-based direct effects of PGSs for ASD and other neurocognitive traits along a genetic ancestry continuum, and identified asymmetrical indirect effects of parental PGSs for body mass index and neurocognitive traits on children's ASD risk. In a trio study of European and Asian orofacial clefts (OFCs) (n = 1,904), PGS-TRI estimated direct and indirect effects of an established PGS and its interaction with maternal risk factors. Finally, we applied PGS-TRI to large-scale, transcriptome-wide and metabolome-wide traits to examine their direct and indirect effects on ASD and OFC risk.
Cheng FF, Liu X, Mi H
… +26 more, Wang L, Ma R, Guo Y, Sidorenko J, Jiang C, Islam T, Meguro A, Hikino K, Ishikawa Y, Tang S, Li T, Chen R, Wang L, Mägi R, Metspalu A, Estonian Biobank Research Team, 23andMe Research Team, Takeuchi M, Mizuki N, Choquet H, Jin ZB, Chen G, Zhou K, Terao C, Zeng J, Yang J