Genome research最新文献_第2页

Dissecting functional regulatory convergence over 160 million years of therian evolution. 剖析1.6亿年兽类进化的功能调控趋同。

IF 6.3 2区生物学

Genome research Pub Date : 2026-10-13 DOI: 10.1101/gr.281284.125

Navya Shukla, Laura E Cook, Davide M Vespasiani, Andrew J Pask, Irene Gallego Romero

{"title":"Dissecting functional regulatory convergence over 160 million years of therian evolution.","authors":"Navya Shukla, Laura E Cook, Davide M Vespasiani, Andrew J Pask, Irene Gallego Romero","doi":"10.1101/gr.281284.125","DOIUrl":"10.1101/gr.281284.125","url":null,"abstract":"Understanding the molecular mechanisms underpinning convergent traits can provide insight into the predictability of the evolutionary process. The thylacine, an extinct marsupial carnivore, has been long known to have a very similar craniofacial morphology to that of eutherian canids, despite having diverged ≈160 million years ago. Using a massively parallel reporter assay (MPRA), we test the regulatory potential of a set of previously identified highly conserved craniofacial enhancers that showed convergent sequence acceleration in thylacine and wolf (TWARs). We compare orthologous sequences from six different taxa, including outgroup taxa with nonconvergent craniofacial phenotypes (Tasmanian devil and giant panda) and ancestral reconstructions for marsupial and placental carnivores (Dasyuromorphia and Carnivora). Dense 10 bp tiling allowed us to thoroughly examine features associated with activity, including percentage GC content and transcription factor binding motifs turnover. We identify marked conservation of levels and patterns of regulatory activity across all six taxa, as well as multiple cases of differentially active TWARs within each clade, with both thylacine and wolf driving functional divergence. However, evidence of convergent divergence relevant to craniofacial biology is limited to a TWAR with reduced activity in both the thylacine and wolf near the developmental gene LMO4 Ultimately our findings suggest that shared gene regulatory potential is not a feature of these convergently accelerated regions in the thylacine and wolf.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identity-by-descent captures shared environmental factors at biobank scale. 血统识别在生物库规模上捕捉了共同的环境因素。

IF 6.3 2区生物学

Genome research Pub Date : 2026-10-13 DOI: 10.1101/gr.282338.126

Franco Marsico, Silvia Buonaiuto, Ernestine K Amos-Abanyie, Lokesh K Chinthala, Akram Mohammed, Rima Zahr, Robert J Rooney, Robert W Williams, Robert L Davis, Terri H Finkel, Chester W Brown, Marcella Vacca, Pjotr Prins, Vincenza Colonna

{"title":"Identity-by-descent captures shared environmental factors at biobank scale.","authors":"Franco Marsico, Silvia Buonaiuto, Ernestine K Amos-Abanyie, Lokesh K Chinthala, Akram Mohammed, Rima Zahr, Robert J Rooney, Robert W Williams, Robert L Davis, Terri H Finkel, Chester W Brown, Marcella Vacca, Pjotr Prins, Vincenza Colonna","doi":"10.1101/gr.282338.126","DOIUrl":"https://doi.org/10.1101/gr.282338.126","url":null,"abstract":"Genealogical ties leave traces beyond shared genetic material: relatives tend to share environmental exposures and cultural practices that persist across generations. Here, using genomic and electronic health record data from 13,143 individuals in the Biorepository and Integrative Genomics, we apply a hierarchical community detection algorithm that groups individuals into four major communities and 17 subcommunities based on the proportion of their genome shared identity-by-descent (IBD). This approach captures a fine-scale demographic structure beyond traditional ancestry classifications. By integrating neighborhood-level geographic data with census-derived environmental metrics, we reveal unequal exposure to environmental stressors between subcommunities, which correlates with differential rates of health conditions, including elevated respiratory condition prevalence in subcommunities under greater pollution burden. Through an interventional mediation analysis we find that a substantial part of the excess subcommunity-level risk remains unexplained by measured environmental factors alone, consistent with a contribution of unmeasured shared exposures captured by IBD-based grouping. Subcommunity-level disparities persist in sensitivity analyses adjusting for self-reported race, indicating that IBD-based clustering captures health-relevant information beyond demographic categories commonly used as proxies for social determinants of health. We implement an open-source dashboard for interactive exploration of IBD-defined communities, disease prevalence, and environmental exposures. Together, we demonstrate that IBD-based clustering jointly captures genetic and environmental determinants of health, offering a scalable framework for precision health and population genetics that translates biobank data into actionable insights.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Combined effects of Ret coding and enhancer loss-of-function alleles cause progressive loss of inhibitory motor neurons in the enteric nervous system. Ret编码和增强子功能缺失等位基因的联合作用导致肠神经系统中抑制性运动神经元的进行性丢失。

IF 6.3 2区生物学

Genome research Pub Date : 2026-10-13 DOI: 10.1101/gr.281450.125

Lauren E Fries, Gabriel Grullon, Lauren Wilkes, Hanna E Berk-Rauch, Aravinda Chakravarti, Sumantra Chatterjee

{"title":"Combined effects of Ret coding and enhancer loss-of-function alleles cause progressive loss of inhibitory motor neurons in the enteric nervous system.","authors":"Lauren E Fries, Gabriel Grullon, Lauren Wilkes, Hanna E Berk-Rauch, Aravinda Chakravarti, Sumantra Chatterjee","doi":"10.1101/gr.281450.125","DOIUrl":"10.1101/gr.281450.125","url":null,"abstract":"Hirschsprung disease (HSCR) is a congenital enteric neuropathy caused by disrupted development of enteric neural crest-derived cells (ENCDCs). Although pathogenic coding variants in RET account for many cases, the largest genetic contribution to HSCR risk arises from a common noncoding variant (rs2435357) within a SOX10-bound RET enhancer (mcs+9.7) that reduces RET gene expression in vivo and triggers expression changes in other ENS genes in the human fetal gut. However, the ENS cell types affected by this enhancer and the mechanisms by which these transcriptional changes lead to HSCR remain unknown. Here, we investigate the role of this enhancer by generating mice carrying a deletion of the orthologous Ret mcs+9.7 enhancer (Δmcs+9.7). Single-cell RNA sequencing of E14.5 embryonic gut demonstrates that enhancer deletion reduces Ret expression by 8% without altering ENS cell composition. However, reduced Ret expression is restricted to differentiating neurons and inhibitory motor neuron lineages, revealing cell type-specific enhancer activity. To determine the functional consequences of further reducing Ret dosage, we generated compound heterozygous mice carrying both the enhancer deletion and a Ret-coding null allele (+/Δmcs+9.7;+/CFP). These mice exhibit additive reductions in Ret expression, altered Sox10 expression, dysregulation of cell-cycle and neuronal differentiation programs, and selective depletion of developing inhibitory motor neuron lineages. These findings establish a cell type-specific role for the mcs+9.7 enhancer in modulating Ret dosage and reveal how subtle enhancer perturbations alter neural subtype specification without overt hypoganglionosis, suggesting that HSCR arises from a cascade of cellular defects triggered by >50% loss of Ret function.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Protein large language model-assisted one-to-one gene homology mapping in cross-species single-cell transcriptome integration. 蛋白质大语言模型辅助跨物种单细胞转录组整合中的一对一基因同源定位。

IF 6.3 2区生物学

Genome research Pub Date : 2026-10-09 DOI: 10.1101/gr.281566.125

Ze-Yu Kuang, Yuan-Chen Sun, Na-Na Wei, Yu-Juan Wang, Hua-Jun Wu

{"title":"Protein large language model-assisted one-to-one gene homology mapping in cross-species single-cell transcriptome integration.","authors":"Ze-Yu Kuang, Yuan-Chen Sun, Na-Na Wei, Yu-Juan Wang, Hua-Jun Wu","doi":"10.1101/gr.281566.125","DOIUrl":"https://doi.org/10.1101/gr.281566.125","url":null,"abstract":"Cross-species integration of single-cell transcriptomes requires establishing gene correspondences to enable comparative analysis of expression profiles across organisms. Current approaches predominantly rely on Ensembl homology tables; although gene-family expansion and contraction can reflect biologically meaningful evolutionary divergence, default many-to-many mappings can overweight expanded gene-family signals during integration and generate mapping-associated microclusters that lack clear cell-type identity, thereby complicating direct cell-type alignment. Although restricting mappings to a one-to-one scheme suppresses such artifacts, it reduces the number of homology gene pairs by ∼8% (about 900 pairs). To address this limitation, we develop a protein large language model (pLLM)-based gene homology mapping strategy that boosts the number of homology gene pairs. By enforcing a one-to-one mapping constraint and integrating pLLM-derived representations with sequence similarity, we construct a fused mapping approach, which achieves top performance in a comprehensive benchmark based on a curated cross-species atlas spanning nine data sets, 11 species, and more than 3.2 million cells. Our method further identifies previously unannotated cell-type marker pairs, facilitating novel cross-species marker discovery. These results establish a robust framework for gene homology mapping in cross-species transcriptome integration, improving both accuracy and biological interpretability.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Single-cell transcriptome analysis reveals onco-fetal reprogramming with implications for drug resistance and clinical outcome. 单细胞转录组分析揭示了同胎重编程与耐药和临床结果的影响。

IF 6.3 2区生物学

Genome research Pub Date : 2026-10-09 DOI: 10.1101/gr.281292.125

Yongle Xu, Shaoyi Chen, Zhenglin Lu, Yuqi Fan, Zhaoxin Liu, Wenhui Liu, Shiqian Zhang, Weijian Lu, Jianing Li, Changbo Yang, Gengdong Chen, Jingyi Shi, Na Ding, Shanshan Liu, Xilin Sun, Qinghua Jiang, Hui Zhi, Haoxiu Sun, Mantang Qiu, Tingting Shao

{"title":"Single-cell transcriptome analysis reveals onco-fetal reprogramming with implications for drug resistance and clinical outcome.","authors":"Yongle Xu, Shaoyi Chen, Zhenglin Lu, Yuqi Fan, Zhaoxin Liu, Wenhui Liu, Shiqian Zhang, Weijian Lu, Jianing Li, Changbo Yang, Gengdong Chen, Jingyi Shi, Na Ding, Shanshan Liu, Xilin Sun, Qinghua Jiang, Hui Zhi, Haoxiu Sun, Mantang Qiu, Tingting Shao","doi":"10.1101/gr.281292.125","DOIUrl":"https://doi.org/10.1101/gr.281292.125","url":null,"abstract":"Onco-fetal reprogramming of the tumor ecosystem induces fetal-like characteristics, leading to tumor growth and malignant progression. Here, we develop a robust computational pipeline to systematically identify onco-fetal (OF) cells, using single-cell transcriptomic data from corresponding fetal and tumor tissues across multiple cancer types. OF cells are consistently detected across diverse malignancies and exhibit pronounced stem-like properties. Core transcription factors involved in onco-fetal reprogramming are identified, including PTMA, ATF5, TCF4, and FOS, whose coordinated activities may promote tumor progression. Strategically positioned OF cells orchestrate tumor microenvironment crosstalk, specifically impairing B cell function. OF cells are further verified in additional cancers, and we find that high OF cell abundance contributes to enhanced drug resistance and cancer recurrence. Critically, pancancer analyses establish that OF cell markers universally portend adverse prognoses. Overall, our study uncovers a clinically consequential cancer cell subpopulation and highlights its potential as a target for precision oncology.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Spatial genome organization in nematodes with programmed DNA elimination. 线虫的空间基因组组织与程序化DNA消除。

IF 6.3 2区生物学

Genome research Pub Date : 2026-10-08 DOI: 10.1101/gr.282223.126

James R Simmons, Tianchun Xue, Rachel Patton McCord, Jianbin Wang

{"title":"Spatial genome organization in nematodes with programmed DNA elimination.","authors":"James R Simmons, Tianchun Xue, Rachel Patton McCord, Jianbin Wang","doi":"10.1101/gr.282223.126","DOIUrl":"10.1101/gr.282223.126","url":null,"abstract":"Programmed DNA elimination (PDE) is a notable exception to genome integrity. In many nematodes, PDE is initiated by DNA double-strand breaks (DSBs), leading to chromosome fragmentation and subsequent DNA loss. However, the mechanism of nematode programmed DNA breakage remains largely unclear. In the human and pig parasitic nematode Ascaris (Ascaris lumbricoides and Ascaris suum), no conserved motif or sequence structures are present at chromosomal breakage regions (CBRs), suggesting the recognition of CBRs may be sequence independent. Using Hi-C, we reveal that Ascaris CBRs engage in three-dimensional (3D) interactions before and during PDE, indicating that physical contacts between break regions may contribute to PDE. The 3D interactions are established in both Ascaris male and female germlines, demonstrating inherent genome organization associated with the CBRs and to-be-eliminated sequences. In contrast, in the unichromosomal horse parasite Parascaris univalens, transient pairwise interactions between neighboring CBRs that will form the ends of future somatic chromosomes are observed only during PDE. We find that Ascaris PDE, which converts 24 germline chromosomes into 36 somatic ones, induces specific compartmentalization changes. Parascaris PDE generates the same set of 36 somatic chromosomes, and the 3D compartment changes following PDE are consistent between the two species. Overall, we suggest that CBRs are associated with the boundaries of distinct 3D genome domains. These domains partition the retained and eliminated DNA into separate spatial compartments. We also demonstrate that following PDE, the 3D genome reorganization of the somatic chromosomes in these nematodes is evolutionarily and developmentally conserved.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SwinePan for pig graph-based pangenome and multiomics data mining. 基于猪图的泛基因组和多组学数据挖掘。

IF 6.3 2区生物学

Genome research Pub Date : 2026-10-08 DOI: 10.1101/gr.281750.125

Meng Lin, Langqing Liu, Gengyuan Cai, Sixiu Huang, Yibin Qiu, Zekai Yao, Shaoxiong Deng, Shiyuan Wang, Yiyi Liu, Donglin Ruan, Fuchen Zhou, Jiajin Wu, Zebin Zhang, Enqin Zheng, Jie Yang, Zhenfang Wu

{"title":"SwinePan for pig graph-based pangenome and multiomics data mining.","authors":"Meng Lin, Langqing Liu, Gengyuan Cai, Sixiu Huang, Yibin Qiu, Zekai Yao, Shaoxiong Deng, Shiyuan Wang, Yiyi Liu, Donglin Ruan, Fuchen Zhou, Jiajin Wu, Zebin Zhang, Enqin Zheng, Jie Yang, Zhenfang Wu","doi":"10.1101/gr.281750.125","DOIUrl":"10.1101/gr.281750.125","url":null,"abstract":"Pigs are one of the most important livestock species worldwide. Although multiple high-quality reference genomes exist, reliance on a single linear reference limits the detection of structural variants (SVs) and the characterization of population-specific genetic diversity. To address this limitation, we developed SwinePan, a comprehensive and integrated multiomic database for pigs built on a graph-based pangenome framework. SwinePan incorporates a variome derived from the graph-based pangenome, covering 2598 individuals across 35 breeds, including 185,759 SVs, 117 million SNPs, and 6.8 million indels. The database also integrates transcriptomic data from liver, loin muscle, abdominal fat, and backfat, along with more than 150,000 phenotypic records. The online toolkit deployed in SwinePan enables genome-wide association studies (GWAS), expression quantitative trait locus (eQTL) mapping, and colocalization, whereas interactive modules visualize population structure and multiomic associations, streamlining candidate gene and variant exploration. Additionally, two proof-of-concept analyses demonstrate how SwinePan pinpoints trait-associated loci and deciphers their potential regulatory mechanisms.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Error correction algorithms for efficient gene expression quantification in single cell transcriptomics with Arcane. 使用Arcane进行单细胞转录组学中有效基因表达定量的纠错算法。

IF 6.3 2区生物学

Genome research Pub Date : 2026-10-07 DOI: 10.1101/gr.282251.126

Jens Zentgraf, Johanna Elena Schmitz, Andreas Keller, Sven Rahmann

{"title":"Error correction algorithms for efficient gene expression quantification in single cell transcriptomics with Arcane.","authors":"Jens Zentgraf, Johanna Elena Schmitz, Andreas Keller, Sven Rahmann","doi":"10.1101/gr.282251.126","DOIUrl":"https://doi.org/10.1101/gr.282251.126","url":null,"abstract":"Technological advances in single-cell RNA sequencing (scRNA-seq) allow us to sequence the transcriptomes of thousands of single cells in parallel, resulting in massive amounts of raw sequence data that must be processed efficiently to obtain a genes × cells expression matrix. In droplet-based scRNA-seq protocols, the sequenced mRNA molecules are tagged with a cell-specific barcode and a unique molecular identifier (UMI) within each cell. Both barcodes and UMIs may contain errors from production, amplification, or sequencing. Correcting and resolving such errors before further processing yields more reliable data and more accurate expression measurements. We propose algorithmic advancements for barcode correction, read-to-gene mapping, and UMI resolution, which we combine into a new method called Arcane for efficient gene expression quantification from scRNA-seq data. We additionally provide an implementation as a workflow- friendly command-line tool, also called Arcane. This work builds on the recently published Fourway method to efficiently discover DNA k-mers with a Hamming distance of 1, speeding up barcode correction and UMI resolution and allowing for distinguishing k-mers into weakly and strongly unique ones during read-to-gene mapping. As a side result of separate interest, we show that for the mapping step, it suffices to store three genes per k-mer in order to cover almost all of the genes almost completely, thus avoiding arbitrarily large color sets in the colored De Bruijn graph index. Arcane is faster than existing methods while producing very similar results, as demonstrated in a comparison with Cell Ranger, kallisto | bustools and alevin-fry.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149127341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Shared transcriptional consequences of epigenetic machinery disruption in murine neuronal progenitors. 小鼠神经元祖细胞表观遗传机制破坏的共同转录后果。

IF 6.3 2区生物学

Genome research Pub Date : 2026-10-07 DOI: 10.1101/gr.281473.125

Juan Ouyang, Kaan Okay, Katrin Möller, Katrin Wang, Adam Davidovich, Stefán Pétursson, Tessa Pierce, Arsalan Amirfallah, Kimberley Anderson, Kasper Daniel Hansen, Hans Björnsson

{"title":"Shared transcriptional consequences of epigenetic machinery disruption in murine neuronal progenitors.","authors":"Juan Ouyang, Kaan Okay, Katrin Möller, Katrin Wang, Adam Davidovich, Stefán Pétursson, Tessa Pierce, Arsalan Amirfallah, Kimberley Anderson, Kasper Daniel Hansen, Hans Björnsson","doi":"10.1101/gr.281473.125","DOIUrl":"https://doi.org/10.1101/gr.281473.125","url":null,"abstract":"The Mendelian disorders of the epigenetic machinery (MDEMs) are an emerging group of disorders which commonly involve disruption of intellect and growth. To investigate consequences of epigenetic machinery (EM) disruption during neurodevelopment, we systematically knocked out (KO) EM factors in neuronal progenitors isolated from the murine hippocampus and established a neurodifferentiation model to interrogate their functions. We then profiled gene expression and DNA methylation (DNAm) in the EM-KOs using RNA sequencing and Nanopore long-read DNA sequencing. While Dnmt1-KO induces extensive DNAm alterations, Kmt2a-KO has little effect on methylation. Nevertheless, the disruption of Kmt2a and Dnmt1 produces convergent transcriptional changes. Loss of either EM factor leads to premature neuronal differentiation, partially explaining this convergence, and MYC emerges as a shared regulatory node linked to downregulation of cell cycle programs in these cells. Extending our methylation analysis to 46 EM genes, we find that loss of DNA methyltransferases induces the strongest DNAm changes, whereas other EM-KOs have subtle or negligible effects. However, clustering of EM-KOs based on promoter DNAm levels reveals three distinct EM subgroups, of which two are enriched for interactions with the DNAm machinery. Allele-specific analysis of DNAm further identifies a single differentially methylated region shared across the 46 EM-KOs, localized to the B6J allele over the Zic4 3'UTR. Furthermore, Zic4 overexpression appears to maintain the neuronal progenitor state, suggesting functional relevance of this locus. Taken together, our results reveal both gene-specific and convergent transcriptional effects across diverse EM-KOs and provide novel insights into the downstream consequences of EM dysfunction.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Resolving missing human polymorphic inversions and other complex variants from ultralong read data. 从超长读取数据中解决缺失的人类多态反转和其他复杂变异。

IF 6.3 2区生物学

Genome research Pub Date : 2026-10-01 DOI: 10.1101/gr.280867.125

Ricardo Moreira-Pinhal, Konstantinos Karakostis, Illya Yakymenko, Oscar Conchillo, Maria Díaz-Ros, Andrés Santos, Miquel Àngel Senar, Jaime Martínez-Urtaza, Marta Puig, Mario Cáceres

{"title":"Resolving missing human polymorphic inversions and other complex variants from ultralong read data.","authors":"Ricardo Moreira-Pinhal, Konstantinos Karakostis, Illya Yakymenko, Oscar Conchillo, Maria Díaz-Ros, Andrés Santos, Miquel Àngel Senar, Jaime Martínez-Urtaza, Marta Puig, Mario Cáceres","doi":"10.1101/gr.280867.125","DOIUrl":"10.1101/gr.280867.125","url":null,"abstract":"Inversions are a unique type of balanced structural variants (SVs) with important consequences in multiple organisms. However, despite considerable effort, these and other complex SVs remain poorly characterized because of the presence of large repeats. New techniques are finally allowing us to identify the full spectrum of human inversions, but the number of individuals analyzed is still quite limited. Here, we take advantage of Oxford Nanopore Technologies (ONT) long reads to characterize an exhaustive catalog of 612 candidate inversions between 197 bp and 4.4 Mb of length, and flanked by <190 kb long inverted repeats (IRs). To that end, we have developed a bioinformatic package to identify inversion alleles reliably from long-read data. Next, using a combination of different DNA extraction, library preparation, and ONT sequencing protocols, we show that ultralong reads (50-100 kb) and adaptive sampling are an efficient method to detect most human inversions. Lastly, by analyzing ONT data from 54 diverse individuals, 87%-99% of the inversions can be genotyped in each sample, depending mainly on read and IR length and genome coverage. Both orientations have been observed for 155 of the analyzed regions (frequency 0.01-0.49), which triples the number of polymorphic IR-mediated inversions studied in detail so far. Moreover, we have found more than 300 additional independent SVs in the studied regions and resolved several complex rearrangements. Therefore, our work provides an accurate benchmark of those inversions that typically escape most analyses, and it demonstrates the potential of nanopore sequencing to characterize missing human genomic variation.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":"2116-2126"},"PeriodicalIF":6.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0