Current Opinion in Genetics & Development最新文献

英文中文

Decoding schizophrenia through postmortem human brain transcriptomics. 通过死后人脑转录组学解码精神分裂症。

IF 3.6 2区生物学 Q2 CELL BIOLOGY

Current Opinion in Genetics & Development

Pub Date : 2026-02-03 DOI: 10.1016/j.gde.2026.102434

W Brad Ruzicka, Sivan Subburaju

Schizophrenia is a highly heritable neuropsychiatric disorder affecting approximately 1% of the population, yet its pathophysiology has remained elusive due to the absence of gross neuropathological changes. In recent years, advances in transcriptomic profiling of postmortem human brain tissue have begun to illuminate the disease's molecular architecture. This mini-review synthesizes findings from case-control bulk tissue and single-nucleus transcriptomics studies, revealing that schizophrenia is characterized by widespread but subtle gene expression changes concentrated in excitatory neurons within the prefrontal cortex. Downregulation of synaptic and metabolic genes emerges as a consistent theme, accompanied by secondary activation of glial populations. Single-cell resolution studies demonstrate that these transcriptional alterations are cell type-specific and heterogeneous across individuals, with upper-layer excitatory neurons showing particular vulnerability. Despite methodological challenges inherent to postmortem tissue analysis, convergent evidence across multiple large-scale consortia establishes transcriptional dysregulation as a core feature of schizophrenia pathophysiology. Future directions include expanded cohorts and additional brain regions, as well as spatial transcriptomics and isoform-level analyses to fully map the molecular landscape of this complex disorder.

精神分裂症是一种高度遗传性的神经精神疾病，影响了大约1%的人口，但由于缺乏明显的神经病理改变，其病理生理学仍然难以捉摸。近年来，人类死后脑组织转录组学分析的进展已经开始阐明这种疾病的分子结构。这篇小型综述综合了来自病例对照的大块组织和单核转录组学研究的发现，揭示了精神分裂症的特征是广泛但微妙的基因表达变化，集中在前额皮质的兴奋性神经元中。突触和代谢基因的下调是一个一致的主题，伴随着胶质细胞群的二次激活。单细胞分辨率研究表明，这些转录改变具有细胞类型特异性和个体异质性，上层兴奋性神经元表现出特别的脆弱性。尽管死后组织分析在方法学上存在固有的挑战，但跨多个大规模联合体的趋同证据表明，转录失调是精神分裂症病理生理学的核心特征。未来的方向包括扩大队列和额外的大脑区域，以及空间转录组学和同型水平分析，以全面绘制这种复杂疾病的分子景观。

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引用次数: 0

Finding the genetic basis of adaptation: reducing complexity to improve trait mapping 发现适应的遗传基础：降低复杂性以改善性状定位。

IF 3.6 2区生物学 Q2 CELL BIOLOGY

Current Opinion in Genetics & Development

Pub Date : 2026-01-20 DOI: 10.1016/j.gde.2025.102432

Yulia Yarkhunova-Kreye , Angela M Hancock

Genome-wide association studies (GWAS) have advanced our understanding of trait variation, yet persistent challenges limit their effectiveness in mapping adaptive traits. Population structure, allelic heterogeneity, trait complexity, and structural variation obscure true causal relationships. However, these factors can often be addressed through strategic simplification. Here, we review factors limiting GWAS success in natural populations and show that reducing complexity improves mapping outcomes. We examine how local population mapping, trait decomposition into endophenotypes, and incorporation of structural variation enable the identification of adaptive loci. Using Arabidopsis thaliana as a model system, we demonstrate how these approaches reveal functionally validated variants missed by traditional studies. Finally, we discuss integration strategies and emerging technologies that will advance our understanding of the genetics of adaptation.

全基因组关联研究（GWAS）促进了我们对性状变异的理解，但持续的挑战限制了它们在定位适应性性状方面的有效性。群体结构、等位基因异质性、性状复杂性和结构变异模糊了真正的因果关系。然而，这些因素通常可以通过战略简化来解决。在这里，我们回顾了限制GWAS在自然种群中成功的因素，并表明降低复杂性可以改善制图结果。我们研究了局部群体定位、性状分解为内表型以及结构变异的结合如何使适应性位点的识别成为可能。以拟南芥为模型系统，我们展示了这些方法如何揭示传统研究遗漏的功能验证变异。最后，我们讨论了整合策略和新兴技术，这将促进我们对适应遗传学的理解。

引用次数: 0

Progress in understanding the biological basis of polygenic disorders 多基因疾病生物学基础的研究进展

IF 3.6 2区生物学 Q2 CELL BIOLOGY

Current Opinion in Genetics & Development

Pub Date : 2026-01-17 DOI: 10.1016/j.gde.2025.102433

NR Wray , T Lin , A Li , V de Almeida , M Ziller , J Zeng

Genome-wide association studies have provided empirical evidence that common diseases have a polygenic architecture, but with differences in estimable genetic architecture parameters such as proportion of the genomic sites associated with trait variation (polygenicity), the proportion of variance explained by those common DNA variants (SNP-based heritability), and signatures of selection evident from the relationship between allele frequency and effect size. Comparisons of genetic parameters across traits highlight that psychiatric disorders and other brain-related traits are significantly more polygenic than most other common diseases. Key questions are to understand in which tissues, cell-types, and biological contexts risk variants have a functional impact. We review recent progress and consider the next generation of experimental data needed to understand the biological basis of polygenic disorders.

全基因组关联研究提供了经验证据，表明常见疾病具有多基因结构，但在可估计的遗传结构参数方面存在差异，如与性状变异相关的基因组位点比例（多基因性）、由这些常见DNA变异解释的变异比例（基于snp的遗传力），以及等位基因频率和效应大小之间关系中明显的选择特征。跨性状的遗传参数比较突出表明，精神疾病和其他脑相关性状的多基因性明显高于大多数其他常见疾病。关键问题是要了解在哪些组织、细胞类型和生物学背景下风险变异具有功能影响。我们回顾了最近的进展，并考虑了解多基因疾病的生物学基础所需的下一代实验数据。

引用次数: 0

Polymer simulations of chromatin: connecting 3D organization and dynamics to function 染色质的聚合物模拟：连接三维组织和动态功能

IF 3.6 2区生物学 Q2 CELL BIOLOGY

Current Opinion in Genetics & Development

Pub Date : 2026-01-14 DOI: 10.1016/j.gde.2025.102429

Shuvadip Dutta , Ranjith Padinhateeri

Polymer physics-based models of chromatin are essential for interpreting experimental observations and gaining mechanistic insights into genome organization and its functional consequences. However, because chromatin is a highly complex polymer, its fundamental physical properties remain poorly understood. Deriving these properties from experiments and using them to simulate chromatin behavior and predict functional outcomes remain key challenges in the field. Another major challenge is to understand how ATP-dependent active forces act along the genome and to incorporate these effects into models of chromatin dynamics. In this review, we discuss recent advances that address these challenges and highlight the strengths, limitations, and predictive capabilities of current modeling approaches for studying interphase chromatin.

基于聚合物物理的染色质模型对于解释实验观察和获得基因组组织及其功能后果的机制见解至关重要。然而，由于染色质是一种高度复杂的聚合物，它的基本物理性质仍然知之甚少。从实验中获得这些特性并使用它们来模拟染色质行为和预测功能结果仍然是该领域的关键挑战。另一个主要挑战是了解atp依赖的活性力量如何沿着基因组发挥作用，并将这些影响纳入染色质动力学模型。在这篇综述中，我们讨论了解决这些挑战的最新进展，并强调了研究间期染色质的当前建模方法的优势、局限性和预测能力。

引用次数: 0

Block copolymer concepts of how transcription organizes the stem cell genome 嵌段共聚物概念的转录如何组织干细胞基因组

IF 3.6 2区生物学 Q2 CELL BIOLOGY

Current Opinion in Genetics & Development

Pub Date : 2026-01-14 DOI: 10.1016/j.gde.2025.102428

Yuzhi Bao , Shaoqian Ma , Xiaohua Shen , Lennart Hilbert

Stem cells display a highly dispersed genome organization that supports flexible gene regulation. Here, we present block copolymer concepts to explore how transcriptional activity from specific genomic regions, or ‘blocks’, shapes and controls several features of this architecture. Nascent transcripts tethered to chromatin can disrupt compaction and promote the formation of a micro-dispersed state of euchromatin, explaining one typical feature of the stem cell genome. A second feature is long-lived transcriptional clusters, which form via condensation at super-enhancer blocks and mediate both long-range interactions and local transcription factor accumulation. Lastly, we conceptualize promoters and gene bodies as a two-block polymer, for which sequential switching on and off of the polymer blocks controls the association and subsequent release of developmental genes with the long-lived clusters. The presented block copolymer framework provides explanations as well as hypotheses of how transcription-associated processes contribute to distinct features of stem cell genome organization.

干细胞显示出高度分散的基因组组织，支持灵活的基因调控。在这里，我们提出嵌段共聚物的概念来探索来自特定基因组区域或“块”的转录活性如何形成和控制这种结构的几个特征。连接在染色质上的新生转录本可以破坏压实并促进微分散状态的形成，这解释了干细胞基因组的一个典型特征。第二个特征是长寿命的转录团簇，它通过超增强子块的凝聚形成，并介导远程相互作用和局部转录因子积累。最后，我们将启动子和基因体概念化为一个两段聚合物，其中聚合物块的顺序开关控制着发育基因与长寿命簇的关联和随后的释放。所提出的嵌段共聚物框架提供了解释以及转录相关过程如何促进干细胞基因组组织的不同特征的假设。

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引用次数: 0

Recent advances in the neurogenomics of autism spectrum disorder 自闭症谱系障碍神经基因组学的最新进展

IF 3.6 2区生物学 Q2 CELL BIOLOGY

Current Opinion in Genetics & Development

Pub Date : 2026-01-13 DOI: 10.1016/j.gde.2025.102431

Ashlesha Gogate , Maria H Chahrour

Neurogenomics has provided exceptional insights into the genetic architecture underlying autism spectrum disorder (ASD), which is increasingly understood as a collection of individually rare disorders. This review synthesizes current advancements in the field, examining how both rare and common genetic variants contribute to ASD etiology. To functionally interpret the convergence on biological pathways that has emerged despite this genetic heterogeneity, multiomic approaches have been applied to identify gene regulatory networks disrupted in ASD. High-throughput technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR) editing and massively parallel reporter assays, have been employed in human induced pluripotent stem cells and organoids to bridge the gap between genetic association and biological function. Finally, machine learning methods play a pivotal role in integrating and leveraging these complex datasets to inform personalized interventions.

神经基因组学为自闭症谱系障碍（ASD）的遗传结构提供了独特的见解，ASD越来越被理解为个体罕见疾病的集合。本文综述了该领域的最新进展，探讨了罕见和常见的遗传变异是如何导致ASD病因的。为了从功能上解释尽管存在这种遗传异质性，但在生物学途径上出现的趋同，多组学方法已被应用于识别ASD中被破坏的基因调控网络。高通量技术，如聚集规律间隔短回文重复序列（CRISPR）编辑和大规模平行报告基因测定，已被用于人类诱导多能干细胞和类器官，以弥合遗传关联和生物功能之间的差距。最后，机器学习方法在整合和利用这些复杂的数据集来通知个性化干预方面发挥着关键作用。

引用次数: 0

Chromosome organization by Structural Maintenance of Chromosomes complexes in C. elegans 秀丽隐杆线虫染色体复合体结构维持的染色体组织。

IF 3.6 2区生物学 Q2 CELL BIOLOGY

Current Opinion in Genetics & Development

Pub Date : 2026-01-12 DOI: 10.1016/j.gde.2025.102430

Sinem Erkan , Kalyan Ghadage , Peter Meister

Genome folding is a key regulator of transcription, chromosome segregation, and genome stability. In Caenorhabditis elegans, chromatin folding strategies have diverged from those observed in mammals or flies, resulting in the absence of visible topologically associating domains (TADs) on autosomes. Here, condensin I, rather than cohesin, serves as the primary long-range loop extruder, while distinct cohesin isoforms specialize in mitotic cohesion and loop extrusion, forming enhancer-associated ‘fountains’ that modulate neuronal gene expression. On the X chromosome, dosage compensation depends on the dosage compensation complex, which incorporates a specialized condensin I^DC to establish TADs, regulate chromatin states, and repress transcription. These multilayered mechanisms illustrate the evolutionary versatility of 3D genome organization and its intimate links to development, physiology, and lifespan, positioning C. elegans as a powerful model for dissecting structural maintenance of chromosomes–mediated genome regulation.

基因组折叠是转录、染色体分离和基因组稳定性的关键调控因子。在秀丽隐杆线虫中，染色质折叠策略与在哺乳动物或苍蝇中观察到的不同，导致常染色体上缺乏可见的拓扑相关结构域（TADs）。在这里，凝缩蛋白I，而不是黏结蛋白，作为主要的远程环挤出剂，而不同的黏结蛋白亚型专门从事有丝分裂内聚和环挤出，形成与增强剂相关的“喷泉”，调节神经元基因表达。在X染色体上，剂量补偿依赖于剂量补偿复合物，该复合物包含一个专门的凝缩蛋白IDC来建立tad，调节染色质状态并抑制转录。这些多层机制说明了三维基因组组织的进化多功能性及其与发育、生理和寿命的密切联系，将秀丽隐杆线虫定位为解剖染色体介导的基因组调控的结构维持的强大模型。

引用次数: 0

Cooperativity between regulatory elements acts as a modulator of enhancer function 调控元件之间的协同作用是增强子功能的调制器

IF 3.6 2区生物学 Q2 CELL BIOLOGY

Current Opinion in Genetics & Development

Pub Date : 2026-01-10 DOI: 10.1016/j.gde.2025.102427

Deevitha Balasubramanian , Margarita Masoura , Yad Ghavi-Helm

Transcription is classically known to be regulated by two key elements, promoters and enhancers. While these remain central to gene regulation, it is now clear that additional regulatory sequences fine-tune enhancer function and transcriptional output. In this review, we focus on two such recently described sequences, promoter-proximal elements and enhancer-like modulators, highlighting representative examples of their function and their proposed mechanisms of action. We further discuss the implications of these discoveries on the current definitions of promoters and enhancers, and highlight an emerging theme that such elements do not fall into discrete classes but instead function along a regulatory continuum. Recognizing this continuum and appreciating transcriptional control as an interconnected network of elements will be essential for understanding gene regulation in complex genomes.

转录通常由两个关键元素调控，启动子和增强子。虽然这些仍然是基因调控的核心，但现在很清楚，额外的调控序列可以微调增强子的功能和转录输出。在这篇综述中，我们重点介绍了最近描述的两个序列，启动子-近端元件和增强子样调节剂，重点介绍了它们的功能和作用机制的代表性例子。我们进一步讨论了这些发现对当前启动子和增强子定义的影响，并强调了一个新兴的主题，即这些元素并不属于离散的类别，而是沿着调控连续体起作用。认识到这种连续统一体，并将转录控制视为相互关联的元件网络，对于理解复杂基因组中的基因调控至关重要。

引用次数: 0

Revitalizing psychopharmacology in the GWAS era: the potential of barcoded screening in drug discovery GWAS时代精神药理学的复兴：条形码筛选在药物发现中的潜力

IF 3.6 2区生物学 Q2 CELL BIOLOGY

Current Opinion in Genetics & Development

Pub Date : 2026-01-08 DOI: 10.1016/j.gde.2025.102425

Sebastian H Heesen , Man-Hsin Chang , Michael C Wehr , Moritz J Rossner

The success of comprehensive genome-wide association studies has substantiated the multigenetic origin of most mental disorders, including schizophrenia, bipolar disorder, and major depression. Non-coding genetic variants are enriched mainly in regulatory regions of genes expressed in excitatory and inhibitory neurons and converge particularly on cellular pathways implicated in neurodevelopment and synaptic functions. Given the molecular and cellular complexity of mental disorders, classical ‘single-drug-target-based’ drug discovery has largely failed in delivering novel pharmacological treatment options. We believe that drug development for complex disorders requires a paradigm shift toward a ‘phenotype or pathway focused’ approach, which integrates multi-parametric assay technologies and stem technology to perform screening and lead compound validation with dramatically enhanced contextual specificity. Moreover, many existing drugs used to treat mental disorders display polypharmacological actions. Therefore, there is a demand for developing assay technologies capable of dissecting the complex modes of action of novel drug candidates in a cost-effective manner. Here, we review technological progress across various fields that hold promise in delivering future breakthrough treatments for mental disorders.

全面全基因组关联研究的成功证实了大多数精神障碍的多基因起源，包括精神分裂症、双相情感障碍和重度抑郁症。非编码遗传变异主要富集在兴奋性和抑制性神经元中表达的基因的调控区域，并集中在涉及神经发育和突触功能的细胞通路上。鉴于精神障碍的分子和细胞复杂性，传统的“基于单一药物靶点”的药物发现在很大程度上未能提供新的药物治疗选择。我们认为，复杂疾病的药物开发需要向“以表型或途径为重点”的方法转变，该方法整合了多参数分析技术和干细胞技术，以显着增强上下文特异性进行筛选和先导化合物验证。此外，许多用于治疗精神障碍的现有药物显示出多种药理作用。因此，需要开发能够以具有成本效益的方式剖析新型候选药物复杂作用模式的分析技术。在这里，我们回顾了各个领域的技术进步，这些技术进步有望为精神障碍提供未来的突破性治疗。

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引用次数: 0

Nonequilibrium polymer models for chromatin 染色质的非平衡聚合物模型

IF 3.6 2区生物学 Q2 CELL BIOLOGY

Current Opinion in Genetics & Development

Pub Date : 2026-01-08 DOI: 10.1016/j.gde.2025.102426

Giada Forte , Chris A. Brackley , Nick Gilbert , Davide Marenduzzo

The cell nucleus is a dynamic environment where ATP-driven processes — like transcription, replication, and epigenetic modifications — continually drive the genome far from thermodynamic equilibrium. Recent interdisciplinary efforts combining cell biology and physics have introduced coarse-grained polymer models that reveal how these active processes shape chromosome organization in space and time. We review how these models have shed light on selected key features of nuclear function: the maintenance of epigenetic memory, the coupling between transcriptional activity and chromatin motion, and the emergence of replication factories. These approaches provide mechanistic insight and predictive power that are beyond experiments alone. We conclude by outlining future directions toward viewing the genome as an active polymer maintained far from equilibrium.

细胞核是一个动态的环境，atp驱动的过程——如转录、复制和表观遗传修饰——不断地使基因组远离热力学平衡。最近的跨学科研究结合了细胞生物学和物理学，引入了粗粒度聚合物模型，揭示了这些活跃过程如何在空间和时间上塑造染色体组织。我们回顾了这些模型如何揭示核功能的关键特征：表观遗传记忆的维持，转录活性和染色质运动之间的耦合，以及复制工厂的出现。这些方法提供了超越实验本身的机械洞察力和预测能力。最后，我们概述了将基因组视为远离平衡的活性聚合物的未来方向。

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全部化学•材料生命科学医学物理工程技术环境•农林材料科学地球科学法学管理学化学环境科学与生态学计算机科学教育学经济学农林科学人文科学生物学数学物理与天体物理心理学综合性期刊其他工业工程理学历史学农学文学信息工程

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