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Probing neuropsychiatric disorders through in vivo CRISPR screening 通过体内CRISPR筛选探查神经精神疾病。
IF 3.6 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-12-29 DOI: 10.1016/j.gde.2025.102424
Tuo Shi , Xin Jin
Although there are many known risk alleles associated with adult-onset psychiatric disorders such as schizophrenia [1–4], bipolar disorder [5–7], and major depressive disorder [8−10], the mechanistic links between these risk alleles and disease pathology, especially on a circuit-level, remain unclear. In vivo pooled CRISPR screening with single‑cell readout (in vivo Perturb‑seq) has begun to fill this gap by mapping causal genes to defined cell states directly in animal tissues [11–14]. Here, we review recent developments and applications of in vivo Perturb-seq in the mouse brain and highlight the potential of utilizing human cellular systems to extend these approaches. Additionally, we discuss how in vivo Perturb-seq can couple genetic perturbation with physiological or environmental perturbations to better model psychiatric diseases with environmental triggers.
虽然有许多已知的风险等位基因与成人发病的精神疾病相关，如精神分裂症[1-4]、双相情感障碍[5-7]和重度抑郁症[8-10]，但这些风险等位基因与疾病病理之间的机制联系，特别是在回路水平上，仍不清楚。利用单细胞读数（In vivo Perturb - seq）在体内汇集CRISPR筛选已经开始填补这一空白，通过直接在动物组织中将致病基因定位到确定的细胞状态[11-14]。在这里，我们回顾了体内Perturb-seq在小鼠大脑中的最新发展和应用，并强调了利用人类细胞系统扩展这些方法的潜力。此外，我们讨论了体内扰动序列如何将遗传扰动与生理或环境扰动耦合起来，以更好地模拟具有环境触发因素的精神疾病。
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引用次数: 0
Enhancer cooperativity in the folded genome 增强折叠基因组中的协同性
IF 3.6 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-12-19 DOI: 10.1016/j.gde.2025.102416
Elias T Friman, Wendy A Bickmore
Transcriptional regulation involves the binding of thousands of transcription factors (TFs) to hundreds of thousands of enhancers and promoters. How do the collective activities of these proteins and cis-regulatory elements achieve precise and dynamic gene regulation? At an individual enhancer, TFs can interact to affect each other’s binding and the recruitment of different co-factors, resulting in cooperative outputs. More recently, new types of cooperative behaviour between enhancers have been discovered. In this review, we consider whether some of the same principles could contribute to both TF and enhancer cooperativity, focusing specifically on positive cooperativity (or synergy) and the role of 3D chromatin organisation.
转录调控涉及成千上万的转录因子（tf）与成千上万的增强子和启动子的结合。这些蛋白质和顺式调控元件的集体活动如何实现精确和动态的基因调控？在单个增强子上，tf可以相互作用，影响彼此的结合和不同辅因子的招募，从而产生合作输出。最近，人们发现了增强子之间新型的合作行为。在这篇综述中，我们考虑是否有一些相同的原理可以促进TF和增强协同性，特别关注积极的协同性（或协同）和三维染色质组织的作用。
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引用次数: 0
Integrating machine learning and functional genomics to study cross-species gene regulatory evolution 结合机器学习和功能基因组学研究跨物种基因调控进化
IF 3.6 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-12-19 DOI: 10.1016/j.gde.2025.102415
Erin N Gilbertson , Steven K Reilly
Understanding the genetic basis of phenotypic differences across species has been a longstanding goal of evolutionary biology since Darwin. While a recent proliferation of mammalian genomes has provided an unprecedented inventory of sequence differences between species, the vast majority are in noncoding loci, where it remains challenging to link genetic changes to function. Cis-regulatory elements (CREs) control gene expression via combinatorial, redundant, and context-dependent interactions that are both evolutionarily amenable to change but render their gene regulatory logic difficult to decipher. Recent advances in comparative genomics, functional profiling across species, and high-throughput perturbation assays have begun to catalog cross-species differences in gene expression and CRE function. In parallel, machine learning approaches trained on these data are beginning to predict cis-regulatory activity differences from DNA sequences alone. Here, we highlight recent advances in both experimental and computational strategies to study gene regulatory evolution.
自达尔文以来，理解物种间表型差异的遗传基础一直是进化生物学的长期目标。虽然最近哺乳动物基因组的激增为物种之间的序列差异提供了前所未有的清单，但绝大多数都在非编码位点，因此将遗传变化与功能联系起来仍然具有挑战性。顺式调控元件（cre）通过组合、冗余和上下文依赖的相互作用来控制基因表达，这些相互作用在进化上都是可以改变的，但使其基因调控逻辑难以破译。比较基因组学、跨物种功能谱分析和高通量扰动分析的最新进展已经开始编录基因表达和CRE功能的跨物种差异。与此同时，在这些数据上训练的机器学习方法开始单独预测DNA序列的顺式调控活性差异。在这里，我们重点介绍了研究基因调控进化的实验和计算策略的最新进展。
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引用次数: 0
Mix-and-match between transposable elements and zinc finger proteins fuels genic and regulatory innovation 转座因子和锌指蛋白之间的混合匹配促进了基因和调控的创新
IF 3.6 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-11-15 DOI: 10.1016/j.gde.2025.102414
Olga Rosspopoff , Didier Trono , Cédric Feschotte
Transposable elements (TEs) are abundant and dynamic components of eukaryotic genomes, subject to regulation by equally adaptive regulatory systems. A coevolution of TEs and zinc finger genes can be documented throughout metazoan evolution. In humans, TEs account for half of the genome, and nearly all TE subfamilies are preferentially bound by at least one of the approximately 400 KRAB zinc finger proteins (ZFPs). The majority of human KRAB-ZFPs appear to tame the cis-regulatory activities of TEs, thereby facilitating their integration within gene regulatory networks. In turn, throughout vertebrate evolution, TE protein domains have fused repeatedly with ZFPs to give rise to new classes of regulatory proteins. Thus, the TE–ZFP interplay has been a powerful catalyst of biological innovation.
转座因子（te）是真核生物基因组中丰富的动态组成部分，受到同样适应性调节系统的调节。te和锌指基因的共同进化可以在后生动物的进化过程中得到证实。在人类中，TE占基因组的一半，几乎所有TE亚家族都优先与大约400个KRAB锌指蛋白（ZFPs）中的至少一个结合。大多数人类KRAB-ZFPs似乎驯服了te的顺式调控活动，从而促进了它们在基因调控网络中的整合。反过来，在整个脊椎动物进化过程中，TE蛋白结构域与ZFPs反复融合，产生新的调节蛋白类别。因此，TE-ZFP相互作用是生物创新的强大催化剂。
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引用次数: 0
Epistatic drift in protein evolution 蛋白质进化中的上位漂变。
IF 3.6 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-11-11 DOI: 10.1016/j.gde.2025.102412
Ricardo Muñiz-Trejo , Jaeda EJ Patton , Santiago Herrera-Álvarez , Joseph W Thornton
New methods are revealing the character of epistatic interactions within proteins and their impacts on evolution. Variation in biochemical phenotypes across protein sequences is determined primarily by the context-independent effects of amino acids and global nonlinearities imposed by biophysical mechanisms. Specific epistasis — primarily pairwise interactions — plays a subsidiary role, but collectively has a major impact on evolution. Every substitution in an evolving protein changes the effects of many potential mutations at epistatically coupled sites. As homologs diverge from common ancestors, the constraints that determine the accessibility of subsequent mutations gradually drift apart. Opportunities for adaptation and functional innovation also change over time, because each substitution epistatically modifies the effects of mutations on existing and new protein phenotypes. Over moderate evolutionary timescales, the outcomes of protein evolution — both their sequences and biochemical properties — thus become strongly contingent on the substitutions that happen to occur in each lineage. This interplay between random chance and each proteins’ epistatic architecture helps explain widely observed lineage-specific patterns of conservation and variation that are not expected under the dominant schools of thought in molecular evolution.
新的方法揭示了蛋白质内部上位相互作用的特征及其对进化的影响。跨蛋白质序列的生化表型变异主要由氨基酸的上下文无关效应和生物物理机制施加的全局非线性决定。特异上位性——主要是成对相互作用——起着辅助作用，但总体上对进化有重要影响。在进化的蛋白质中，每一次替换都会改变上位偶联位点上许多潜在突变的影响。随着同系物从共同祖先中分化出来，决定后续突变可及性的限制逐渐消失。适应和功能创新的机会也会随着时间的推移而改变，因为每次替代都会在上位性上改变突变对现有和新蛋白质表型的影响。在适度的进化时间尺度上，蛋白质进化的结果——包括它们的序列和生化特性——因此在很大程度上取决于每个谱系中发生的替代。这种随机机会和每种蛋白质上位结构之间的相互作用有助于解释广泛观察到的谱系特异性保护和变异模式，这在分子进化的主流思想流派中是不被期望的。
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引用次数: 0
New methodological approaches and insights gained toward understanding the evolved human skeleton 为理解进化的人类骨骼获得了新的方法和见解。
IF 3.6 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-11-06 DOI: 10.1016/j.gde.2025.102413
Gayani Senevirathne , Terence D Capellini
Modern humans exhibit marked musculoskeletal changes when compared to those of our African ape relatives, such as chimpanzees, bonobos, and gorillas. These changes reflect adaptive shifts during hominin evolution in spine, pelvis, knee, and foot morphology toward obligate bipedalism, shoulder, elbow, and hand morphology for propulsive throwing and precision object manipulation, and brain size expansion and craniofacial morphology for enhanced cognition related to complex culture and language. The molecular basis for these traits remains unknown, in part owing to the experimental difficulties in connecting DNA base-pairs to phenotypes. Here, we discuss recent methodological advances in the life sciences that help to connect genotype to phenotype and pave the way for understanding the molecular basis for human skeletal evolution. In this context, we also discuss the importance of recent findings in how adaptive evolution shapes modern disease risk.
与我们的非洲猿类亲戚，如黑猩猩、倭黑猩猩和大猩猩相比，现代人表现出明显的肌肉骨骼变化。这些变化反映了古人类进化过程中脊柱、骨盆、膝关节和足部形态向专性两足行走的适应性转变，肩部、肘部和手部形态向推进投掷和精确物体操作的适应性转变，以及脑容量扩张和颅面形态向复杂文化和语言相关认知增强的适应性转变。这些特征的分子基础仍然未知，部分原因是在将DNA碱基对与表型联系起来的实验困难。在这里，我们讨论了生命科学中最近的方法进展，这些进展有助于将基因型与表型联系起来，并为理解人类骨骼进化的分子基础铺平道路。在此背景下，我们还讨论了适应性进化如何塑造现代疾病风险的最新发现的重要性。
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引用次数: 0
Editorial overview: Molecular and genetic basis of disease (2025): post-transcriptional regulation of neurodevelopment and associated disorders 编辑概述：疾病的分子和遗传基础（2025）：神经发育和相关疾病的转录后调控
IF 3.6 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-10-31 DOI: 10.1016/j.gde.2025.102409
Naiara Akizu , Jozef Gecz
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引用次数: 0
Evolutionary genetics meets ecological immunology: insights into the evolution of immune systems 进化遗传学满足生态免疫学：洞察免疫系统的进化。
IF 3.6 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-10-29 DOI: 10.1016/j.gde.2025.102411
Alexander E Downie , Jenny Tung
Immune genes show remarkably consistent evidence of selection, modification, and diversification across the tree of life. Parasites are a key force in this process, but many questions remain about the genetic and phenotypic targets of parasite-mediated selection and how these connect to each other. Ecological immunology — the study of immune variation in natural settings — can complement genetic inference by providing an organismal perspective on immune evolution, including how immune adaptation may be explained or constrained by host life history and ecological context. In this review, we outline key questions in immune evolution where ecological immunology offers insights for evolutionary geneticists, and we explore the value of evolutionary genetic approaches for testing fundamental assumptions in ecological immunology.
免疫基因在整个生命树中表现出显著一致的选择、修饰和多样化证据。寄生虫是这一过程中的关键力量，但关于寄生虫介导的选择的遗传和表型目标以及这些目标如何相互联系仍然存在许多问题。生态免疫学——对自然环境中免疫变异的研究——可以通过提供免疫进化的有机视角来补充遗传推断，包括免疫适应如何被宿主生活史和生态环境所解释或限制。在这篇综述中，我们概述了免疫进化中的关键问题，其中生态免疫学为进化遗传学家提供了见解，我们探讨了进化遗传学方法在检验生态免疫学基本假设方面的价值。
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引用次数: 0
Editorial Overview: Developmental mechanisms patterning and evolution (2025) 编辑概述：发展机制、模式和进化（2025）
IF 3.6 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-10-25 DOI: 10.1016/j.gde.2025.102410
Saher S Hammoud, Yukiko Yamashita
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引用次数: 0
Human gut evolution: insights from stem cell models and single-cell genomics 人类肠道进化：来自干细胞模型和单细胞基因组学的见解。
IF 3.6 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-09-24 DOI: 10.1016/j.gde.2025.102398
Rubén López-Sandoval , Stefano Secchia , Joep Beumer , Jarrett Gray Camp
The gastrointestinal (GI) tract evolved in response to dietary changes and pathogen exposures that varied throughout history. As a major interface between the host and environment, the GI epithelia have evolved specialized barrier and immune functions while optimizing nutrient processing and absorption. Recent technological breakthroughs in modeling human biology in vitro and comparative single-cell genomics are providing novel insights into the genetic, cellular, and ontogenic basis of human evolution. In this review, we provide a broad overview of human-specific gut changes and how GI organoids and single-cell technologies can offer a mechanistic understanding of the specific features of human GI tract physiology.
在整个历史中，胃肠道随着饮食变化和病原体暴露而进化。胃肠道上皮作为宿主和环境之间的主要接口，在优化营养物质加工和吸收的同时，进化出了专门的屏障和免疫功能。最近在体外模拟人类生物学和比较单细胞基因组学方面的技术突破，为人类进化的遗传、细胞和个体基础提供了新的见解。在这篇综述中，我们提供了人类特异性肠道变化的广泛概述，以及胃肠道类器官和单细胞技术如何提供对人类胃肠道生理学特定特征的机制理解。
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引用次数: 0
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