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A new hypothesis to explain disease dominance. 一个解释疾病优势的新假说。
IF 13.6 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-03-01 Epub Date: 2025-01-08 DOI: 10.1016/j.tig.2024.11.009
Brian Juvik, Lara Falcucci, Pia R Lundegaard, Didier Y R Stainier

The onset and progression of dominant diseases are thought to result from haploinsufficiency or dominant negative effects. Here, we propose transcriptional adaptation (TA), a newly identified response to mRNA decay, as an additional cause of some dominant diseases. TA modulates the expression of so-called adapting genes, likely via mRNA decay products, resulting in genetic compensation or a worsening of the phenotype. Recent studies have challenged the current concepts of haploinsufficiency or poison proteins as the mechanisms underlying certain dominant diseases, including Brugada syndrome, hypertrophic cardiomyopathy, and frontotemporal lobar degeneration. We hypothesize that for these and other dominant diseases, when the underlying mutation leads to mRNA decay, the phenotype is due at least partly to the dysregulation of gene expression via TA.

显性疾病的发生和进展被认为是由单倍功能不全或显性负作用引起的。在这里,我们提出转录适应(TA),一种新发现的对mRNA衰变的反应,作为一些显性疾病的另一个原因。TA调节所谓的适应性基因的表达,可能通过mRNA衰变产物,导致遗传补偿或表型恶化。最近的研究挑战了单倍体功能不全或毒性蛋白作为某些显性疾病(包括Brugada综合征、肥厚性心肌病和额颞叶变性)机制的现有概念。我们假设,对于这些和其他显性疾病,当潜在的突变导致mRNA衰减时,表型至少部分是由于基因表达通过TA失调。
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引用次数: 0
Advances in euglenoid genomics: unravelling the fascinating biology of a complex clade. 曙光基因组学的进展:揭开一个复杂支系迷人的生物学面纱。
IF 13.6 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-03-01 Epub Date: 2024-08-14 DOI: 10.1016/j.tig.2024.07.007
Oskar Fields, Michael J Hammond, Xiao Xu, Ellis C O'Neill

Euglenids have long been studied due to their unique physiology and versatile metabolism, providing underpinnings for much of our understanding of photosynthesis and biochemistry, and a growing opportunity in biotechnology. Until recently there has been a lack of genetic studies due to their large and complex genomes, but recently new technologies have begun to unveil their genetic capabilities. Whilst much research has focused on the model organism Euglena gracilis, other members of the euglenids have now started to receive due attention. Currently only poor nuclear genome assemblies of E. gracilis and Rhabdomonas costata are available, but there are many more plastid genome sequences and an increasing number of transcriptomes. As more assemblies become available, there are great opportunities to understand the fundamental biology of these organisms and to exploit them for biotechnology.

长期以来,人们一直在研究藻类,因为它们具有独特的生理结构和多变的新陈代谢,为我们了解光合作用和生物化学提供了基础,也为生物技术提供了越来越多的机会。直到最近,由于其庞大而复杂的基因组,一直缺乏遗传研究,但最近的新技术已经开始揭示其遗传能力。虽然许多研究都集中在模式生物褐飞虱上,但褐飞虱的其他成员现在也开始受到应有的关注。目前,我们只能获得 E. gracilis 和 Rhabdomonas costata 较差的核基因组序列,但有更多的质粒基因组序列和越来越多的转录组。随着更多的基因组序列的出现,我们将有很大的机会了解这些生物的基本生物学特性,并将其用于生物技术研究。
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引用次数: 0
The ABCs of the H2Bs: The histone H2B sequences, variants, and modifications.
IF 13.6 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-02-20 DOI: 10.1016/j.tig.2025.01.003
Anna J Voss, Erica Korb

Histone proteins are the building blocks of chromatin, and function by wrapping DNA into complex structures that control gene expression. Histone proteins are regulated by post-translational modifications (PTMs) and by histone variant exchange. In this review, we will provide an overview of one of these histones: H2B. We will first define the sequences of human and mouse H2B proteins and discuss potential designations for canonical H2B. We will also describe the differential functions of H2B variants compared with canonical H2B. Finally, we will summarize known H2B modifications and their functions in regulating transcription. Through review of H2B genes, proteins, variants, and modifications, we aim to highlight the importance of H2B for epigenetic and transcriptional regulation of the cell.

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引用次数: 0
Transposon-host arms race: a saga of genome evolution.
IF 13.6 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-02-19 DOI: 10.1016/j.tig.2025.01.009
Yuka W Iwasaki, Keisuke Shoji, Shinichi Nakagwa, Tomoichiro Miyoshi, Yukihide Tomari

Once considered 'junk DNA,' transposons or transposable elements (TEs) are now recognized as key drivers of genome evolution, contributing to genetic diversity, gene regulation, and species diversification. However, their ability to move within the genome poses a potential threat to genome integrity, promoting the evolution of robust host defense systems such as Krüppel-associated box (KRAB) domain-containing zinc finger proteins (KRAB-ZFPs), the human silencing hub (HUSH) complex, 4.5SH RNAs, and PIWI-interacting RNAs (piRNAs). This ongoing evolutionary arms race between TEs and host defenses continuously reshapes genome architecture and function. This review outlines various host defense mechanisms and explores the dynamic coevolution of TEs and host defenses in animals, highlighting how the defense mechanisms not only safeguard the host genomes but also drive genetic innovation through the arms race.

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引用次数: 0
Empowering continuous evolution of proteins by in vivo mutagenesis.
IF 13.6 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-02-11 DOI: 10.1016/j.tig.2025.01.007
Zhanzhi Liu, Jing Wu

In vivo mutagenesis enriches genetic polymorphism within cells, which is pivotal for triggering continuous evolution. Remarkable strides have been made in this field. Here, we summarize the current in vivo mutagenesis methods focusing on the theme of mutation range and provide an outlook on their future directions, offering inspiration to relevant researchers.

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引用次数: 0
The Genomic Code: the genome instantiates a generative model of the organism.
IF 13.6 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-02-10 DOI: 10.1016/j.tig.2025.01.008
Kevin J Mitchell, Nick Cheney

How does the genome encode the form of the organism? What is the nature of this genomic code? Inspired by recent work in machine learning and neuroscience, we propose that the genome encodes a generative model of the organism. In this scheme, by analogy with variational autoencoders (VAEs), the genome comprises a connectionist network, embodying a compressed space of 'latent variables', with weights that get encoded by the learning algorithm of evolution and decoded through the processes of development. The generative model analogy accounts for the complex, distributed genetic architecture of most traits and the emergent robustness and evolvability of developmental processes, while also offering a conception that lends itself to formalization.

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引用次数: 0
Mitochondrial-derived microproteins: from discovery to function. 线粒体来源的微蛋白:从发现到功能。
IF 13.6 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-02-01 Epub Date: 2024-12-16 DOI: 10.1016/j.tig.2024.11.010
Kelvin Yen, Brendan Miller, Hiroshi Kumagai, Ana Silverstein, Pinchas Cohen

Given the uniqueness of the mitochondria, and the fact that they have their own genome, mitochondrial-derived microproteins (MDPs) are similar to, but different from, nuclear-encoded microproteins. The discovery of an increasing number of microproteins from this organelle and the importance of mitochondria to cellular and organismal health make it a priority to study this novel class of proteins in search of possible therapeutic targets and cures. In this review, we discuss the history of MDP discovery, describe the function of each MDP, and conclude with future goals and techniques to help discover more MDPs.

鉴于线粒体的独特性,以及它们有自己的基因组这一事实,线粒体衍生的微蛋白(MDPs)与核编码的微蛋白相似,但不同。越来越多来自线粒体细胞器的微蛋白的发现,以及线粒体对细胞和机体健康的重要性,使得研究这类新型蛋白质以寻找可能的治疗靶点和治愈方法成为当务之急。在本文中,我们讨论了MDP发现的历史,描述了每个MDP的功能,并总结了未来的目标和技术,以帮助发现更多的MDP。
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引用次数: 0
Exploring the world of small proteins in plant biology and bioengineering. 探索植物生物学和生物工程中的小蛋白质世界。
IF 13.6 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-02-01 Epub Date: 2024-10-14 DOI: 10.1016/j.tig.2024.09.004
Louise Petri, Anne Van Humbeeck, Huanying Niu, Casper Ter Waarbeek, Ashleigh Edwards, Maurizio Junior Chiurazzi, Ylenia Vittozzi, Stephan Wenkel

Small proteins are ubiquitous in all kingdoms of life. MicroProteins, initially characterized as small proteins with protein interaction domains that enable them to interact with larger multidomain proteins, frequently modulate the function of these proteins. The study of these small proteins has contributed to a greater comprehension of protein regulation. In addition to sequence homology, sequence-divergent small proteins have the potential to function as microProtein mimics, binding to structurally related proteins. Moreover, a multitude of other small proteins encoded by short open reading frames (sORFs) and peptides, derived from diverse sources such as long noncoding RNAs (lncRNAs) and miRNAs, contribute to a variety of biological processes. The potential of small proteins is evident, offering promising avenues for bioengineering that could revolutionize crop performance and reduce reliance on agrochemicals in future agriculture.

小蛋白质在生命的各个领域无处不在。微小蛋白质最初被描述为具有蛋白质相互作用结构域的小蛋白质,这些结构域使它们能够与较大的多结构域蛋白质相互作用,并经常调节这些蛋白质的功能。对这些小蛋白的研究有助于加深对蛋白质调控的理解。除了序列同源性外,序列差异小蛋白还有可能作为微蛋白模拟物,与结构相关的蛋白结合。此外,由短开放阅读框(sORFs)和肽编码的大量其他小蛋白,来自长非编码 RNAs(lncRNAs)和 miRNAs 等不同来源,有助于各种生物过程。小蛋白质的潜力显而易见,为生物工程提供了大有可为的途径,可彻底改变作物的性能,减少未来农业对农用化学品的依赖。
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引用次数: 0
Finding functional microproteins. 寻找功能性微蛋白。
IF 13.6 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-02-01 Epub Date: 2025-01-02 DOI: 10.1016/j.tig.2024.12.001
Sikandar Azam, Feiyue Yang, Xuebing Wu

Genome-wide translational profiling has uncovered the synthesis in human cells of thousands of microproteins, a class of proteins traditionally overlooked in functional studies. Although an increasing number of these microproteins have been found to play critical roles in cellular processes, the functional relevance of the majority remains poorly understood. Studying these low-abundance, often unstable proteins is further complicated by the challenge of disentangling their functions from the noncoding roles of the associated DNA, RNA, and the act of translation. This review highlights recent advances in functional genomics that have led to the discovery of >1000 human microproteins required for optimal cell proliferation. Ongoing technological innovations will continue to clarify the roles and mechanisms of microproteins in both normal physiology and disease, potentially opening new avenues for therapeutic exploration.

全基因组翻译分析揭示了人类细胞中数千种微蛋白的合成,这是一类传统上在功能研究中被忽视的蛋白质。尽管越来越多的这些微蛋白被发现在细胞过程中发挥关键作用,但大多数的功能相关性仍然知之甚少。研究这些低丰度、通常不稳定的蛋白质,将其功能与相关DNA、RNA的非编码作用和翻译行为分离开来,这一挑战使研究变得更加复杂。这篇综述强调了功能基因组学的最新进展,这些进展导致发现了最佳细胞增殖所需的1000个人类微蛋白。正在进行的技术创新将继续阐明微蛋白在正常生理和疾病中的作用和机制,可能为治疗探索开辟新的途径。
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引用次数: 0
Cis to trans: small ORF functions emerging through evolution. 从顺式到反式:进化过程中出现的小型 ORF 功能。
IF 13.6 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2025-02-01 Epub Date: 2024-11-27 DOI: 10.1016/j.tig.2024.10.012
Casimiro Baena-Angulo, Ana Isabel Platero, Juan Pablo Couso

Hundreds of thousands of small open reading frames (smORFs) of less than 100 codons exist in every genome, especially in long noncoding RNAs (lncRNAs) and in the 5' leaders of mRNAs. smORFs are often discarded as nonfunctional, but ribosomal profiling (RiboSeq) reveals that thousands are translated, while characterised smORF functions have risen from anecdotal to identifiable trends: smORFs can either have a cis-noncoding regulatory function (involving low translation of nonfunctional peptides) or full coding function mediated by robustly translated peptides, often having cellular and physiological roles as membrane-associated regulators of canonical proteins. The evolutionary context reveals that many smORFs represent new genes emerging de novo from noncoding sequences. We suggest a mechanism for this process, where cis-noncoding smORF functions provide niches for the subsequent evolution of full peptide functions.

每个基因组中,尤其是在长非编码 RNA(lncRNA)和 mRNA 的 5' 首部中,都存在成千上万个密码子少于 100 个的小型开放阅读框(smORF)。smORF 通常被认为是无功能的,但核糖体图谱分析(RiboSeq)显示,成千上万的 smORF 被翻译,而 smORF 的功能特征已从传闻上升为可识别的趋势:smORF 既可以具有顺式非编码调控功能(涉及无功能肽的低翻译),也可以通过强翻译肽介导的完全编码功能,通常作为典型蛋白的膜相关调控因子发挥细胞和生理作用。进化背景显示,许多 smORF 代表了从非编码序列中新出现的新基因。我们为这一过程提出了一种机制,即顺式非编码 smORF 功能为随后完整多肽功能的进化提供了龛位。
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Trends in Genetics
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