Core Viewpoint - The article discusses the significance of synonymous mutations, traditionally considered "silent," in influencing phenotypic traits through epitranscriptomic regulation, particularly in cucumber domestication [4][11][13]. Group 1: Research Findings - A study published in the journal Cell demonstrates that synonymous mutations can regulate important traits in cucumber by altering m6A modifications and mRNA structural conformations [4][11]. - The specific synonymous mutation identified is 1287C>T in the ACS2 gene, which affects m6A modification and RNA structure, leading to changes in cucumber fruit length [9][11]. - The research provides a complete molecular evidence chain showing how synonymous mutations can influence complex traits, challenging the traditional view of these mutations as harmless [11][13]. Group 2: Mechanisms and Implications - The study reveals a dual mechanism by which synonymous mutations affect gene expression and protein synthesis efficiency: by disrupting m6A modifications and altering RNA structure [13]. - This research enhances the understanding of the molecular basis of crop domestication and suggests new strategies for crop improvement through precise editing, such as designing synonymous mutations [13][14]. - The findings have broader implications for understanding the relationship between synonymous mutations and diseases or phenotypes in other organisms, including humans [14].

Core Insights - The article highlights significant research advancements published in the journal Cell, with a focus on studies led by Chinese scholars, covering topics such as organoid development, vascular dementia mechanisms, autoimmune disease treatments, and the role of synonymous mutations in cucumber domestication [2][4][8][12][17]. Group 1: Highly Vascularized Lung and Gut Organoids - A collaborative study from Cincinnati Children's Hospital and UCLA successfully constructed highly vascularized lung and gut organoids using human induced pluripotent stem cells (iPSCs), providing a platform for studying organ development and disease [4]. Group 2: Mechanisms of Vascular Dementia Repair - Research from UCLA identified key signaling pathways involved in brain repair for vascular dementia, specifically the CD39-A3AR pathway, and demonstrated that the A3AR agonist Piclidenoson could promote brain tissue repair and restore memory and gait functions [8]. Group 3: LAG-3/TCR Dual Antibody for Autoimmune Diseases - A study from NYU and Chinese institutions revealed a novel mechanism of LAG-3 receptor activation, which could lead to the development of dual-specific T cell inhibitory antibodies targeting LAG-3 and TCR, offering new therapeutic avenues for autoimmune diseases [12][13]. Group 4: Synonymous Mutations in Cucumber Domestication - Research from the Chinese Academy of Agricultural Sciences demonstrated that synonymous mutations can regulate important traits in cucumber domestication through epitranscriptomic mechanisms, challenging traditional views and suggesting new strategies for crop improvement [17].

Core Viewpoint - The article discusses the significance of synonymous mutations in genetic research, particularly their role in cucumber domestication through epitranscriptomic regulation, challenging traditional views on these mutations [2][3]. Group 1: Research Findings - The study published in the journal Cell demonstrates that synonymous mutations can regulate important traits in cucumber by altering m6A modifications and mRNA structural conformations [2][3]. - The research identifies two closely linked genes, YTH1 and ACS2, that interact epistatically to influence cucumber fruit length [5][9]. - A specific synonymous mutation, 1287C>T in the ACS2 gene, is identified as a pathogenic mutation that disrupts m6A methylation and alters RNA structure, leading to changes in fruit length [6][9]. Group 2: Genetic Mechanisms - The YTH1 gene encodes an m6A reader protein, while the ACS2 gene encodes a rate-limiting enzyme for ethylene synthesis in plants, both of which are crucial for cucumber domestication [5][9]. - The study reveals that the wild-type cucumber's ACS2 1287C leads to m6A modification and a loose RNA structure, while the cultivated cucumber's ACS2 1287T results in a compact RNA structure, affecting protein levels and fruit length [6][9].

Core Viewpoint - The article discusses the emerging understanding of synonymous mutations in human cells, challenging the traditional view of these mutations as neutral and highlighting their potential impact on cellular adaptability and disease [2][5][6]. Group 1: Research Background - A study by a team from the University of Michigan suggested that synonymous mutations in yeast may not be neutral and could affect cellular adaptability, reigniting interest in their biological effects [1]. - Previous research has linked a small number of synonymous mutations to human diseases, indicating their potential role as cancer drivers, but experimental confirmation remains limited [6]. Group 2: New Research Findings - A new study published by researchers from Peking University developed a high-throughput screening technology named PRESENT to investigate functional synonymous mutations in the human genome [4]. - The research utilized an advanced prime editing system (PEmax) to create a library targeting 3,644 human protein-coding genes, allowing for large-scale screening of synonymous mutations [7]. Group 3: Methodology and Tools - The study integrated single-cell screening methods with the PRESENT technology, termed DIRECTED-seq, to systematically evaluate the impact of identified synonymous mutations on gene expression [8]. - A specialized machine learning model called DS Finder was developed to analyze the effects of functional synonymous mutations on various biological processes, such as mRNA splicing and transcription [9][11]. Group 4: Key Findings - The research indicated that synonymous mutations exhibit different fitness effects compared to non-synonymous mutations, although their phenotypic distribution was similar to negative controls [9]. - The study identified that synonymous mutations could alter RNA folding and affect translation, with PLK1_S2 being a notable example, and combined screening data with predictive models to identify clinically relevant synonymous mutations [9].