小柯机器人

美国劳伦斯伯克利国家实验室Diane E. Dickel等研究人员合作发现，超保守的增强子功能不需要完美的序列保守。相关论文于2021年3月29日在线发表在《自然—遗传学》杂志上。

研究人员对23种超保守增强子进行了不同程度的诱变，总同引入了1547个突变，并在转基因小鼠报告基因分析中测试了它们的活性。总体而言，研究人员发现超保守增强子的调控特性对突变具有鲁棒性。诱变后，几乎所有（19/23，83％）仍在某个发育阶段起增强子的作用。通过用突变的等位基因替代小鼠中的内源性增强子，研究人员证实了转基因测定的结果，包括超保守增强子对突变的功能适应性。

这些发现表明，超保守增强子的已知活性并不一定需要在进化中观察到的完美保守性，并且表明其他调控或其他功能也对其序列限制有贡献。 

据了解，超保守的增强子序列在人和啮齿动物的基因组之间显示出完美的保守性，表明它们的功能对突变高度敏感。但是，目前的增强子功能模型不足以解释这种极端的进化限制。

附：英文原文

Title: Ultraconserved enhancer function does not require perfect sequence conservation

Author: Valentina Snetkova, Athena R. Ypsilanti, Jennifer A. Akiyama, Brandon J. Mannion, Ingrid Plajzer-Frick, Catherine S. Novak, Anne N. Harrington, Quan T. Pham, Momoe Kato, Yiwen Zhu, Janeth Godoy, Eman Meky, Riana D. Hunter, Marie Shi, Evgeny Z. Kvon, Veena Afzal, Stella Tran, John L. R. Rubenstein, Axel Visel, Len A. Pennacchio, Diane E. Dickel

Issue&Volume: 2021-03-29

Abstract: Ultraconserved enhancer sequences show perfect conservation between human and rodent genomes, suggesting that their functions are highly sensitive to mutation. However, current models of enhancer function do not sufficiently explain this extreme evolutionary constraint. We subjected 23 ultraconserved enhancers to different levels of mutagenesis, collectively introducing 1,547 mutations, and examined their activities in transgenic mouse reporter assays. Overall, we find that the regulatory properties of ultraconserved enhancers are robust to mutation. Upon mutagenesis, nearly all (19/23, 83%) still functioned as enhancers at one developmental stage, as did most of those tested again later in development (5/9, 56%). Replacement of endogenous enhancers with mutated alleles in mice corroborated results of transgenic assays, including the functional resilience of ultraconserved enhancers to mutation. Our findings show that the currently known activities of ultraconserved enhancers do not necessarily require the perfect conservation observed in evolution and suggest that additional regulatory or other functions contribute to their sequence constraint. Mutagenesis of 23 ultraconserved enhancers and examination of their activities in transgenic mouse reporter assays show that overall their regulatory properties are robust to mutation. Manipulation of endogenous loci in mice corroborates reporter assay data.

DOI: 10.1038/s41588-021-00812-3

Source: https://www.nature.com/articles/s41588-021-00812-3

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