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。
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
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.