德国马克斯·普朗克分子遗传学研究所Daniel M. Ibrahim团队在研究中取得进展。他们提出了具有高度分化序列的调控元件在大进化距离上的保守性。相关论文于2025年5月27日发表于国际顶尖学术期刊《自然—遗传学》杂志上。

小组分析了小鼠和鸡胚胎心脏在相同发育阶段的调控基因组，发现大多数CRE缺乏序列保守性。为了识别位置保守的CRE，课题组研究人员引入了基于同步性的种间点投影算法，该算法比基于对齐的方法识别出多达5倍的同源物。研究人员将位置保守的同源物称为“间接保守的”，并表明它们表现出与序列保守的同源物相似的染色质特征和序列组成，但同源物之间转录因子结合位点发生了更大的重排。最后，该课题组研究人员在小鼠中验证了间接保守的鸡增强子在体内的报告性实验。通过克服基于比对的限制，小组揭示了序列发散CRE广泛的功能守恒性。

据介绍，发育基因表达是一个非常保守的过程，然而大多数顺式调控元件（CRE）缺乏序列保守性，特别是在较大的进化距离上。一些证据表明，相同基因组位置的CRE保持独立于序列保守的功能保守。然而，这种位置守恒的程度仍不清楚。

附：英文原文

Title: Conservation of regulatory elements with highly diverged sequences across large evolutionary distances

Author: Phan, Mai H. Q., Zehnder, Tobias, Puntieri, Fiona, Magg, Andreas, Majchrzycka, Blanka, Antonovi, Milan, Wieler, Hannah, Lo, Bai-Wei, Baranasic, Damir, Lenhard, Boris, Mller, Ferenc, Vingron, Martin, Ibrahim, Daniel M.

Issue&Volume: 2025-05-27

Abstract: Developmental gene expression is a remarkably conserved process, yet most cis-regulatory elements (CREs) lack sequence conservation, especially at larger evolutionary distances. Some evidence suggests that CREs at the same genomic position remain functionally conserved independent of sequence conservation. However, the extent of such positional conservation remains unclear. Here, we profiled the regulatory genome in mouse and chicken embryonic hearts at equivalent developmental stages and found that most CREs lack sequence conservation. To identify positionally conserved CREs, we introduced the synteny-based algorithm interspecies point projection, which identifies up to fivefold more orthologs than alignment-based approaches. We termed positionally conserved orthologs ‘indirectly conserved’ and showed that they exhibited chromatin signatures and sequence composition similar to sequence-conserved CREs but greater shuffling of transcription factor binding sites between orthologs. Finally, we validated indirectly conserved chicken enhancers using in vivo reporter assays in mouse. By overcoming alignment-based limitations, we revealed widespread functional conservation of sequence-divergent CREs.

DOI: 10.1038/s41588-025-02202-5

Source: https://www.nature.com/articles/s41588-025-02202-5