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Updated: Jan 7, 2026

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对人类特异性缺失的 cis 和 trans 调节性基因进行映射

Tyler Fair^1,2,3, Bryan J Pavlovic^1,3, Dani Swope^1,3

¹Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.

Nature communications

|December 20, 2025

概括

人类特有的大型缺失 (hDels) 影响细胞增殖和基因表达. 这项研究揭示了它们的分子和细胞作用,强调了两个关键删除的脑特异效应.

科学领域:

进化遗传学的进化遗传学
基因组学就是基因组学.
分子生物学分子生物学

背景情况:

在分子进化过程中,功能序列会丢失.
数以千计的人类特异性删除 (hDels) 存在.
大hDels (≥50个基对) 对细胞过程的影响尚不清楚.

研究的目的:

系统地研究大型人类特异性缺失 (hDels) 对细胞增殖和基因表达在它们原生基因组环境中的功能影响.
确定影响细胞过程的特定hDels,特别是在大脑中.
建立一个研究人类特异性遗传变异的框架.

主要方法:

设计了基因组规模的单指导RNA库,目标是7.2 Mb的6358 hDels.
在黑猩猩多能干细胞中使用CRISPR干扰 (CRISPRi) 查,以识别影响细胞增殖的hDels.
综合色素状态数据和执行单细胞CRISPRi (Perturb-seq) 来映射 cis-和 trans-调节性点基因.

主要成果:

确定了20个hDels,可以显著控制基因表达.
发现两个hDel (hDel_2247和hDel_585) 在大脑中表现出组织特异性活性.
证明大型hDels可以修改细胞增殖和基因调节.

结论:

在人类进化过程中丢失的序列具有重要的分子和细胞功能.
大型hDels在调节基因表达和细胞过程中发挥作用,包括大脑中的特定组织效应.
开发了一个强大的CRISPRi查框架,用于对人类特异性遗传变异的功能性询问.

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