快速进化的人类特异性神经增强因子与衰老相关疾病有关。
Fast-Evolving Human-Specific Neural Enhancers Are Associated with Aging-Related Diseases.
机构信息
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, 100101 Beijing, China.
出版信息
Cell Syst. 2018 May 23;6(5):604-611.e4. doi: 10.1016/j.cels.2018.04.002.
The antagonistic pleiotropy theory hypothesizes that evolutionary adaptations maximizing the fitness in early age increase disease burden after reproduction. This theory remains largely untested at the molecular level. Here, we analyzed enhancer evolution in primates to investigate the relationships between aging-related diseases and enhancers acquired after the human-chimpanzee divergence. We report a 5-fold increased evolutionary rate of enhancers that are activated in neural tissues, leading to fixation of ∼100 human-specific enhancers potentially under adaptation. These enhancers show prognostic expression levels and correlations with driver genes in cancer, and their nearby genes are enriched in known loci associated with aging-related diseases. Using CRISPR/Cas9, we further functionally validated an enhancer on chr8p23.1 as activator counteracting REST, a master regulator known to be a transcriptional suppressor of Alzheimer disease. Our results suggest an evolutionary origin of aging-related diseases: the side effects of human-specific, neural-tissue expressed enhancers. Thus, adaptive molecular changes in human macroevolution may introduce vulnerabilities to disease development in modern populations.
拮抗多效性理论假设，在早期最大限度地提高适应性的进化适应会增加繁殖后的疾病负担。这一理论在分子水平上仍未得到充分验证。在这里，我们分析了灵长类动物的增强子进化，以研究与衰老相关的疾病和人类与黑猩猩分化后获得的增强子之间的关系。我们报告说，在神经组织中起作用的增强子的进化速度增加了 5 倍，导致大约 100 个人类特有的增强子固定下来，这些增强子可能受到了适应性的影响。这些增强子显示出与癌症中驱动基因的预后表达水平和相关性，其附近的基因富集了与衰老相关疾病相关的已知基因座。使用 CRISPR/Cas9，我们进一步对 chr8p23.1 上的一个增强子进行了功能验证，该增强子作为一种激活剂对抗 REST，REST 是一种已知的阿尔茨海默病转录抑制剂的主调控因子。我们的结果表明衰老相关疾病具有进化起源：人类特异性、神经组织表达的增强子的副作用。因此，人类宏观进化中的适应性分子变化可能会给现代人群的疾病发展带来脆弱性。
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