一个细胞类型意识框架,用于指定孟德尔调节障碍中的非编码变异.
Arthur S Lee1,2,3,4, Lauren J Ayers1, Michael Kosicki5
1Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA.
medRxiv : the preprint server for health sciences
|January 18, 2024
概括
研究人员开发了一种单细胞多基因框架,以识别先天性头失神障碍 (CCDD) 的非编码变异. 这种方法有助于通过确定影响基因表达的调节因素来诊断罕见的遗传疾病.
科学领域:
- 基因组学和发育生物学:专注于理解神经发育中的基因调节及其在遗传疾病中的作用.
背景情况:
- 许多门德尔乱缺乏可识别的编码变体,这表明涉及非编码区域.
- 先天性头骨神经衰竭障碍 (CCDD) 是一组影响头骨运动神经元发育的孟德尔病.
研究的目的:
- 开发一个单细胞多原子框架,以发现脑运动神经元 (cMN) 中的 cis 调节元件.
- 在基因未解决的CCDD谱系中提名候选非编码变体.
- 建立一种可通用的方法来识别孟德尔乱中的功能性非编码变异.
主要方法:
- 在胚胎小鼠cMNs和相关细胞类型中进行了综合单细胞染色质可访问性,基因变和基因表达测试.
- 产生了大约8.6万个细胞的表观基因组概况,识别了约25万个可访问的调节元素.
- 使用体内转基因记者测定验证了增强剂活性,并将cMN图谱应用于270个未解决的CCDD谱系的全基因组序列.
主要成果:
- 确定了约145,000种假定增强剂,其中75%在体内验证,证实了单细胞可访问性作为增强剂活性的预测指标.
- 从270个CCDD血统中显著减少了899个全基因组序列的变异搜索空间.
- 提名的候选非编码变异调节已知的CCDD基因 (MAFB,PHOX2A,CHN1,EBF3) 和在反复突变增强剂中确定了新的候选者.
结论:
- 该研究提供了与CCDD相关的新型非编码变异发现.
- 介绍了在其他门德尔乱中命名高影响非编码变体的可概括框架.
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