循环染色体揭示了疾病相关变异对基因调节的影响
Ziwei Zhang1,2, Surya B Chhetri1,3,4, Karl Semaan1,3
1Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
bioRxiv : the preprint server for biology
|November 26, 2025
概括
我们使用表观遗传液体活检开发了无细胞色素定量特征位点 (cfcQTLs),以绘制各种组织中对基因调节的遗传影响. 这种方法将DNA变异与1,011种特征和疾病联系起来,包括癌症突变.
科学领域:
- 人类遗传学 人类遗传学
- 表观基因组学是指表观基因组学.
- 癌症生物学 癌症生物学
背景情况:
- 了解调节性DNA的遗传变异如何影响复杂的特征和疾病风险是人类遗传学的关键挑战.
- 染色体定量特征位点 (cQTLs) 有助于识别基因变异对调节元素活性的影响,但很难在相关组织中发现它们.
研究的目的:
- 克服在各种组织和疾病中发现cQTLs的局限性.
- 为了利用表观基因组液体活检进行cQTLs的可扩展识别.
- 研究调控DNA中的遗传变异在复杂特征和疾病风险中的作用.
主要方法:
- 从癌症患者的循环染色体中分析基因组修饰,以确定无细胞染色体QTLs (cfcQTLs).
- 利用血样本从各种非血液学和重新激活的发育受限组织中捕获影响调节元素的cfcQTL.
- 应用一个全囊体关联研究 (CWAS) 来将cfcQTL与特征和疾病联系起来.
主要成果:
- 确定了影响不同非血液组织的调节元素的cfcQTLs,以及在癌症中重新激活的发展受限元素 (16倍丰富).
- 使用CWAS将4,891个cfcQTL与1,011个特征和疾病联系起来.
- 证明,在白细胞中未发现的发育受限cfcQTL与特征相关性明显高 (22.7特征/100 QTL),与WBC受限cQTL (0.58特征/100 QTL) 相比.
- 扩展了该方法,以检测循环染色体中体质TERT促进子突变的激活作用.
结论:
- 表观基因组液体活检使得跨组织,疾病和人群可扩展地发现cQTL.
- cfcQTLs通过捕捉调控变异,为剖析常见疾病的遗传基础提供了强大的工具.
- 这种方法促进了对影响基因调节的生殖线和体质非编码变异的研究.
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