人类一生中血液形成的克隆动态
Emily Mitchell1,2,3, Michael Spencer Chapman1, Nicholas Williams1
1Wellcome Sanger Institute, Hinxton, UK.
Nature
|June 1, 2022
概括
由于造血干细胞 (HSC/MPP) 的多样性减少,老年人血液细胞的产量急剧下降. 这种与年龄相关的变化是由对突变的积极选择驱动的, 不仅仅是已知的癌症驱动.
科学领域:
- 血液学
- 基因组学
- 老龄化研究
背景情况:
- 人类血液形成的年龄相关变化导致再生能力下降,细胞衰竭,免疫功能障碍和癌症风险增加.
- 70岁后血液形成功能急剧下降的根本原因尚不清楚.
研究的目的:
- 研究人类血液形成的基因组和克隆动态.
- 了解老年人血液形成功能下降和血液癌症风险增加的原因.
主要方法:
- 从10名人体 (0-81岁) 的单细胞生成细胞群中测序了3,579个基因组.
- 血液构造干细胞或多能基因细胞 (HSC/MPP) 突变积累,端粒长度和克隆多样性的分析.
- 基因组范围内的选择分析和模拟以模型化造血变化.
主要成果:
- 随着年龄的增长,HSC/MPP会积累突变并减少端粒的长度.
- 65岁以下的成年人表现出高克隆多样性的多克隆造血.
- 75岁以上的个体表现出严重减少的克隆多样性,少数克隆占主导地位,通常没有已知的驱动突变.
- 积极选择对许多非同义突变起作用,Y染色体的损失在男性中产生了好处.
结论:
- 快速减少的克隆多样性是人类衰老的普遍特征.
- 在已知癌症驱动因素之外,许多基因的普遍积极选择是与年龄相关的克隆结构转变的基础.
- 模拟支持恒定的干细胞种群和驱动突变解释了老年人观察到的变化.
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