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研究揭示人类终生的造血克隆动态
2022-06-04 23:17
来源：小柯机器人

英国威康桑格研究所Peter J. Campbell等研究人员合作揭示人类终生的造血克隆动态。相关论文于2022年6月1日在线发表在《自然》杂志上。

研究人员对10名0至81岁的人类受试者的单细胞造血细胞群的3,579个基因组进行了测序。造血干细胞或多能祖细胞（HSC/MPP）在出生后平均每年积累17个突变，每年损失30个碱基对的端粒长度。65岁以下的成年人的造血功能是大规模的多克隆的，具有高度的克隆多样性和20,000-200,000个造血干细胞/MPP的稳定群体，均匀地贡献于造血。相比之下，75岁以上的人的造血功能显示出深刻的克隆多样性下降。在每个老年受试者中，30-60%的造血是由12-18个独立的克隆完成的，每个克隆对造血有1-34%的贡献。大多数克隆在受试者40岁之前就开始扩张，但只有22%有已知的驱动突变。
 
全基因组选择分析估计，每34个和每12个非同义突变中就有一个是驱动因素，在整个生命中以恒定的速度累积，影响的基因比血癌中发现的更多。Y染色体的缺失给男性带来了选择性的好处。模拟造血，其干细胞数量不变，且不断获得驱动突变，从而赋予适度的健身效益，这完全解释了老年人的克隆结构的突然变化。迅速减少的克隆多样性是老年人类造血的一个普遍特征，其基础是作用于更多基因的普遍正向选择。
 
据介绍，人类造血功能的年龄变化导致再生能力下降、细胞减少、免疫功能障碍和血癌风险增加，但70岁后功能突然下降的原因仍不清楚。
 
附：英文原文
 
Title: Clonal dynamics of haematopoiesis across the human lifespan

Author: Mitchell, Emily, Spencer Chapman, Michael, Williams, Nicholas, Dawson, Kevin J., Mende, Nicole, Calderbank, Emily F., Jung, Hyunchul, Mitchell, Thomas, Coorens, Tim H. H., Spencer, David H., Machado, Heather, Lee-Six, Henry, Davies, Megan, Hayler, Daniel, Fabre, Margarete A., Mahbubani, Krishnaa, Abascal, Federico, Cagan, Alex, Vassiliou, George S., Baxter, Joanna, Martincorena, Inigo, Stratton, Michael R., Kent, David G., Chatterjee, Krishna, Parsy, Kourosh Saeb, Green, Anthony R., Nangalia, Jyoti, Laurenti, Elisa, Campbell, Peter J.

Issue&Volume: 2022-06-01

Abstract: Age-related change in human haematopoiesis causes reduced regenerative capacity1, cytopenias2, immune dysfunction3 and increased risk of blood cancer4,5,6, but the reason for such abrupt functional decline after 70 years of age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies of haematopoietic cells across 10 human subjects from 0 to 81 years of age. Haematopoietic stem cells or multipotent progenitors (HSC/MPPs) accumulated a mean of 17 mutations per year after birth and lost 30 base pairs per year of telomere length. Haematopoiesis in adults less than 65 years of age was massively polyclonal, with high clonal diversity and a stable population of 20,000–200,000 HSC/MPPs contributing evenly to blood production. By contrast, haematopoiesis in individuals aged over 75 showed profoundly decreased clonal diversity. In each of the older subjects, 30–60% of haematopoiesis was accounted for by 12–18 independent clones, each contributing 1–34% of blood production. Most clones had begun their expansion before the subject was 40 years old, but only 22% had known driver mutations. Genome-wide selection analysis estimated that between 1 in 34 and 1 in 12 non-synonymous mutations were drivers, accruing at constant rates throughout life, affecting more genes than identified in blood cancers. Loss of the Y chromosome conferred selective benefits in males. Simulations of haematopoiesis, with constant stem cell population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure in the elderly. Rapidly decreasing clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently identified.

DOI: 10.1038/s41586-022-04786-y

Source: https://www.nature.com/articles/s41586-022-04786-y

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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