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论文标题:Clonal dynamics of haematopoiesis across the human lifespan
作者:Emily Mitchell, Michael Spencer Chapman, Nicholas Williams, Kevin J. Dawson, Nicole Mende, Emily F. Calderbank, Hyunchul Jung, Thomas Mitchell, Tim H. H. Coorens, David H. Spencer, Heather Machado, Henry Lee-Six, Megan Davies, Daniel Hayler, Margarete A. Fabre, Krishnaa Mahbubani, Federico Abascal, Alex Cagan, George S. Vassiliou, Joanna Baxter, Inigo Martincorena, Michael R. Stratton, David G. Kent, Krishna Chatterjee, Kourosh Saeb Parsy, Anthony R. Green, Jyoti Nangalia, Elisa Laurenti, Peter J. Campbell
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期刊:Nature
发表时间:2022/06/01
数字识别码:10.1038/s41586-022-04786-y
摘要: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.
2019年,受此类“联体共生”实验启发,Tony Wyss-Coray团队在Nature medicine发表题为“Undulating changes in human plasma proteome profiles across the lifespan”的研究,再次对人的“血浆蛋白”与“衰老”之间的关系进行了深入探索[2]。通过对4263名年龄在18-95岁的受试者的2925种血浆蛋白轨迹进行相似分组,筛选出了与年龄增长最为相关的蛋白,分析了它们的整体变化趋势。
[1]Villeda SA, Plambeck KE, Middeldorp J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014 Jun;20(6):659-63. doi: 10.1038/nm.3569. Epub 2014 May 4. PMID: 24793238; PMCID: PMC4224436.
[2]Lehallier B, Gate D, Schaum N, et al. Undulating changes in human plasma proteome profiles across the lifespan. Nat Med. 2019 Dec;25(12):1843-1850. doi: 10.1038/s41591-019-0673-2. Epub 2019 Dec 5. PMID: 31806903; PMCID: PMC7062043.
[3]Mitchell E, Spencer Chapman M, Williams N, et al. Clonal dynamics of haematopoiesis across the human lifespan. Nature. 2022 Jun;606(7913):343-350. doi: 10.1038/s41586-022-04786-y. Epub 2022 Jun 1. PMID: 35650442; PMCID: PMC9177428.