Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA.
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Nat Commun. 2024 Nov 26;15(1):10268. doi: 10.1038/s41467-024-54711-2.
Clonal hematopoiesis becomes increasingly common with age, but its cause is enigmatic because driver mutations are often absent. Serial observations infer weak selection indicating variants are acquired much earlier in life with unexplained initial growth spurts. Here we use fluctuating CpG methylation as a lineage marker to track stem cell clonal dynamics of hematopoiesis. We show, via the shared prenatal circulation of monozygotic twins, that weak selection conferred by stem cell variation created before birth can reliably yield clonal hematopoiesis later in life. Theory indicates weak selection will lead to dominance given enough time and large enough population sizes. Human hematopoiesis satisfies both these conditions. Stochastic loss of weakly selected variants is naturally prevented by the expansion of stem cell lineages during development. The dominance of stem cell clones created before birth is supported by blood fluctuating CpG methylation patterns that exhibit low correlation between unrelated individuals but are highly correlated between many elderly monozygotic twins. Therefore, clonal hematopoiesis driven by weak selection in later life appears to reflect variation created before birth.
克隆性造血随着年龄的增长变得越来越普遍，但由于驱动突变通常不存在，其原因仍然是个谜。连续观察推断出弱选择，表明变体在生命早期很早就获得了，并且最初的生长突增没有得到解释。在这里，我们使用波动的 CpG 甲基化作为谱系标记来跟踪造血干细胞的克隆动力学。我们通过同卵双胞胎的共享产前循环表明，出生前由干细胞变异赋予的弱选择可以可靠地在以后的生活中产生克隆性造血。理论表明，只要有足够的时间和足够大的种群规模，弱选择就会导致优势。人类造血满足这两个条件。在发育过程中，干细胞谱系的扩张自然会防止弱选择变体的随机丢失。出生前创造的干细胞克隆的优势得到了血液波动的 CpG 甲基化模式的支持，这些模式在无关个体之间相关性较低，但在许多老年同卵双胞胎之间相关性很高。因此，由晚年弱选择驱动的克隆性造血似乎反映了出生前的变异。
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