Modelling the age-related deceleration of clonal haematopoiesis in UK Biobank
Modelling the age-related deceleration of clonal haematopoiesis in UK Biobank
复制标题
英国生物银行模拟与年龄相关的克隆造血减速
DOI：
10.1101/2023.12.21.572706
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
MacGregor H
中科院分区：
文献类型：
--
作者：
MacGregor H
在造血干细胞中获得的体细胞突变可以驱动克隆性扩张，这种现象被称为克隆性造血(CH)。CH与血液病、心血管疾病和较低的预期寿命相关，并且与年龄密切相关，在老年人中几乎无处不在。然而，CH的动力学尚不完全清楚，一个准确的健康人克隆扩张的定量模型可以为早期检测策略提供信息。在这里，我们分析了来自400,000名无癌症英国生物库参与者的外显体中常见的CH驱动变异的变异等位基因频率(VAF)分布的年龄相关性。我们发现有证据表明，随着年龄的增长，克隆扩张的速度大大减慢，发生在年轻人身上。这种减速似乎是普遍的：不同的CH热点变体在年轻人和老年人之间的生长速度都显示出∼3倍的下降。我们开发了几个克隆动力学的替代模型，可以解释这种与年龄相关的减速。首先，我们证明了个体间变异适应度的变化(例如，由于遗传易感性)不能产生所需的减速。其次，我们考虑了一个克隆竞争模型，在这个模型中，克隆在生命后期的扩张受到竞争的抑制，而其他扩张的克隆的背景是不可观察的。最后，我们考虑了一个老龄化模型，其中HSC部门随着年龄的增长而放缓。观察到的特定年龄的VAF分布与具有可信参数的老化模型一致。为了进一步询问这些模型，我们考虑了从连续的血液样本中获得的纵向生长率的大量数据集。这些数据表明，HSC分裂速度的普遍放缓在塑造老化血液的遗传多样性方面发挥了关键作用。
Somatic mutations acquired in haematopoietic stem cells can drive clonal expansions, a phenomenon called clonal haematopoiesis (CH). CH has been associated with higher risk of haematological cancer, cardiovascular disease and lower life expectancy and is strongly age-dependent, becoming almost ubiquitous in older adults. However, the dynamics of CH are not yet fully understood, and an accurate quantitative model of clonal expansion in healthy people could inform early detection strategies. Here, we analyse the age-dependence of the variant allele frequency (VAF) distributions of common CH driver variants from the exomes of 400,000 cancer-free UK Biobank participants. We find evidence of a substantial deceleration of clonal expansion with age taking place in younger people. This deceleration appears to be general: different CH hotspot variants all displayed a ∼ 3-fold reduction in growth rate between young and old. We develop several alternative models of clonal dynamics that might explain this age-related deceleration. First we show that variation in fitness of variants among individuals (e.g., due to genetic susceptibility) is unable to produce the required deceleration. Second, we consider a clonal competition model in which clonal expansion in later life is inhibited by competition with an unobserved background of other expanding clones. Finally, we consider an ageing model where HSC division slows down with increasing age. The observed age-specific VAF distributions are consistent with the ageing model with plausible parameters. To further interrogate these models, we consider a large data set of longitudinal growth rates obtained from serial samples of blood. These data suggest that a general slowdown of HSC division rates plays a key role in shaping the genetic diversity of ageing blood.
登录
查看更多内容
血液中镶嵌染色体改变的突变率和适应性后果
DOI：
10.1101/2022.05.07.491016
发表时间：
2022
期刊：
--
影响因子：
--
作者：
Watson C
通讯作者：
Watson C
DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
30.8
作者：
Kar, Siddhartha P.;Quiros, Pedro M.;Gu, Muxin;Jiang, Tao;Mitchell, Jonathan;Langdon, Ryan;Iyer, Vivek;Barcena, Clea;Vijayabaskar, M. S.;Fabre, Margarete A.;Carter, Paul;Petrovski, Slave;Burgess, Stephen;Vassiliou, George S.
通讯作者：
Vassiliou, George S.
影响因子：
20.3
作者：
Hinds, David A.;Barnholt, Kimberly E.;Gotlib, Jason
通讯作者：
Gotlib, Jason
影响因子：
64.8
作者：
通讯作者：
--