Establishing the dynamics of lymphoid clonal hematopoiesis and its aging-related disease consequences

项目摘要 随着年龄的增长，分裂细胞获得DNA突变。这些体细胞突变中的一小部分赋予了选择性的 这一优点导致携带体细胞突变的细胞的克隆增殖。在血液中，这个过程是 称为“克隆造血”。这些突变包括癌症驱动基因中的点突变（例如，克隆 不确定潜能“CHIP”的造血）和大碱基规模缺失、重复和拷贝中性 杂合性缺失（例如，嵌合染色体改变，“mCA”）。CHIP和mCA已分别 约5%的60岁以上人群中检测到这种病毒。虽然两者都预测寿命较短，但CHIP导致骨髓偏向 干细胞分化，而mCA导致淋巴偏向干细胞分化。因此，CHIP和 mCAs与感染、心血管疾病、癌症和其他疾病有明显的疾病相关性， 衰老虽然CHIP一直是一个重要的研究活动领域，但我们的知识仍存在多个缺口 mCAs及其对老龄化和人口健康的影响。mCA克隆可以扩展成更大的 血液比例预测更糟糕的健康后果。然而，我们不知道为什么一些mCA克隆 而不是其他的扩展，什么因素预测克隆扩展的速度，以及扩展速度如何关联 疾病的结果。总的来说，我们假设具有较高克隆扩增率的mCA赋予了 对健康的影响更大，而且扩张的倾向具有遗传和环境基础， 是通过基因表达来调节的。解决这一差距的一个障碍是缺乏大量注释良好的 收集的血液样本幸运的是，我们的团队最近取得了两项成就， 我们致力于解决这一差距：1）在67，000个全基因组中调查mCA，2）开发一种新的 计算方法来估计单个时间点的mCA扩增速率。在目标1中，我们 通过利用独特的系列血液样本（间隔长达19年采集）测量mCA扩增率 来自三个深度表型队列的729名mCA患者。在目标2中，我们将改进我们的方法， 克隆扩展速率估计，并将该方法应用于种群规模的mCA克隆扩展估计 在来自几个不同队列的130万人中，我们将确定遗传和环境因素 诱发克隆扩增，并建立mCA克隆扩增和疾病之间的关系。在 目的3，我们将分析原液和单细胞RNA测序，以确定细胞类型特异性生物学影响 并确定导致克隆扩增的途径。我们的多学科团队拥有深厚的专业知识， 计算基因组学、统计学、血液学和人类流行病学在这方面取得了独特的成功。 努力成功实现我们的目标将为风险模型提供信息，以便对具有mCA的个人进行分层， 个性化预防，如干预或加强筛查，并确定新的生物途径， 用于治疗发展的目标。最后，我们的研究作为一个模型，对体细胞镶嵌的见解， 血液以外的其他组织和疾病部位，以支持健康老龄化和改善人口健康。

Project Summary With age, dividing cells acquire DNA mutations. A small number of these somatic mutations confer a selective advantage leading to a clonal proliferation of cells harboring the somatic mutation. In blood, this process is termed ‘clonal hematopoiesis’. These mutations include both point mutations in cancer driver genes (eg. clonal hematopoiesis of indeterminate potential ‘CHIP’) and megabase-scale deletions, duplications and copy-neutral loss-of-heterozygosity (eg, mosaic chromosomal alterations, ‘mCAs’). CHIP and mCAs have each been detected in ~5% of individuals over 60. While both predict shorter lifespans, CHIP leads to a myeloid biased stem cell differentiation while mCAs lead to a lymphoid biased stem cell differentiation. As a result, CHIP and mCAs have distinct disease associations with infection, cardiovascular disease, cancer and other diseases of aging. Although CHIP has been an area of significant research activity, multiple gaps persist in our knowledge of mCAs and their impacts on aging and population health. mCA clones that expand to make up a larger proportion of the blood predict worse health consequences. However, we do not know why some mCA clones but not others expand, what factors predict the rate of clonal expansion and how rate of expansion associates with disease outcomes. Overall, we hypothesize that mCAs with higher rates of clonal expansion confer a greater impact on health and that the propensity to expand has genetic and environmental underpinnings that are mediated through gene expression. A barrier to addressing this gap is a paucity of large well-annotated collections of longitudinally-sampled blood. Fortuitously, our team has two recent accomplishments that enable us to address this gap: 1) a survey of mCAs in 67,000 whole genomes and 2) development of a novel computational method to estimate the rate of mCA expansion from single timepoints. In Aim 1, we will measure the rate of mCA expansion by leveraging unique serial blood samples (collected up to 19 years apart) from 729 individuals with mCAs from three deeply phenotyped cohorts. In Aim 2, we will refine our method for clonal expansion rate estimation and apply this method at population scale to estimate mCA clonal expansion rates in 1.3 million individuals from several diverse cohorts. We will identify genetic and environmental factors predisposing to clonal expansion and establish the relationship between mCA clonal expansion and disease. In Aim 3, we will analyze bulk and single-cell RNA-sequencing to ascertain the cell type specific biological impact of mCAs and identify pathways leading to clonal expansion. Our multidisciplinary team with deep expertise in computational genomics, statistics, hematology and human epidemiology is uniquely poised for success in this effort. Successful execution of our aims will inform risk models to stratify individuals with mCAs for personalized prevention, such as interventions or enhanced screening, and identify new biological pathways to target for therapeutic development. Finally, our study serves as a model for insights on somatic mosaicism in other tissues and disease sites beyond the blood to support healthy aging and improve population health.