Characterizing evolutionary models driving stem cell and somatic tissue development

人们对驱动干细胞行为的进化因素知之甚少。我实验室的研究项目借鉴经典进化论和群体遗传学，开发新的群体遗传模型，研究突变对个体体细胞和干细胞进化的影响。以前，我们已经使用大量的群体基因组数据集，无论是生成的还是在公共领域中的，来估计影响突变积累的参数，如突变率、选择模型以及作用于单个干细胞群体的选择速率。这些将被用来开发人类干细胞进化的统计模型。我们将考虑克隆有丝分裂系统中出现的不同突变类别的交互作用。这些模型将实现与体细胞突变在不同组织中积累相关的关键因素的相似参数化，并通过捕捉对体细胞突变起作用的有益和有害选择的相互作用，允许更可靠地评估净选择环境对干细胞进化的贡献。*指的是参与生产细胞血液成分的所有器官和组织，造血系统是最具再生性和最具特点的系统之一。造血系统是由一群造血干细胞(HSCs)衍生而来的，这些干细胞负责每天产生一万亿个细胞。从根本上说，造血干细胞的特征是干性；这是指它们1)自我更新，2)不对称分裂产生多个细胞，3)静止，以及4)移植时再生组织的能力。由于其独特的自我更新和维持成熟血细胞库的能力，HSC群体必须受到高度的调控，随着年龄的增长，调节的减少被观察到，最近与不良后果有关。*更好地理解强调干细胞动力学的进化背景将为理解干细胞背景下的发育和衰老提供更深层次的框架，但在不同组织中的应用。用来开发进化模型的统计方法将对多个模式生物有用，并将从根本上提高我们研究时间生长和发育动态的能力。**

Little is understood about the evolutionary factors that drive stem cell behaviour. The research program of my laboratory draws from classic evolutionary theory and population genetics to develop novel population genetic models to study the impact of mutation on an individual's somatic and stem cell evolution. Previously, we have used large population genomic datasets, either generated or in the public domain, to estimate the parameters impacting mutation accumulation such as mutation rate, models of selection as well as rates of selection acting on individual stem cell populations. These will be used to develop statistical models of human stem cell evolution. We will consider the interaction effects of different mutation classes arising in clonal mitotic systems. These models will enable similar parameterization of key factors associated with somatic mutation accumulation in different human tissues and allow for a more robust assessment of the net selective environment contribution to stem cell evolution through capturing the interaction of both beneficial and deleterious selection acting on somatic mutations. ******Referring to the full host of organs and tissues involved in the production of cellular blood components, the hematopoietic system is one of the most highly regenerative and best characterised systems. The hematopoietic system is derived from a population of hematopoietic stem cells (HSCs) which are responsible for the production of one trillion cells per day. Fundamentally, HSCs are characterised by stemness; a quality which refers to their ability to 1) self-renew, 2) asymmetrically divide to produce multiple cells, 3) quiesce, and 4) regenerate tissue when transplanted. Owing to their unique ability to self-renew and maintain the mature blood cell pool, HSC populations have to be highly regulated and reductions in regulation are observed with aging and recently have been associated with adverse outcomes.******A better understanding of the evolutionary context underscoring stem cell dynamics will provide a deeper framework for understanding development and aging in a stem cell context but with application across different tissues. The statistical methods employed to develop evolutionary models will have utility across multiple model organisms and will fundamentally improve our ability to study temporal growth and development dynamics. **