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。我的实验室的研究计划借鉴经典的进化理论和群体遗传学，开发新的群体遗传模型，研究突变对个体的体细胞和干细胞进化的影响。此前，我们使用生成的或公共领域的大型群体基因组数据集来估计影响突变累积的参数，例如突变率、选择模型以及作用于单个干细胞群体的选择率。这些将用于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不同突变类型的相互作用。这些模型将使与不同人体组织中体细胞突变积累相关的关键因素的类似参数化成为可能，并通过捕获作用于体细胞突变的有益和有害选择的相互作用，允许对净选择环境对干细胞进化的贡献进行更稳健的评估。** 指的是参与生产细胞血液成分的器官和组织的完整宿主，造血系统是最具再生性和最佳特征的系统之一。造血系统来源于造血干细胞（HSC）群体，其负责每天产生一万亿个细胞。从根本上讲，HSC的特征在于干细胞性;干细胞性是指它们能够1）自我更新，2）不对称分裂以产生多个细胞，3）静止，以及4）在移植时再生组织。由于其独特的自我更新和维持成熟血细胞池的能力，HSC群体必须受到高度调节，并且随着年龄的增长观察到调节的减少，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入的框架，但适用于不同的组织。用于开发进化模型的统计方法将在多个模型生物中具有实用性，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. **