Using directed evolution to study the origins of multicellular development.

利用定向进化研究多细胞发育的起源。

• 批准号: 10027973
• 负责人: William Croft Ratcliff
• 金额: $ 38.45万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10027973
• 关键词: 3-Dimensional; Age; Behavior; Biological Models; Biophysics; Cells; Communicable Diseases; Complex; Data; Development; Developmental Biology; Directed Molecular Evolution; Disease; Evolution; Extinction (Psychology); Gene Expression; Generations; Knowledge; Location; Malignant Neoplasms; Mechanics; Microbial Biofilms; Modeling; Molecular Chaperones; Organism; Pattern; Proteins; Research; Structure; Work; Yeast Model System; Yeasts; cell age; cell behavior; cell type; insight; laboratory experiment; novel; programs; simulation; tumorigenesis

ABSTRACT Little is known about how novel multicellular developmental programs arise in evolution, largely because multicellularity arose deep in the past and early steps have been lost to extinction. The PI has circumvented this constraint by creating a new model system, using directed evolution to directly study the origin of multicellularity and development. The proposed research will help resolve two major knowledge gaps in the field of developmental biology: 1) How does development evolve de novo? 2) What are the long-term evolutionary consequences of development? After thousands of generations of directed evolution, the PI has observed the evolution of autonomous cell type specification in snowflake yeast, his model system of early multicellularity. Specifically, snowflake yeast form multicellular groups that are far more mechanically tough by adaptively differentiating into two cell types, in which cells deep in the cluster interior change their budding angle by 90 degrees and interlock neighboring cellular branches. In this model system (and in most simple multicellular organisms), a cell’s age provides key information about its location, allowing temporal changes in gene expression to drive spatial patterns of cellular differentiation. Preliminary data suggests that the chaperone protein Hsp90 has been co-opted to act as an age (and thus location)-dependent developmental switch, regulating the transition between cell types. The proposed research will further examine the evolution of this novel developmental mechanism, and will contextualize these wet-lab experiments with both 3D biophysical simulations and evolutionary models, allowing the PI to derive general principles from these experimental results. The proposed research will also examine how stochastic cellular behaviors can be co-opted for symmetry breaking, allowing snowflake yeast to evolve more complex multicellular structures. Finally, the proposed research will examine the evolutionary consequences of development: namely, how cellular differentiation can entrench a lineage into a multicellular state. This work will examine how cellular differentiation strips cells of their evolutionary autonomy by limiting the potential for reversion to unicellularity. Development would thus have a doubly-profound impact on an organism’s evolutionary dynamics: opening new avenues for increased multicellular complexity while closing off opportunities for ancestral, unicellular behaviors.

摘要 关于新的多细胞发育程序是如何在进化中出现的，人们知之甚少，主要是因为 多细胞生物在过去很久就出现了，早期的步骤已经灭绝了。私家侦探绕过了这一点 通过建立一个新的模型系统，利用定向进化直接研究多细胞生物的起源 发展先行者的要求拟议的研究将有助于解决该领域的两个主要知识差距， 发育生物学：1）发育是如何从头进化的？2)什么是长期的进化 发展的后果？经过数千代的定向进化，PI观察到， 雪花酵母中自主细胞类型规范的进化，他的早期多细胞模型系统。 具体来说，雪花酵母形成多细胞群体，这些群体通过适应性的方式在机械上更加坚韧。 分化成两种细胞类型，其中细胞群内部深处的细胞将其出芽角度改变90 度和联锁相邻的细胞分支。在这个模型系统中（以及在大多数简单的多细胞系统中）， 细胞的年龄提供了关于其位置的关键信息，允许基因的时间变化， 表达以驱动细胞分化的空间模式。初步数据显示， 蛋白Hsp90已被增选作为年龄（和因此位置）依赖性发育开关， 调节细胞类型之间的转换。拟议的研究将进一步研究这一演变 新的发展机制，并将这些湿实验室实验与三维生物物理 模拟和进化模型，允许PI从这些实验中推导出一般原则 结果拟议的研究还将研究如何随机细胞行为可以增选对称性 使雪花酵母进化出更复杂的多细胞结构。最后，建议 研究将检查发育的进化后果：即细胞分化如何 将一个谱系巩固为多细胞状态。这项工作将研究细胞分化如何剥夺细胞的 通过限制逆转为单细胞生物的可能性来限制它们的进化自主性。因此，发展将 对生物体的进化动力学有双重深远的影响：为增加 多细胞复杂性，同时关闭了祖先的单细胞行为的机会。