Collaborative Research: The Role of Gene Duplication in the Evolution of Chordate Developmental Regulation

合作研究：基因复制在脊索动物发育调控进化中的作用

• 批准号: 0321470
• 负责人: Frank Ruddle
• 金额: $ 58.5万
• 依托单位: Yale University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0321470&HistoricalAwards=false
• 关键词: Collaborative; Research; Role; Gene; Duplication

0321470RuddleThe interconnection between development and evolution (Devo-Evo) was recognized in the mid-1800's by Darwin and Haeckel, though it has not been until very recently that the mechanistic basis for this crucial link has been readily addressable to experimental biology. In this collaborative project a question concerning the developmental evolution of the vertebrate bauplan is addressed: what are the developmental and evolutionary consequences of gen(om)e duplication during vertebrate phylogeny? It has been known for a long time that the evolution of the vertebrates was associated with a major expansion of genome size, either by gene or genome duplications. The present project focuses on the Hox gene clusters, a complex of genes that encode transcription factors known to be involved in a wide range of biological activities, including the development of the body axis, fins and limbs and many other organs. Vertebrates have the peculiar tendency to duplicate and retain Hox clusters, while no such tendency is apparent in invertebrates. It is not known why vertebrates have this tendency and whether these duplication events had an influence on the evolution of the vertebrate body plan. The goals of this project are to understand the extent and history of Hox cluster duplications among the vertebrates (specifically focusing on the teleosts), and to determine whether such duplications have facilitated evolutionary change both functionally and morphologically. We will use the ray finned fish radiation, in which the most recent Hox cluster duplication has been documented, as our experimental focus. The experimental approach involves: (1) tracing the patterns of molecular evolution of the Hox clusters and their genes, with the aim to determine whether the teleost Hox cluster duplication was coincident with the teleost radiation; (2) using Bacterial Artificial Chromosome technology and computational genomics methods in order to detect changes in the organization of clusters as well as identify changes in the pattern of non-coding sequence conservation; (3) employing BAC-reporter transgenesis as a comparative tool to draw inferences with respect to the effects of gene duplication on expression patterns; and (4) employing statistical tests to both coding and non-coding regions of Hox clusters to draw inferences with regard to the evolutionary forces (selection/drift) acting on duplicated genes and clusters. This investigation represents a part of an ongoing collaboration between three investigators of diverse backgrounds: Frank Ruddle (Yale University) has expertise in mammalian developmental biology, mouse transgenesis and homeobox genes; Gunter Wagner (Yale University) has an extensive background in quantitative-mathematical approaches to evolution and developmental evolution; and Chris Amemiya (formerly Boston University and now at Virginia Mason Research Center) has expertise in vertebrate zoology, genetics, and genomics. Each investigator is focussing on different aspects of the project but with the same overall goals in mind. This consortial approach has proven effective in the past and considerable progress has been made since the previous funding cycle. The broad impact of this proposal is measured in two ways: (1) by employing a highly interdisciplinary and novel approach for evaluating a complex problem in biology; and (2) by providing a wealth of research and educational resources. These training opportunities, including new summer traineeships for teachers and undergraduates of underrepresented minorities.

19世纪中期，达尔文和海克尔认识到了发育和进化之间的相互联系（Devo-Evo），尽管直到最近，这一关键联系的机制基础才被实验生物学所证实。在这个合作项目中，一个关于脊椎动物鲍普兰发育进化的问题得到了解决：什么是基因（om）e复制在脊椎动物生殖发育和进化的后果？长期以来，人们已经知道脊椎动物的进化与基因组大小的重大扩张有关，无论是通过基因还是基因组复制。本项目的重点是Hox基因簇，这是一个编码转录因子的基因复合体，已知转录因子参与广泛的生物活动，包括体轴、鳍和四肢以及许多其他器官的发育。 脊椎动物具有复制和保留Hox簇的特殊倾向，而无脊椎动物中没有这种倾向。目前尚不清楚为什么脊椎动物有这种倾向，以及这些复制事件是否对脊椎动物身体计划的进化产生了影响。该项目的目标是了解脊椎动物中Hox簇复制的程度和历史（特别关注硬骨鱼），并确定这种复制是否促进了功能和形态上的进化变化。我们将使用射线鳍鱼辐射，其中最近的Hox集群复制已被记录，作为我们的实验重点。实验方法包括：（1）追踪Hox簇及其基因的分子进化模式，以确定硬骨鱼Hox簇复制与硬骨鱼辐射是否一致;（2）利用细菌人工染色体技术和计算基因组学方法，以检测集群组织的变化以及识别非-编码序列保守性;（3）采用BAC-报告基因转基因作为比较工具，以推断基因复制对表达模式的影响;以及（4）对Hox簇的编码区和非编码区采用统计检验，以推断作用于复制基因和簇的进化力（选择/漂移）。这项调查是三名不同背景的调查人员正在进行的合作的一部分：（耶鲁大学）在哺乳动物发育生物学、小鼠转基因和同源盒基因方面具有专长;冈特瓦格纳（耶鲁大学）在进化和发展进化的定量数学方法方面有广泛的背景; Chris Amemiya（原波士顿大学，现就职于弗吉尼亚梅森研究中心）在脊椎动物学、遗传学和基因组学方面具有专长。 每个调查员都专注于项目的不同方面，但心中有着相同的总体目标。 这种联合体办法过去证明是有效的，自上一个供资周期以来取得了相当大的进展。 这一建议的广泛影响可以从两个方面来衡量：（1）采用高度跨学科和新颖的方法来评估生物学中的复杂问题;（2）提供丰富的研究和教育资源。 这些培训机会，包括为代表性不足的少数族裔的教师和本科生提供新的夏季培训。