Evolution of the insulin superfamily in teleosts: diversification, sub-functionalization and role in euryhaline adaptation

硬骨鱼胰岛素超家族的进化：多样化、亚功能化和广盐适应中的作用

• 批准号: RGPIN-2014-06203
• 负责人: Good, Sara
• 金额: $ 1.75万
• 依托单位: University of Winnipeg
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=679711
• 关键词: Evolution; insulin; superfamily; teleosts; diversification

There has been phenomenal progress in our understanding of vertebrate genome evolution and its profound impact on the emergence of diverse arrays of gene families in modern day vertebrates. One of these findings is that the diversification of vertebrate gene families has been strongly influenced by whole genome duplication (WGD) events, one of which occurred early in ray-finned fish evolution. Some classes of genes were preferentially retained during these WGD events, such as transmembrane receptors and other signalling molecules; it is thought that duplication of gene networks involved in signalling pathways opened up opportunities for the development of complex physiological and neurological responses to environmental cues, a hallmark of vertebrate organisms. In my research program, we are investigating the evolutionary and functional mechanisms driving the diversification of 2 sub-classes of insulin superfamily hormone-receptor signalling systems: 1) relaxin-like peptides (including RLN and insulin like peptides, INSL) and 2) insulin (INS) and insulin-like growth factors (IGF), and their cognate receptors in non-mammalian vertebrates, primarily teleosts. In previous work we showed that all of the ligands and receptors in the insulin superfamily were greatly diversified by WGD events and furthermore that fish retained a large number of the genes derived from the fish-specific WGD. Additionally, we uncovered that fish have greatly amplified the number of receptor compared to ligand (hormone) genes suggesting that ligand-receptor pairs may adopt new or specialized functions because receptors differ in their temporal (stage) or spatial (tissue) expression or in the signalling responses they elicit. In this proposal, we outline three major research projects on the insulin superfamily. In the first project, we focus on pinpointing the specific ligand-receptor pairings and functional diversification of a diverse subgroup of Rln/Insl peptides putatively involved in neuroendocrine regulation. In the second project, we propose a full evolutionary analyses of INS/IGF and their receptors in teleosts. Surprisingly, although INS/IGF genes have been well studied in mammals due to their application in health sciences, the evolutionary relationship, origin and diversity of INS/IGF and receptor genes in teleosts is not well understood, which limits functional studies. Understanding this evolutionary framework is fundamental to completing our third project, in which we propose to perform the first population-level analyses of insulin superfamily genes in a non-mammalian species to test hypotheses about the role of selection on insulin superfamily genes during fresh-water (FW) adaptation in stickleback. Several members of the insulin superfamily are hypothesized to play direct roles in salt water (SW) to FW adaptation because of their hypothesized roles in osmoregulation while other members of the family may influence SW/FW adaptation indirectly via physiological changes that occur in growth and reproduction in SW vs FW environments. Collectively, these projects will contribute fundamental knowledge regarding genome evolution and regulation in teleosts, particularly the process of sub-functionalization of ligand-receptor systems at the levels of species and populations, long-term research themes in our laboratory. Secondly, projects 2 and 3 will also provide fundamental knowledge regarding the evolution and function of insulin superfamily genes in teleosts, in particular their role in adaptation between SW and FW, a process that is relevant and important for all anadromous or euryhaline teleost species, including several economically important fisheries species for Canada.

在我们对脊椎动物基因组进化及其对现代脊椎动物不同基因家族阵列出现的深刻影响方面，我们已经取得了惊人的进展。这些发现之一是脊椎动物基因家族的多样性受到全基因组复制(WGD)事件的强烈影响，其中之一发生在鳍鱼进化的早期。在这些WGD事件中，某些类别的基因被优先保留，如跨膜受体和其他信号分子；人们认为，信号通路中涉及的基因网络的复制为发展对环境线索的复杂生理和神经反应打开了机会，这是脊椎动物的一个特征。在我的研究计划中，我们正在研究推动胰岛素超家族激素受体信号系统多样化的两个亚类的进化和功能机制：1)松弛素样多肽(包括RLN和胰岛素样多肽，INSL)和2)非哺乳动物脊椎动物(主要是硬骨鱼)中的胰岛素(Ins)和胰岛素样生长因子(IGF)及其同源受体。在以前的工作中，我们发现胰岛素超家族中的所有配体和受体都因WGD事件而发生了极大的变化，而且鱼类保留了大量来自鱼类特有的WGD的基因。此外，我们发现，与配体(激素)基因相比，FISH大大扩大了受体的数量，这表明配体-受体对可能采用新的或专门的功能，因为受体在时间(阶段)或空间(组织)表达或在它们引发的信号反应方面不同。在这个提案中，我们概述了关于胰岛素超家族的三个主要研究项目。在第一个项目中，我们专注于定位与神经内分泌调节有关的RLN/Ins1多肽的不同亚群的特定配体-受体配对和功能多样化。在第二个项目中，我们对硬骨鱼中的INS/IGF及其受体进行了全面的进化分析。令人惊讶的是，尽管INS/IGF基因在哺乳动物中的应用已经在健康科学中得到了很好的研究，但硬骨鱼中INS/IGF基因和受体基因的进化关系、起源和多样性还不是很清楚，这限制了功能研究。理解这个进化框架是完成我们的第三个项目的基础，在我们的第三个项目中，我们提议对非哺乳动物物种中的胰岛素超家族基因进行第一次种群水平的分析，以测试关于胰岛素超家族基因在刺鱼淡水适应(FW)过程中的选择作用的假设。胰岛素超家族中的几个成员被认为在盐水对FW的适应中起直接作用，因为他们在渗透调节中的假设作用，而该家族的其他成员可能通过在SWVFW环境中发生的生长和生殖的生理变化间接影响SW/FW的适应。总的来说，这些项目将贡献关于硬骨鱼基因组进化和调控的基础知识，特别是在物种和种群水平上配体-受体系统的亚功能化过程，这是我们实验室的长期研究主题。其次，项目2和3还将提供关于硬骨鱼中胰岛素超家族基因的进化和功能的基本知识，特别是它们在西南和FW之间适应中的作用，这一过程对所有淡水型或泛盐碱型硬骨鱼物种都是相关和重要的，包括几个对加拿大具有重要经济意义的渔业物种。