Opioid-coding Genes: Evolution in Lungfish and Amphibians

阿片类药物编码基因：肺鱼和两栖动物的进化

• 批准号: 9810516
• 负责人: Robert Dores
• 金额: $ 35.3万
• 依托单位: University of Denver
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9810516&HistoricalAwards=false
• 关键词: Opioid; coding; Genes; Evolution; Lungfish

PROJECT SUMMARY Robert Dores Gene duplication is a recurring theme in the evolution of vertebrate polypeptide hormones and neuropeptides. These duplication events lead to the formation of gene families in which divergence of function is the usual outcome. In the case of the opioid-coding genes, duplication events have proceeded along two paths: a) an apparent duplication of function (both Proenkephalin and Prodynorphin circuits function as inhibitory networks in the central nervous system); or b) divergence of function as seen in analgesic activity of Proenkephalin and Prodynorphin products, as compared to the heightened pain responsiveness (nociceptic) activity of Pronociceptin products, or the melanocortin (color change and chronic stress regulation) activity of Proopiomelanocortin products. Are these duplication events entirely random, or do they correspond to discrete points of radiation of the vertebrates? This proposal develops the hypothesis that the duplication-driven expansion of the opioid-coding gene family (Proenkephalin, Prodynorphin, Pronociceptin, and Proopiomelanocortin) corresponds to periods when polyploidization (replication of the entire genome) altered the course of vertebrate evolution. To identify these "burst" periods, Dr Dores and colleagues have combined a comparative approach with a molecular approach. The species selected for this analysis (lungfish, urodele amphibians, and a ancient lineage of anuran amphibians) represent lineages that bracketed one of the predicted genome duplication events (the rise of the lobed finned fish and tetrapods in the Devonian). Thus, by taking a comparative approach it is possible to select taxa that fit into a logical phylogenetic hypothesis based on the fossil record. By employing the molecular approach, it is possible to test that hypothesis. In this study, the opioid-coding gene family will be used as a model to analyze how natural selection acts on duplicated genes to alter sequence, and potenti ally alter function. The key to the molecular approach is to focus on an ancestral character common to all members of this gene family - the opioid core sequence YGGF(M/L). By taking this approach, we have already detected genes in ray-finned fish and lobe finned fish (previous period of support) which were previously unsuspected. In addition, novel opioid peptides have been revealed whose opiate agonist potential has not been evaluated. While it is appreciated that none of the taxa used in this study are a "living fossil," by taking a comparative/molecular approach it is possible to reconstruct, through cladistic paradigms (maximum parsimony), the most likely pathways which have lead to the extant opioid-coding genes, and the potential ramifications of these genes with respect to evolution of neuronal circuits in the vertebrate central nervous system.

项目摘要Robert Dores基因复制是脊椎动物多肽激素和神经肽进化中反复出现的主题。这些重复事件导致了基因家族的形成，在这些家族中，功能分化是常见的结果。在阿片编码基因的情况下，复制事件沿着两条途径进行：a)明显的功能复制(前脑啡肽和前强啡肽回路在中枢神经系统中作为抑制网络发挥作用)；或b)功能的差异，如前脑啡肽和前强啡肽产物的止痛活性，与前阿片皮质素产品的高疼痛反应(伤害性)活性，或前阿片黑素皮质素产品的黑素皮质素(颜色变化和慢性应激调节)活性相比。这些复制事件是完全随机的，还是对应于脊椎动物的离散辐射点？这一建议发展了一种假设，即阿片编码基因家族(前脑啡肽原、前强啡肽原、前阿片肽和前阿片黑素皮质素)的复制驱动的扩展对应于多倍化(整个基因组的复制)改变脊椎动物进化过程的时期。为了识别这些“爆发期”，Dores博士和他的同事结合了比较方法和分子方法。选择用于这项分析的物种(肺鱼、尾目两栖动物和无尾两栖动物的古老谱系)代表了与预测的基因组复制事件之一(泥盆纪有裂鳍鱼类和四足动物的兴起)有关的谱系。因此，通过采取比较的方法，有可能选择符合基于化石记录的逻辑系统发育假说的分类群。通过使用分子方法，有可能检验这一假设。在这项研究中，阿片编码基因家族将被用作一个模型来分析自然选择如何作用于复制的基因来改变序列，并潜在地改变功能。分子方法的关键是关注该基因家族所有成员共有的祖先特征--阿片核心序列YGGF(M/L)。通过采取这种方法，我们已经在鱼鳍鱼和叶鳍鱼(之前的支持期)中检测到了以前没有被怀疑的基因。此外，还发现了新的阿片肽，其阿片激动剂的潜力尚未被评估。虽然人们意识到，本研究中使用的分类群都不是“活化石”，但通过采取比较/分子方法，有可能通过分支范例(最简约)重建最有可能导致现存阿片编码基因的途径，以及这些基因在脊椎动物中枢神经系统中神经回路进化方面的潜在分支。