Phylogenomic Studies on the Evolution of Morphological Complexity

形态复杂性演化的系统基因组学研究

• 批准号: 8750667
• 负责人: Andreas Baxevanis
• 金额: $ 37.15万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8750667
• 关键词: Animal Model; Animals; Binding Sites; Biogenesis; Bioinformatics; Bioluminescence; Calcium; Case Study; Cells; Cnidaria; Collection; Communities; Ctenophora; Data; Data Set; Deltastab; Development; Developmental Biology; Disease; Disease Outbreaks; Etiology; Evaluation; Event; Evolution; Explosion; Eye; Family; Future; Genbank; Gene Duplication; Gene Expression Regulation; Gene Family; Generations; Genes; Genetic Variation; Genome; Genomics; Goals; Health; Hereditary Disease; Homeodomain Proteins; Homologous Gene; Human; Human Genetics; Length; Light; Link; Luminescent Proteins; Manuscripts; Marines; Mediating; Mesoderm Cell; Methods; MicroRNAs; Mind; Mnemiopsis; Modeling; Molecular; Neurons; Nuclear Proteins; Opsin; Organism; Pattern Formation; Phylogenetic Analysis; Phylogeny; Play; Porifera; Positioning Attribute; Preparation; Production; Protein Family; Proteins; RNA Sequences; Recording of previous events; Relative (related person); Reporting; Research; Resources; Role; Signal Transduction; Sister; Standardization; Stimulus; Structure; Study models; Techniques; Time; Trees; Vision; Work; base; cell type; comparative genomics; cost effectiveness; document outlines; functional genomics; genome sequencing; homeodomain; human disease; innovation; insight; novel; programs; protein function; protein protein interaction; three dimensional structure; user-friendly

This research program focuses on the use of phylogenetic and comparative genomic techniques to study developmental proteins that play a fundamental role in the specification of body plan, pattern formation, and cell fate determination during metazoan development. A variety of bioinformatic approaches are used to understand the evolution and function of these proteins and their ultimate role in human disease. Building upon our prior work on the origin and early evolution of the Hox genes, our focus has turned to analyzing the genomes of early branching metazoan phyla to better-understand the relationship between genomic complexity and morphological complexity, as well as the molecular basis for the evolution of novel cell types. Thematically, our research program aligns quite well with a significant number of themes elucidated in NHGRIs most recent document outlining a vision for the future of genomic research - most importantly, the need to probe the interface between genomics and developmental biology, as well as to conduct comparative, genomics-based research with an evolutionary point-of-view. Until recently, only three of the four non-bilaterian metazoan lineages (Porifera, Placozoa, and Cnidaria) had at least one species whose genome had been sequenced. Ctenophora (the comb jellies) remained as the last non-bilaterian animal phylum without a sequenced genome, and its phylogenetic position remained uncertain. With the goal of understanding the molecular innovations that drove the outbreak of diversity and increasing complexity in the early evolution of animals, we sequenced, assembled, annotated, and analyzed the 150-megabase genome of the ctenophore, Mnemiopsis leidyi (Ryan et al., submitted). Our sequence assembly is available through GenBank, with additional comprehensive genomic information available through our Mnemiopsis Genome Portal (http://research.nhgri.nih.gov/mnemiopsis). Our phylogenomic analyses of the Mnemiopsis genome strongly suggest that the ctenophores are sister to all other animals. Based on analyses of gene content, our results suggest that neural and mesodermal cell types were either lost in Porifera and Placozoa, or that they evolved independently at least twice. These findings challenge long-held ideas regarding not only the phylogenetic position of the ctenophores, but of the evolution of the aforementioned cell types as well. The availability of these sequence data has already begun to benefit multiple scientific communities (i.e., marine, evolutionary, and developmental biologists) and has enabled us to answer some important questions regarding phylogenetic diversity and the evolution of proteins that play a fundamental role in metazoan development. One such example focuses on the vital role that microRNAs play in the regulation of gene expression. Using short RNA sequencing data and the assembled Mnemiopsis genome, we were able to show that this species appears to lack any recognizable microRNAs, as well as the nuclear proteins Drosha and Pasha, which are critical to canonical microRNA biogenesis. (Maxwell et al., 2012). This finding represents the first reported case of a metazoan lacking a Drosha protein. Since our recent phylogenomic analyses suggest that Mnemiopsis may be the earliest branching metazoan lineage, then these findings provide support for the origins of canonical microRNA biogenesis and microRNA-mediated gene regulation post-dating the last common metazoan ancestor. Alternatively, canonical microRNA functionality may have been lost independently in early lineages, suggesting that microRNA functionality was not critical until much later in metazoan evolution. In either case, these data shed light on a point in evolutionary time that may have predated the need for additional plasticity in developmental signaling networks. Our recent completion of the sequencing of Mnemiopsis has also provided us with the opportunity to examine the genome of an organism that uses calcium-activated photoproteins for bioluminescence. We found two genomic clusters containing a total of at least 10 full-length photoprotein genes that likely arose due to multiple gene duplication events, providing the basis for the first metazoan phylogeny for the photoprotein gene family; the phylogeny indicates that this gene family arose at the base of the Metazoa (Schnitzler et al., 2012). We also were able to demonstrate co-localized expression of photoprotein genes and two putative opsin genes in developing Mnemiopsis photocytes, showing for the first time that these cells have the capacity to both sense and respond to stimuli. This is the first reported instance of photoreception and light production co-occurring and being functionally linked in the same cell of a single organism. These findings may shed new light on the evolution of the eye, especially during the Cambrian explosion. Most recently, we have given significant consideration to how these early branching animals could be used in the context of human disease research. While the standardization of methods for studying human diseases in traditional animal models has yielded many clinically actionable results, it has effectively narrowed the breadth of species in which we choose to look for insights. The recent expansion of whole-genome sequence data available from a diverse array of animal lineages provides an opportunity to investigate the feasibility of using non-traditional model organisms to advance human disease research. Cases in which traditional animal models have led to conclusions that are not applicable to humans are becoming more commonplace, and the concern that this may be a growing problem calls for a re-evaluation of how appropriate models are selected for different disease classes. To that end, we have used a comparative genomics approach that encompasses a wide range of animals across the metazoan tree to determine which organisms could serve as viable models for studying various classes of human diseases (manuscript in preparation). We show that some emerging non-bilaterian model organisms have surprisingly high proportions of human disease gene homologs despite their great evolutionary distance from humans; these organisms may confer advantages as animal models in terms of their ease of use, short generation times and cost-effectiveness. Conversely, while it has been previously shown that the genes implicated in the causation of most human diseases are of ancient origin, our results indicate that some disease classes involve a significantly large proportion of genes that appear to have emerged relatively recently within the Metazoa. These disease classes, having a more recent evolutionary history, may be difficult to replicate phenotypically outside of our closest animal relatives. Taken together, these findings demonstrate why model organism selection should be done on a disease-by-disease basis, with evolutionary profiles in mind. Finally, as an outgrowth of our studies on the homeodomain class of proteins, we have developed and continue to maintain the Homeodomain Resource, a curated collection of sequence, structure, interaction, genomic, and functional information on the homeodomain family (Moreland et al., 2009). The Resource is organized in a compact form and provides user-friendly interfaces for both querying and assembling customized datasets. The current release contains 1,623 full-length homeodomain-containing sequences from 32 distinct organisms, 107 experimentally-derived three-dimensional structures, 101 homeodomain protein-protein interactions, 122 homeodomain binding sites, 53 homeodomain proteins with documented allelic variants, and 186 homeodomain proteins implicated in human genetic disorders. The Homeodomain Resource is freely available at http://research.nhgri.nih.gov/homeodomain/.

该研究项目的重点是利用系统发育和比较基因组技术来研究发育蛋白，这些蛋白在后生动物发育过程中的身体规划、模式形成和细胞命运决定的规范中发挥着基础作用。多种生物信息学方法用于了解这些蛋白质的进化和功能及其在人类疾病中的最终作用。 基于我们之前关于 Hox 基因起源和早期进化的工作，我们的重点转向分析早期分支后生动物门的基因组，以更好地理解基因组复杂性和形态复杂性之间的关系，以及新型细胞类型进化的分子基础。从主题上看，我们的研究计划与 NHGRI 最新文件中阐明的大量主题非常吻合，概述了基因组研究的未来愿景 - 最重要的是，需要探索基因组学和发育生物学之间的接口，以及从进化的角度进行基于基因组学的比较研究。 直到最近，四种非对称动物后生动物谱系（多孔动物门、扁动物门和刺胞动物门）中只有三个至少有一个物种的基因组已被测序。栉水母（栉水母）仍然是最后一个没有基因组测序的非对称动物门，其系统发育位置仍然不确定。为了了解动物早期进化中推动多样性爆发和复杂性增加的分子创新，我们对栉水母 Mnemiopsis leidyi 的 150 兆碱基基因组进行了测序、组装、注释和分析（Ryan 等人提交）。我们的序列组装可通过 GenBank 获得，其他全面的基因组信息可通过我们的 Mnemiopsis 基因组门户 (http://research.nhgri.nih.gov/mnemiopsis) 获得。我们对栉水母基因组的系统发育分析强烈表明，栉水母是所有其他动物的姐妹。根据基因内容分析，我们的结果表明，多孔动物和扁动物中的神经和中胚层细胞类型要么丢失，要么独立进化至少两次。这些发现不仅挑战了长期以来关于栉水母的系统发育位置的观点，而且也挑战了上述细胞类型进化的观点。 这些序列数据的可用性已经开始使多个科学界（即海洋、进化和发育生物学家）受益，并使我们能够回答一些有关系统发育多样性和在后生动物发育中发挥基本作用的蛋白质进化的重要问题。其中一个例子关注的是 microRNA 在基因表达调控中发挥的重要作用。使用短 RNA 测序数据和组装的 Mnemiopsis 基因组，我们能够证明该物种似乎缺乏任何可识别的 microRNA，以及核蛋白 Drosha 和 Pasha，这对典型的 microRNA 生物发生至关重要。 （麦克斯韦等人，2012）。这一发现代表了第一个报告的后生动物缺乏 Drosha 蛋白的病例。由于我们最近的系统发育分析表明 Mnemiopsis 可能是最早分支的后生动物谱系，因此这些发现为经典的 microRNA 生物发生和 microRNA 介导的基因调控的起源提供了支持，这些基因调控可追溯到最后一个常见的后生动物祖先。或者，典型的 microRNA 功能可能在早期谱系中独立丢失，这表明 microRNA 功能直到很晚的后生动物进化中才变得至关重要。无论哪种情况，这些数据都揭示了进化时间中的一个点，该点可能早于发育信号网络中额外可塑性的需要。 我们最近完成的 Mnemiopsis 测序也为我们提供了检查使用钙激活光蛋白进行生物发光的生物体基因组的机会。我们发现了两个基因组簇，总共包含至少 10 个全长发光蛋白基因，这些基因可能是由于多个基因重复事件而产生的，为发光蛋白基因家族的第一个后生动物系统发育提供了基础；系统发育表明该基因家族起源于后生动物的基础（Schnitzler et al., 2012）。我们还能够证明发光蛋白基因和两个假定的视蛋白基因在发育中的 Mnemiopsis 光细胞中的共定位表达，首次表明这些细胞具有感知和响应刺激的能力。这是第一个报道的光接收和光产生在单个生物体的同一细胞中同时发生并在功能上联系在一起的实例。这些发现可能为眼睛的进化提供新的线索，特别是在寒武纪大爆发期间。 最近，我们认真考虑了如何将这些早期分支动物用于人类疾病研究。虽然在传统动物模型中研究人类疾病的方法标准化已经产生了许多临床上可行的结果，但它有效地缩小了我们选择寻找见解的物种范围。最近，来自多种动物谱系的全基因组序列数据的扩展提供了研究使用非传统模型生物体推进人类疾病研究的可行性的机会。传统动物模型得出不适用于人类的结论的情况变得越来越普遍，人们担心这可能是一个日益严重的问题，因此需要重新评估如何为不同的疾病类别选择合适的模型。为此，我们使用了比较基因组学方法，涵盖后生动物树中的各种动物，以确定哪些生物体可以作为研究各类人类疾病的可行模型（手稿正在准备中）。我们发现，一些新兴的非对称动物模式生物尽管与人类的进化距离很远，但其人类疾病基因同源物的比例却惊人地高。这些生物体作为动物模型可能具有易于使用、世代时间短和成本效益方面的优势。相反，虽然之前已经表明与大多数人类疾病病因有关的基因起源于古代，但我们的结果表明，某些疾病类别涉及相当大比例的基因，这些基因似乎是在后生动物中相对较新出现的。这些疾病类别具有更近的进化历史，可能很难在我们最亲近的动物亲戚之外复制表型。总而言之，这些发现证明了为什么模型生物的选择应该在逐个疾病的基础上进行，并考虑到进化概况。 最后，作为我们对同源域类蛋白质研究的成果，我们开发并继续维护同源域资源，这是同源域家族的序列、结构、相互作用、基因组和功能信息的精选集合（Moreland 等，2009）。该资源以紧凑的形式组织，并为查询和组装定制数据集提供用户友好的界面。当前版本包含来自 32 个不同生物体的 1,623 个全长包含同源结构域的序列、107 个实验衍生的三维结构、101 个同源结构域蛋白质-蛋白质相互作用、122 个同源结构域结合位点、53 个具有记录的等位基因变体的同源结构域蛋白以及与人类遗传性疾病有关的 186 个同源结构域蛋白。 Homeodomain 资源可在 http://research.nhgri.nih.gov/homeodomain/ 上免费获取。