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: 9152710
• 负责人: Andreas Baxevanis
• 金额: $ 37.56万
• 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/9152710
• 关键词: Address; Animal Model; Animals; Biogenesis; Bioinformatics; Case Study; Cells; Chronic Obstructive Airway Disease; Clinical; Cnidaria; Cohort Studies; Collection; Communities; Ctenophora; Data; Data Analyses; Data Set; Development; Developmental Biology; Disease; Disease Outbreaks; Distant; Evolution; Exhibits; Future; Genbank; Gene Expression Regulation; Generations; Genes; Genome; Genomic approach; Genomics; Goals; Health; Heterogeneity; Homologous Gene; Human; Human Genome; International; Internet; Link; Mammals; Marines; Mesoderm Cell; Methods; MicroRNAs; Mind; Mnemiopsis; Molecular; Neurons; Nuclear Proteins; Nucleotides; Organism; Pattern; Pattern Formation; Phylogenetic Analysis; Play; Porifera; Positioning Attribute; Probability; Protein Family; Proteins; RNA Sequences; Regulation; Relative (related person); Research; Resolution; Role; Sister; Site; Study models; Techniques; Testing; Translating; Trees; Validation; Variant; Vertebrates; Vision; Work; base; cell type; comparative genomics; design; disease phenotype; document outlines; genetic regulatory protein; genetic variant; genome analysis; genome sequencing; genome-wide; genome-wide analysis; human disease; innovation; insight; interest; knowledge base; novel; open source; pluripotency; pressure; programs; protein function; regenerative; stem cell biology; tool; transcriptome sequencing

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. Our group uses a variety of bioinformatic approaches to understand the evolution and function of these proteins and their ultimate role in human disease. Our focus is on the analysis of the genomes of early branching metazoan phyla in an effort to better-understand the relationship between genomic and morphological complexity, as well as the molecular basis for the evolution of novel cell types. Thematically, our current research interests are centered on probing the interface between genomics and developmental biology and conducting comparative, genomics-based research with an evolutionary point of view, themes elucidated in NHGRI's most recent document outlining a vision for the future of genomic research. 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., 2013). By addressing the void in the availability of high-quality, genome-scale sequence data in a critical part of the evolutionary tree, we were able to bring resolution to the question of the phylogenetic position of the ctenophores, with the results of our phylogenomic analyses strongly suggesting that ctenophores are the sister group to all other animals. Based on analyses of gene content, our results also suggest that neural and mesodermal cell types were either lost in Porifera and Placozoa or that (to some extent) these cell types evolved independently in the ctenophore lineage. 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 sequence data generated in the course of this project are available through GenBank, and we continue to add to the collection of additional comprehensive genomic information available through our Mnemiopsis Genome Project Portal (http://research.nhgri.nih.gov/mnemiopsis; Moreland et al., 2014) as new data becomes available. 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 regulatory mechanisms that play a fundamental role in metazoan development. Previously, we demonstrated the vital role that microRNAs play in the regulation of gene expression by analyzing short RNA sequencing data and additional data from the assembled Mnemiopsis genome; in that study, 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). Building on this knowledgebase, we sought to better-understand how genomic variants alter miRNA regulation by modifying miRNA target sites; this question is of particular importance since multiple human disease phenotypes have been linked to such miRNA target site variants (miR-TSVs). However, systematic genome-wide identification of functional miR-TSVs is difficult due to high false positive rates; functional miRNA recognition sequences can be as short as six nucleotides, with the human genome encoding thousands of miRNAs. Furthermore, while large-scale clinical genomic data sets are becoming increasingly commonplace, existing miR-TSV prediction methods are not designed to analyze these data. To fill this gap, we developed and released an open-source tool called SubmiRine that is designed to perform efficient miR-TSV prediction systematically on variants identified in novel clinical genomic data sets (Maxwell et al., 2015). Most importantly, SubmiRine allows for the prioritization of predicted miR-TSVs according to their relative probability of being functional. SubmiRine was tested using integrated clinical genomic data from a large-scale cohort study on chronic obstructive pulmonary disease (COPD), identifying a number of high-scoring, novel miR-TSV predictions. We also demonstrated SubmiRine's ability to predict and prioritize known miR-TSVs that have undergone experimental validation in previous studies. Since non-bilaterians contain a surprisingly high number of human disease gene homologs within their genomes despite their evolutionarily distant position with respect to humans, some of our most recent work has focused on the enticing proposition that these early branching animals be used as 'emerging model organisms' in the context of human disease research. We used a comparative genomics approach encompassing a broad phylogenetic range of animals with sequenced genomes to determine the evolutionary patterns exhibited by human genes associated with different disease classes (Maxwell et al., 2014). Our results support previous claims that most human disease genes are of ancient origin but, more importantly, we also demonstrate that several specific disease classes have a significantly large proportion of genes that emerged relatively recently within the metazoans and/or the vertebrates. An independent assessment of the synonymous to non-synonymous substitution rates of human disease genes found in mammals reveals that disease classes that arose more recently also display unexpected rates of purifying selection between their mammalian and human counterparts. Our results reveal the heterogeneity underlying the evolutionary origins of (and selective pressures on) different classes of human disease genes. For example, some disease gene classes appear to be of uncommonly recent origin (specifically, vertebrate-specific genes) and, as a whole, have been evolving at a faster rate within mammals than the majority of disease classes having more ancient origins. The novel patterns that we have identified may provide new insight into cases where studies using traditional animal models were unable to produce results that translated to humans. Conversely, we note that the larger set of disease classes do have ancient origins, supporting the proposition that non-bilaterian animals have the potential to serve as viable models for studying various important classes of human diseases. Taken together, these findings emphasize why model organism selection should be done on a disease-by-disease basis, with evolutionary profiles in mind. Our current work continues to focus on how these early branching animals can be used in the context of human disease research. We are now leading an international effort to sequence two Hydractinia species. The regenerative abilities of these hydrozoan cnidarians make them excellent models for the study of key questions related to pluripotency, allorecognition, and stem cell biology, work that will be significantly advanced by the availability of high-quality whole-genome sequencing data from these organisms. As with the Mnemiopsis whole-genome sequencing project described above, we intend to create a new Web portal allowing for easy access to sequencing and annotation data generated in the course of this project.

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。我们的小组使用各种生物信息学方法来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。我们的重点是分析早期分支后生动物门的基因组，以更好地理解基因组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，我们当前的研究兴趣集中在探索基因组学和发育生物学之间的接口，并从进化的角度进行基于基因组学的比较研究，NHGRI 最新文件中阐述的主题概述了基因组研究的未来愿景。 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，2013）。通过解决进化树关键部分中高质量、基因组规模序列数据的缺乏，我们能够解决栉水母的系统发育位置问题，我们的系统发育分析结果强烈表明栉水母是所有其他动物的姐妹类群。基于基因内容的分析，我们的结果还表明，神经和中胚层细胞类型要么在多孔动物门和扁动物中丢失，要么（在某种程度上）这些细胞类型在栉水母谱系中独立进化。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。该项目过程中生成的序列数据可通过 GenBank 获取，并且随着新数据的出现，我们将继续通过我们的 Mnemiopsis 基因组项目门户 (http://research.nhgri.nih.gov/mnemiopsis; Moreland et al., 2014) 添加额外的综合基因组信息集合。 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调控机制进化的重要问题。此前，我们通过分析短RNA测序数据和来自组装的Mnemiopsis基因组的附加数据，证明了microRNA在基因表达调控中发挥的重要作用；在那项研究中，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，它们对于典型的 microRNA 生物发生至关重要（Maxwell 等人，2012）。在此知识库的基础上，我们试图更好地了解基因组变异如何通过修改 miRNA 靶位点来改变 miRNA 调控；这个问题特别重要，因为多种人类疾病表型已与此类 miRNA 靶位点变异 (miR-TSV) 相关。然而，由于假阳性率较高，对功能性 miR-TSV 进行系统性全基因组鉴定很困难；功能性 miRNA 识别序列可短至 6 个核苷酸，而人类基因组编码数千个 miRNA。此外，虽然大规模临床基因组数据集变得越来越普遍，但现有的 miR-TSV 预测方法并非旨在分析这些数据。为了填补这一空白，我们开发并发布了一个名为 SubmiRine 的开源工具，该工具旨在对新的临床基因组数据集中发现的变异进行系统有效的 miR-TSV 预测 (Maxwell et al., 2015)。最重要的是，SubmiRine 允许根据预测的 miR-TSV 发挥功能的相对概率对它们进行优先级排序。使用来自慢性阻塞性肺疾病 (COPD) 大规模队列研究的综合临床基因组数据对 SubmiRine 进行了测试，确定了许多高分、新颖的 miR-TSV 预测。我们还证明了 SubmiRine 预测已知 miR-TSV 并对其进行优先排序的能力，这些 miR-TSV 已在之前的研究中经过实验验证。 由于非两侧对称动物的基因组中含有数量惊人的人类疾病基因同源物，尽管它们在进化上与人类相比距离很远，因此我们最近的一些工作集中在一个诱人的主张上，即这些早期分支动物在人类疾病研究中可以用作“新兴模式生物”。我们使用比较基因组学方法，涵盖具有测序基因组的广泛系统发育范围的动物，以确定与不同疾病类别相关的人类基因所表现出的进化模式（Maxwell et al., 2014）。我们的结果支持了之前的观点，即大多数人类疾病基因起源于古老，但更重要的是，我们还证明了几种特定疾病类别具有相当大比例的基因，这些基因是在后生动物和/或脊椎动物中相对较新出现的。对哺乳动物中发现的人类疾病基因的同义与非同义替换率的独立评估表明，最近出现的疾病类别在哺乳动物和人类对应基因之间也显示出意想不到的纯化选择率。我们的结果揭示了不同类别人类疾病基因的进化起源（及其选择压力）背后的异质性。例如，某些疾病基因类别似乎具有罕见的新起源（特别是脊椎动物特异性基因），并且总体而言，在哺乳动物中比大多数具有更古老起源的疾病类别以更快的速度进化。我们发现的新模式可能会为使用传统动物模型的研究无法产生可转化为人类的结果的案例提供新的见解。相反，我们注意到更大的疾病类别确实有古老的起源，这支持了非两侧对称动物有潜力作为研究各种重要人类疾病的可行模型的主张。总而言之，这些发现强调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。 我们目前的工作继续关注如何将这些早期分支动物用于人类疾病研究。我们现在正在领导一项国际努力，对两种水螅属物种进行测序。这些水螅类刺胞动物的再生能力使它们成为研究与多能性、同种异体识别和干细胞生物学相关的关键问题的优秀模型，这些生物体的高质量全基因组测序数据的可用性将显着推进这些工作。与上述 Mnemiopsis 全基因组测序项目一样，我们打算创建一个新的 Web 门户，以便轻松访问该项目过程中生成的测序和注释数据。