Comparative Genomic Studies on the Evolution of Morphological Complexity

形态复杂性进化的比较基因组研究

• 批准号: 10913904
• 负责人: Andreas Baxevanis
• 金额: $ 104.5万
• 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/10913904
• 关键词: Adenosine; Aging; Ally; Amputation; Animals; Arthropods; Bilateral; Binding; Biological; Biological Models; Biology; Cell Aging; Cells; Chromatin; Chromosomes; Cnidaria; Complex; DNA Transposable Elements; Data; Databases; Development; Developmental Biology; Dioxygenases; Disease; Disease Outbreaks; Elements; Epigenetic Process; Evolution; Genbank; Gene Expression; Gene Family; Generations; Genes; Genetic Transcription; Genome; Genomics; Graft Rejection; Head; Health; Hi-C; Homologous Gene; Human; Human Biology; Human Genome; ITAM; ITIM; Individual; Injury; Invertebrates; Laboratories; Manuscripts; Mediating; Methylation; Mnemiopsis; Modeling; Molecular; Morphology; N-terminal; Natural regeneration; Organism; Orthologous Gene; Pattern; Pattern Formation; Phylogenetic Analysis; Play; Positioning Attribute; Protein Family; Proteins; Publishing; RNA Sequences; Regulatory Element; Reporting; Research; Role; Signal Transduction; Sister; Source; Specific qualifier value; Sting Injury; Structure; System; Techniques; Time; Tissues; Transcript; Transcription Initiation; Transcriptional Regulation; Trees; Untranslated RNA; Visualization; animal tissue; cell type; comparative genomics; data sharing; database structure; experimental study; genome annotation; genome sequencing; genome-wide; genomic data; homeodomain; human disease; innovation; insight; interstitial cell; invertebrate genome; model organism; neurodevelopment; neurogenesis; novel; pluripotency; prevent; programs; scaffold; senescence; sex determination; single cell analysis; stem cell biology; stem cells; tissue regeneration; translational study; whole genome

Genomic sequencing of non-bilaterian animal species has provided invaluable insight into the molecular innovations that have fueled the outbreak of diversity and complexity in the early evolution of animals. The cnidarians are organisms unified in a single phylum based on their use of cnidocytes (stinging cells) for capturing prey and defense from predators, and they occupy a key phylogenetic position as the sister group to bilaterian animals. Cnidarian genomes are remarkably similar to the human genome in terms of gene content and structure, and what makes these organisms particularly attractive for study is our observation that the genomes of cnidarians encode more homologs to human disease genes than do classic invertebrate models (1). We are leading efforts to establish selected cnidarians as new model organisms that have the potential to inform important questions in human biology and human health, laying the groundwork for translational studies focused on specific human diseases. We have sequenced and annotated the genomes of two Hydractinia species: H. echinata and H. symbiolongicarpus (manuscript submitted). What makes these simple organisms particularly well-suited as a model system lies in the fact that they possess a specific type of interstitial cell (an i-cell) that is pluripotent and provides the basis for tissue regeneration, expressing genes whose bilateral homologs are known to be involved in stem cell biology. Hydractinia is also colonial, possessing an allorecognition system that may provide insights into important questions related to host-graft rejection. Our sequencing approach involved performing both PacBio long-read sequencing and Dovetail long-range scaffolding, yielding very high coverage for both genomes; the N50 value of the assembled H. symbiolongicarpus genome make it one of the most contiguous invertebrate genomes sequenced to date. The vast majority of a set of evolutionarily conserved single-copy orthologs can be easily identified in these assemblies, and analyses of these whole-genome sequencing data have already provided important insights into the evolution of chromatin compaction (2) and animal neurogenesis (3). Allorecognition. The availability of our Hydractinia sequence data has enabled us to characterize the genomic structure of the allorecognition complex (ARC) in greater detail, revealing its inherent complexity. The gene family is surprisingly large, containing a total of 41 loci with all but two being located within one of three Alr clusters. Structural studies using Colabfold indicate that the N-terminal domains of these Alr proteins are Ig domains. This is the first time that V-set Ig domains have been identified outside of the Bilateria, indicating that this domain was present in the last common ancestor of cnidarians and humans, over 700 million years ago. Several of these genes also encode for ITAMs and ITIMs, providing evidence that ITAM-mediated signaling may play a key role in invertebrate allorecognition (4). The Hydra Genome. Given the evolutionarily important position of cnidarians as the sister group to the bilaterians, our group has been involved in the Hydra genome sequencing project, an effort that has produced the first chromosome-level genome assembly for H. vulgaris strain AEP, the most common laboratory Hydra strain (5). This assembly has enabled phylogenetic footprinting to reveal conserved cis-regulatory elements and the prediction of functional transcriptional binding motifs. Hi-C experiments have provided evidence of localized contact domains in chromatin that likely influence gene expression; these have different features than the topologically associated domains identified in bilaterians, providing clues as to the evolution of transcriptional regulation in animals. Finally, single-cell analyses identified novel candidate regulators of cell-type-specific transcription that have likely been conserved across two cnidarian clades that diverged over 200 million years ago. Senescence. Cellular senescence has long been thought to be related to aging and disease. During our studies of Hydractinia, we noted that small pieces of tissues from the animals head can regenerate a fully functional individual even though the head does not contain any stem cells that are normally required for regeneration in this animal. Using a variety of techniques, we were able to determine that amputation injury induces senescence in adjacent cells, with these senescent cells emitting a signal that causes the surrounding cells to reprogram to pluripotency. Senescent cells are then expelled from the tissue. Inhibition of senescence prevented cellular reprogramming and regeneration, while ectopic induction of senescence induced stem cells, leading to faster regeneration (6). Additional studies published during the reporting period include the determination that Hydractinia uses an XY sex determination system, the first time that the basis of sex determination has been identified unambiguously in any cnidarian or non-bilaterian species (7). Also, a study aimed at understanding the downstream effects of adenosine methylation showed that randomly incorporated 6mA delays zygotic transcription initiation in Hydractinia and that the dioxygenase Alkbh1 acts as a 6mA 'cleaner', facilitating timely zygotic genome activation (8). Data Sharing: The Hydractinia and Hydra Genome Project Portals. We have developed the Hydractinia Genome Project Portal, located at https://research.nhgri.nih.gov/hydractinia. The scope of data available through the Portal goes well-beyond the sequence data available through GenBank, providing additional biological information intended to increase the utility of the sequencing data generated by our group. It also provides a customized, interactive JBrowse front-end for visualizing assemblies, gene predictions, assembled, transcripts, predicted functional domains, non-coding RNA sequences, and methylation data from both species. The structure of the database parallels that of our Mnemiopsis Genome Project Portal (9), providing access to value-added data that is not available elsewhere, and we have used the same approach in building and maintaining an allied public portal for genomic data from our Hydra genome project studies, located at https://research.nhgri.nih.gov/hydra (5). Identification of Conserved Non-Coding Elements Across the Metazoa. Previous studies of conserved non-coding elements (CNEs) have been rather limited in scope, focusing on comparisons between a small number of species given the sheer amount of computational power needed to perform these analyses at scale. We were able to overcome this computational barrier and systematically explored patterns of CNE conservation across the animal kingdom (manuscript submitted). In addition to the large-scale identification of thousands of CNEs in over 50 genomes, we find that CNEs from cnidarians, molluscs, and arthropods have evolved repeatedly and cluster around the same genes, particularly homeodomain genes and those involved in neural development. We also have shown that transposable elements are a major source of CNEs, strongly suggesting that these elements play a critical role in the evolution of regulatory potential within genomes. (1) Maxwell, E.K. et al. BMC Evolutionary Biology 14: 212, 2014 (2) Torok, A. et al., Epigenetics & Chromatin 9: 36, 2016 (3) Gahan, J.M. et al., Dev. Biol. 428: 224-231, 2017 (4) Huene et al., Proc. Natl. Acad. Sci. USA 119: e2207374119, 2022 (5) Cazet et al., Genome Res. 33: 283-293, 2023 (6) Salinas-Saavedra et al., Cell Rep. 112687, 2023 (7) Chen et al., BMC Biology 21: 32, 2023 (8) Febrimarsa et al., EMBO J. e112934, 2023 (9) Moreland et al., Database 1-9, 2020

对非两侧动物物种的基因组测序，为我们提供了宝贵的见解，让我们了解到在动物早期进化中，分子创新推动了多样性和复杂性的爆发。刺胞动物是统一在一个门的生物，它们利用刺胞细胞（刺细胞）来捕获猎物和防御捕食者，它们作为双边动物的姐妹群占据了关键的系统发育地位。刺胞动物基因组在基因含量和结构方面与人类基因组非常相似，我们观察到与经典无脊椎动物模型相比，刺胞动物基因组编码的与人类疾病基因的同源物更多，这使得这些生物特别具有研究吸引力(1)。我们正在努力建立选定的刺胞动物作为新的模式生物，有可能为人类生物学和人类健康的重要问题提供信息，为特定人类疾病的转化研究奠定基础。

项目成果

SubmiRine: assessing variants in microRNA targets using clinical genomic data sets.

• DOI: 10.1093/nar/gkv256
• 发表时间: 2015-04-30
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Maxwell EK;Campbell JD;Spira A;Baxevanis AD
• 通讯作者: Baxevanis AD

Senescence-induced cellular reprogramming drives cnidarian whole-body regeneration

衰老诱导的细胞重编程驱动刺胞动物全身再生

• DOI: 10.1016/j.celrep.2023.112687
• 发表时间: 2023
• 期刊: Cell Reports
• 影响因子: 8.8
• 作者: Salinas-Saavedra, Miguel;Febrimarsa;Krasovec, Gabriel;Horkan, Helen R.;Baxevanis, Andreas D.;Frank, Uri
• 通讯作者: Frank, Uri

The diversification of the LIM superclass at the base of the metazoa increased subcellular complexity and promoted multicellular specialization.

• DOI: 10.1371/journal.pone.0033261
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Koch BJ;Ryan JF;Baxevanis AD
• 通讯作者: Baxevanis AD

A customized Web portal for the genome of the ctenophore Mnemiopsis leidyi.

栉水母 Mnemiopsis leidyi 基因组的定制门户网站。

• DOI: 10.1186/1471-2164-15-316
• 发表时间: 2014
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Moreland,RTravis;Nguyen,Anh-Dao;Ryan,JosephF;Schnitzler,ChristineE;Koch,BernardJ;Siewert,Katherine;Wolfsberg,TyraG;Baxevanis,AndreasD
• 通讯作者: Baxevanis,AndreasD

Functional studies on the role of Notch signaling in Hydractinia development.

关于Notch信号在Hydractinia发育中的作用的功能研究。

• DOI: 10.1016/j.ydbio.2017.06.006
• 发表时间: 2017-08-01
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: Gahan JM;Schnitzler CE;DuBuc TQ;Doonan LB;Kanska J;Gornik SG;Barreira S;Thompson K;Schiffer P;Baxevanis AD;Frank U
• 通讯作者: Frank U