Identification of Genetic and Molecular Bases of Derived Phenotypes in Primate Brain Development

灵长类动物大脑发育中衍生表型的遗传和分子基础的鉴定

• 批准号: 10841947
• 负责人: NENAD SESTAN
• 金额: $ 36.45万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-16 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10841947
• 关键词: ATAC-seq; Affect; Atlases; Automobile Driving; Autopsy; Biological Assay; Biology; Brain; Brain Diseases; CRISPR/Cas technology; Cataloging; Catalogs; Cell Differentiation process; Cell Nucleus; Cells; Cerebral cortex; Chromatin; Coculture Techniques; Cognition; Collection; Complement; Complex; Data; Development; Disease; Electroporation; Epigenetic Process; Episodic memory; Ethics; Evolution; Exhibits; Fetal Development; Fibroblasts; Freezing; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Variation; Genome; Genomics; Gorilla gorilla; Grant; Hominidae; Human; Individual; Knowledge; Language; Macaca; Methods; Molecular; Mus; Neonatal; Neuroanatomy; Nucleotides; Organ; Organoids; Pan Genus; Phenotype; Phylogenetic Analysis; Pongidae; Pongo pygmaeus; Population; Prefrontal Cortex; Primates; Regulatory Element; Reporter; Research; Resources; Single Nucleotide Polymorphism; Social Behavior; Specificity; Surveys; Taxonomy; Thinking; Tissues; Variant; base; cell type; cognitive ability; comparative; epigenetic regulation; epigenomics; experimental study; fetal; functional genomics; genetic variant; genome editing; genome resource; genomic variation; in utero; in vivo; induced pluripotent stem cell; infancy; insertion/deletion mutation; lymphoblastoid cell line; molecular phenotype; mouse model; multimodal data; nanopore; neglect; neurodevelopment; neuropsychiatric disorder; nonhuman primate; rare variant; single cell technology; single nucleus RNA-sequencing; species difference; stem cell model; stem cells; syntax; tool; transcriptome; transcriptomics; whole genome

PROJECT SUMMARY (from original grant) Increasingly persuasive evidence suggests genomic variants driving derived features in humans and among primates are enriched in regulatory elements, but the vast majority of these evolutionarily relevant variants have yet to be discovered or characterized. This is unfortunate, as among the approximately 35 million single nucleotide substitutions (SNPs), 5 million insertions or deletions (indels), and 90 megabases of structural variants where the human and chimpanzee genomes differ are countless variants associated with development, function, or disease. Identifying evolutionarily relevant genetic variants, as well as those implicated in disease or function, can be guided by the analysis of species differences in intermediate molecular phenotypes (e.g., transcriptomic and epigenomic signatures), which are most likely the primary effects determined by genomic variation. In this proposal, we propose to perform primate comparative functional genomics to uncover genetic variants explaining lineage-specific phenotypes affecting the human and non-human primate (NHP) brain, an organ exhibiting pronounced molecular and functional differences between species. To do so, in our first aim we will develop a taxonomy of gene expression and open chromatin across primates, applying single nucleus RNA-seq and single nucleus ATAC-seq to study the mid- fetal and neonatal (late fetal and early infancy) development of the post-mortem human and NHP brain, as well as brain organoid co-cultures containing cells differentiated from multiple primate stem cells and fibroblasts and lymphoblastoid cell lines. In our second aim, we will complement this atlas of species differences in gene expression and open chromatin by cataloguing SNPs, indels, and large, complex structural variants in multiple primate species. This will allow us to differentiate between lineage-specific (i.e., human versus chimpanzee and macaque) and Hominidae-specific (i.e., human and chimpanzee versus macaque) genomic variants. Finally, in our third aim we will integrate and functionally validate, using the Massively Parallel Reporter Assay, CRISPR/Cas9 genome editing, human induced pluripotent stem cells, and mouse models of neural development, key regulatory elements and de novo genes identified through these experiments. Through these aims, we will identify and functionally validate genomic variants and patterns of gene expression and open chromatin potentially driving derived phenotypes in the human and non-human brain and consequently plausibly associated with human cognition, social behaviour, and neuropsychiatric disease.

项目摘要（来自原始赠款） 越来越有说服力的证据表明，基因组变异驱动人类和群体中的衍生特征 灵长类动物富含调控元件，但绝大多数这些与进化相关的变异 尚未被发现或表征。这是不幸的，因为在大约 3500 万单身人士中 核苷酸取代 (SNP)、500 万个插入或缺失 (indel) 以及 90 个兆碱基的结构 人类和黑猩猩基因组不同的变异有无数的变异 发育、功能或疾病。识别进化相关的遗传变异，以及那些 涉及疾病或功能，可以通过中间体的物种差异分析来指导 分子表型（例如转录组和表观基因组特征），这很可能是主要的 由基因组变异决定的效应。在本提案中，我们建议进行灵长类动物比较 功能基因组学揭示遗传变异，解释影响人类的谱系特异性表型 和非人类灵长类动物 (NHP) 大脑，该器官表现出明显的分子和功能差异 物种之间。为此，我们的首要目标是开发基因表达和开放染色质的分类法 在灵长类动物中，应用单核 RNA-seq 和单核 ATAC-seq 研究中期胎儿和 新生儿（胎儿晚期和婴儿早期）死后人类和 NHP 大脑以及大脑的发育 类器官共培养物含有多种灵长类干细胞和成纤维细胞分化的细胞， 淋巴母细胞系。我们的第二个目标是补充这份基因物种差异图谱 通过对多个中的 SNP、插入缺失和大型复杂结构变体进行编目来表达和开放染色质 灵长类物种。这将使我们能够区分谱系特异性（即人类与黑猩猩和 猕猴）和人科动物特异性（即人类和黑猩猩与猕猴）基因组变异。最后，在 我们的第三个目标将使用大规模并行报告分析进行整合和功能验证， CRISPR/Cas9基因组编辑、人类诱导多能干细胞和小鼠神经模型 通过这些实验确定了发育、关键调控元件和从头基因。通过这些 目标，我们将识别和功能验证基因组变异和基因表达模式，并开放 染色质可能驱动人类和非人类大脑中的衍生表型，从而 似乎与人类认知、社会行为和神经精神疾病有关。

项目成果

Primary Feline Tauopathy: Clinical, Morphological, Immunohistochemical, and Genetic Studies.

• DOI: 10.3390/ani13182985
• 发表时间: 2023-09-21
• 期刊: Animals : an open access journal from MDPI

Epigenomic profiling of primate lymphoblastoid cell lines reveals the evolutionary patterns of epigenetic activities in gene regulatory architectures.

灵长类动物淋巴细胞细胞系的表观基因组分析揭示了基因调节结构中表观遗传活性的进化模式。

• DOI: 10.1038/s41467-021-23397-1
• 发表时间: 2021-05-25
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: García-Pérez R;Esteller-Cucala P;Mas G;Lobón I;Di Carlo V;Riera M;Kuhlwilm M;Navarro A;Blancher A;Di Croce L;Gómez-Skarmeta JL;Juan D;Marquès-Bonet T
• 通讯作者: Marquès-Bonet T

Population dynamics and genetic connectivity in recent chimpanzee history.

• DOI: 10.1016/j.xgen.2022.100133
• 发表时间: 2022-06-08
• 期刊: CELL GENOMICS
• 作者: Fontsere, Claudia;Kuhlwilm, Martin;Morcillo-Suarez, Carlos;Alvarez-Estape, Marina;Lester, Jack D.;Gratton, Paolo;Schmidt, Joshua M.;Dieguez, Paula;Aebischer, Thierry;Alvarez-Varona, Paula;Agbor, Anthony;Angedakin, Samuel;Assumang, Alfred K.;Ayimisin, Emmanuel A.;Bailey, Emma;Barubiyo, Donatienne;Bessone, Mattia;Carretero-Alonso, Andrea;Chancellor, Rebecca;Cohen, Heather;Danquah, Emmanuel;Deschner, Tobias;Dunn, Andrew;Dupain, Jef;Egbe, Villard E.;Feliu, Olga;Goedmakers, Annemarie;Granjon, Anne-Celine;Head, Josephine;Hedwig, Daniela;Hermans, Veerle;Hernandez-Aguilar, R. Adriana;Imong, Inaoyom;Jones, Sorrel;Junker, Jessica;Kadam, Parag;Kaiser, Mike;Kambere, Mbangi;Kambale, Magloire V.;Kalan, Ammie K.;Kienast, Ivonne;Kujirakwinja, Deo;Langergraber, Kevin;Lapuente, Juan;Larson, Bradley;Laudisoit, Anne;Lee, Kevin;Llana, Manuel;Llorente, Miquel;Marrocoli, Sergio;Morgan, David;Mulindahabi, Felix;Murai, Mizuki;Neil, Emily;Nicholl, Sonia;Nixon, Stuart;Normand, Emma;Orbell, Chris;Ormsby, Lucy J.;Pacheco, Liliana;Piel, Alex;Riera, Laura;Robbins, Martha M.;Rundus, Aaron;Sanz, Crickette;Sciaky, Lilah;Sommer, Volker;Stewart, Fiona A.;Tagg, Nikki;Tedonzong, Luc Roscelin;Ton, Els;van Schijndel, Joost;Vergnes, Virginie;Wessling, Erin G.;Willie, Jacob;Wittig, Roman M.;Yuh, Yisa G.;Yurkiw, Kyle;Zuberbuehler, Klaus;Hecht, Jochen;Vigilant, Linda;Boesch, Christophe;Andres, Aida M.;Hughes, David A.;Kuhl, Hjalmar S.;Lizano, Esther;Arandjelovic, Mimi;Marques-Bonet, Tomas
• 通讯作者: Marques-Bonet, Tomas

Two hundred and five newly assembled mitogenomes provide mixed evidence for rivers as drivers of speciation for Amazonian primates.

• DOI: 10.1111/mec.16554
• 发表时间: 2022-07
• 期刊: MOLECULAR ECOLOGY
• 影响因子: 4.9
• 作者: Janiak, Mareike C.;Silva, Felipe E.;Beck, Robin M. D.;de Vries, Dorien;Kuderna, Lukas F. K.;Torosin, Nicole S.;Melin, Amanda D.;Marques-Bonet, Tomas;Goodhead, Ian B.;Messias, Mariluce;da Silva, Maria N. F.;Sampaio, Iracilda;Farias, Izeni P.;Rossi, Rogerio;de Melo, Fabiano R.;Valsecchi, Joao;Hrbek, Tomas;Boubli, Jean P.
• 通讯作者: Boubli, Jean P.

A high-quality, long-read genome assembly of the endangered ring-tailed lemur (Lemur catta).

• DOI: 10.1093/gigascience/giac026
• 发表时间: 2022-04-01
• 期刊: GigaScience
• 影响因子: 9.2
• 作者: Palmada-Flores M;Orkin JD;Haase B;Mountcastle J;Bertelsen MF;Fedrigo O;Kuderna LFK;Jarvis ED;Marques-Bonet T
• 通讯作者: Marques-Bonet T