EDGE CMT: Genomic characterization of mammalian adaptation to frugivory

EDGE CMT：哺乳动物适应果食的基因组特征

• 批准号: 10551234
• 负责人: Nadav Ahituv
• 金额: $ 47.22万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-14 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551234
• 关键词: ATAC-seq; Acceleration; Alleles; Area; Bioinformatics; Biological Assay; Candidate Disease Gene; Cell Line; Cells; ChIP-seq; Chiroptera; Collaborations; Comparative Biology; Comparative Genomic Analysis; Complex; Diabetes Mellitus; Diet; Discipline; Disease; Eating; Ecology; Educational process of instructing; Endocrine; Engineering; Environment; Ethnic Population; Evolution; Fasting; Festival; Fruit; Funding; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Engineering; Genome; Genomics; Genotype; Health education; High School Student; Human; In Vitro; Insecta; Internships; Kidney; Laboratories; Learning; Learning Module; Liver; Mammals; Mentorship; Metabolic; Metabolic Diseases; Modeling; Molecular; Molecular Evolution; Morphology; Mus; Pancreas; Persons; Phenotype; Positioning Attribute; Primates; Proteins; RNA; Reagent; Regulator Genes; Regulatory Element; Regulatory Pathway; Reporter; Research; Resources; San Francisco; Schools; Science; Scientist; Skeletal Muscle; Small Intestines; Students; Techniques; Technology; Testing; Thick; Time; Tissues; Training; Universities; Validation; Variant; Work; career; cell type; comparative genomics; cost; design; diabetes risk; dietary; epigenomics; functional genomics; functional outcomes; genome analysis; human disease; improved; interest; kidney medulla; member; mouse genetics; outreach; science education; single-cell RNA sequencing; sugar; therapeutic development; trait; transcriptome sequencing; transcriptomics; undergraduate student

PROJECT SUMMARY Overview: A comprehensive molecular understanding of how mammals ascertain complex traits to adapt to specific environments remains largely unknown. Here, we will take advantage of comparative and functional genomics to systematically dissect dietary adaptation in mammals using frugivory as a model. Mammals evolved from a common dietary ancestor to have an extremely broad range of diets. Amongst these, frugivorous adaptation is of particular significance, as fruit-eating arose in multiple lineages within primate and bat orders. Frugivorous adaptation is also of general interest as diets rich in sugar increase risk for diabetes and metabolic disease in many mammals, including humans. Conversely, frugivorous primates and bats can eat large quantities of fruit/sugar without apparent disease consequences. Supported by recent advances in genome availability and genomic technologies, we plan to take a systematic approach to uncover frugivorous molecular factors by: 1) carrying out comparative genomic analyses of primates and bats to identify sequences that were specifically accelerated in frugivorous species combined with a wide-range of genomic techniques, including RNA-seq, ATAC-seq, ChIP-seq and combined single-cell RNA-seq and ATAC-seq on metabolically pertinent insect and fruit bat tissues; and 2) functionally validate frugivory-associated sequences using cell-based gene assays, massively parallel reporter assays (MPRAs) and swapping these sequences into mice. Our work will comprehensively identify the molecular components leading to frugivory and functionally characterize the genes, regulatory elements and pathways involved in this complex trait. Intellectual Merit: As bats and primates encompass broad dietary ranges, and the evolutionary distances within each order are sufficiently small, they offer ideal models for comparison within each group and between groups to analyze the genetic determinants of dietary specializations. In addition, the use of mouse genetic engineering can allow for functional validation of genetic candidates. We plan to not only identify protein changes that lead to phenotypic differences but also gene regulatory elements that have been shown to be important drivers of morphological change and the evolution of new traits. We have all the needed reagents in place to carry out this project, including necessary bat and primate genomes as well as tissues from both insectivorous and frugivorous bats, fasted and treated or untreated with fruit, and phenotypically relevant bat and primate cell lines for MPRA. Importantly, we have all the needed expertise in our lab, routinely carrying out comparative and functional genomic assays, MPRAs and mouse engineering. With our resources and proficiency, we are in the apt position to advance understanding of the complex trait that is frugivory and ultimately genotype-phenotype relationships. Broader Impacts: This research will improve genotype-phenotype predictions with regards to diet and environment and genetic factors elucidated here have the potential to assist therapeutic developments for people with metabolic diseases like diabetes. Thus, this work will have broad-ranging impacts across disciplines of comparative biology, gene expression, bioinformatics, molecular ecology, molecular evolution and human disease. We already have numerous collaborations with several scientists established from this project, which are discussed in further detail in the project description. PI Ahituv and members of his lab working on this project will contribute to the design of teaching modules from this work. This includes teaching both at UCSF in graduate courses and at San Francisco State University (SFSU) both in undergraduate and graduate courses, where PI Ahituv and his lab members have been actively involved in teaching for years. The lab has also been enthusiastically expanding outreach through the UCSF Science and Health Education Partnership (SEP), educating at local public K-12 schools and the Bay Area Science Festival and will use project materials and findings for these. The Ahituv lab has trained over 30 undergraduate students and 10 high school students, primarily from ethnic groups lacking sufficient representation in STEM. PI Ahituv will continue to offer internships for these students to learn the details of genome analysis and manipulation through this project and encourage careers across the aforementioned disciplines through inclusive mentorship.

项目摘要 概述： 对哺乳动物如何确定复合特征以适应特定的综合分子理解 环境在很大程度上仍然未知。在这里，我们将利用比较和功能基因组学 系统地以淡化为模型为模型，系统地剖析哺乳动物的饮食适应性。哺乳动物从 常见的饮食祖先具有极为广泛的饮食。其中，节俭的适应是 特别重要的是，在灵长类动物和蝙蝠命令中的多个谱系中出现了吸食果实。节俭 适应也是一般感兴趣的，因为富含糖的饮食会增加糖尿病和代谢疾病的风险 许多哺乳动物，包括人类。相反，节俭的灵长类动物和蝙蝠可以吃大量 没有明显疾病后果的水果/糖。在基因组可用性的最新进展和 基因组技术，我们计划采用一种系统的方法来揭示淡出的分子因素：1） 对灵长类动物和蝙蝠进行比较基因组分析，以识别专门的序列 加速在节俭的物种中加入了多种基因组技术，包括RNA-Seq， ATAC-SEQ，芯片seq和单细胞RNA-seq和Atac-Seq合并在代谢相关的昆虫和 水果蝙蝠组织； 2）使用基于细胞的基因测定，在功能上验证了淡牙相关序列， 大规模平行的记者测定（MPRA）并将这些序列交换为小鼠。我们的工作将 全面确定导致淡化的分子成分，并在功能上表征 这个复杂性状涉及的基因，调节元素和途径。 知识分子的优点： 随着蝙蝠和灵长类动物包含广泛的饮食范围，每个顺序的进化距离是 它们足够小，它们为每个组内以及组之间的比较提供了理想的模型，以分析 饮食专业的遗传决定因素。此外，使用鼠标基因工程可以允许 遗传候选物的功能验证。我们计划不仅鉴定导致表型的蛋白质变化 差异和基因调节元件已被证明是形态学的重要驱动因素 变化和新特征的演变。我们有所有需要的试剂来执行此项目， 包括必要的蝙蝠和灵长类动物基因组以及来自昆虫和奶酪蝙蝠的组织， 对MPRA的果实和表型相关的蝙蝠和灵长类动物细胞系进行了禁食，处理或未经处理。 重要的是，我们在实验室中拥有所有必要的专业知识，并经常进行比较和功能 基因组测定，MPRA和小鼠工程。凭借我们的资源和熟练程度，我们处于公寓之中 促进对淡化和最终基因型 - 表型的复杂性状的理解的位置 关系。 更广泛的影响： 这项研究将在饮食和环境和遗传方面改善基因型 - 表型预测 此处阐明的因素有可能为具有代谢的人提供治疗发展 糖尿病等疾病。因此，这项工作将在比较学科之间产生广泛的影响 生物学，基因表达，生物信息学，分子生态学，分子进化和人类疾病。我们 已经与该项目建立的几位科学家进行了许多合作， 在项目描述中进一步讨论。 Pi Ahituv及其实验室成员从事这个项目 将为这项工作的教学模块设计做出贡献。这包括在UCSF教授 研究生课程以及旧金山州立大学（SFSU）在本科和研究生课程中， Pi Ahituv和他的实验室成员多年来一直积极参与教学。实验室也是 通过UCSF科学与健康教育合作伙伴关系（SEP）热情地扩大外展活动， 在当地的K-12学校和湾区科学节进行教育，并将使用项目材料和 这些发现。 Ahituv实验室已经培训了30多名本科生和10名高中生， 主要来自在STEM中缺乏足够代表的种族。 Pi Ahituv将继续提供 这些学生通过该项目学习基因组分析和操纵的细节，并 通过包容性指导来鼓励上述学科的职业。