Center for Mouse Genomic Variation at Single Cell Resolution

单细胞分辨率小鼠基因组变异中心

• 批准号: 10474393
• 负责人: Seyed Ali Mortazavi
• 金额: $ 253.43万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-24 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10474393
• 关键词: ATAC-seq; Adult; Affect; Alternative Splicing; Alzheimer' s Disease; Alzheimer' s disease model; Astrocytes; Biological Assay; Biology; Blood Cells; Brain; Breathing; Catalogs; Cell Line; Cell Nucleus; Cells; Chromatin; Communities; Complex; Computer Models; Disease; Disease model; Ensure; Female; Foundations; Gene Expression; Genes; Genetic; Genetic Engineering; Genetic Variation; Genetic study; Genome; Genomic approach; Genomics; Health; Height; Human; Human Genetics; Inbred Mouse; Inbreeding; Individual; Inflammation; Joints; Libraries; Life; Link; Maps; Measures; Mission; Modeling; Mouse Strains; Mus; National Human Genome Research Institute; Neurons; Nucleotides; Organ; Organism; Organoids; Persons; Phenotype; Pre-Clinical Model; Predisposition; Protein Isoforms; Proteins; Protocols documentation; Quantitative Trait Loci; RNA; RNA Splicing; Recombinants; Regulatory Element; Resolution; Resources; Rest; Role; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Source; Split-Pool Ligation Transcriptome sequencing; TREM2 gene; Techniques; Tissue Sample; Tissues; Transcript; United States National Institutes of Health; Variant; Work; XCL1 gene; cell type; computational pipelines; design; differential expression; epigenome; gene function; genetic variant; genomic variation; human disease; human model; human reference genome; human tissue; insertion/deletion mutation; interest; macrophage; male; member; mouse model; pre-clinical; programs; promoter; response; single-cell RNA sequencing; tool; transcriptome; transcriptome sequencing; transcriptomics

Any human being has on average 5 million single-nucleotide variants and 13 million nucleotides of insertions, deletions, and other regions present in variable copy numbers compared to the human reference genome. Together these variants must account for all of the genetic contributions to every phenotype of that person, whether it is their height or their familial predisposition to complex diseases. While we can quickly measure the presence of these variants in a genome, we lack the framework to understand which of the variants impact genomic function or how they interact with each other in living, breathing organisms. A core mission of the IGVF Consortium is to identify variants that impact the expression of genes using single-cell techniques and computational modeling. Applying a single-cell genomics approach to selected diverse mouse strains can make a powerful contribution to the mission and to resources of the Consortium. Our Center for Mouse Genomic Variation at Single Cell Resolution will first use 38 mouse Collaborative Cross recombinant inbred lines that possess similar levels of sequence diversity to humans to identify variants that influence gene expression levels and chromatin accessibility at the single-nucleus level in 8 distinct tissues. We will sequence simultaneously a subset of single-nuclei with both short-read sequencing and long-read sequencing to identify variants that impact the expression of different transcript isoforms in different cells across the different mouse strains. We will also measure the relationship of variants in these CC Lines in the response of macrophages in these tissues in response to LPS stimulation. The resulting resource catalogs of cell-type expression QTL, chromatin accessibility QTL, splicing QTL, and response QTL maps will be useful for IGVF modeling groups; for characterizing important variants; and for use by the wider community studying the function of these tissues as well as for designing better pre-clinical models of human diseases.

任何人平均有500万个单核苷酸变异和1300万个单核苷酸变异 插入、缺失和其他区域的核苷酸以可变拷贝数存在 与人类参考基因组进行比较。这些变种加在一起必须解释所有 遗传对该人的每一种表型都有影响，无论是身高还是家族性 易患复杂疾病。虽然我们可以快速测量这些物质的存在 对于基因组中的变异，我们缺乏了解哪些变异影响的框架 基因组功能或它们如何在活的、会呼吸的有机体中相互作用。一个核心 IGVF联盟的任务是识别影响基因表达的变异，使用 单细胞技术和计算模型。应用单细胞基因组学方法 选择不同的小鼠品系可以为这项任务和 财团的资源。我们的单细胞分辨率小鼠基因组变异中心 将首先使用38个具有相似水平的小鼠合作杂交重组近交系 以确定影响基因表达水平的变异和 8种不同组织中染色质在单核水平上的可及性。我们将按顺序排列 同时具有短读测序和长读测序的单核的子集 测序以确定影响不同转录异构体表达的变体 不同品系的小鼠身上有不同的细胞。我们还将衡量两国之间的关系 这些CC基因在这些组织中巨噬细胞对内毒素反应中的变异 刺激。由此得到的细胞类型表达QTL、染色质的资源目录 可及性QTL、剪接QTL和响应QTL图将对IGVF建模有用 群体；用于表征重要的变体；供更广泛的社区研究 这些组织的功能以及设计更好的人类疾病临床前模型。