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: 10643874
• 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/10643874
• 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; Chromosome Mapping; Communities; Complex; Computer Models; Disease; Disease model; Dissociation; 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; Macrophage; 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; interest; male; member; mouse model; pre-clinical; programs; promoter; response; single nucleus RNA-sequencing; single-cell RNA sequencing; tool; transcriptome; 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.

每个人平均有500万个单核苷酸变异， 以可变拷贝数存在的插入、缺失和其他区域的核苷酸 与人类参考基因组相比。这些变量必须一起解释所有 遗传贡献的每一个表型的人，无论是他们的身高或他们的家族 易患复杂疾病。虽然我们可以快速测量这些 基因组中的变异，我们缺乏框架来了解哪些变异会影响 基因组功能或它们如何在活着的、呼吸的生物体中相互作用。核心 IGVF联盟的使命是利用基因组学方法， 单细胞技术和计算机建模。应用单细胞基因组学方法 选择不同的小鼠品系可以为使命做出强大的贡献， 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个小鼠协作杂交重组近交系， 对人类的序列多样性，以确定影响基因表达水平的变异， 8种不同组织中单核水平的染色质可及性。我们将测序 同时使用短读取测序和长读取测序两者的单核的子集 测序以鉴定影响不同转录物同种型表达的变体， 不同品系小鼠的不同细胞。我们还将测量 这些组织中的巨噬细胞响应LPS时这些CC系中的变体 刺激.由此产生的细胞类型表达QTL，染色质 易接近性QTL、剪接QTL和响应QTL图谱将有助于IGVF建模 组;用于表征重要的变体;并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的临床前模型。

项目成果

Biophysically Interpretable Inference of Cell Types from Multimodal Sequencing Data.

从多模式测序数据中对细胞类型进行生物物理解释的推断。

• DOI: 10.1101/2023.09.17.558131
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Chari,Tara;Gorin,Gennady;Pachter,Lior
• 通讯作者: Pachter,Lior