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Functional Genetics Approaches to Investigate Human Evolution

研究人类进化的功能遗传学方法

基本信息

批准号：
10315626
负责人：
Tyler Fair
金额：
$ 4.34万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-11 至 2025-08-10
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10315626
关键词：
Apoptosis Area Base Pairing Brain CRISPR interference Cell Proliferation Cell physiology Cells Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Code Collaborations Computational Biology Computational Technique Computing Methodologies Data Set Differentiated Gene Embryo Equilibrium Evolution Foundations Gene Dosage Gene Expression Gene Targeting Genes Genetic Genetic Transcription Genetic Variation Genome Genomics Goals Growth Guide RNA High-Throughput Nucleotide Sequencing Hominidae Human Human Genome Libraries Link Macaca Macaca mulatta Machine Learning Maps Molecular Mutation Nucleotides Organoids Pan Genus Phenotype Pluripotent Stem Cells Pollen Population Genetics Proteins Regulation Regulatory Element Repetitive Sequence Research Personnel Scientist Single Nucleotide Polymorphism Site Statistical Methods Structure System Techniques Telencephalon Testing Untranslated RNA Variant Work XCL1 gene cell motility cell type comparative genomics experience genetic approach genetic variant genome-wide genomic locus genomic predictors induced pluripotent stem cell loss of function migration mouse model nerve stem cell nonhuman primate public health relevance screening single-cell RNA sequencing skills stable cell line statistics stem cell differentiation stem cell model transcriptome sequencing transcriptomics

项目摘要

Analyses of human and chimpanzee genomes have catalogued the single-nucleotide and structural variants that have emerged since humans diverged from nonhuman primates. Nearly all of these genetic variants remain functionally uncharacterized. Contained within these genetic variants are alterations to cis-regulatory elements, protein-coding genes, noncoding RNAs, gene copy number, repetitive elements, and other genomic features that underlie phenotypic differences between humans and nonhuman primates. Because it is difficult to predict how genomic differences within the hominid lineage contribute to phenotypic differences, there is a critical need for high-throughput, systematic approaches to interrogate functional genetic variation. Therefore, I seek to develop a quantitative genome-scale platform for identifying the phenotypic consequences of human-specific evolutionary mutations at a cellular and molecular level. To accomplish this objective, I will combine advances in chimpanzee pluripotent stem cell-derived models with CRISPR interference (CRISPRi), single-cell RNAsequencing (scRNA-seq), and single-cell ATAC-sequencing (scATAC-seq). This project is of great

对人类和黑猩猩基因组的分析已经对单核苷酸和结构变体进行了分类在人类从非人类灵长类动物分化出来后出现了。几乎所有这些基因变异都保留了下来在功能上没有特征化。这些基因变体中包含顺式调控元件的变化，蛋白质编码基因、非编码RNA、基因拷贝数、重复元件和其他基因组特征这是人类和非人类灵长类动物表型差异的基础。因为很难预测原始人血统中的基因组差异如何影响表型差异，这是一个关键的需要用于高通量、系统化的方法来询问功能性遗传变异。因此，我寻求开发一个定量基因组规模的平台，用于识别人类特异性的表型后果在细胞和分子水平上的进化突变。为了实现这一目标，我将结合先进在具有CRISPR干扰(CRISPRi)、单细胞RNA测序(scRNA-seq)和单细胞ATAC-测序(scATAC-seq)的黑猩猩多能干细胞衍生模型中。这项工程意义重大。