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Development of iPSCs for comparative genomics in primates

灵长类动物比较基因组学 iPSC 的开发

基本信息

批准号：
10655911
负责人：
Yoav Gilad
金额：
$ 57.13万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10655911
关键词：
ATAC-seq Address Adult Affect Autopsy Biocompatible Materials Biological Assay Biological Models Cardiac Catalogs Cell Differentiation process Cell Line Cells Chromatin Collection Communities Comparative Study Complex Data Data Set Development Disease Ethics Fibroblasts Foundations Freezing Future Gene Expression Gene Expression Regulation Genes Human Individual Letters Maps Mesenchymal Molecular Mutation Organoids Pan Genus Phenotype Pilot Projects Pongidae Population Primates Process Property Regulator Genes Research Research Personnel Resources Risk Sampling Series Tissue Sample Tissues cell type clinically relevant comparative comparative genomics differential expression differentiation protocol experience functional genomics genetic architecture human stem cells induced pluripotent stem cell insight lymphoblastoid cell line nonhuman tissue response single-cell RNA sequencing tool trait transcriptome sequencing virtual

项目摘要

Abstract This is a competitive renewal application for a second term of this project (years 5-8). Characterizing gene regulatory differences between humans and our close primate relatives is essential for understanding the molecular basis of human-specific traits. Comparative genomics provides us with the tools to identify both species-specific and conserved regulatory features, which has provided valuable insight into the genetic architecture of adaptation in gene regulation. However, ethical and practical considerations preclude comparative studies of molecular traits in live primates, particularly apes. Frozen post-mortem tissues from non-human apes are difficult to obtain, and even when they are available, they are not optimal templates for many functional genomic assays. Thus, we are generally unable to collect samples from enough individuals to map and study gene regulatory loci in non-human apes; we are unable to study gene regulation in more than a few tissues from apes; we are unable to study the dynamics of gene regulation during development; and we are unable to study regulatory responses to evolutionarily and clinically relevant exposures. In the first term of this project, we proposed to address this challenge by establishing a comparative panel of induced pluripotent stem cells (iPSCs) from humans and chimpanzees. We have successfully done this, and we have shared these lines freely and without restriction with more than 30 labs (see letters of support), facilitating comparative functional genomic studies by investigators who would not otherwise have been able to obtain appropriate samples to conduct their research. We now request support to continue to maintain and distribute this community resource, which we will expand in two ways. First, we will generate additional chimpanzee iPSC lines using the remaining samples we collected prior to the moratorium on chimpanzee research. We expect that these lines will soon become the only population-sample resource for future studies involving chimpanzees in the USA. Second, we will use human and chimpanzee iPSCs to develop a series of dynamically differentiating organoids, which we will also share freely to allow other groups to effectively utilize the comparative iPSC panel. The unique property of these dynamically differentiating organoids is that they contain asynchronously differentiating cells. While they do not produce pure cell populations that can be meaningfully analyzed with bulk RNA-seq data, single-cell RNA-seq can be used to deconvolve the organoids into dozens of cell types and developmental stages, allowing us to explore dynamic regulatory processes that cannot be observed in adult tissues10.

摘要