权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

From a Long List to Causal Variants: High-Throughput Gene Regulatory Assays in Developing Tissues

从一长串到因果变异：发育组织中的高通量基因调控分析

基本信息

批准号：
10251147
负责人：
Craig Barrett Lowe
金额：
$ 47万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-06-30
项目状态：
未结题

项目摘要

Abstract My laboratory is pursuing the genetic basis of recently evolved human traits that are not observed in chimpanzees, or other great apes. We are working towards this goal by identifying and functionally characterizing the fastest evolving regions in the human genome. While this line of research has been pursued before, the studies have always focused on the 5% of the genome that shows strong cross-species sequence constraint in non-human mammals, and is therefore clearly functional. However, we now know there are many functional regions that do not show strong cross-species constraint across diverse mammals. It is also true that many phenotypic transitions seen on the branch to humans, such as brain expansion and upright posture, are also seen in other mammalian lineages. For example, dolphins and elephants have larger brains than humans. Lemurs and macropods (e.g. kangaroos) also have a spine that is generally perpendicular to the ground. For these reasons, we hypothesize that many genomic elements underlying human adaptations and disease risks will not be restricted to the 5% of the genome showing strong cross-species conservation in other mammals. My laboratory is therefore venturing into the other 95% of the human genome, in search of regions that have rapidly changed in humans, but may also vary among other species. This has caused us to be faced with the problems that originally restricted researchers to the 5% of mammalian genomes that is highly constrained. How do we identify which of our 2089 regions are functional, and how do we know if the sequence changes on the human lineage change their function? This is a common disconnect in genomics research: a computational screen has generated thousands of interesting mutations, whether it be fast evolving regions in humans, or haplotypes from genome-wide association studies, but making mouse models for in depth study of these mutations can only be done for one to ten mutations. This results in a disconnect of two orders of magnitude between the mutations we can identify for further analysis and those we can further analyze. The vast majority of the 2089 fastest evolving regions in the human genome are located outside of protein-coding exons and are likely regulating the spatial and temporal expression of genes during development. While there are high-throughput methods for testing enhancer activity in cell lines, the cell type of activity is not usually known beforehand, and cell lines do not capture the complexity of cell types transiently present during development. To address this problem for our own work, and with the intention of it being adopted by other groups, we are developing a method to assay the gene regulatory potential of thousands of DNA segments in developing tissue and at single cell resolution.

摘要