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Mobile element derived chromatin looping variability in human populations

人群中移动元件衍生的染色质循环变异

基本信息

批准号：
10708736
负责人：
Alan P Boyle
金额：
$ 39万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-23 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10708736
关键词：
3-Dimensional Affect Automobile Driving Binding CRISPR/Cas technology Catalogs Chromatin Chromatin Conformation Capture and Sequencing Chromatin Loop Code Computer Analysis Computing Methodologies DNA Insertion Elements DNA Transposable Elements Data Development Elements Etiology Evolution Failure Gene Expression Gene Expression Regulation Genetic Genome Genomics Goals Human Human Biology Human Genome Individual Knowledge Length Location Maps Mediating Methods Molecular Mutagenesis Outcome Pattern Phenotype Play Population Process Regulator Genes Retinal blind spot Role Sampling Site Technology Tissue-Specific Gene Expression Untranslated RNA Variant Work computational basis cost disorder risk genome sequencing genome-wide human disease improved innovation nanopore novel study population three dimensional structure transcription factor whole genome

项目摘要

Project Summary Mobile element insertions (MEIs), or transposable elements, have been established to contribute to ongoing mutagenesis of the human genome, leading to widespread variability and sporadic cases of human disease. Recent work has begun to illuminate underlying roles through which MEIs affect regulatory processes through their combined effects on transcription factor binding and 3D chromatin looping. Recent work from our group has demonstrated the importance of MEIs in establishing chromatin looping variability in driving differential gene expression. These observations have precipitated development of molecular and computational approaches to study their impact on human biology, including whole-genome and target-capture strategies leveraging short- read sequencing technologies. However, these methods fail to accurately capture the entire landscape of MEIs within the human genome because of their limited ability to identify non-reference polymorphic MEIs. This failure derives in part from a blind-spot of short-read genome sequencing: because the human genome harbors over 1 million MEIs, unambiguous alignment of short reads is problematic. Given the demonstrated importance of MEIs to human biology and evolution, it is imperative that novel methods capable of comprehensively mapping their locations across many human genomes be developed. In this proposal we aim to 1) Quantify the effects of TE activity on CTCF binding in a human population sample of 51 well-studied individuals using computational meth- ods, 2) Map invariant and polymorphic LTR13 insertions in the CEU population and investigate their effects on intraspecies variability in CTCF binding, chromatin looping, and gene regulation, and 3) Directly map HARVK/LTR13-anchored chromatin loops through enrichment-capture combined with ONT-based chromatin conformation capture sequencing. We expect completion of these aims to yield the following outcomes: We will: 1) Present the first reliable estimate of the contribution of polymorphic MEIs to CTCF-mediated chromatin looping variation in a human population. 2) Improve understanding of how fixed and polymorphic MEIs contribute to population-level variability in regulatory activity, gene expression, and disease risk. 3) Demonstrate causality of ongoing MEI activity regarding population-level looping variation and differential gene expression. The new meth- ods proposed here will address the shortcomings of existing short-read sequencing technologies, allowing us to comprehensively and cost-effectively map target MEIs across a broad population sample, bridging important gaps in our knowledge of how gene regulatory processes evolve in the human genome.

项目总结