Statistical Methods for High-Resolution Multiscale Analysis in DNA Interactions

基因组生物学的一个基本谜团是，哺乳动物DNA序列（大约2米长）的30亿个碱基对是如何折叠、成圈和盘绕起来的，以适应直径大约5-10微米的细胞核。在过去几年中，我们对基因组如何在三维（3D）中折叠的理解取得了快速进展，这主要是由测序技术的进步所推动的。该项目的目标是开发数学模型，以更深入地了解3D基因组结构如何与健康发育中的基因表达相关联，以及这些折叠模式如何在疾病的发生和发展过程中出错。该项目旨在通过染色质构象捕获实验揭示控制基因组折叠的组织原则。迄今为止，还没有明确的最佳实践计算方法存在于跨细胞类型或生物扰动的基因组组织比较中。该项目的目的是开发数学模型和计算方法，以获得关于遗传物质在不同细胞状态下如何折叠的新见解，并灵敏地检测这些折叠模式如何受到药物、生长因子和基因组编辑等生物扰动的动态改变。该项目专注于开发方法，以灵敏地检测两大类三维染色质特征的动态变化：(1)亚兆基拓扑相关域呈现块结构，以及(2)两个遥远基因组位点之间的精确远程相互作用，导致中间基因组DNA的环出。用于阐明这些特征的参数化和非参数化归一化方法都将被探索和测试。这些特征的模型将被开发出来，导致扫描统计，以便在标准化的3D接触图中识别它们。在非均相泊松场分析的基础上，对这些扫描统计量进行错误发现率控制。

A fundamental mystery in genome biology is how the three billion base pairs of a mammalian DNA sequence (approximately 2 meters long) are folded, looped, and coiled to fit into a cell nucleus that is roughly 5-10 microns in diameter. Rapid progress has been made over the last few years in advancing our understanding of how the genome folds in three dimensions (3D), primarily driven by advances in sequencing technologies. The goal of this project is to develop mathematical models that will provide a deeper understanding of how 3D genome structure is connected to gene expression in healthy development, and how these folding patterns go awry during the onset and progression of disease. This project aims to shed new light into the organizing principles governing genome folding through chromatin conformation capture experiments. To date, no clear best practice computational methods exist for the comparison of genome organization across cell types or biological perturbations. The aim of this project is to develop mathematical models and computational methods to gain new insight into how the genetic material folds in different cellular states, and to sensitively detect how these folding patterns are dynamically altered by biological perturbations such as drugs, growth factors, and genome editing. This project focuses on developing methods to sensitively detect dynamic changes in two broad categories of 3D chromatin features: (1) sub-megabase topologically associating domains exhibiting a block structure, and (2) precise long-range interactions between two distant genomic loci, leading to looping out of the intervening genomic DNA. Both parametric and non-parametric normalization approaches for elucidating these features will be explored and benchmarked. Models for these features will be developed, leading to scan statistics for identifying them in normalized 3D contact maps. Methods for false discovery rate control for these scan statistics will be developed based on analysis of heterogeneous Poisson fields.