Statistical Methods for High-Resolution Multiscale Analysis in DNA Interactions

基因组生物学中的一个基本谜团是，哺乳动物DNA序列(约2米长)的30亿个碱基对是如何折叠、环状和卷曲的，以适合直径约5-10微米的细胞核。在过去的几年里，在推动我们对基因组如何在三维(3D)中折叠的理解方面取得了快速进展，这主要是由测序技术的进步推动的。该项目的目标是开发数学模型，以便更深入地了解3D基因组结构如何与健康发育中的基因表达有关，以及这些折叠模式在疾病的发生和发展过程中是如何出错的。该项目旨在通过染色质构象捕获实验揭示管理基因组折叠的组织原理。到目前为止，还没有明确的最佳实践计算方法来比较不同细胞类型或生物扰动的基因组组织。该项目的目的是开发数学模型和计算方法，以获得新的见解，以了解遗传物质如何在不同的细胞状态下折叠，并敏感地检测这些折叠模式是如何因生物扰动(如药物、生长因子和基因组编辑)而动态改变的。该项目专注于开发方法来灵敏地检测两大类3D染色质特征的动态变化：(1)呈现块状结构的亚兆基拓扑关联结构域；(2)两个遥远基因组座位之间精确的远程相互作用，导致介于其间的基因组DNA环路。将探索和确定用于阐明这些特征的参数和非参数归一化方法。将开发这些功能的模型，从而产生扫描统计数据，以便在标准化的3D联系人地图中识别它们。这些扫描统计的错误发现率控制方法将基于对非均匀泊松场的分析而开发。

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.