New approaches for leveraging single-cell data to identify disease-critical genes and gene sets

项目总结/摘要 提名候选风险基因和基因集潜在的疾病关键过程是至关重要的 用于开发药物靶点和为CRISPR筛选实验提供信息。为此，大规模的单细胞 基因组和表观基因组数据（来自RNA-seq、ATAC-seq、Perturb-seq）可以与全基因组数据整合， 关联研究（GWAS），以提高我们对人类复杂的遗传结构的理解 疾病和特征。在这个建议中，我计划开发新的计算方法来整合单- 细胞功能基因组和表观基因组数据与GWAS数据，用于识别复杂疾病和性状 并对疾病关键基因和表征功能过程的基因集进行排名， 与这些疾病相关基因相关的短基因组区域。我的K99培训将在 哈佛T. H.陈博士的公共卫生学院，以及广泛的研究所，在博士的指导下。 价格我的培训的关键领域将是开发和评估基因水平和基因集水平的方法 疾病和性状的功能结构和单细胞的综合分析，以及批量，功能 基因组学数据与人类疾病遗传学。我提出的方法将试图弥合以下两个方面之间的差距： 功能基因组学和人类遗传学以及下游临床药物/基因干预实验。很长的- 这项研究的长期目标是产生一套计算工具，用于识别和排名顶级疾病关键 基因、表征细胞类型或细胞过程的顶级疾病关键基因集和基因连锁的基因组 每个疾病/特征的区域。这些方法将重塑我们对功能架构的理解 它将为未来的药物扰动和CRISPR筛选实验提供信息。 该提案的第一个目的是开发方法，通过整合 常见和罕见变异疾病与来自单细胞的基因水平功能信息的关联 基因组学实验在这里，我将开发，比较和对比不同的多个基因优先级策略， 他们如何注释基因的SNPs，如何在基因水平上聚合变异水平的关联，以及如何 在执行基因优先级排序中使用功能数据。第二个目标是开发新的 计算策略来评估构成细胞类型或细胞的基因组中的疾病信息， 在组织中的细胞类型内或跨细胞类型活跃的过程。这项建议的第三个目的是确定和优先考虑 与疾病近端或功能性连接（例如，作为增强子）的短基因组区域， 来自目标1和2的关键基因和基因组。在这里，我计划将GWAS关联信号整合到这些附近， 具有深度学习模型的基因连锁区域，可以在碱基对分辨率和单细胞水平上推断等位基因效应 ATAC-seq数据。所有疾病关键基因、基因集和基因连锁区域沿着以及相关计算 工具将向科学界公开分发。

PROJECT SUMMARY/ABSTRACT Nominating candidate risk genes and gene sets underlying disease-critical processes is of utmost importance for developing drug targets and informing CRISPR screening experiments. To this end, large scale single-cell genomic and epigenomic data (from RNA-seq, ATAC-seq, Perturb-seq) can be integrated with genome wide association studies (GWAS) to enhance our understanding of the genetic architecture of human complex diseases and traits. In this proposal, I plan to develop new computational approaches to integrate single- cell functional genomic and epigenomic data with GWAS data for complex diseases and traits to identify and rank disease-critical genes and gene sets characterizing functional processes, as well as pinpoint short genomic regions linked to these disease-associated genes. My K99 training will be conducted at the Harvard T.H. Chan School of Public Health, as well as the Broad Institute, under the mentorship of Dr. Alkes Price. The key areas of my training will be to develop and evaluate approaches for gene-level and gene set-level functional architecture of diseases and traits and integrative analysis of single-cell, as well as bulk, functional genomics data with human disease genetics. My proposed approaches will attempt to bridge the gap between functional genomics and human genetics and downstream clinical drug/gene intervention experiments. The long- term goal of this research is to produce a set of computational tools that identify and rank top disease-critical genes, top disease-critical gene sets characterizing cell types or cellular processes and gene-linked genomic regions for each disease/trait. These approaches will reshape our understanding of the functional architecture of human diseases at cellular level and will inform future drug perturbation and CRISPR screening experiments. The first aim of this proposal is to develop methods to identify and rank disease-critical genes by integrating common and rare variant disease associations with gene-level functional information derived from single-cell genomics experiments. Here I will develop, compare and contrast multiple gene prioritization strategies that differ in how they annotate SNPs for a gene, how they aggregate variant level associations at gene level and how they use functional data in performing the gene prioritization. The second aim of this proposal is to develop new computational strategies to assess disease information in sets of genes that underlie a cell type or cellular processes active within or across cell types in a tissue. The third aim of this proposal is to pinpoint and prioritize short genomic regions that are either proximally or functionally linked (for example, as an enhancer) to disease- critical genes and gene sets from Aims 1 and 2. Here, I plan to integrate GWAS association signal near these gene-linked regions with deep learning models that can infer allelic effects at base pair resolution and single-cell ATAC-seq data. All disease-critical genes, gene sets and gene-linked regions along with relevant computational tools will be distributed publicly to the scientific community.