Collaborative Research: III: Medium: Algorithms for scalable inference and phylodynamic analysis of tumor haplotypes using low-coverage single cell sequencing data

癌症是一个动态的进化过程，其中肿瘤细胞群体不断进化以竞争资源、转移以及逃避免疫应答和治疗。因此，量化癌症演变动力学对于理解癌症进展的机制至关重要。单细胞测序使得能够以最好的分辨率表征肿瘤组成，从而为研究人员提供可能允许这种定量所需的数据。然而，要实现这一潜力，需要适当的算法和数据分析工具。通过整合遗传学、群体遗传学和统计学习从基因组数据中提取进化参数的计算学科被称为遗传动力学。虽然几乎所有现有的生物动力学方法都是针对病毒开发的，但人们越来越认识到这种方法与癌症生物学也高度相关。然而，癌症基因组动力学算法的发展面临着与癌症基因组学数据的性质相关的许多挑战。该提案的总体目标是通过开发一个用于从单细胞DNA测序（scDNA-Seq）数据联合推断癌症系统发育树和进化参数的动态框架来应对这些挑战。这一框架将使癌症研究人员能够对特定基因组改变或其组合的影响进行统计和计算上的合理评估。此外，该项目将支持开发创新的跨学科课程，并为格鲁吉亚州立大学（标题三指定的主要黑人机构），康涅狄格大学和康州大学健康的本科生和研究生提供生物信息学培训。首先，研究人员将开发用于联合重建克隆频率和分期癌症克隆基因组谱（包括拷贝数变异谱和单核苷酸变异）的算法。该项目将专注于低覆盖率的scDNA-seq，它可以提供足够的克隆数据，以保证肿瘤动力学分析所需的癌症基因中分支事件的密度。其次，研究人员将设计一种新的肿瘤内肿瘤动力学推断方法。这包括可扩展的建设合理的克隆系统发育树，使用一种新的基于二分的中位数树的方法，连同最大的后验推理的癌症健身和突变景观。所提出的方法的显着特点是使用凸优化技术，而不是MCMC采样，这将保证开发的计算工具的可扩展性和准确性。最后，将进行一系列全面的实验，以验证和评估所开发方法的准确性。 这些将包括对模拟和公开的scDNA-Seq数据的计算实验，以及使用由康州大学健康中心进行的体外和体内实验生成的scDNA-Seq数据集。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

Cancer is a dynamical evolutionary process, where populations of tumor cells are continuously evolving to compete for resources, to metastasize, and to escape immune responses and therapy. Quantification of cancer evolutionary dynamics is therefore essential to understanding the mechanisms of cancer progression. Single-cell sequencing has enabled characterization of tumor composition at the finest possible resolution, thus providing researchers with the data needed to potentially allow for such quantification. However, to realize this potential, appropriate algorithms and data analysis tools are needed. The computational discipline that extracts evolutionary parameters from genomic data by integrating phylogenetics, population genetics and statistical learning is called phylodynamics. While almost all existing phylodynamics methods are developed for viruses, there is a growing realization that this methodology is also highly relevant to cancer biology. However, the development of cancer phylodynamics algorithms faces many challenges associated with the nature of cancer genomics data. The overarching goal of this proposal is to address these challenges by developing a phylodynamic framework for joint inference of cancer phylogenetic trees and evolutionary parameters from single-cell DNA sequencing (scDNA-Seq) data. This framework will allow cancer researchers to carry out a statistically and computationally sound evaluation of the effects of particular genome alterations or their combinations. In addition, this project will support development of innovative cross-disciplinary curricula, and bioinformatics training for diverse cohorts of undergraduate and graduate students at Georgia State University (Title III designation of Predominantly Black Institution), University of Connecticut, and UConn Health.The project has three interrelated technical aims. First, investigators will develop algorithms for joint reconstruction of clonal frequencies and phased cancer clone genomic profiles (including copy number variation profiles and single nucleotide variants). The project will concentrate on low-coverage scDNA-seq that can provide enough clonal data to guarantee the density of branching events in the cancer phylogenies necessary for phylodynamics analysis. Second, the researchers will design a novel methodology for intra-tumor phylodynamics inference. This includes scalable construction of plausible clone phylogenetic trees using a novel bipartition-based median-tree approach, together with maximum a posteriori inference of cancer fitness and mutability landscapes. The distinguishing feature of the proposed approach is the use of convex optimization techniques rather than MCMC sampling, which will guarantee scalability and accuracy of developed computational tools. Finally, a comprehensive set of experiments will be conducted to validate and assess the accuracy of developed methods. These will include computational experiments on simulated and publicly available scDNA-Seq data, as well as using scDNA-Seq datasets generated by in vitro and in vivo experiments conducted at UConn Health.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.