Algorithmic approaches to systems biology, data integration, and evolution

Przytycka的团队继续开发和应用计算方法，利用和整合专注于基因调控和疾病的大型数据集。 我继续研究癌症中的突变信号。癌症基因组中存在的大多数突变都是无害的乘客突变。人们越来越认识到，对这些突变模式的分析可以提供关于作用于癌症基因组的突变过程的有用信息。最近，我们开始利用概念突变特征来研究环境因素的关系，如吸烟和特定组织中的细胞过程。结合基因表达和突变特征，我们研究了吸烟和其他诱变剂暴露与健康组织中生物过程的关系，旨在了解这些诱变剂暴露如何影响细胞和组织的功能。我们的初步结果表明，突变特征可以用于研究诱变环境因素对组织的分子途径和细胞组成的影响，方法是对这些诱变剂的强度进行量化。这种方法的分析结果与最近的发现一致，将这些途径的扰动与吸烟联系在一起，但也提供了更多的新见解。我们的研究表明，吸烟改变了许多基因和途径的表达，特别是与免疫反应有关的基因和途径。它还改变了肺组织中的细胞类型组成，增加了粘蛋白产生杯状细胞的数量，并减少了纤毛细胞的数量。这些研究的初步结果发表在BioRxiv上。一份期刊投稿正在准备中。 为了更深入地了解突变过程和细胞水平变化之间的关系，我们开发了一种基于网络的方法，GenSigNet，它捕获基因表达和签名之间的关系。该构造利用其他统计技术中的稀疏偏相关来揭示网络节点的活动之间的主导影响关系。当应用于癌症数据时，GenSigNet发现了突变特征和细胞过程之间的重要联系，而这些联系是以前的方法难以检测到的。这些研究的初步结果发表在BioRxiv上。一份期刊投稿正在准备中。 我的团队还参与了国际苍蝇细胞图谱联盟，该联盟为果蝇社区提供了一个资源，以单细胞分辨率研究遗传扰动和疾病。该联盟的旗舰论文最近发表在《科学》杂志上。整个成人的单细胞图谱包括58万个细胞和250多种注释细胞类型。与NIDDK的布莱恩·奥利弗的团队一起，我的团队领导了对性别二形性的分析。在这篇旗舰论文之后，将进行进一步的深入分析，包括对我们两个小组共同领导的性二态现象的额外分析。 最后，继续我们与Marit Nilsen-Hamilton(爱荷华州大学和Aptalogic)的长期合作，我们致力于应用计算方法来辅助适体设计。核酸适配子是新一代分子识别元件，基于它们的合成性质、在广泛温度范围内的稳定性以及对不同传感平台的适应性，正在成为新一代诊断分子识别元件。适配子可以进一步在序列和化学上进行修饰，以增加它们与目标分子的特异性和亲和力，并增强它们在核酸酶存在下的稳定性。我们为NGAL适配子提交了Aptalogic-NIH联合专利申请。NGAL是急性肾损伤的早期预测指标，NGAL适配子可能为早期发现提供重要工具。

Przytycka's group continued to develop and apply computational methods that utilize and integrate large data sets with a focus on gene regulation and diseases. I continued the research on mutation signatures in cancer. Most of the mutations present in cancer genomes are harmless passenger mutations. It has been increasingly appreciated that analyses of the patterns of these mutations can provide useful information regarding mutational processes acting on cancer genomes. Recently we began to leverage the concept mutational signatures to study the relationship of environmental factors, such as smoking and cellular processes in specific tissues. Integrating gene expression and mutational signatures, we examined the relationship of the exposure to smoking and other mutagens with biological processes in healthy tissues, aiming to understand how the exposure to these mutagens impact functioning of cells and tissues. Our preliminary results demonstrated that mutational signatures can be utilized to study the impact of mutagenic environmental factors on molecular pathways and cellular compositions of tissues by allowing a quantification of the strength of these mutagens. The analysis results with this approach are consistent with recent findings linking perturbations of these pathways to smoking but also provided additional novel insights. Our studies indicate that smoking changes expression of many genes and pathways, especially these relater to immune response. It also changes cell type composition in lung tissue increasing the number on mucin producing goblet cells and reducing the number of ciliated cells. Preliminary results of these studies are reported in BioRxiv. A journal submission is in preparation. To gain additional insights into relationships between mutagenic processes and cellular-level changes we developed a network-based approach, GenSigNet, that captures the relations between gene expression and signatures. The construction leverages a sparse partial correlation among other statistical techniques to uncover dominant influence relations between the activities of network nodes. When applied to cancer data, GenSigNet uncovered important connections between mutational signatures and cellular processes that were difficult to detect using previous approaches. Preliminary results of these studies are reported in BioRxiv. A journal submission is in preparation. My group also participates in the international Fly Cell Atlas Consortium that provides a resource for the Drosophila community to study genetic perturbations and diseases at single-cell resolution. The flagship paper of the consortium has been recently published in Science. The single-cell atlas of the entire adult includes 580,000 cells and more than 250 annotated cell types. Together with Brian Oliver's group at NIDDK, my group has lead the analysis of sexual dimorphism. This flagship paper will be followed with further in-depth analyses, including additional analyses of sexual dimorphism co-lead by our two groups. Finally, continuing our long-standing collaboration with Marit Nilsen-Hamilton (Iowa University and Aptalogic), we work on applying computational methods to aid aptamer design. Nucleic acid aptamers are emerging as the new generation molecular recognition elements for diagnostics based on their synthetic nature, stability under a wide range of temperatures and amenability to different sensing platforms. Aptamers can further be modified in sequence and chemically to increase their specificities and affinities for their target molecule and to enhance their stabilities in the presence of nucleases. We filed a joint Aptalogic- NIH patent application for NGAL aptamer. NGAL is an early predictor for acute kidney injury and NGAL aptamer might provide important tool for early detection.