Computational genomic analysis of genomic variations in human tissues

摘要 尽管所有体细胞的发育谱系都可以追溯到单个受精卵， 发育和衰老过程、各种诱变暴露、DNA复制错误和不完善的DNA 修复导致体细胞突变的积累-导致组织中体细胞之间的遗传变异。 虽然体细胞突变主要是在表型条件下研究的， 色素沉着模式，疾病，如癌症，自身免疫等，或疾病的前兆，如领域 癌变和克隆造血，新的证据表明，体细胞突变，显然， 健康的组织可能比以前预期的更常见， 在整个生命周期中不断进化。尽管如此，我们对“正常”躯体模式的理解 病理正常组织中的变化仍然有限-就受影响的组织类型、 基因组改变及其病因-部分原因是技术障碍。特别是，许多类型的 嵌合体细胞组织中的基因组改变仍然缺乏表征。最近的技术发展 能够检查基因组改变的复杂模式及其在组织背景中的意义， 前所未有的分辨率和高精度。在这里，利用新兴的基因组技术和计算 基因组学资源，并专注于具有不同类型暴露和再生能力的器官， 我们将提出两个相关的问题： 病理正常的组织这种基因组改变在多大程度上有助于转录组和 细胞和组织水平的表型变异？这项研究有助于了解 人类正常病理组织中的体细胞变异景观。健康组织的规律性 这是理所当然的，它低估了内部的遗传和非遗传变异。我们的努力有潜力 挑战与发育、衰老和包括癌症在内的许多疾病有关的教条， 免疫和神经系统疾病。重要的是，它将为我们提供一个基线， 在疾病和病前状况中观察到，这将对早期检测、疾病产生影响 预防和减少过度诊断。我们还将开发计算基因组资源， 走向可复制的研究和社区层面的资源共享，以促进我们对 人体组织中的体细胞变异。

Abstract Even though all somatic cells trace their developmental lineages traced back to a single fertilized egg, during the course of development and aging, various mutagenic exposures, DNA replication errors, and imperfect DNA repair lead to accumulation of somatic mutations – resulting in genetic variations among somatic cells in a tissue. While somatic mutations have primarily been investigated in the contexts of phenotypic conditions such as pigmentation patterns, diseases such as cancer, autoimmunity etc, or disease precursors such as field cancerization and clonal hematopoiesis, emerging evidence suggests that somatic mutations in apparently healthy tissues might be more common than previously anticipated, and that clonal makeups of somatic tissues continue to evolve throughout the lifetime. Nonetheless, our understanding of the patterns of ‘normal’ somatic variations in pathologically normal tissues remains limited –in terms of the types of tissues affected, classes of genomic alterations, and their etiologies – in part, due to technological barriers. In particular, many types of genomic alterations in mosaic somatic tissues remain poorly characterized. Recent technological developments have enabled examining complex patterns of genomic alterations and their significance in tissue contexts at unprecedented resolution and high accuracy. Here, utilizing emerging genomic technologies and computational genomics resources, and focusing on organs that have different types of exposure and regeneration abilities, we will ask two related questions: What are the prevalence and patterns of somatic genomic alterations in pathologically normal tissues? To what extent such genomic alterations contribute towards transcriptomic and phenotypic variations at the cellular and tissue-level? This research contributes towards understanding the landscape of somatic variations in pathologically normal tissues in human. Regularity of healthy tissues is taken for granted, which under-appreciates the genetic and non-genetic variations within. Our efforts have potentials to challenge the dogma, that have relevance for development, aging, and many disease types including cancer, immune and neurological disorders. Importantly, it will provide us with a baseline to compare the alterations observed in disease and pre-disease conditions, which would have implications for early detection, disease prevention, and minimizing over-diagnosis. We will also develop computational genomic resources contributing towards reproducible research and community-level resource sharing for advancing our understanding of somatic variations in human tissues.