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一个受精卵，但在 发育和衰老的过程、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进行研究的，例如 色素沉着模式、疾病，如癌症、自身免疫等，或疾病先兆，如视野 癌变和克隆性造血，新出现的证据表明，体细胞突变明显 健康组织可能比之前预期的更常见，而体细胞组织的克隆构成 在一生中不断进化。尽管如此，我们对“正常”体细胞模式的理解 病理上正常组织的变异仍然有限--就受影响的组织类型、类别 基因组改变及其原因--部分原因是技术障碍。特别是，许多类型的 镶嵌体细胞组织中的基因组变化仍然没有得到很好的描述。最近的技术发展 已经能够检查复杂的基因组改变模式及其在组织上下文中的意义 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，并关注具有不同类型暴露和再生能力的器官， 我们将问两个相关的问题：什么是体细胞基因组变化的流行率和模式 病理上正常的组织？这种基因组改变在多大程度上有助于转录和 细胞和组织水平的表型变异？这项研究有助于理解 人类病理正常组织的体细胞变异景观。定期取健康组织 这是理所当然的，它低估了内在的遗传和非遗传差异。我们的努力是有潜力的 为了挑战与发育、衰老和包括癌症在内的许多疾病类型相关的教条， 免疫性和神经系统疾病。重要的是，它将为我们提供比较变化的基线 在疾病和疾病前的情况下观察到的，这将对早期发现疾病有影响 预防，并将过度诊断降至最低。我们还将开发计算基因组资源，为 走向可重复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.