Comprehensively assessing human somatic variability and its influence on gene exp

尽管通常认为人体内数万亿个细胞拥有相同的DNA序列，但在 事实上，我们是基因组的马赛克。这种马赛克的程度在很大程度上是未知的，但无论是理论上的还是 经验研究表明，体细胞突变给人类带来了相当大的负担。事实上，除此之外， 到癌症和衰老，这两个过程中，体细胞突变已知发挥了不可或缺的作用，超过30 其他疾病表型可归因于体细胞变异性。体细胞突变也一直是 假设在其他复杂疾病中发挥作用，并解释了一些“缺失的遗传性” 观察到许多特征。尽管如此，对人类的系统和全面研究还很少。 组织和个体之间的体细胞变异，因此体细胞突变的格局仍然存在 很大程度上是未知的。这种知识上的差距是许多正在进行的和未来的研究的重大障碍 人类表型变异和疾病易感性，如对体细胞变异的解释 癌症基因组测序项目。为此，拟议项目的目标是利用 GTEx项目创建的资源，用于严格和系统地分析人类体细胞模式 可变性。在目标1中，我们将对从40个组织中收集的15个组织进行深度外显子组测序 每个个体(总共600个外显子)，并识别体细胞序列和结构变异。重要的是，我们 精心设计了这项研究和特定的组织研究，以便于检测具有生物学重要性的 假设，如体细胞突变的模式和水平，以及这些特征如何作为函数变化 组织类型、年龄和性别。此外，我们将在实验上验证大量推定的体细胞 突变，这将允许调整筛选标准，从而产生强大的体细胞突变目录。在……里面 目标2，我们将利用GTEx项目产生的RNA-Seq数据，并使用创新的方法 来检验体细胞突变对基因表达可变性的影响这一假设。总的来说，这些数据 将深刻地加深我们对人类体细胞突变及其模式和特征的理解 在组织和个体之间，以及它们对转录丰度的影响。此外，我们的数据将成为 为GTEx和科学界提供大量资源，我们将轻松地使所有项目数据 无障碍。

Although it is generally assumed that the trillions of cells in a human body share identical DNA sequences, in reality we are a mosaic of genomes. The extent of this mosaicism is largely unknown, but both theoretical and empirical studies suggest that the burden of somatic mutations in humans is considerable. Indeed, in addition to cancer and ageing, two processes where somatic mutations are known to play an integral role, over thirty additional disease phenotypes are attributable to somatic variability. Somatic mutations have also been hypothesized to play a role in other complex diseases and account for some of the "missing heritability" observed for many traits. Nonetheless, there have been few systematic and comprehensive studies of human somatic variability among tissues and individuals, and therefore the landscape of somatic mutations remains largely unknown. This gap in knowledge is a significant impediment to many ongoing and future studies of human phenotypic variation and disease susceptibility, such as the interpretation of somatic variability in cancer genome sequencing projects. To this end, the goals of the proposed project are to leverage the resources created by the GTEx Project to rigorously and systematically analyze patterns of human somatic variability. In Aim 1, we will perform deep exome sequencing on 15 tissues that have been collected from 40 individuals each (600 total exomes) and identify somatic sequence and structural variation. Importantly, we have carefully designed the study and particular tissues to study to facilitate testing biologically important hypotheses such as patterns and levels of somatic mutation and how these characteristics vary as a function of tissue type, age, and sex. Moreover, we will experimentally validate a large number of putative somatic mutations, which will allow filtering criteria to be adjusted resulting in a robust catalog of somatic mutations. In Aim 2, we will capitalize on the RNA-Seq data generated by the GTEx Project and use innovative approaches to test the hypothesis that somatic mutations contribute to gene expression variability. Collectively, these data will profoundly increase our understanding of human somatic mutations, their patterns and characteristics among tissues and individuals, and their influence on transcript abundance. Moreover, our data will be a considerable resource to the GTEx and scientific community, and we will make all project data easily accessible.