Comprehensively assessing human somatic variability and its influence on gene exp

尽管人们通常认为人体内数万亿个细胞共享相同的DNA序列， 事实上我们是基因组的马赛克。这种镶嵌的程度在很大程度上是未知的，但无论是理论上和 经验研究表明，人体中的体细胞突变负担相当大。事实上，此外， 癌症和衰老，这两个过程中，体细胞突变是众所周知的发挥不可或缺的作用，超过30 其它疾病表型可归因于体细胞变异性。体细胞突变也被 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。然而，很少有系统和全面的研究， 组织和个体之间的体细胞变异性，因此体细胞突变的景观仍然存在 大部分未知。这种知识上的差距是许多正在进行的和未来的研究的一个重大障碍。 人类表型变异和疾病易感性，如解释体细胞变异， 癌症基因组测序项目。为此，拟议项目的目标是利用 由GTEx项目创建的资源，用于严格和系统地分析人体的 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个外显子组），并确定体细胞序列和结构变异。重要的是我们 我仔细设计了研究和研究的特定组织，以促进生物学重要性的测试 体细胞突变的模式和水平，以及这些特征如何作为一个功能而变化 组织类型年龄和性别此外，我们将通过实验验证大量假定的体细胞 突变，这将允许调整过滤标准，从而产生稳健的体细胞突变目录。在 目标2，我们将利用GTEx项目产生的RNA-Seq数据，并使用创新方法 以检验体细胞突变导致基因表达变异性的假设。这些数据共同 将深刻地增加我们对人类体细胞突变，其模式和特征的理解 以及它们对转录本丰度的影响。此外，我们的数据将是一个 我们将为GTEx和科学界提供可观的资源，我们将使所有项目数据轻松 容易接近

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.