Functional and Fitness Consequences of Human Genetic Variation

项目摘要 随着环境的变化，细胞、个体、种群和物种之间的遗传差异 生物组织各层次的表型差异。我的研究项目开发了计算机 以及量化自然遗传变异的功能和适合性影响的统计方法。使用人类 作为模型，具体的研究主题包括研究遗传基础、分子机制和功能 以及1)人类非整倍体和2)人类表型差异的适合性后果。 非整倍体影响了超过一半的人类胚胎，是导致妊娠丢失的主要原因。我的实验室 旨在了解各种形式的非整倍体和亚倍体的程度和表型后果 染色体结构变异，从基因表达水平向上扩展到细胞和有机 表型。为此，我开发了一种统计方法来量化复制之间的关系 单个基因的数量和表达。将这种方法应用于DNA和RNA结合的样品 对数据进行测序，我们将测量拷贝数改变的表达后果和可能性 某些基因被“缓冲”，不受其影响。我们还将改进检测花叶病毒的方法 单细胞数据中的非整倍体，有助于解决关于其发病率和对人类的影响的争议 胚胎发育。除了胚胎，我们将挖掘单细胞基因组数据集来描述组织- 广泛的染色体嵌合体景观和特定细胞类型的剂量敏感性图谱。 一种研究改变健康的突变的补充方法集中在进化时间尺度上。 先前的研究已经证实，影响基因表达的调节变化在 表型分化。尼安德特人和丹尼索瓦人序列在现代人类基因组中的导入 提供了一个独特的机会来描述这种监管替代的特征。通过大规模的分析 等位基因特有的表达，我最近证明了四分之一的持久尼安德特人序列赋予 显著的顺式监管效应。我们将通过测量等位基因特异性将这项工作扩展到Denisovan导入 在来自海洋个体的细胞系中的表达。这将使我们能够对比 在不同的人类群体中出现的突变，测试关于特定血统和共同模式的假设 原始人的调节进化。除了基因表达水平外，遗传变异还会影响另一种 剪接构成了表型变异和疾病的主要联系。为了了解它在人类进化中的作用， 我们将量化古老等位基因对选择性剪接模式的影响。通过对比表达和 非古老起源的导入和控制突变的剪接效应，我们将寻求对 驱动表型分化的调控变化的特征。

Project Summary Along with the environment, genetic differences between cells, individuals, populations, and species drive phenotypic differences at each level of biological organization. My research program develops computational and statistical methods to quantify the functional and fitness effects of natural genetic variation. Using humans as a model, specific research themes include studying the genetic basis, molecular mechanisms, and functional and fitness consequences of 1) human aneuploidy and 2) hominin phenotypic divergence. Aneuploidy affects more than half of human embryos and is the leading cause of pregnancy loss. My lab seeks to understand the extent and phenotypic consequences of various forms of aneuploidy and sub- chromosomal structural variation, scaling from the level of gene expression up to cellular and organismal phenotypes. To this end, I have developed a statistical approach to quantify the relationship between copy number and expression of individual genes. By applying this approach to samples with combined DNA and RNA sequencing data, we will measure the expression consequences of copy number alteration and the possibility that certain genes are “buffered” against its effects. We will also improve methods for detecting mosaic aneuploidy in single-cell data, helping resolve controversy about its incidence and implications for human embryonic development. Extending beyond embryos, we will mine single-cell genomic datasets to profile tissue- wide landscapes of chromosomal mosaicism and cell-type-specific maps of dosage sensitivity. A complementary approach for studying fitness-altering mutations focuses on evolutionary timescales. Previous research has established that regulatory changes influencing gene expression play a primary role in phenotypic divergence. Introgression of Neandertal and Denisovan sequences into modern human genomes provides a unique opportunity to characterize such regulatory substitutions. Through a large-scale analysis of allele-specific expression, I recently demonstrated that one quarter of persisting Neandertal sequences confer significant cis-regulatory effects. We will extend this work to Denisovan introgression by measuring allele-specific expression in cell lines derived from Oceanic individuals. This will allow us to contrast expression effects of mutations that arose in different hominin groups, testing hypotheses about lineage-specific and shared patterns of hominin regulatory evolution. In addition to gene expression levels, genetic variation influencing alternative splicing constitutes a primary link to phenotypic variation and disease. To understand its role in hominin evolution, we will quantify the effects of archaic alleles on patterns of alternative splicing. By contrasting expression and splicing effects of introgressed and control mutations of non-archaic origin, we will seek general insights into the characteristics of regulatory changes that drive phenotypic divergence.