Functional and Fitness Consequences of Human Genetic Variation

项目摘要 沿着环境因素，细胞、个体、种群和物种之间的遗传差异 表型差异在每个生物组织水平。我的研究项目开发了计算 和统计方法来量化自然遗传变异的功能和健身效果。利用人类 作为一种模式，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）人类非整倍性和2）人类表型分歧的适应性后果。 非整倍体影响超过一半的人类胚胎，是导致妊娠失败的主要原因。我的实验室 试图了解各种形式的非整倍体和亚整倍体的程度和表型后果， 染色体结构变异，从基因表达水平到细胞和生物体 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。通过将这种方法应用于具有组合DNA和RNA的样品， 测序数据，我们将测量拷贝数改变的表达后果和可能性， 某些基因对它的影响有"缓冲"作用我们还将改进检测马赛克的方法 单细胞数据中的非整倍体，有助于解决有关其发病率和对人类的影响的争议 胚胎发育除了胚胎，我们还将挖掘单细胞基因组数据集来分析组织- 广泛的染色体镶嵌现象和细胞类型特异性剂量敏感性图谱。 研究适应性改变突变的补充方法侧重于进化时间尺度。 先前的研究已经确定，影响基因表达的调节变化在以下方面起主要作用： 表型趋异尼安德特人和丹尼索瓦人基因序列渗入现代人类基因组 提供了一个独特的机会来表征这样的监管取代。通过大规模的分析， 等位基因特异性表达，我最近证明，四分之一的持续尼安德特人序列赋予 显著的顺式调节作用。我们将通过测量等位基因特异性， 在源自大洋个体的细胞系中表达。这将使我们能够对比 在不同的人类群体中出现的突变，测试关于谱系特异性和共享模式的假设 人类进化的规律除了基因表达水平外，遗传变异还影响替代性 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可变剪接模式的影响。通过对比表达和 非古老起源的渐渗和控制突变的剪接效应，我们将寻求对非古老起源的基因组的一般见解。 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.