Functional and Fitness Consequences of Human Genetic Variation

人类遗传变异的功能和健康后果

• 批准号: 10000185
• 负责人: Rajiv Champion McCoy
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-21 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000185
• 关键词: Admixture; Affect; Alleles; Alternative Splicing; Aneuploidy; Biological; Biological Assay; Buffers; Cell Line; Cells; Characteristics; Complex; Computing Methodologies; DNA sequencing; Data; Disease; Embryo; Embryonic Development; Environment; Evolution; Gene Expression; Genes; Genetic; Genetic Variation; Genetic study; Genomics; Human; Human Genetics; Human Genome; Incidence; Individual; Link; Maps; Measures; Methods; Modeling; Modernization; Molecular; Mosaicism; Mutation; Oceans; Pattern; Phenotype; Play; Population; Pregnancy loss; RNA Splicing; Research; Role; Sampling; Shapes; Statistical Methods; Structure; Testing; Tissues; Variant; Work; cell type; dosage; fitness; functional genomics; genomic data; improved; insight; programs; trait; transcriptome sequencing

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.

项目概要 除了环境之外，细胞、个体、种群和物种之间的遗传差异也驱动着 生物组织各个层面的表型差异。我的研究计划开发计算 以及量化自然遗传变异的功能和适应性影响的统计方法。利用人类 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 1) 人类非整倍性和 2) 人类表型差异的适应性后果。 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性和亚型的程度和表型后果 染色体结构变异，从基因表达水平到细胞和生物体水平 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。通过将此方法应用于含有 DNA 和 RNA 组合的样本 测序数据，我们将测量拷贝数改变的表达后果以及可能性 某些基因可以“缓冲”其影响。我们还将改进检测马赛克的方法 单细胞数据中的非整倍性，有助于解决有关其发生率及其对人类影响的争议 胚胎发育。除了胚胎之外，我们还将挖掘单细胞基因组数据集来分析组织- 染色体嵌合体的广泛景观和剂量敏感性的细胞类型特异性图。 研究适应度改变突变的补充方法侧重于进化时间尺度。 先前的研究已经证实，影响基因表达的调控变化在 表型分歧。尼安德特人和丹尼索瓦人序列渗入现代人类基因组 提供了一个独特的机会来描述这种监管替代的特征。通过大规模分析 等位基因特异性表达，我最近证明四分之一的持久尼安德特人序列赋予 显着的顺式调节作用。我们将通过测量等位基因特异性将这项工作扩展到丹尼索瓦人基因渗入 在来自海洋个体的细胞系中表达。这将使我们能够对比表达效果 不同古人类群体中出现的突变，检验有关谱系特异性和共享模式的假设 古人类的调节进化。除了基因表达水平外，遗传变异也会影响替代方案 剪接构成表型变异和疾病的主要联系。为了了解它在古人类进化中的作用， 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 为了了解基因渗入和非古老起源的控制突变的剪接效应，我们将寻求对 驱动表型分歧的监管变化的特征。