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: 10424543
• 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/10424543
• 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; 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.

项目摘要 与环境一起，细胞，个体，人群和物种之间的遗传差异驱动 生物组织每个级别的表型差异。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。使用人类 作为模型，特定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）人类表型差异的后果。 非整倍性会影响一半以上的人类胚胎，是妊娠丧失的主要原因。我的实验室 试图了解各种形式的非整倍性和子的程度和表型后果 染色体结构变异，从基因表达水平缩放到细胞和生物体 表型。为此，我开发了一种统计方法来量化副本之间的关系 单个基因的数量和表达。通过将这种方法应用于混合DNA和RNA的样品 测序数据，我们将衡量拷贝数更改的表达后果和可能性 某些基因对其作用“缓冲”。我们还将改善检测马赛克的方法 单细胞数据中的非整倍性，有助于解决有关其事件的争议和对人类的影响 胚胎发展。延伸以外的胚胎，我们将挖掘单细胞基因组数据集以介绍组织 - 染色体镶嵌物和剂量敏感性特异性图的广泛景观。 研究改变健身突变的完整方法集中在进化时段。 先前的研究已经确定，调节变化影响基因表达在 表型差异。将尼安德特尔和丹尼索汤序列渗入现代人类基因组中 提供了一个独特的机会来表征此类监管替代。通过大规模分析 等位基因特定的表达，我最近证明了尼安德特尔序列的四分之一会议会议 显着的顺式调节作用。我们将通过测量等位基因特异性来将这项工作扩展到Denisovan的渗入 来自海洋个体的细胞系中的表达。这将使我们能够对比 在不同的人类组中产生的突变，测试有关谱系特异性和共享模式的假设 人类调节性进化。除了基因表达水平，遗传变异还会影响替代 剪接构成了与表型变异和疾病的主要联系。要了解其在人类进化中的作用， 我们将量化存档等位基因对替代剪接模式的影响。通过对比表达和 侵入性和控制非亲流起源突变的剪接影响，我们将寻求一般见解 驱动表型差异的调节变化的特征。