The origin, the function and the phenotypic impact of human alleles

人类等位基因的起源、功能和表型影响

• 批准号: 10623515
• 负责人: SHAMIL SUNYAEV
• 金额: $ 90.48万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-11 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623515
• 关键词: Alleles; Biology; Computing Methodologies; DNA; DNA Repair; DNA biosynthesis; Data Set; Elements; Evolution; Explosion; Genetic Variation; Genetic study; Genome; Genotype; Human; Human Genetics; Medical Genetics; Molecular; Mutagenesis; Natural Selections; Penetrance; Phenotype; Polygenic Traits; Population; Rare Diseases; Research; Risk; Somatic Cell; Statistical Data Interpretation; Statistical Methods; Techniques; Variant; cancer genomics; genetic variant; programs; Alleles; Biology; Computing Methodologies; DNA; DNA Repair; DNA biosynthesis; Data Set; Elements; Evolution; Explosion; Genetic Variation; Genetic study; Genome; Genotype; Human; Human Genetics; Medical Genetics; Molecular; Mutagenesis; Natural Selections; Penetrance; Phenotype; Polygenic Traits; Population; Rare Diseases; Research; Risk; Somatic Cell; Statistical Data Interpretation; Statistical Methods; Techniques; Variant; cancer genomics; genetic variant; programs

Project Summary All populations are genetically variable, and humans, as well as the populations of somatic cells in their bodies, are no exception. Genetic variation explains much of phenotype variation and partially determines the risk of common and rare disease. Analysis of the functional effects of allelic variants opens a unique perspective on molecular function in the broad organismal context. Study of genetic variation provides understanding of the actions of evolution over short timescales and helps detect footprints of natural selection that point to uncharacterized functional elements of the genome. The explosion of sequencing datasets in combination with new computational and statistical techniques, propel genetic variation research. Our lab plans to be at the forefront of this endeavor. Our broad research program will analyze genetic variation from multiple angles. We will study mutagenesis as the origin of genetic variation, and use statistical analysis—in the context of known DNA replication and repair biology—to infer mutagenic mechanisms. We will develop computational methods to analyze and predict the effect of human allelic variants on molecular function. We will also study the evolutionary forces governing the fate of alleles in populations, in order to better understand the persistence of deleterious variation. Additionally, we will examine the principles of the relationship between genotype and phenotype, including both polygenic inheritance and the partial penetrance of rare disease variants. These topics—the origins, persistence, and effects of variants—are intertwined, and their integrated understanding is critical to the progress of human medical genetics and cancer genomics.

项目摘要 所有种群都是遗传上可变的，人类以及体内体细胞的种群， 也不例外。遗传变异解释了表型的大部分变异，并部分决定了 常见和稀有疾病。分析Allic变体的功能效应，对 在广泛的有机环境中的分子功能。遗传变异的研究提供了对 在短时间内进化的动作，并有助于检测自然选择的足迹 基因组的未表征功能元素。测序数据集的爆炸与结合 新的计算和统计技术，推动遗传变异研究。我们的实验室计划在 这项努力的最前沿。我们广泛的研究计划将从多个角度分析遗传变异。我们 将研究诱变作为遗传变异的起源，并使用统计分析 - 在已知的背景下 DNA复制和修复生物学 - 推断诱变机制。我们将开发计算方法 分析和预测人类等位基因变体对分子功能的影响。我们还将研究 为了更好地理解人口中等位基因命运的进化力量 有害变化。此外，我们将研究基因型与 表型，包括多基因遗传和稀有疾病变体的部分渗透率。这些 主题 - 变体的起源，持久性和效果 - 都交织在一起，它们的综合理解是 对于人类医学遗传学和癌症基因组学的进步至关重要。