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

项目摘要 所有的种群都是遗传变异的，人类，以及他们体内的体细胞种群， 也不例外。遗传变异解释了大部分表型变异，并部分决定了 常见和罕见的疾病。分析等位基因变体的功能效应为以下方面提供了独特的视角： 分子功能在广泛的有机体背景下。遗传变异的研究提供了对 在短时间尺度上的进化行为，并有助于检测自然选择的足迹， 基因组的未表征的功能元件。测序数据集的爆炸式增长， 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 这一奋进的前沿。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复制与修复生物学--推断诱变机制。我们将发展计算方法 分析和预测人类等位基因变异对分子功能的影响。我们亦会研究 控制种群中等位基因命运的进化力量，以便更好地理解 有害变异此外，我们还将研究基因型与 表型，包括多基因遗传和罕见疾病变异的部分突变。这些 主题--变异的起源、持续性和影响--是相互交织的，对它们的综合理解是 对人类医学遗传学和癌症基因组学的进展至关重要。

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.