Incomplete Penetrance via Edgetic Suppression

通过边缘抑制实现不完全渗透

• 批准号: 10013247
• 负责人: Michael A Calderwood
• 金额: $ 59.12万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013247
• 关键词: Affect; Alleles; Animal Model; Applications Grants; Attention; Biochemical; Biological; Biological Models; Biological Process; Cell physiology; Complex; DNA; DNA-Protein Interaction; Development; Disease; Environment; Essential Genes; Genes; Genetic; Genetic Phenomena; Genome; Genotype; Heterogeneity; Histone Deacetylase; Human; Human Genome; Impairment; Individual; Lead; Learning; Maps; Mendelian disorder; Methods; MicroRNAs; Modeling; Molecular; Molecular Genetics; Mutation; Penetrance; Phenotype; Population Genetics; Property; Proteins; Proteome; Resources; Saccharomyces cerevisiae; Site; System; Testing; Variant; Yeast Model System; Yeasts; base; causal variant; disease phenotype; exhaustion; exome sequencing; functional genomics; gene environment interaction; gene interaction; gene product; genetic variant; genomic data; genomic locus; genomic tools; human disease; human reference genome; improved; mutation screening; network models; protein protein interaction; resilience; tool; trait; yeast genome; yeast protein

Abstract A decade and a half after the release of the human genome sequence, how well do we understand the molecular mechanisms underlying genotype-phenotype relationships? Importantly, as we generate ever- increasing numbers of genome sequences from diseased but also healthy individuals, how well can we predict the phenotype of an individual from information available about their genotype? The more we learn about the human genome, the further we seem to deviate from the simple model: “mutation in gene X leads to perturbation of gene product X, which leads to disease A”. Among the most prevailing and mysterious deviations from this simple model are: (i) incomplete penetrance, whereby only a subset of individuals carrying a mutation are affected by the disease, and (ii) variable expressivity, whereby not all individuals affected by a given mutation are affected equally. These two interconnected phenomena have recently attracted attention because sequencing of exomes and genomes of healthy individuals shows an unanticipated burden of damaging mutations, with an average of ~300 damaging variants and >50 variants causing Mendelian disorders. This burden of damaging variants suggests a heretofore-unrecognized level of genetic resilience. It is becoming increasingly clear that gene products function in the context of complex interactome networks that need to be considered to fully illuminate genotype-phenotype relationships. Proteome-scale systematic interactome maps, which model these networks of molecular components and interactions between them as “nodes” and “edges”, respectively, are rapidly becoming available to initiate such approaches. We have started to dissect how disease-associated mutations impair interactions in the context of interactome networks. We have found that while common variants from healthy individuals rarely affect protein-protein interactions or DNA-protein interactions, a majority of disease-associated alleles perturb interactions, with about half corresponding to what we refer to as “edge-specific” or ``edgetic'' alleles, i.e. alleles affecting a single or a subset of interactions while leaving other interactions unperturbed. This grant application is focused on understanding incomplete penetrance based on gene-gene interactions. Our central hypothesis is that incomplete penetrance can very often be best explained by edgetic alleles that are genetically suppressed by compensatory alleles in interacting partners. Due to a huge limitation in statistical power to test this “edgetic suppression” hypothesis in human, we will first concentrate on S. cerevisiae as a model organism to develop the necessary concepts, methods and tools. We will leverage the recent release of ~1,000 yeast genome sequences to identify and characterize large numbers of pairs of natural variants that are damaging individually, but cooperatively functional. The strategies developed and general mechanisms discovered will be directly applicable to solving incomplete penetrance in humans.

抽象的 人类基因组序列发布后的十年半，我们对 基因型 - 表型关系的分子机制？重要的是，随着我们的产生 - 越来越多的基因组序列来自被剥离的人，也增加了健康的个体，我们如何预测 从有关其基因型的信息中获得的个人表型？我们了解的越多 人类基因组，我们似乎越偏离简单模型：“基因X中的突变导致 基因产物X的扰动，导致疾病A”。 与这个简单模型的背离是：（i）不完整的外观，仅一部分携带的个体 突变受该疾病的影响，（ii）可变表达性，因此并非所有受A的个人影响 给定突变受到平等影响。这两个互连现象最近引起了人们的注意 因为对健康个体的外来体和基因组的测序显示出意外的伯嫩 破坏性突变，平均约300个破坏性变体，> 50个变体引起Mendelian 疾病。破坏性变体的这种燃烧表明，迄今为止未经认可的遗传弹性水平。 越来越清楚的是，基因产物在复杂的Interactome网络的背景下起作用 需要考虑这一点才能完全照亮基因型 - 表型关系。蛋白质组规模系统 Interactome图，将这些分子组件的这些网络及其之间的相互作用建模为 “节点”和“边缘”分别迅速启动这种方法。我们已经开始了 为了剖析疾病相关的突变如何在相互作用网络的背景下损害相互作用。我们 已经发现，尽管来自健康个体的常见变体很少影响蛋白质 - 蛋白质相互作用或 DNA蛋白相互作用，大多数与疾病相关的等位基因的扰动相互作用，大约一半 对应于我们所谓的“特定于边缘”或``'edgetic'等位基因，即影响一个或一个的等位基因 相互作用的子集，而其他互动不受干扰。 该赠款应用的重点是理解基于基因 - 基因相互作用的不完整的渗透率。 我们的核心假设是，不完整的外渗通常可以通过饰面等位基因来解释 相互作用的伙伴中的补偿性等位基因通常被抑制。由于限制很大 统计能力测试人类中的“剂量抑制”假设，我们将首先专注于S。 酿酒酵母作为一种模型生物体，以开发必要的概念，方法和工具。我们将利用 最近发布了约1,000个酵母基因组序列，以识别和表征大量对 自然变体单独损坏但合作起作用。制定的策略和 发现的一般机制将直接适用于解决人类中不完整的渗透率。