Molecular phenotyping of ~100,000 coding variants across Mendelian disease genes

孟德尔疾病基因约 100,000 个编码变异的分子表型分析

• 批准号: 10631108
• 负责人: Marc Vidal
• 金额: $ 184.84万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-23 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631108
• 关键词: Affect; American; Benign; Biomedical Research; Catalogs; Cell Survival; Cellular Morphology; Classification; ClinVar; Code; Collection; Communities; Complex; DNA sequencing; Data; Data Set; Databases; Development; Disease; Frustration; General Population; Genes; Genetic; Genetic Diseases; Genotype; Goals; Health; Hereditary Disease; Human; Human Genetics; Individual; Laboratories; Lead; Measures; Mediating; Mendelian disorder; Modeling; Molecular; National Human Genome Research Institute; Online Mendelian Inheritance In Man; Pathogenesis; Pathogenicity; Phenotype; Property; Proteins; Proteome; RNA Splicing; Resources; Source; Technology; Therapeutic Intervention; Translating; Variant; Work; causal variant; functional genomics; gene product; genetic information; genetic variant; genomic variation; human genomics; human reference genome; insertion/deletion mutation; insight; molecular phenotype; novel; outcome prediction; phenotypic data; predictive modeling; protein protein interaction; therapeutically effective; trait; variant of unknown significance

Abstract The last four decades have produced an enormous catalog of human genomic variants which has the potential to revolutionize human genetics. Among the variants identified in the human “variome” so far, some appear benign, i.e. they don’t seem to confer any particular phenotype, a significant proportion are associated or potentially associated with one or more genetically inherited disorders, but an even greater percentage of observed human variants, 99% of missense variants, remain uninterpreted or annotated as variants of unknown significance (VUSs). To translate this huge amount of genetic information into general principles underlying genotype-phenotype relationships as well as molecular mechanisms responsible for the development of inherited disease, there is an urgent need for large-scale, systematic, high throughput “functional characterization” projects such as those envisioned within the new “Impact of Genomic Variation on Function” (IGVF) Consortium proposed by NHGRI. Although most monogenic Mendelian disorders are individually rare, when combined these diseases affect 20 million Americans. The ClinVar database describes within 3,671 Mendelian disease genes over 260,000 missense variants classified as pathogenic, benign, or VUSs. We currently lack strong and comprehensive evidence to systematically analyze coding variants across the spectrum of human Mendelian diseases. We propose to functionally characterize ~100,000 variants across most of the known Mendelian disease- associated genes by comparing wild-type, or “reference”, gene products and their corresponding variants for a rich array of fundamental protein properties and phenotypic impacts, including protein stability (expression), subcellular localization, cell viability, cell morphology, and the ability to mediate macromolecular interactions with protein partners. Our Variant Characterization Across the Mendelian Proteome (VarChAMP) Center will generate a searchable and widely available catalog of these variant effects via the IGVF Data and Administrative Coordinating Centers (DACCs), and assist in the “Predictive Modeling Projects” to carry out variant effect predictive modeling using this data. In addition to providing a rich source of functional information on tens of thousands of genomic variants in the next five years, all of our concepts, technologies and resources generated during this project are exportable and will be shared to enable others, both inside and outside the IGVF consortium, to leverage our approach in their own studies and expand the catalog.

抽象的 过去四十年产生了大量人类基因组变异目录，这些变异具有潜在的潜力 迄今为止，在人类“变异组”中发现的变异中，有一些出现了。 良性的，即它们似乎没有赋予任何特定的表型，很大一部分是相关的或 可能与一种或多种遗传性疾病有关，但更大比例的 观察到的人类变异中，99% 的错义变异仍未解释或注释为未知变异 意义（VUS）将大量的遗传信息转化为基本原理。 基因型-表型关系以及负责遗传发展的分子机制 疾病，迫切需要大规模、系统、高通量的“功能表征” 诸如新的“基因组变异对功能的影响”（IGVF）联盟中设想的项目 由国家人类健康研究所提出。 虽然大多数单基因孟德尔疾病单独罕见，但当这些疾病组合在一起时，会影响 20 ClinVar 数据库描述了 3,671 个孟德尔疾病基因，超过 260,000 个。 我们目前缺乏强大且全面的错义变异，分为致病性、良性或 VUS。 系统分析人类孟德尔疾病谱系变异编码的证据。 我们建议对大多数已知孟德尔疾病的约 100,000 个变异进行功能表征 - 通过比较野生型或“参考”基因产物及其相应的变体来分析相关基因 丰富的基本蛋白质特性和表型影响，包括蛋白质稳定性（表达）， 亚细胞定位、细胞活力、细胞形态以及介导大分子相互作用的能力 蛋白质伙伴。 我们的孟德尔蛋白质组变异表征 (VarChAMP) 中心将生成一个可搜索的 以及通过 IGVF 数据和行政协调中心广泛提供的这些变异效应的目录 （DACC），并协助“预测建模项目”利用 这些数据除了提供有关数以万计的基因组变异的丰富的功能信息之外。 未来五年，我们在这个项目中产生的所有概念、技术和资源都可以输出 并将被共享，以使 IGVF 联盟内部和外部的其他人能够利用我们的方法 自己研究并扩大目录。

项目成果

Characterizing glucokinase variant mechanisms using a multiplexed abundance assay.

使用多重丰度测定表征葡萄糖激酶变异机制。

• DOI: 10.1101/2023.05.24.542036
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Gersing,Sarah;Schulze,TheaK;Cagiada,Matteo;Stein,Amelie;Roth,FrederickP;Lindorff-Larsen,Kresten;Hartmann-Petersen,Rasmus
• 通讯作者: Hartmann-Petersen,Rasmus

Homo cerevisiae-Leveraging Yeast for Investigating Protein-Protein Interactions and Their Role in Human Disease.

• DOI: 10.3390/ijms24119179
• 发表时间: 2023-05-24
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Genome-scale mapping of DNA damage suppressors through phenotypic CRISPR-Cas9 screens.

• DOI: 10.1016/j.molcel.2023.06.025
• 发表时间: 2023-07
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Yichao Zhao;Daniel Tabet;Diana Rubio Contreras;Linjiang Lao;A. N. Kousholt;Jochen Weile;Henrique Melo;Lisa Hoeg;Sumin Feng;Atina G. Coté;Zhen-Yuan Lin;Dheva Setiaputra;J. Jonkers;A. Gingras;Fernando Gómez Herreros;F. Roth;D. Durocher