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 在过去的四十年中，产生了人类基因组变异的巨大目录，具有潜力 彻底改变人类遗传学。到目前为止，在人类“ variome”中确定的变体中，有些外观 良性，即他们似乎没有赋予任何特定的表型，相关的很大比例是相关的或 可能与一种或多种遗传遗传的疾病相关，但更大的百分比 观察到的人类变体（99％的错义变体）仍然没有解释或注释为未知的变体 意义（vuss）。将这些大量遗传信息转化为基础的一般原则 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，系统的，高通量的“功能表征” 诸如新的“基因组变异对功能的影响”（IGVF）财团中所设想的项目 由NHGRI提出。 尽管大多数单基因孟德尔疾病是个体罕见的，但是当这些疾病组合时会影响20 百万美国人。 Clinvar数据库描述了超过260,000的Mendelian病基因的3,671个 错义变体被归类为致病性，良性或范围。我们目前缺乏强大而全面的 系统地分析人类孟德尔疾病范围内的编码变体的证据。 我们建议在大多数已知的孟德尔病 - 通过比较野生型或“参考”，基因产物及其相应变体的相关基因 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 蛋白质伴侣。 我们在Mendelian Proteome（Varchamp）中心中的变体表征将生成可搜索的 并通过IGVF数据和管理协调中心广泛使用这些变体效应的目录 （DACC），并协助使用“预测建模项目”，以使用 这个数据。除了提供数万个基因组变体的丰富功能信息来源 在接下来的五年中，我们在本项目中产生的所有概念，技术和资源都是可导出的 并将分享以使其他人内部和外部的其他人都在 他们自己的研究并扩大目录。

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