The construction and utility of reference pan-genome graphs

参考泛基因组图的构建和利用

• 批准号: 10379369
• 负责人: Heng Li
• 金额: $ 80万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379369
• 关键词: Address; Adoption; Algorithms; Awareness; Back; Base Sequence; Biological Assay; Biomedical Research; Companions; Complement; Complex; Computer software; Data; Data Analyses; Diagnostic; Disease; Ecosystem; Frequencies; Future; Genetic Research; Genetic Variation; Genome; Genotype; Graph; Haplotypes; Heart; Human; Human Resources; Individual; Informatics; Libraries; Mainstreaming; Maps; Medical; Methods; Modeling; Morphologic artifacts; Mosaicism; Phenotype; Play; Population; Population Genetics; Population Heterogeneity; Problem Solving; Research; Research Personnel; Role; Sequence Alignment; Speed; System; Time; Update; Variant; Work; base; bioinformatics tool; cancer genomics; design; experience; human population genetics; human reference genome; indexing; linear transformation; pan-genome; programs; reference genome; success; support tools; tool; user-friendly

PROJECT SUMMARY The current human reference genome, GRCh38, plays a central role in medical and population human genetics. It primarily models a single human individual and is missing hundreds of thousands of large structural variations segregating in the population. This underrepresentation of genetic diversity leads to various artifacts in data analysis and significantly hampers our understanding of the functional and medical relevance of these large human variations, which may collectively have pervasive impact. To address this issue, we will extend our previous work on sequence graphs and alignment algorithms and construct a pan-genome reference graph from hundreds of long-read human assemblies that more completely represent genetic diversity. Specifically, we will (1) design a reference graph model with a stable coordinate system compatible with GRCh38 and develop toolkits and libraries to interact with this model; (2) develop minimizer-based sequence-to-graph alignment algorithms for short and long sequences; (3) incrementally construct a reference graph by mapping assemblies to an existing graph and updating the graph; and (4) develop a graph-based genotyping algorithm and apply it to short-read based projects to call structural variations missed by the current pipelines. Upon completion, the proposed project could replace the current practices based on a linear genome and will enable the profiling and study of complex human variations missed in most current research.

项目概要 当前的人类参考基因组 GRCh38 在医学和人口人类遗传学中发挥着核心作用。 它主要模拟单个人类个体，并且缺少数十万个大型结构变化 人口中的隔离。遗传多样性的代表性不足导致数据中存在各种伪影 分析并极大地妨碍了我们对这些大的功能和医学相关性的理解 人类的差异，这些差异可能共同产生普遍的影响。为了解决这个问题，我们将延长我们的 之前关于序列图和比对算法的工作，并从构建泛基因组参考图 数百个长读的人类组合更完整地代表了遗传多样性。具体来说，我们将 (1)设计兼容GRCh38的稳定坐标系的参考图模型并开发 与该模型交互的工具包和库； (2) 开发基于最小化的序列到图的对齐 短序列和长序列的算法； (3) 通过映射程序集增量构建参考图 到现有图表并更新该图表； (4) 开发基于图的基因分型算法并应用 基于短读的项目来调用当前管道遗漏的结构变化。完成后，将 拟议的项目可以取代基于线性基因组的当前实践，并将能够进行分析和 目前大多数研究都忽略了对复杂人类变异的研究。