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: 10112282
• 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 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112282
• 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; Structure; 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.

项目摘要 当前的人类参考基因组GRCH38在医学和人群人遗传学中起着核心作用。 它主要是建模一个人，并且缺少数十万个大型结构变化 人口隔离。遗传多样性的这种代表性不足会导致数据中的各种文物 分析并显着阻碍我们对这些大型功能和医学相关性的理解 人类的变化，可能会产生普遍影响。为了解决这个问题，我们将扩展我们的 先前在序列图和对齐算法上的工作，并从 数百种更完全代表遗传多样性的长阅读人类集会。具体来说，我们会的 （1）设计具有与GRCH38兼容的稳定坐标系的参考图模型并开发 工具包和库与此模型交互； （2）开发基于最小化器的序列到射线对齐 短序列和长序列的算法； （3）通过映射组件逐步构建参考图 到现有图并更新图形； （4）开发基于图的基因分算法并应用它 基于简短的项目，以调用当前管道错过的结构变化。完成后， 拟议的项目可以基于线性基因组替代当前实践，并将实现分析和 在大多数当前研究中，对复杂的人类变异的研究缺失。