The construction and utility of reference pan-genome graphs

项目摘要 目前的人类参考基因组GRCh 38在医学和人口人类遗传学中起着核心作用。 它主要是模拟一个单一的人类个体，并遗漏了数十万个大的结构变化 在人群中隔离。这种遗传多样性的代表性不足导致了数据中的各种人为因素 分析和显着妨碍我们的功能和医疗相关性的理解，这些大的 人类的变异，这些变异可能共同产生广泛的影响。为了解决这个问题，我们将扩大我们的 以前的工作序列图和比对算法，并构建一个泛基因组参考图，从 数百个长时间阅读的人类组装，更完整地代表了遗传多样性。具体来说，我们将 (1)设计一个具有与GRCh 38兼容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）开发基于最小化器的序列到图比对 短序列和长序列的算法;（3）通过映射程序集来增量地构造参考图 现有的图和更新图;和（4）开发基于图的基因分型算法并应用它 以短读为基础的项目，以调用当前管道遗漏的结构变化。建成后 拟议的项目可以取代目前基于线性基因组的做法，并将使分析和 目前大多数研究都忽略了复杂的人类变异。

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.