The construction and utility of reference pan-genome graphs

项目总结 目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，缺少数十万个大的结构变化 人口中的种族隔离。这种对遗传多样性的低估导致了数据中的各种伪像 分析并显著阻碍了我们对这些大的 人类的变异，这些变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 以前在序列图和比对算法方面的工作，并构建了一个泛基因组参考图 数百个长期阅读的人类组合，更完整地代表了遗传多样性。具体来说，我们将 (1)设计与GRCH38兼容的具有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比对 针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 (4)开发了一种基于图形的基因分型算法，并将其应用于 以短文为基础的项目，以调用当前管道错过的结构变化。完成后， 拟议的项目可以取代目前基于线性基因组的做法，并将使分析和 对复杂的人类变异的研究在大多数当前的研究中遗漏了。

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.