Representing structural haplotypes and complex genetic variation in pan-genome graphs

表示泛基因组图中的结构单倍型和复杂的遗传变异

基本信息

批准号：
10832934
负责人：
Mark Chaisson
金额：
$ 26.76万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2024-01-31
项目状态：
已结题

项目摘要

Project Summary The initial phase of sequencing the human pangenome has resulted in the assembly of a diverse collection of genomes. In parallel, an ecosystem of sophisticated computational methods were developed to organize the pangenome a graphical data structure that efficiently reflects the diversity of a global population, as well as sequence analysis methods required for geneticists to use the pangenome to improve how their studies are performed relative to a single reference genome. The pangenome revealed important factors about human genetic variation. In particular, there is a considerable amount of sequence diversity and novel sequences in the pangenome that arise from repetitive DNA. Because the initial methods developed to analyze variation in the pangenome were created for relatively simplistic variation outside of repetitive DNA, it is necessary to develop novel methods to discover, genotype, and organize, and validate variation in repetitive regions of the genome. The scope of this analysis spans short repeated DNA sequences that are hundreds of bases long, to entire regions that encompass genes. We will specifically develop methods to discover rare variation in variable-number tandem repeat sequences, and perform paralog-specific discovery of copy-number variation of genes. These methods will be developed to analyze short-read sequencing data so that large scale datasets such as those generated by TOPMed can take advantage of these methods to improve variant discovery in their cohorts. We will additionally develop methods to improve the representation of repetitive or rearranged sequences in the graphical representation of the pangenome. This will be accomplished by modeling the evolutionary relationships of repetitive sequences while building the graph, and validating assembly organization using public datasets from the single-cell sequencing technique, Strand-Seq. All of our development will be performed collaboratively with other members of the Human Pangenome Reference Consortium. We will share methods for variant discovery with other researchers who are studying large cohorts. Finally, any improvements in the pangenome graph will be released in coordination with production and other groups so that there is a standardized pangenome graph for other researchers in the public to base research from.

项目摘要测序的人斑点的初始阶段导致了A组装各种基因组收集。同时，复杂计算的生态系统开发了组织pangenome的图形数据结构的方法反映了全球人群的多样性，以及所需的序列分析方法遗传学家使用pangenome来改善其研究的方式单个参考基因组。 pangenome揭示了有关人遗传的重要因素变化。特别是，有相当多的序列多样性和新颖由重复DNA引起的pangenome中的序列。因为初始方法为分析pangenome的变异而开发的是为了相对简单的变化而创建的在重复的DNA之外，有必要开发出新的方法来发现，基因型和组织并验证基因组重复区域的变化。该分析的范围跨越短的重复的DNA序列，该序列长度为数百个碱基，到整个区域包含基因。我们将专门开发发现罕见变化的方法可变数字的串联重复序列，并执行旁系同源的发现基因的拷贝数变异。这些方法将开发以分析短阅读测序数据使得大规模数据集（例如由Topmed生成的数据集）可以接受这些方法的优势可以改善同类群体中的变异发现。我们还将开发方法来改善重复或重新排列序列的表示 Pangenome的图形表示。这将通过建模重复序列的进化关系，并在构建图形并验证使用单细胞测序技术中的公共数据集的组装组织， Strand-seq。我们所有的发展都将与其他成员合作人类pangenome参考联盟。我们将与其他正在研究大型队列的研究人员。最后，pangenome的任何改进图将与生产和其他组协调发布，以便有一个公众其他研究人员的标准化pangenome图。