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.

项目概要人类泛基因组测序的初始阶段已经组装了不同的基因组集合。与此同时，一个由复杂计算组成的生态系统开发了方法来组织泛基因组，这是一种有效的图形数据结构反映了全球人口的多样性，以及所需的序列分析方法遗传学家使用泛基因组来改进他们的研究相对于单一参考基因组。全基因组揭示了人类遗传的重要因素变化。特别是，存在大量的序列多样性和新颖性泛基因组中由重复 DNA 产生的序列。因为最初的方法开发用于分析全基因组变异，是为相对简单的变异而创建的除了重复的 DNA 之外，有必要开发新的方法来发现、基因分型和组织并验证基因组重复区域的变异。本次分析的范围跨越数百个碱基长的短重复DNA序列，到整个区域涵盖基因。我们将专门开发方法来发现罕见的变异可变数量串联重复序列，并执行旁系同源特异性发现基因的拷贝数变异。这些方法将被开发来分析短读对数据进行排序，以便大规模数据集（例如由 TOPMed 生成的数据集）可以采用利用这些方法来改善其群体中的变异发现。我们还将另外开发方法来改善重复或重新排列序列的表示全基因组的图形表示。这将通过建模来完成构建图表并验证时重复序列的进化关系使用单细胞测序技术的公共数据集进行组装组织，链序列。我们所有的开发都将与其他成员合作进行人类泛基因组参考联盟。我们将与您分享变异发现的方法其他正在研究大型队列的研究人员。最后，泛基因组的任何改进图表将与生产和其他小组协调发布，以便有一个标准化的全基因组图，供公众中的其他研究人员作为基础研究。