The design and construction of reference pangenome graphs with minigraph
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The design and construction of reference pangenome graphs with minigraph Heng Li1,2*
, Xiaowen Feng1,2 and Chong Chu2
*Correspondence: [email protected] 1 Department of Data Sciences, Dana-Farber Cancer Institute, Boston 02215, MA, USA 2 Department of Biomedical Informatics, Harvard Medical School, Boston 02215, MA, USA
Abstract The recent advances in sequencing technologies enable the assembly of individual genomes to the quality of the reference genome. How to integrate multiple genomes from the same species and make the integrated representation accessible to biologists remains an open challenge. Here, we propose a graph-based data model and associated formats to represent multiple genomes while preserving the coordinate of the linear reference genome. We implement our ideas in the minigraph toolkit and demonstrate that we can efficiently construct a pangenome graph and compactly encode tens of thousands of structural variants missing from the current reference genome. Keywords: Bioinformatics, Genomics, Pangenome
Background The human reference genome is a fundamental resource for human genetics and biomedical research. The primary sequences of the reference genome GRCh38 [1] are a mosaic of haplotypes with each haplotype segment derived from a single human individual. They cannot represent the genetic diversity in human populations, and as a result, each individual may carry thousands of large germline variants absent from the reference genome [2]. Some of these variants are likely associated with phenotype [3] but are often missed or misinterpreted when we map sequence data to GRCh38, in particular with short reads [4]. This under-representation of genetic diversity may become a limiting factor in our understanding of genetic variations. Meanwhile, the advances in long-read sequencing technologies make it possible to assemble a human individual to a quality comparable to GRCh38 [1, 5]. There are already a dozen of high-quality human assemblies available in GenBank [6]. Properly integrating these genomes into a reference pangenome, which refers to a collection of genomes [7], would potentially address the issues with a single linear reference.
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