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The Collaborative Cross Graphical Genome

The mouse reference is one of the most widely used and accurately assembled mammalian genomes, and is the foundation for a wide range of bioinformatics and genetics tools. However, it represents the genomic organization of a single inbred mouse strain. Recently, inexpensive and fast genome sequencing has enabled the assembly of other common mouse strains at a quality approaching that of the reference. However, using these alternative assemblies in standard genomics analysis pipelines presents significant challenges. It has been suggested that a pangenome reference assembly, which incorporates multiple genomes into a single representation, are the path forward, but there are few standards for, or instances of practical pangenome representations suitable for large eukaryotic genomes. We present a pragmatic graph-based pangenome representation as a genomic resource for the widely-used recombinant-inbred mouse genetic reference population known as the Collaborative Cross (CC) and its eight founder genomes. Our pangenome representation leverages existing standards for genomic sequence representations with backward-compatible extensions to describe graph topology and genome-specific annotations along paths. It packs 83 mouse genomes (8 founders + 75 CC strains) into a single graph representation that captures important notions relating genomes such as identity-by-descent and highly variable genomic regions. The introduction of special anchor nodes with sequence content provides a valid coordinate framework that divides large eukaryotic genomes into homologous segments and addresses most of the graph-based position reference issues. Parallel edges between anchors place variants within a context that facilitates orthogonal genome comparison and visualization. Furthermore, our graph structure allows annotations to be placed in multiple genomic contexts and simplifies their maintenance as the assembly improves. The CC reference pangenome provides an open framework for new tool chain development and analysis.