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Unbiased pangenome graphs

Garrison, Erik, Guarracino, Andrea·2023·Bioinformatics
DOI 10.1093/bioinformatics/btac743PMC PMC9805579

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Abstract

Motivation: Pangenome variation graphs model the mutual alignment of collections of DNA sequences. A set of pairwise alignments implies a variation graph, but there are no scalable methods to generate such a graph from these alignments. Existing related approaches depend on a single reference, a specific ordering of genomes or a de Bruijn model based on a fixed k-mer length. A scalable, self-contained method to build pangenome graphs without such limitations would be a key step in pangenome construction and manipulation pipelines. Results: We design the seqwish algorithm, which builds a variation graph from a set of sequences and alignments between them. We first transform the alignment set into an implicit interval tree. To build up the variation graph, we query this tree-based representation of the alignments to reduce transitive matches into single DNA segments in a sequence graph. By recording the mapping from input sequence to output graph, we can trace the original paths through this graph, yielding a pangenome variation graph. We present an implementation that operates in external memory, using disk-backed data structures and lock-free parallel methods to drive the core graph induction step. We demonstrate that our method scales to very large graph induction problems by applying it to build pangenome graphs for several species. Availability and implementation: seqwish is published as free software under the MIT open source license. Source code and documentation are available at https://github.com/ekg/seqwish. seqwish can be installed via Bioconda https://bioconda.github.io/recipes/seqwish/README.html or GNU Guix https://github.com/ekg/guix-genomics/blob/master/seqwish.scm.

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Figures

Fig. 1. A visual description of variation graph induction. (Top) An alignment graph model for three sequences and their alignments. Nodes are single characters (DNA base pairs, of which the forward strand is shown) in individual sequences. Solid edges link successive characters in each sequence, and are colored (red, green and blue) to identify each. Dashed edges indicate aligned pairs of characters. (Bottom) A variation graph model induced from the alignment graph. Each transitive match closure (gray shaded edges, of increasing darkness) in the alignment graph results in a single node in the output graph, which is labeled by the rank of the transitive closure operation that produced it. By recording the full set of match closures, we can project the sequences in the input through to paths in the variation graph (colored edges). The unique set of node pairings in the paths provide the edges of the output graph. Closures 1 and 6 imply pairwise relationships between sequences seq1 and seq3, and seq1 and seq2, respectively, that are both absent in the input alignments
Fig. 1. A visual description of variation graph induction. (Top) An alignment graph model for three sequences and their alignments. Nodes are single characters (DNA base pairs, of which the forward strand is shown) in individual sequences. Solid edges link successive characters in each sequence, and are colored (red, green and blue) to identify each. Dashed edges indicate aligned pairs of characters. (Bottom) A variation graph model induced from the alignment graph. Each transitive match closure (gray shaded edges, of increasing darkness) in the alignment graph results in a single node in the output graph, which is labeled by the rank of the transitive closure operation that produced it. By recording the full set of match closures, we can project the sequences in the input through to paths in the variation graph (colored edges). The unique set of node pairings in the paths provide the edges of the output graph. Closures 1 and 6 imply pairwise relationships between sequences seq1 and seq3, and seq1 and seq2, respectively, that are both absent in the input alignmentsCC BY · PubMed Central
Fig. 2. Experimental results from the application of seqwish to four different pangenomes. Each plot shows the runtime (in hours) versus the average input genome length calculated as the total length of all sequences in the pangenome divided by the number of included haplotypes. Multiple minimum identity settings for the mapping (wfmash -p) and different minimum match length filter settings (seqwish -k) result in a collection of graph builds per pangenome input. We compare the runtime in hours with the size of the resulting graphs relative to the average size of an input genome in the particular set. Lower limits on pairwise identity result in more compact graphs. Similarly, filtering short matches increases graph size relative to not (seqwish -k = 0, red). The other way around, increasing the seqwish -k parameter tends to increase the size of the graph
Fig. 2. Experimental results from the application of seqwish to four different pangenomes. Each plot shows the runtime (in hours) versus the average input genome length calculated as the total length of all sequences in the pangenome divided by the number of included haplotypes. Multiple minimum identity settings for the mapping (wfmash -p) and different minimum match length filter settings (seqwish -k) result in a collection of graph builds per pangenome input. We compare the runtime in hours with the size of the resulting graphs relative to the average size of an input genome in the particular set. Lower limits on pairwise identity result in more compact graphs. Similarly, filtering short matches increases graph size relative to not (seqwish -k = 0, red). The other way around, increasing the seqwish -k parameter tends to increase the size of the graphCC BY · PubMed Central
Fig. 3. Base-pair lengths of graphs built from 100 permutations of yeast chrV. Each point corresponds to the length of a graph built from a specific permutation and the given method. We color each point by the first genome in the order (the ‘reference’ in minigraph). A boxplot per first genome group provides the mean and the first and third quartile intervals for each reference grouping
Fig. 3. Base-pair lengths of graphs built from 100 permutations of yeast chrV. Each point corresponds to the length of a graph built from a specific permutation and the given method. We color each point by the first genome in the order (the ‘reference’ in minigraph). A boxplot per first genome group provides the mean and the first and third quartile intervals for each reference groupingCC BY · PubMed Central

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Cites

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Research works printed but not linked: 23

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Metadata

Authors
Garrison, E., & Guarracino, A.
Affiliations
  • Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center , Memphis, TN 38163, USA
  • Genomics Research Centre, Human Technopole , Viale Rita Levi-Montalcini 1 , Milan 20157, Italy
ORCID
Venue
Bioinformatics
Publisher
Oxford University Press (OUP)
Published
2022-11-30
Volume
39
Issue
1
ISSN
1367-4811
DOI
10.1093/bioinformatics/btac743
PMC
PMC9805579
Cited by
95
References
3
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • NIH
  • NIDA (U01DA047638)
  • NSF PPoSS (#2118709)
  • Human Technopole in Milan

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Garrison, E., & Guarracino, A. (2023). Unbiased pangenome graphs. Bioinformatics. https://doi.org/10.1093/bioinformatics/btac743