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Gramtools enables multiscale variation analysis with genome graphs.

ABSTRACT: Genome graphs allow very general representations of genetic variation; depending on the model and implementation, variation at different length-scales (single nucleotide polymorphisms (SNPs), structural variants) and on different sequence backgrounds can be incorporated with different levels of transparency. We implement a model which handles this multiscale variation and develop a JSON extension of VCF (jVCF) allowing for variant calls on multiple references, both implemented in our software gramtools. We find gramtools outperforms existing methods for genotyping SNPs overlapping large deletions in M. tuberculosis and is able to genotype on multiple alternate backgrounds in P. falciparum, revealing previously hidden recombination.

SUBMITTER: Letcher B

PROVIDER: S-EPMC8420074 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Gramtools enables multiscale variation analysis with genome graphs.

Letcher Brice B Hunt Martin M Iqbal Zamin Z

Genome biology 20210906 1

Genome graphs allow very general representations of genetic variation; depending on the model and implementation, variation at different length-scales (single nucleotide polymorphisms (SNPs), structural variants) and on different sequence backgrounds can be incorporated with different levels of transparency. We implement a model which handles this multiscale variation and develop a JSON extension of VCF (jVCF) allowing for variant calls on multiple references, both implemented in our software gr ...[more]

PMID: 34488837

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Project description:BackgroundGenotyping of sequence variants typically involves, as a first step, the alignment of sequencing reads to a linear reference genome. Because a linear reference genome represents only a small fraction of all the DNA sequence variation within a species, reference allele bias may occur at highly polymorphic or divergent regions of the genome. Graph-based methods facilitate the comparison of sequencing reads to a variation-aware genome graph, which incorporates a collection of non-redundant DNA sequences that segregate within a species. We compared the accuracy and sensitivity of graph-based sequence variant genotyping using the Graphtyper software to two widely-used methods, i.e., GATK and SAMtools, which rely on linear reference genomes using whole-genome sequencing data from 49 Original Braunvieh cattle.ResultsWe discovered 21,140,196, 20,262,913, and 20,668,459 polymorphic sites using GATK, Graphtyper, and SAMtools, respectively. Comparisons between sequence variant genotypes and microarray-derived genotypes showed that Graphtyper outperformed both GATK and SAMtools in terms of genotype concordance, non-reference sensitivity, and non-reference discrepancy. The sequence variant genotypes that were obtained using Graphtyper had the smallest number of Mendelian inconsistencies between sequence-derived single nucleotide polymorphisms and indels in nine sire-son pairs. Genotype phasing and imputation using the Beagle software improved the quality of the sequence variant genotypes for all the tools evaluated, particularly for animals that were sequenced at low coverage. Following imputation, the concordance between sequence- and microarray-derived genotypes was almost identical for the three methods evaluated, i.e., 99.32, 99.46, and 99.24% for GATK, Graphtyper, and SAMtools, respectively. Variant filtration based on commonly used criteria improved genotype concordance slightly but it also decreased sensitivity. Graphtyper required considerably more computing resources than SAMtools but less than GATK.ConclusionsSequence variant genotyping using Graphtyper is accurate, sensitive and computationally feasible in cattle. Graph-based methods enable sequence variant genotyping from variation-aware reference genomes that may incorporate cohort-specific sequence variants, which is not possible with the current implementation of state-of-the-art methods that rely on linear reference genomes.

Dataset Information

Gramtools enables multiscale variation analysis with genome graphs.

Publications

Gramtools enables multiscale variation analysis with genome graphs.

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