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GraphTyper2 enables population-scale genotyping of structural variation using pangenome graphs.

ABSTRACT: Analysis of sequence diversity in the human genome is fundamental for genetic studies. Structural variants (SVs) are frequently omitted in sequence analysis studies, although each has a relatively large impact on the genome. Here, we present GraphTyper2, which uses pangenome graphs to genotype SVs and small variants using short-reads. Comparison to the syndip benchmark dataset shows that our SV genotyping is sensitive and variant segregation in families demonstrates the accuracy of our approach. We demonstrate that incorporating public assembly data into our pipeline greatly improves sensitivity, particularly for large insertions. We validate 6,812 SVs on average per genome using long-read data of 41 Icelanders. We show that GraphTyper2 can simultaneously genotype tens of thousands of whole-genomes by characterizing 60 million small variants and half a million SVs in 49,962 Icelanders, including 80 thousand SVs with high-confidence.

SUBMITTER: Eggertsson HP

PROVIDER: S-EPMC6881350 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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GraphTyper2 enables population-scale genotyping of structural variation using pangenome graphs.

Eggertsson Hannes P HP Kristmundsdottir Snaedis S Beyter Doruk D Jonsson Hakon H Skuladottir Astros A Hardarson Marteinn T MT Gudbjartsson Daniel F DF Stefansson Kari K Halldorsson Bjarni V BV Melsted Pall P

Nature communications 20191127 1

Analysis of sequence diversity in the human genome is fundamental for genetic studies. Structural variants (SVs) are frequently omitted in sequence analysis studies, although each has a relatively large impact on the genome. Here, we present GraphTyper2, which uses pangenome graphs to genotype SVs and small variants using short-reads. Comparison to the syndip benchmark dataset shows that our SV genotyping is sensitive and variant segregation in families demonstrates the accuracy of our approach. ...[more]

PMID: 31776332

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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

GraphTyper2 enables population-scale genotyping of structural variation using pangenome graphs.

Publications

GraphTyper2 enables population-scale genotyping of structural variation using pangenome graphs.

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