Structural variant-based pangenome construction has low sensitivity to variability of haplotype-resolved bovine assemblies

Leonard, Alexander S.; Crysnanto, Danang; Fang, Zih-Hua; Heaton, Michael P.; Ley, B. L. Vander; Herrera, Carolina; Bollwein, Heinrich; Bickhart, Derek M.; Kuhn, Kristen L.; Smith, Timothy P. L.; Rosen, Benjamin D.; Pausch, Hubert

doi:10.1101/2021.11.02.466900

Cited by 9 publications

(7 citation statements)

References 138 publications

(184 reference statements)

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“…Code used for generating the results and subsequent analyses in this work can be found at https://github.com/AnimalGenomicsETH/bovine-assembly and on Zenodo at 10.5281/zenodo.6503779 106 .…”

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confidence: 99%

Structural variant-based pangenome construction has low sensitivity to variability of haplotype-resolved bovine assemblies

et al. 2022

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Advantages of pangenomes over linear reference assemblies for genome research have recently been established. However, potential effects of sequence platform and assembly approach, or of combining assemblies created by different approaches, on pangenome construction have not been investigated. Here we generate haplotype-resolved assemblies from the offspring of three bovine trios representing increasing levels of heterozygosity that each demonstrate a substantial improvement in contiguity, completeness, and accuracy over the current Bos taurus reference genome. Diploid coverage as low as 20x for HiFi or 60x for ONT is sufficient to produce two haplotype-resolved assemblies meeting standards set by the Vertebrate Genomes Project. Structural variant-based pangenomes created from the haplotype-resolved assemblies demonstrate significant consensus regardless of sequence platform, assembler algorithm, or coverage. Inspecting pangenome topologies identifies 90 thousand structural variants including 931 overlapping with coding sequences; this approach reveals variants affecting QRICH2, PRDM9, HSPA1A, TAS2R46, and GC that have potential to affect phenotype.

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Structural variant-based pangenome construction has low sensitivity to variability of haplotype-resolved bovine assemblies

et al. 2022

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“…We created the pangenome variant panel using 16 HiFi-based haplotype-resolved cattle assemblies, including four previously published assemblies (two Original Braunvieh, one Brown Swiss, and one Piedmontese; (Crysnanto et al 2021;Leonard et al 2022)), eight newly generated assemblies from previously published data (four Original Braunvieh and four Brown Swiss; (Leonard et al 2023)), and four assemblies from new data (four Brown Swiss). All assemblies were aligned to the cattle reference genome, ARS-UCD1.2 (Rosen et al 2020), followed by calling variants from the alignments in confident regions (as described by PanGenie).…”

Section: Resultsmentioning

confidence: 99%

Pangenome-genotyped structural variation improves molecular phenotype mapping in cattle

Leonard,

Mapel,

Pausch

2024

Genome Res.

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Expression and splicing quantitative trait loci (e/sQTL) are large contributors to phenotypic variability. Achieving sufficient statistical power for e/sQTL mapping requires large cohorts with both genotypes and molecular phenotypes, and so the genomic variation is often called from short-read alignments which are unable to comprehensively resolve structural variation. Here we build a pangenome from 16 HiFi haplotype-resolved assemblies to identify small and structural variation and genotype them with PanGenie in 307 short-read samples. We find high (>90%) concordance of PanGenie-genotyped and DeepVariant-called small variation, and confidently genotype close to 21M small and 43k structural variants in the larger population. We validate 85% of these structural variants (with MAF>0.1) directly with a subset of 25 short-read samples that also have medium coverage HiFi reads. We then conduct e/sQTL mapping with this comprehensive variant set in a subset of 117 cattle that have testis transcriptome data and find 92 structural variants as causal candidates for eQTL and 73 for sQTL. We find that roughly half of top associated structural variants affecting expression or splicing are transposable elements, such as SV-eQTLs forSTN1andMYH7and SV-sQTLs forCEP89andASAH2. Extensive linkage disequilibrium between small and structural variation results in only 28 additional eQTL and 17 sQTL discovered when including SVs, although many top associated SVs are compelling candidates.

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Section: Resultsmentioning

confidence: 99%

Pangenome genotyped structural variation improves molecular phenotype mapping in cattle

Leonard

Mapel

Pausch

2023

Preprint

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Expression and splicing quantitative trait loci (e/sQTL) are large contributors to phenotypic variability. Achieving sufficient statistical power for e/sQTL mapping requires large cohorts with both genotypes and molecular phenotypes, and so the genomic variation is often called from short read alignments which are unable to comprehensively resolve structural variation. Here we build a pangenome from 16 HiFi haplotype-resolved assemblies to identify small and structural variation and genotype them with PanGenie in 307 short read samples. We find high (>90%) concordance of PanGenie-genotyped and DeepVariant-called small variation, and confidently genotype close to 21M small and 43k structural variants in the larger population. We validate 85% of these structural variants (with MAF>0.1) directly with a subset of 25 short read samples that also have medium coverage HiFi reads. We then conduct e/sQTL mapping with this comprehensive variant set in a subset of 117 cattle that have testis transcriptome data and find 92 structural variants as causal candidates for eQTL and 73 for sQTL. We find that roughly half of top associated structural variants affecting expression or splicing are transposable elements, such as SV-eQTLs for STN1 and MYH7 and SV-sQTLs for CEP89 and ASAH2. Extensive linkage disequilibrium between small and structural variation results in only 28 additional eQTL and 17 sQTL discovered when including SVs, although many top associated SVs are compelling candidates.

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Structural variant-based pangenome construction has low sensitivity to variability of haplotype-resolved bovine assemblies

Cited by 9 publications

References 138 publications

Structural variant-based pangenome construction has low sensitivity to variability of haplotype-resolved bovine assemblies

Structural variant-based pangenome construction has low sensitivity to variability of haplotype-resolved bovine assemblies

Pangenome-genotyped structural variation improves molecular phenotype mapping in cattle

Pangenome genotyped structural variation improves molecular phenotype mapping in cattle

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