A survey of algorithms for the detection of genomic structural variants from long-read sequencing data

Ahsan, Mian Umair; Liu, Qian; Perdomo, Jonathan Elliot; Fang, Li; Wang, Kai

doi:10.1038/s41592-023-01932-w

Cited by 21 publications

(11 citation statements)

References 128 publications

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“…While historically challenging, functional analysis of SVs has started taking off because of recent breakthroughs in long-read sequencing [9,[51][52][53][54][55][56][57][58][59]. As the latest long-read technology, HiFi sequencing has markedly improved read accuracy to >99.8% [50] and will likely become increasingly important in SV discovery [39,60,61]. Concurrently, new SV detection algorithms, including both long-read aligners and SV callers, are under rapid development [38,39].…”

Section: Discussionmentioning

confidence: 99%

“…As the latest long-read technology, HiFi sequencing has markedly improved read accuracy to >99.8% [50] and will likely become increasingly important in SV discovery [39,60,61]. Concurrently, new SV detection algorithms, including both long-read aligners and SV callers, are under rapid development [38,39]. Given these advancements, there is a pressing necessity to assess the performance of these bioinformatic tools, especially for the intricate plant genomes.…”

Section: Discussionmentioning

confidence: 99%

“…However, given that the random insertion error in previous PacBio long reads has been addressed in HiFi sequencing [39,50], we speculated that the coverage of HiFi sequencing may not strongly affect the false positive rate of SV calling. To test the hypothesis, we downsampled the HiFi reads of strangulata, the diploid wheat accession that was sequenced at the coverage of 6.6×, to examine the performance of the 20 ACCs at different levels of sequencing depth.…”

Section: Low-coverage Hifi Sequencing For Sv Discoverymentioning

confidence: 99%

“…Recently, a growing number of long-read algorithms, including both aligners (e.g., pbmm2, NGMLR [31], Winnowmap2 [32], and Minimap2 [33]) and SV callers (e.g., pbsv, cuteSV [34], SVIM [35], SVDSS [36], and Sniffles2 [37]), have been developed for SV detection [38,39]. With the great stride in sequencing technology and toolset development, it is important to benchmark bioinformatic tools to optimize the use of HiFi reads while performing SV detection in plant genomes.…”

Section: Introductionmentioning

confidence: 99%

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Structural variation discovery in wheat using PacBio high-fidelity sequencing

Zhang,

Kang

et al. 2023

Preprint

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BackgroundStructural variations (SVs) pervade plant genomes and contribute substantially to the phenotypic diversity. However, most SVs were ineffectively assayed because of their complex nature and the limitations of early genomic technologies. The recent advance in third-generation sequencing, particularly the PacBio high-fidelity (HiFi) sequencing technology, produces highly accurate long-reads and offers an unprecedented opportunity to characterize SVs’ structure and functionality. As HiFi sequencing is relatively new to population genomics, it is imperative to evaluate and optimize HiFi sequencing based SV detection before applying the technology at scale.ResultsWe sequenced wheat genomes using HiFi reads, followed by a comprehensive evaluation of mainstream long-read aligners and SV callers in SV detection. The results showed that the accuracy of deletion discovery is markedly influenced by callers, which account for 87.73% of the variance, while both aligners (38.25%) and callers (49.32%) contributed substantially to the accuracy variance for insertions. Among the aligners, Winnowmap2 and NGMLR excelled in detecting deletions and insertions, respectively. For SV callers, SVIM achieved the best performance. We demonstrated that combining the aligners and callers mentioned above is optimal for SV detection. Furthermore, we evaluated the effect of sequencing depth on the accuracy of SV detection, showing that low-coverage HiFi sequencing is sufficiently robust for high-quality SV discovery.ConclusionsThis study thoroughly evaluated SV discovery approaches using HiFi reads, establishing optimal workflows to investigate structural variations in the wheat genome. The notable accuracy of SV discovery from low-coverage HiFi sequencing indicates that skim HiFi sequencing is effective and preferable to characterize SVs at the population level. This study will help advance SV discovery and decipher the biological functions of SVs in wheat and many other plants.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Low-coverage Hifi Sequencing For Sv Discoverymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structural variation discovery in wheat using PacBio high-fidelity sequencing

Zhang,

Kang

et al. 2023

Preprint

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“…Long-read sequencing has addressed this problem by generating reads with lengths of tens of kilobases without the need for PCR amplification, compared to the 150-300 bp lengths of short-read technologies. Long-read sequencing can generate reads spanning the entire structural variant and flanking regions, allowing for more confident identification of variants present in repetitive regions of the genome [18][19][20]. Long-read sequencing also enables detection of germline-derived and somatic retrotransposon insertions, including those present in only a single cell, as demonstrated in Drosophila melanogaster head and midgut using singleton reads (somatic insertions supported by a single read) [21].…”

Section: Introductionmentioning

confidence: 99%

Nanopore-based DNA long-read sequencing analysis of the aged human brain

Ramirez,

Sun,

Kazempour Dehkordi

et al. 2024

Preprint

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Aging disrupts cellular processes such as DNA repair and epigenetic control, leading to a gradual buildup of genomic alterations that can have detrimental effects in post-mitotic cells. Genomic alterations in regions of the genome that are rich in repetitive sequences, often termed “dark loci,” are difficult to resolve using traditional sequencing approaches. New long-read technologies offer promising avenues for exploration of previously inaccessible regions of the genome. Using nanopore-based long-read whole-genome sequencing of DNA extracted from aged 18 human brains, we identify previously unreported structural variants and methylation patterns within repetitive DNA, focusing on transposable elements (“jumping genes”) as crucial sources of variation, particularly in dark loci. Our analyses reveal potential somatic insertion variants and provides DNA methylation frequencies for many retrotransposon families. We further demonstrate the utility of this technology for the study of these challenging genomic regions in brains affected by Alzheimer’s disease and identify significant differences in DNA methylation in pathologically normal brains versus those affected by Alzheimer’s disease. Highlighting the power of this approach, we discover specific polymorphic retrotransposons with altered DNA methylation patterns. These retrotransposon loci have the potential to contribute to pathology, warranting further investigation in Alzheimer’s disease research. Taken together, our study provides the first long-read DNA sequencing-based analysis of retrotransposon sequences, structural variants, and DNA methylation in the aging brain affected with Alzheimer’s disease neuropathology.

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