Variant calling tool evaluation for variable size indel calling from next generation whole genome and targeted sequencing data

Wang, Ning; Lysenkov, Vladislav; Orte, Katri; Kairisto, Veli; Aakko, Juhani; Khan, Sofia; Elo, Laura L.

doi:10.1101/2021.07.15.452444

Cited by 3 publications

(2 citation statements)

References 52 publications

(87 reference statements)

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“…The true dominance of Delta-ORF7a Δ17del genomes in Australia could also be underestimated in this study since the dataset includes travellers who returned to Australia (who more likely lacked the mutation that was characteristic of the Australian cases) and genomes with potentially incomplete ORF7a sequences (i.e., those potentially lacking coverage at some or all positions 27,607–27,623). Additionally, variant calling software can have difficulties with correctly calling insertion/deletions (indels) [ 25 ], and GISAID does not release submissions that contain a frameshift mutation by default (unless it is specifically requested). Finally, the ongoing transmission of Delta-ORF7a Δ17del occurred despite the cocirculation of a virus that would be presumably more “fit” (Delta-ORF7a intact ) because truncation of the ORF7a C-terminus which leads to a loss of the transmembrane domain has been associated with decreased viral fitness in some (but not all) studies by negating the anti-immune properties of the protein [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Persistence of a Frameshifting Deletion in SARS-CoV-2 ORF7a for the Duration of a Major Outbreak

Foster

Bull

Tedla

et al. 2023

Viruses

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Australia experienced widespread COVID-19 outbreaks from infection with the SARS-CoV-2 Delta variant between June 2021 and February 2022. A 17-nucleotide frameshift-inducing deletion in ORF7a rapidly became represented at the consensus level (Delta-ORF7aΔ17del) in most Australian outbreak cases. Studies from early in the COVID-19 pandemic suggest that frameshift-inducing deletions in ORF7a do not persist for long in the population; therefore, Delta-ORF7aΔ17del genomes should have disappeared early in the Australian outbreak. In this study, we conducted a retrospective analysis of global Delta genomes to characterise the dynamics of Delta-ORF7aΔ17del over time, determined the frequency of all ORF7a deletions worldwide, and compared global trends with those of the Australian Delta outbreak. We downloaded all GISAID clade GK Delta genomes and scanned them for deletions in ORF7a. For each deletion we identified, we characterised its frequency, the number of countries it was found in, and how long it persisted. Of the 4,018,216 Delta genomes identified globally, 134,751 (~3.35%) possessed an ORF7a deletion, and ORF7aΔ17del was the most common. ORF7aΔ17del was the sole deletion in 28,014 genomes, of which 27,912 (~99.6%) originated from the Australian outbreak. During the outbreak, ~87% of genomes were Delta-ORF7aΔ17del, and genomes with this deletion were sampled until the outbreak’s end. These data demonstrate that, contrary to suggestions early in the COVID-19 pandemic, genomes with frameshifting deletions in ORF7a can persist over long time periods. We suggest that the proliferation of Delta-ORF7aΔ17del genomes was likely a chance founder effect. Nonetheless, the frequency of ORF7a deletions in SARS-CoV-2 genomes worldwide suggests they might have some benefit for virus transmission.

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Section: Discussionmentioning

confidence: 99%

Persistence of a Frameshifting Deletion in SARS-CoV-2 ORF7a for the Duration of a Major Outbreak

Foster

Bull

Tedla

et al. 2023

Viruses

View full text Add to dashboard Cite

show abstract

“…The true dominance of Delta-ORF7a Δ17del genomes in Australia could even be underestimated here since the data set includes returned travellers to Australia (more likely to lack the mutation characteristic of Australian cases), and genomes with potentially incomplete ORF7a sequences (i.e., those potentially lacking coverage at some or all of positions 27607–27623). Additionally, variant calling software can have difficulties with correctly calling insertion/deletions (indels) (14), and by default GISAID does not release submissions that contain a frameshift mutation (unless specifically requested). Finally, the ongoing transmission of Delta-ORF7a Δ17del occurred despite cocirculation of presumably a more “fit” virus (Delta-ORF7a intact ).…”

Section: Discussionmentioning

confidence: 99%

Persistence of a SARS-CoV-2 variant with a frameshifting deletion for the duration of a major outbreak

Foster

Bull

Tedla

et al. 2022

Preprint

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Australia experienced widespread COVID-19 outbreaks from infection with the SARS-CoV-2 Delta variant between June 2021 and February 2022. Whole-genome sequencing of virus from an early case revealed a sub-consensus level of sequencing reads supporting a 17-nucleotide frameshift-inducing deletion in ORF7a that truncated the peptide sequence. The variant rapidly became represented at the consensus level (Delta-ORF7aΔ17del) in most of the outbreak cases in Australia. Retrospective analysis of ORF7a deletions in all GISAID clade GK Delta genomes showed that of 4,018,216 genomes, 134,751 (~3.35%) possessed a deletion in ORF7a, with the ORF7aΔ17del mutation by far the most common. Approximately 99.05% of Delta-ORF7aΔ17del genomes on GISAID originated from the Australian Delta outbreak, and comprised 87% of genomes in the outbreak. In vitro comparison of lineages in cell culture showed a significantly greater proportion of cells were infected with Delta-ORF7aΔ17del than with a contemporaneous Delta variant without ORF7aΔ17del (Delta-ORF7aintact), and the proportion was also measurably higher than an early SARS-CoV-2 strain (A.2.2). These results showed that Delta-ORF7aΔ17del potentially has a slight growth advantage compared to Delta-ORF7aintact. Delta-ORF7aΔ17del viruses still produced ORF7a protein, but significantly less than A.2.2, in a different cellular distribution with a more diffuse expression throughout the cytoplasm of infected cells. These data suggest that the proliferation of Delta-ORF7aΔ17del genomes during the Australian Delta outbreak was likely not a result of an intrinsic benefit of the ORF7aΔ17del mutation, but rather a chance founder effect. Nonetheless, the abundance of different ORF7a deletions in genomes worldwide suggests these have some benefit to virus transmission. IMPORTANCE Deletions in the ORF7a region of SARS-CoV-2 have been noted since early in the COVID-19 pandemic, but are generally reported as transient mutations that are quickly lost in the population. Consequently, ORF7a deletions are considered disadvantageous to the virus through possible loss-of-function effects. In constrast to these earlier reports, we present the first report of a SARS-CoV-2 variant with an ORF7a deletion that dominated for the entirety of a protracted outbreak, and found no associated fitness disadvantage or advantage in cell culture. The relatively common rise and fall of ORF7a deletion variants over time likely represent chance founder events followed by proliferation until a more fit variant(s) is introduced to the population. Our global clade-level survey of ORF7a deletions will be a useful resource for future studies into this gene region.

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Optimizing Insertion and Deletion Detection Using Next-Generation Sequencing in the Clinical Laboratory

Craven

Fischer²,

Jiang³

et al. 2022

The Journal of Molecular Diagnostics

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Variant calling tool evaluation for variable size indel calling from next generation whole genome and targeted sequencing data

Cited by 3 publications

References 52 publications

Persistence of a Frameshifting Deletion in SARS-CoV-2 ORF7a for the Duration of a Major Outbreak

Persistence of a Frameshifting Deletion in SARS-CoV-2 ORF7a for the Duration of a Major Outbreak

Persistence of a SARS-CoV-2 variant with a frameshifting deletion for the duration of a major outbreak

Optimizing Insertion and Deletion Detection Using Next-Generation Sequencing in the Clinical Laboratory

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