Probabilistic Inference of Viral Quasispecies Subject to Recombination

Töpfer, Armin; Zagordi, Osvaldo; Prabhakaran, Sandhya; Röth, Volker; Halperin, Eran; Beerenwinkel, Niko

doi:10.1089/cmb.2012.0232

Cited by 127 publications

(118 citation statements)

References 27 publications

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“…The assembly of SPFMV used the reference genome already described (13), and was driven with Quasirecomb (23). The same procedure was applied to SPVC and SPV2.…”

Section: Plant and Virus Materials Commercial Sweet Potato (Ipomea Bmentioning

confidence: 99%

The P1N-PISPO trans -Frame Gene of Sweet Potato Feathery Mottle Potyvirus Is Produced during Virus Infection and Functions as an RNA Silencing Suppressor

Mingot

Vallí

Rodamilans

et al. 2016

J Virol

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The positive-sense RNA genome of Sweet potato feathery mottle virus (SPFMV) (genus Potyvirus, family Potyviridae) contains a large open reading frame (ORF) of 3,494 codons translatable as a polyprotein and two embedded shorter ORFs in the ؊1 frame: PISPO, of 230 codons, and PIPO, of 66 codons, located in the P1 and P3 regions, respectively. PISPO is specific to some sweet potato-infecting potyviruses, while PIPO is present in all potyvirids. In SPFMV these two extra ORFs are preceded by conserved G 2 A 6 motifs. We have shown recently that a polymerase slippage mechanism at these sites could produce transcripts bringing these ORFs in frame with the upstream polyprotein, thus leading to P1N-PISPO and P3N-PIPO products (B. Rodamilans, A. IMPORTANCEGene products of potyviruses include P1, HCPro, P3, 6K1, CI, 6K2, VPg/NIaPro, NIb, and CP, all derived from the proteolytic processing of a large polyprotein, and an additional P3N-PIPO product, with the PIPO segment encoded in a different frame within the P3 cistron. In sweet potato feathery mottle virus (SPFMV), another out-of-frame element (PISPO) was predicted within the P1 region. We have shown recently that a polymerase slippage mechanism can generate the transcript variants with extra nucleotides that could be translated into P1N-PISPO and P3N-PIPO. Now, we demonstrate by mass spectrometry analysis that P1N-PISPO is indeed produced in SPFMV-infected plants, in addition to P1. Interestingly, while in other potyviruses the suppressor of RNA silencing is HCPro, we show here that P1N-PISPO exhibited this activity in SPFMV, revealing how the complexity of the gene content could contribute to supply this essential function in members of the Potyviridae family. P otyviruses (family Potyviridae) are important viral pathogens with positive-sense, single-stranded RNA genomes that are able to infect a wide range of plant species. The genomic RNA of potyviruses, around 10 kb in size with a viral protein (VPg) at its 5= end and polyadenylated at the 3= end, contains a large open reading frame (ORF) that encodes a polyprotein comprising the following gene products from the N to the C terminus: P1, HCPro, P3, 6K1, CI, 6K2, VPg/NIaPro, NIb, and CP (1, 2). Despite the abundant sequence information available on potyviruses, it was not until 2008 that the presence of a well-conserved second short ORF of around 60 codons, termed PIPO (Pretty Interesting Potyviral ORF) by its discoverers, was predicted as an overlapping product within the P3 region in all members of the family. Thus, this ORF yields a fusion product with the upstream portion of P3 after frameshift (P3N-PIPO), as found in plants infected with turnip mosaic virus (TuMV) (3). More recently, another short ORF termed PISPO (Pretty Interesting Sweet potato Potyviral ORF) was predicted by bioinformatics analysis within the P1-coding sequence of a few members of the Potyvirus genus, all related to sweet potato feathery mottle virus (SPFMV), including sweet po-

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“…The assembly of SPFMV used the reference genome already described (13), and was driven with Quasirecomb (23). The same procedure was applied to SPVC and SPV2.…”

Section: Plant and Virus Materials Commercial Sweet Potato (Ipomea Bmentioning

confidence: 99%

The P1N-PISPO trans -Frame Gene of Sweet Potato Feathery Mottle Potyvirus Is Produced during Virus Infection and Functions as an RNA Silencing Suppressor

Mingot

Vallí

Rodamilans

et al. 2016

J Virol

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“…QuasiRecomb [37] uses a hidden Markov model solution taking into account recombination events. We tested QuasiRecomb on the gag region of the HIV dataset, and it predicted over 9000 haplotypes.…”

Section: Methodsological Comparison Of Our Approachmentioning

confidence: 99%

Probabilistic recovery of cryptic haplotypes from metagenomic data

Nicholls

Aubrey²,

Grave

et al. 2017

Preprint

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The cryptic diversity of microbial communities represent an untapped biotechnological resource for biomining, biorefining and synthetic biology. Revealing this information requires the recovery of the exact sequence of DNA bases (or "haplotype") that constitutes the genes and genomes of every individual present. This is a computationally difficult problem complicated by the requirement for environmental sequencing approaches (metagenomics) due to the resistance of the constituent organisms to culturing in vitro.Haplotypes are identified by their unique combination of DNA variants. However, standard approaches for working with metagenomic data require simplifications that violate assumptions in the process of identifying such variation. Furthermore, current haplotyping methods lack objective mechanisms for choosing between alternative haplotype reconstructions from microbial communities. To address this, we have developed a novel probabilistic approach for reconstructing haplotypes from complex microbial communities and propose the "metahaplome" as a definition for the set of haplotypes for any particular genomic region of interest within a metagenomic dataset. Implemented in the twin software tools Hansel and Gretel, the algorithm performs incremental probabilistic haplotype recovery using Naive Bayes -an efficient and effective technique. Our approach is capable of reconstructing the haplotypes with the highest likelihoods from metagenomic datasets without a priori knowledge or making assumptions of the distribution or number of variants. Additionally, the algorithm is robust to sequencing and alignment error without altering or discarding observed variation and uses all available evidence from aligned reads. We validate our approach using synthetic metahaplomes constructed from sets of real genes, and demonstrate its capability using metagenomic data from a complex HIV-1 strain mix. The results show that the likelihood framework can allow recovery from microbial communities of cryptic functional isoforms of genes with 100% accuracy. 1. CC-BY 4.0 International license not peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/117838 doi: bioRxiv preprint first posted online Mar. 17, 2017; Genomic research is progressing beyond the use of consensus DNA sequences to represent species, towards the ultimate goal of complete characterisation of the genetic diversity that exists across their populations.So far, research has focused on characterising specific aspects of this diversity, for example: identifying the entire gene-set of all strains of a species (the pangenome) [1]; identifying the groups of genes (or genetic variants within) that are inherited together in organisms across entire populations (the haplome) [2] or in viruses, identifying strains related by mutations in a highly mutagenic environment (the quasispecies) [3].However many communities (and especially microbial communities) maintain a fine balance b...

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“…This was necessary, as the official HIV reference sequence is very divergent from our set of reads, and thus the initial mapping was only able to place an unsatisfyingly low number of reads onto this sequence. The second individual mapping was able to use a higher number of reads and to create sufficient alignments, which were used as input for the quasispecies reconstruction tool QuasiRecomb (49). This tool uses an expectation maximization algorithm not only to reconstruct the single sequences present in the viral population but also to assign their relative proportions.…”

Section: Methodsmentioning

confidence: 99%

“…Between 780 and 10,000 EnvV1V3 sequences were first reconstructed using QuasiRecomb (49). The 50 most frequent sequences/population were aligned, and sequences were compared (Fig.…”

Section: Cd25mentioning

confidence: 99%

CD25⁺FoxP3⁺Memory CD4 T Cells Are Frequent Targets of HIV InfectionIn Vivo

Chachage¹,

Pollakis

Kuffour

et al. 2016

J Virol

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Interleukin 2 (IL-2) signaling through the IL-2 receptor alpha chain (CD25) facilitates HIV replication in vitro AIDS is caused by human immunodeficiency virus (HIV) infection and is characterized by the failure of the immune system to control diverse opportunistic infections facilitated by the progressive loss of CD4 T cells. The rate of CD4 T cell depletion correlates with set point levels of HIV-1 viral load in plasma (1) and is critically dependent on ongoing viral replication. Antiretroviral therapy (ART) blocks viral replication, reverses CD4 T cell depletion (2), and reconstitutes immunity to most opportunistic pathogens. Replication of HIV within CD4 T cells significantly contributes to plasma viral load and thus to HIV disease progression (3). It is well established that intracellular HIV DNA loads in vivo are influenced by CD4 T cell differentiation (4-6), functional properties of CD4 T cells (7), and pathogen specificity (8-10) and that T cell activation and proliferation contribute to productive HIV infection of memory CD4 T cells (11)(12)(13)(14)(15). Together these results imply that, depending on their biological properties, different CD4 T cell subsets might differ in their susceptibilities to HIV infection and their contributions to virion production in vivo. Perhaps the best characterized CD4 T cell subset in this re-

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Probabilistic Inference of Viral Quasispecies Subject to Recombination

Cited by 127 publications

References 27 publications

The P1N-PISPO trans -Frame Gene of Sweet Potato Feathery Mottle Potyvirus Is Produced during Virus Infection and Functions as an RNA Silencing Suppressor

The P1N-PISPO trans -Frame Gene of Sweet Potato Feathery Mottle Potyvirus Is Produced during Virus Infection and Functions as an RNA Silencing Suppressor

Probabilistic recovery of cryptic haplotypes from metagenomic data

CD25⁺FoxP3⁺Memory CD4 T Cells Are Frequent Targets of HIV InfectionIn Vivo

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Probabilistic Inference of Viral Quasispecies Subject to Recombination

Cited by 127 publications

References 27 publications

The P1N-PISPO trans -Frame Gene of Sweet Potato Feathery Mottle Potyvirus Is Produced during Virus Infection and Functions as an RNA Silencing Suppressor

The P1N-PISPO trans -Frame Gene of Sweet Potato Feathery Mottle Potyvirus Is Produced during Virus Infection and Functions as an RNA Silencing Suppressor

Probabilistic recovery of cryptic haplotypes from metagenomic data

CD25+FoxP3+Memory CD4 T Cells Are Frequent Targets of HIV InfectionIn Vivo

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CD25⁺FoxP3⁺Memory CD4 T Cells Are Frequent Targets of HIV InfectionIn Vivo