Jason Yeung
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jayeung12.bsky.social
Jason Yeung
@jayeung12.bsky.social
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MD-PhD candidate @utmbhealth interested in viruses and data science | Former ballet dancer using publicly available dance data for advocacy
https://jason-yeung.netlify.app/
https://datapointesguide.com/
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jayeung12.bsky.social
More interesting work that furthers this thread between SARS-CoV-2 recombination, the RTC complex, polymerase backtracking, and antiviral drug mechanisms of action. The biochemistry behind viral recombination is still very much open. Some personal notes on these:
Text reading - Broader principle of multimeric polymerase structures dictating possible recombination mechanisms - 'Engineering' demands for greater control over transcription - [[@Viral Genome Principles]] - [[@Segmentation in viruses may allow for more precise gene regulation]] - [[Evolution and Emergence of RNA Viruses]] by [[Edward C. Holmes]] - [[Genome Modularity]] - Demarcation by or acquisition of TRS allows for viral reassortment or new gene formation in a relatively modularized fashion - High fidelity of replication needed to be evolutionarily acquired first before expansion of the genome/elaboration of the TRS subgenomic recombination gene regulation system(?) - How does this work in that bisegmented coronavirus? - [[@Identification and genomic characterization of a novel bisegmented coronavirus in the lesser panda]] - Categorizing everything as the copy choice model is imprecise as there can be many distinct routes to this outcome - [[Viral Recombination Mechanisms]] - Polymerase processivity, fidelity, and speed all relate to backtracking probability - [[Polymerase Backtracking]], [[RdRp Backtracking]] Text reading - What is the trigger for TRS sequences? Backtracking related? - Maybe - No direct demonstration that they are related that I've noted - Most definitely secondary structure dependent in my mind - arteriviruses and coronaviruses both employ TRS - Many different TRS sequences, so not strictly sequence dependent - Engineerability with non-natural TRS in recombination-deficient viruses - Doesn't even need to be a linear piece of nucleic acid, can be circular with TRS and still work - [[@Discontinuous template switching generates coronavirus subgenomic RNAs from the 3ʹ viral genome end by 5ʹ to 3ʹ transcription]] - [[@An atomistic model of the coronavirus replication-transcription complex as a hexamer assembled around nsp15]] - > Finally, the original template would need to unwind from the nascent strand for polymerization to continue on the new template. As with proofreading, we propose the shift in the dsRNA position upon base pairing of the nascent strand to the TRS-L triggers activation of nsp13 and backtracking of the template. This would unwind the original template from the nascent strand, while leaving it base paired with the new template (Fig. 7E). Once unwinding is complete, the dsRNA formed at the TRS-L juncture with the new template could shift back into the polymerase active site and finish synthesis on the remaining nucleotides of the 5′ leader (Fig. 7F) - > We should note that binding of the N protein to the nsp13 dimer appears to block access to the nsp13.1 RNA-binding groove, suggesting that nsp13.2 may govern backtracking in this situation. While the template has so far been seen by cryo-EM only engaging with nsp13.1, modeling of the relevant states indicates that nsp13.2 could perform this backtracking function as well. Thus, it may be that nsp13.1 governs backtracking for proofreading during positive-strand synthesis, but nsp13.2 governs backtracking for proofreading and transcription during negative-strand s… Text reading - nucleoside/nucleotide analogs influence backtracking probability because they are incorporated on the growing strand, what about nucleic acid modifications on the template strand? - I think it's unlikely but recombination probabilities could be correlated with modification maps across coronavirus genomes - m6a or 5mc not a sequence dependent minimal trigger for programmed backtracking - can still replicate virus in KO cell lines for writer proteins so presumably does not eliminate sgmRNA production - Other proteins besides core RTC complex involved? - Exo and endonucleases - [[@Commentary on Routh Menachery nsp15 paper]] - [[@SARS-CoV-2 EndoU-ribonuclease regulates RNA recombination and impacts viral fitness]] - [[Coronavirus nsp14]] - [[@The coronavirus proofreading exoribonuclease mediates extensive viral recombination]] collapsed:: true - > significant preference for a UUG motif - > MHV-ExoN(-) mutants showed decreased recombination junction frequency and altered populations of sgmRNAs and DVGs - > whether nsp14 ExoN alleviates backtracking as proposed - quote from [[@Template switching by coronavirus polymerase requires helicase activity and is stimulated by remdesivir and molnupiravir]] - This prediction does not align with what was observed in [[@The coronavirus proofreading exoribonuclease mediates extensive viral recombination]] collapsed:: true - If ExoN increases recombination, shouldn't it promote backtracking in certain contexts if that is what mediates all non-homologous recombination (including sgmRNA formation)? - Sequence specificity and preference for recombination at poly U tracts perhaps due to polymerase slipping and subsequent backtracking - A bit surprised to see copyback events [[Copy-Back RNAs]] detected given no(?) reports of these being generated based on sequencing data - [[@Defective viral genome detection review]] -
October 8, 2025 at 3:55 PM
jayeung12.bsky.social
A picture of organized text. The text reads: - Do homologous, non-homologous, and sgRNA non-homologous recombination all involve the same copy-choice process? - I'm leaning towards some aspects are shared but sgRNA production is generally a more "regulated" process. - Can the frequency of de novo non-sgRNA, non-homologous recombination events be explained by polymerase processivity? - Recombination frequency for SARS-CoV-2 is much higher than other human coronaviruses (MERS-CoV, OC43). Is polymerase processivity correlated with recombination frequency for these viruses? The presence of hotspots already suggests a more complex mechanism than the traditional "fall off, reattach" copy-choice model but this would also. Measurement of processivity is complicated by to processivity-improving proteins nsp7 and nsp8. - Multiple potential mechanisms for promotion of inflammation in nsp15 mutant - Increased dsRNA-induced signaling pathways - Accumulation of DVGs may itself be immunomodulatory - How much of the transcriptomic signal is due to each component? - > "This ~2-3 fold reduction in recombination JFreq indicates that the in vivo environment restricts accumulation of recombination events." - Wonder if this is true in bats as well? Host cells that tolerate high recombination frequencies and multiple coronaviruses could be sites that allow for novel coronavirus emergence through recombination
November 16, 2024 at 9:14 PM
jayeung12.bsky.social
A picture of organized text. The text reads: - Comparing recombination breakpoints from cell culture vs virions vs *in vivo* vs genomic surveillance has information - A sort of deep mutational scanning dataset for deletions - Comparison of virion enriched sequences and intracellular sequences could support packaging sequence for SARS-CoV-2 (believed to be in nsp12-nsp13) - Terasaki K, Narayanan K, Makino S: **Identification of a 1.4-kb-Long Sequence Located in the nsp12 and nsp13 Coding Regions of SARS-CoV-2 Genomic RNA That Mediates Efficient Viral RNA Packaging**. *Journal of Virology* 2023, **97**:e00659. - Another UTMB lab ☺ - Comparison of cell culture with *in vivo* indicates which are subject to additional (likely immune) selective pressures in hamsters - Comparison of virions with genomic surveillance could indicate which are replication viable and demonstrate sufficient amounts of fitness
November 16, 2024 at 9:14 PM
jayeung12.bsky.social
What a paper. I somehow missed all of the UTMB seminars about this work. There sorely needs to be an updated review article on the molecular basis for coronavirus recombination because I keep getting lost in the weeds. Some thoughts:
A picture of text organized in a list. The text reads: - *__Recombination at poly-U regions still occurred with catalytic inactivation of nsp15__* and *__delDVGs increased while sgmRNA decreased__*. Three potential ways nsp15 catalytic mutants increase non-homologous recombination (not mutually exclusive): - Perhaps this is tied to switch between genome replication and transcription? - > "It is conceivable that the endoU activity of NSP15 may play a role in mediating the template switching between +gRNA and -sgmRNA to give rise to +sgmRNA." - If delDVGs are only generated during genome replication, the increase in delDVGs could be due to a deficit in switching to sgmRNA-production mode. - The lower overall replication for the nsp15 mutant is likely tied to increased immune activation limiting the number of infected cells but the amount of genomic RNA per infected cell could be higher and sgRNA lower. This is suggested by *in vivo* results. - nsp15 catalytic mutants lead to increased dsRNA in highly concentrated puncta - High amounts of dsRNA provide increased opportunities for successful template switches - See the other paper on nsp15 H234A: - Otter CJ, Bracci N, Parenti NA, Ye C, Asthana A, Blomqvist EK, Tan LH, Pfannenstiel JJ, Jackson N, Fehr AR, et al.: **SARS-CoV-2 nsp15 endoribonuclease antagonizes dsRNA-induced antiviral signaling**. *Proceedings of the National Academy of Sciences* 2024, **121**:e2320194121. - These findings may tie in with the SARS-CoV-2 polymerase backtracking story that is developing for coronavirus recombination. - Poly-U tracts and induction of polymerase backtracking have been linked for other RNA polymerases. - Theoretically, anything that could cause polymerase backtracking (poly-U, TRS secondary structures, nucleotide antivirals) has some probability of producing a recombinant viral RNA. Hence why abolishing nsp15 endoU does not get rid of the poly-U enriched pattern
November 16, 2024 at 9:14 PM
jayeung12.bsky.social
As someone who uses R for bioinformatics/data science, I was seduced by the idea of learning Rust after noticing an uptick in high performance Rust tools on my feed. I briefly talk about my approach to learning the language and my frustrations: jason-yeung.netlify.app/posts/2024_6...
A 3D rendering of a red crab (the mascot for the programming language Rust) with a lit cigarette in one of its claws. Text on a blue background reads "> DAY 7 OF LEARNING RUST".
June 19, 2024 at 4:32 PM
jayeung12.bsky.social
Viral persistence is the most important theory for #LongCovid at the moment. What are challenges researchers face studying viral persistence? In this post, I discuss scientific barriers and criteria I use to evaluate models of #SARSCoV2 #viralpersistence: jason-yeung.netlify.app/posts/2023_1...
A banner with an anthropomorphic rendering of a virus with a mask and fedora in front of a purple gradient. The text reads Long COVID's Viral Persistence Hypothesis: Scientific Sticking Points - Challenges creating translational long COVID models. By Jason Yeung @jayeung12.
January 23, 2024 at 3:04 PM
jayeung12.bsky.social
Complement is important for tissue and humoral innate immunity. It also has roles in brain development and function. What happens when these roles collide in the virus-infected brain?🧠🦠

Check out my post about viruses (incl SARS-2), the brain, and complement: jason-yeung.netlify.app/posts/2023_4...
A picture of a cracked, ceramic brain with viruses spilling out of it. Text says Viruses in the Brain Part I: Complement. How viruses change our thinking and feeling. Written by Jason Yeung
October 3, 2023 at 12:45 AM