Biology subjects

Ivanov, P.

Publications and source records attributed to Ivanov, P..

At least 19 recordsLinked to original sources

bioRxiv2026

A tRNA-derived small RNA orchestrates cardioprotection through distinct cell-type-specific mechanisms

Pathological cardiac fibrosis and hypertrophy, key contributors to adverse remodeling that drives heart failure (HF), are not adequately targeted by current therapies. We identified tRNA-Asp-GTC-3'tDR, an ischemia-induced tRNA-derived small RNA (tDR), as an endogenous regulator of both remodeling processes across cardiac fibroblasts and cardiomyocytes. In murine models of myocardial ischemia- and pressure overload-induced HF, cardiac delivery of tRNA-Asp-GTC-3'tDR reduced fibrosis and hypertrophy, preserved cardiac function, and improved survival, with limited three doses conferring durable protection after ischemia, whereas silencing it worsened both. Strikingly, tRNA-Asp-GTC-3'tDR acts through distinct mechanisms in different cell types: in fibroblasts, it assembles stress granules that sequester ribosome-loaded profibrotic transcripts, whereas in cardiomyocytes it engages pseudouridine synthase PUS7 to activate RNA autophagy. Its regulation and functions were confirmed in human cardiac cells and tissues. These findings demonstrate that a single tDR coordinates cell-type-specific protective programs in the heart, suggesting a new therapeutic axis to mitigate HF progression.

cell biology↗

bioRxiv2026

tRNA-derived fragments are elevated in the aging brain and may contribute to neurodegeneration

tRNA-derived fragments (tRFs) are a class of small noncoding RNAs with emerging roles in stress responses and gene regulation, yet their dynamics across tissues and brain regions during aging remain poorly understood. Here, we systematically profiled age-associated changes in tRFs using three independent mouse small RNA-seq datasets spanning multiple organs and brain regions. Nuclear-encoded tRFs were the only small RNA class showing a strong, progressive accumulation with age, a pattern that was specific to the brain and broadly distributed across brain regions. Fragment length distributions, boundary profiles, and coverage maps were consistent with amplified cleavage at conserved sites, implicating angiogenin as a primary driver. Age-associated increases in specific tRF species, including 5CysGCA, 5GluCTC, and 5GlyGCC, were validated by northern blotting and RT-qPCR. Analogous upregulation was observed in human frontal lobe tissue from frontotemporal dementia patients and in cerebrospinal fluid from traumatic brain injury patients, suggesting that tRF accumulation is further amplified under neurological stress. Together, these findings establish nuclear-encoded tRFs as a small RNA class that accumulates selectively in the aging brain, with potential roles in neurodegeneration, and as biomarkers and targets for therapeutic intervention.

neuroscience↗

bioRxiv2026

tRNA-derived fragments elevated in Alzheimer's disease facilitate Tau aggregation

Tauopathies, including Alzheimers disease (AD), are driven by pathological Tau aggregation, a process that requires co-factors. Small RNAs (sRNA) have been proposed as such co-factors, yet little is known about endogenous transcripts that promote Tau pathology. We identify stress-induced tRNA-derived RNAs or fragments (tDRs/tRFs) as the most dysregulated sRNA class in human AD brains, PS19 mice overexpressing mutant human Tau, and human neuronal tauopathy models. Notably, the highly accumulating 5GluCTC and 5GlyGCC tRFs directly bind Tau and induce its phosphorylation, oligomerization, fibril formation, and impact neurite growth. 5GluCTC is enriched in pathological Tau precipitates and co-localizes with oligomeric Tau in PS19 mouse brains. Inhibiting 5GluCTC mitigates Tau pathology. Furthermore, these tRFs are highly secreted by neurons and can be taken up by recipient cells, contributing to Tau pathology. Our findings establish 5GluCTC as a key regulator of Tau aggregation and suggest its inhibition as a promising therapeutic strategy for tauopathies. HighlightsO_LISpecific stress-induced 5tRFs strongly accumulate in Alzheimers disease brains C_LIO_LI5GluCTC binds and co-localizes with pathologic Tau in neurons and in the brain C_LIO_LI5GluCTC promotes pathologic Tau species while its inhibition reverses these effects C_LIO_LISpecific 5tRFs are horizontally transferred between neurons C_LI

neuroscience↗

bioRxiv2026

Ribonuclease L Regulates Antiviral Responsiveness through Cleavage of XBP1 mRNA

During viral infection, viral replication perturbs endoplasmic reticulum (ER) homeostasis and triggers the unfolded protein response (UPR). XBP1s, a transcription factor generated by one branch of the UPR, is known to potentiate both innate and adaptive immunity, but its role in antiviral responses remains incompletely understood beyond its ability to augment type I interferon (IFN) mRNA induction. Here, we show that XBP1s positively regulates the RIG-I-like receptors (RLRs), ribonuclease L (RNase L), and protein kinase R (PKR) pathways, indicating that it enhances all three major antiviral response pathways. We further show that RNase L activation rapidly decreases XBP1 mRNA levels in an RNase activity-dependent manner, leading to a prompt reduction in XBP1s expression. Consistent with this, RNase L deletion significantly increased both thapsigargin-mediated XBP1s induction and XBP1s expression following Japan encephalitis virus infection. Poly(I:C)-induced IFNB mRNA expression was significantly enhanced in RNase L-knockout cells. This enhancement was completely abolished by RNase L reconstitution. XBP1 knockdown also significantly attenuated IFNB mRNA expression in RNase L-knockout cells. These findings suggest a negative-feedback loop in which RNase L suppresses XBP1s, thereby fine-tuning antiviral responsiveness during viral infection. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/713401v1_ufig1.gif" ALT="Figure 1000"> View larger version (19K): org.highwire.dtl.DTLVardef@112d312org.highwire.dtl.DTLVardef@df79a9org.highwire.dtl.DTLVardef@1ac571borg.highwire.dtl.DTLVardef@18ac610_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2026

Chronic stress disrupts the network among stress granules, P-bodies, and motor proteins

Stress granules (SGs) are dynamic RNA granules that rapidly form in response to various stresses concurrent with mRNA translation shutdown, contributing to cellular adaptation and disease pathogenesis. While SG assembly and disassembly under acute stress have been extensively characterized, how SGs behave under chronic stress remains poorly understood. We previously reported that chronic stress preconditioning inhibits the earliest steps of SG assembly via translation-dependent mechanisms. In contrast, the regulation of SG maturation under chronic stress has not yet been investigated. Here, we show that chronic stress decreases SG size by disrupting the MYH9-dependent myosin crosstalk with core SG nucleator G3BP1. This defect leads to impaired SG and processing body (PB) docking as well, limiting the biogenesis of early SGs. Furthermore, chronic stress reduces expression of the SG nucleator UBAP2L, required for SG-PB docking, thus exacerbating these deficiences. In summary, chronic stress disrupts the myosin-SG-PB network and inhibits SG maturation in a translation-independent manner. SummaryChronic stress disrupts the MYH9 network with G3BP1, which inhibits stress granule (SG) assembly. It also decreases UBAP2L levels, which inhibits SG and processing body docking. Disrupted MYH9 network further inhibits this docking, thus blocking maturation of SGs.

cell biology↗

bioRxiv2025

Differentiation stage-specific use of cap-independent and cap-dependent translation initiation in hematopoiesis

Cell stress can increase the use of m7G-cap-independent, IRES-mediated translation initiation relative to cap-dependent translation (IRES/Cap). Reporters that quantify IRES/Cap have demonstrated differential activity across cultured cell types and stress conditions. By generating an IRES/Cap reporter mouse, we were able to systematically evaluate IRES/Cap across distinct tissues and cell types during physiological stresses and lineage commitment. Caloric stress invoked the expected boost in IRES/Cap translation regardless of differentiation state, but unexpectedly IRES/Cap progressively increased during hematopoietic and epithelial (hair follicle) differentiation under normal, homeostatic conditions. This was independent of total protein output or cell cycle. Even within cells of a given differentiation state, cells with lower relative-IRES utilization had markedly higher multipotent capability in vivo. The RNA processing protein PTBP1 is a mediator of this translation initiation preference. Therefore, low IRES/Cap is a signature of high stemness and suggests modulation of translation initiation participates in cell differentiation state.

developmental biology↗

bioRxiv2025

Processing bodies promote lysosomal quality control and cell survival during recovery from lysosomal damage

Lysosomes are essential for cell survival but are highly susceptible to diverse physical and pathological stressors. Thus, the ability to initiate an acute damage response and promote recovery after stressor resolution is critical for maintaining cellular homeostasis and viability. Although recent studies have advanced our understanding of acute responses to lysosomal injury, the molecular mechanisms governing the recovery stage and distinguishing it from the acute phase remain poorly defined. Here, we delineate a key difference between these two stages in translational regulation and uncover lysosomal recovery from acute damage as a novel trigger for processing body (PB) formation. PBs are membraneless biomolecular condensates involved in RNA metabolism and translational reprogramming. We provide the first evidence that PBs are critical for lysosomal quality control and cell survival during recovery. Mechanistically, PBs are induced selectively during the recovery phase, but not during the acute damage response, through interactions with stress granules (SGs), distinct membraneless biomolecular condensates formed upon acute injury to stabilize damaged lysosomal membranes for repair. Functional analyses reveal that PBs promote lysosomal quality control by collaborating with SG-mediated membrane stabilization, while independently recruiting released cathepsins, thereby collectively supporting cell survival. Together, these findings establish PBs as central effectors of the lysosomal recovery program and underscore the broader relevance of biomolecular condensates in cellular responses to lysosomal damage and related disease processes.

cell biology↗

bioRxiv2024

G-quadruplex topologies determine the functional outcome of guanine-rich bioactive oligonucleotides

Guanine-rich nucleic acid sequences can exert sequence and/or structure specific activities to influence biological and pathobiological cellular processes. As such, it has been reported that different G-rich oligonucleotides (both DNA and RNA) can have cytotoxic as well as cytoprotective effects to the cells. However, the mechanisms of such a biological outcome are unclear. In this report, we report that G-rich DNA oligonucleotides (ODNs) that can form four stranded secondary structures called G-quadruplexes (G4s) can have topology-dependent biological outcome. Using different biochemical, biophysical, and cellular approaches, we demonstrate that only the parallel topology G4-forming ODNs can repress eukaryotic translation by directly interacting with eukaryotic translation initiation protein 1 (EIF4G1), while the antiparallel topology G4s do not have inhibitory effect on mRNA translation To the best of our knowledge, this is the first report to directly connect the G4 topological differences with differential functional biological impacts. Our study provides the foundation for the rational design of G-rich oligonucleotides for a desired therapeutic outcome.

biochemistry↗

bioRxiv2024

Chronic stress antagonizes formation of Stress Granules

Chronic stress mediates cellular changes that can contribute to human disease. However, fluctuations in RNA metabolism caused by chronic stress have been largely neglected in the field. Stress granules (SGs) are cytoplasmic ribonucleoprotein condensates formed in response to stress-induced inhibition of mRNA translation and polysome disassembly. Despite the broad interest in SG assembly and disassembly in response to acute stress, SG assembly in response to chronic stress has not been extensively investigated. In this study, we show that cells pre-conditioned with low dose chronic (24-hour exposure) stresses such as oxidative stress, endoplasmic reticulum stress, mitochondrial stress, and starvation, fail to assemble SGs in response to acute stress. While translation is drastically decreased by acute stress in pre-conditioned cells, polysome profiling analysis reveals the partial preservation of polysomes resistant to puromycin-induced disassembly. We showed that chronic stress slows down the rate of mRNA translation at the elongation phase and triggers phosphorylation of translation elongation factor eEF2. Polysome profiling followed by RNase treatment confirmed that chronic stress induces ribosome stalling. Chronic stress-induced ribosome stalling is distinct from ribosome collisions that are known to trigger a specific stress response pathway. In summary, chronic stress triggers ribosome stalling, which blocks polysome disassembly and SG formation by subsequent acute stress. Significant statementsStress granules (SGs) are dynamic cytoplasmic biocondensates assembled in response to stress-induced inhibition of mRNA translation and polysome disassembly. SGs have been proposed to contribute to the survival of cells exposed to toxic conditions. Although the mechanisms of SG assembly and disassembly in the acute stress response are well understood, the role of SGs in modulating the response to chronic stress is unclear. Here, we show that human cells pre-conditioned with chronic stress fail to assemble SGs in response to acute stress despite inhibition of mRNA translation. Mechanistically, chronic stress induces ribosome stalling, which prevents polysome disassembly and subsequent SG formation. This finding suggests that chronically stressed or diseased human cells may have a dysfunctional SG response that could inhibit cell survival and promote disease.

cell biology↗

bioRxiv2024

Stress granule formation enables anchorage-independence survival in cancer cells

Stress granules (SGs) are dynamic cytoplasmic structures assembled in response to various stress stimuli that enhance cell survival under adverse environmental conditions. Here we show that SGs contribute to breast cancer progression by enhancing the survival of cells subjected to anoikis stress. SG assembly is triggered by inhibition of Focal Adhesion Kinase (FAK) or loss of adhesion signals. Combined proteomic analysis and functional studies reveal that SG formation enhances cancer cell proliferation, resistance to metabolic stress, anoikis resistance, and migration. Importantly, inhibiting SG formation promotes the sensitivity of cancer cells to FAK inhibitors being developed as cancer therapeutics. Furthermore, we identify the Rho-ROCK- PERK-eIF2 axis as a critical signaling pathway activated by loss of adhesion signals and inhibition of the FAK-mTOR-eIF4F complex in breast cancer cells. By triggering SG assembly and AKT activation in response to anoikis stress, PERK functions as an oncoprotein in breast cancer cells. Overall, our study highlights the significance of SG formation in breast cancer progression and suggests that therapeutic inhibition of SG assembly may reverse anoikis resistance in treatment-resistant cancers such as triple-negative breast cancer (TNBC). HighlightsO_LIEither anoikis stress or loss of adhesion induce stress granule (SG) formation C_LIO_LIThe Rho-ROCK-PERK-eIF2 axis is a crucial signaling pathway triggered by the absence of adhesion signals, leading to the promotion of SG formation along with the inhibition of the FAK- AKT/mTOR-eIF4F complex under anoikis stress. C_LIO_LIPERK functions as an oncogene in breast cancer cells, initiating SG formation and activating AKT under anoikis stress. C_LIO_LIInhibiting SG formation significantly enhances the sensitivity to Focal Adhesion Kinase (FAK) inhibitors, suggesting a potential for combined therapy to improve cancer treatment efficacy. C_LI

cell biology↗

bioRxiv2024

Repurposing tRNA isodecoders for non-canonical functions via tRNA cleavage

Transfer RNAs (tRNAs) are the key adaptor molecules aiding protein synthesis. Hundreds of tRNA genes are found in the human genome but the biological significance of this genetic excess is still enigmatic. The tRNA repertoires are variable between tissues and cells as well as during development. Such variations can only be partially explained by the correlation to the physiological needs in protein production, e.g. by changes in the expression of tRNA isoacceptor sets (tRNAs charged with the same amino acid but bearing different anticodons). However, changes in the expression levels of individual isodecoders (tRNAs with the same anticodon) are less understood. Besides canonical functions in mRNA translation, tRNAs are implicated in non-canonical functions unrelated to protein synthesis. tRNAs are rich source of small non-protein coding RNAs called tRNA-derived RNAs (tDRs), which include tRNA-derived stress-induced RNAs (tiRNAs) formed in response to stress. Here, we show that tiRNAs derived from isodecoders different in a single nucleotide can also differ in their activities. Specifically, we show that isodecoder sets for tRNAHis-GTG, tRNAGly-GCC and tRNACys-GCA are cleaved by ribonucleases to yield 5-tiRNAs showing differential activity towards mRNA reporter translation. Our data propose a model where cleavage repurposes specific tRNA isodecoders for non-canonical functions. Significance StatementThe human genome encodes hundreds of transfer RNA (tRNA) genes to decode 61 codons. The basis for such genetic redundancy is unclear but the increase in the number of tRNA genes goes in concert with the complexity of an organism. While changes in the expression of isoacceptor tRNA pools can reflect adaptation to demanding protein synthesis needs and/or codon usage, the variations in the expression of the individual tRNA isodecoders are documented but poorly understood. Such expression variations are hypothesized to contribute to non-canonical tRNA functions, yet physiological relevance remains ambiguous. We report here that specific tRNA isodecoders can be functionally repurposed through cleavage that produces tRNA-derived RNAs (tDRs). The repurposing employs nucleotide variations in isodecoders leading to the production of distinct sets of tDRs with variable bioactivities.

molecular biology↗

bioRxiv2023

HOXDeRNA activates a cancerous transcription program and super-enhancers genome-wide

BackgroundThe origin and genesis of highly malignant and heterogenous glioblastoma brain tumors remain unknown. We previously identified an enhancer-associated long non-coding RNA, LINC01116 (named HOXDeRNA here), that is absent in the normal brain but is commonly expressed in malignant glioma. HOXDeRNA has a unique capacity to transform human astrocytes into glioma-like cells. This work aimed to investigate molecular events underlying the genome-wide function of this lncRNA in glial cell fate and transformation. ResultsUsing a combination of RNA-Seq, ChIRP-Seq, and ChIP-Seq, we now demonstrate that HOXDeRNA binds in trans to the promoters of genes encoding 44 glioma-specific transcription factors distributed throughout the genome and derepresses them by removing the Polycomb repressive complex 2 (PRC2). Among the activated transcription factors are the core neurodevelopmental regulators SOX2, OLIG2, POU3F2, and SALL2. This process requires an RNA quadruplex structure of HOXDeRNA that interacts with EZH2. Moreover, HOXDeRNA-induced astrocyte transformation is accompanied by the activation of multiple oncogenes such as EGFR, PDGFR, BRAF, and miR-21, and glioma-specific super-enhancers enriched for binding sites of glioma master transcription factors SOX2 and OLIG2. ConclusionsOur results demonstrate that HOXDeRNA overrides PRC2 repression of glioma core regulatory circuitry with RNA quadruplex structure. These findings help reconstruct the sequence of events underlying the process of astrocyte transformation and suggest a driving role for HOXDeRNA and a unifying RNA-dependent mechanism of gliomagenesis.

molecular biology↗

bioRxiv2022

Exact global alignment using A* with seed heuristic and match pruning

MotivationSequence alignment has been at the core of computational biology for half a century. Still, it is an open problem to design a practical algorithm for exact alignment of a pair of related sequences in linear-like time (Medvedev, 2022b). MethodsWe solve exact global pairwise alignment with respect to edit distance by using the A* shortest path algorithm. In order to efficiently align long sequences with high divergence, we extend the recently proposed seed heuristic (Ivanov et al., 2022) with match chaining, gap costs, and inexact matches. We additionally integrate the novel match pruning technique and diagonal transition (Ukkonen, 1985) to improve the A* search. We prove the correctness of our algorithm, implement it in the A*PA aligner, and justify our extensions intuitively and empirically. ResultsOn random sequences of divergence d=4% and length n, the empirical runtime of A*PA scales near-linearly with length (best fit n1.06, n[≤]107 bp). A similar scaling remains up to d=12% (best fit n1.24, n[≤]107 bp). For n=107 bp and d=4%, A*PA reaches >500x speedup compared to the leading exact aligners EDLIB and BIWFA. The performance of A*PA is highly influenced by long gaps. On long (n>500 kbp) ONT reads of a human sample it efficiently aligns sequences with d<10%, leading to 3x median speedup compared to EDLIB and BIWFA. When the sequences come from different human samples, A*PA performs 1.7x faster than EDLIB and BIWFA. Availabilitygithub.com/RagnarGrootKoerkamp/astar-pairwise-aligner Contactragnar.grootkoerkamp@inf.ethz.ch, pesho@inf.ethz.ch

bioinformatics↗

bioRxiv2022

Nicked tRNAs are stable reservoirs of tRNA halves in cells and biofluids

Nonvesicular extracellular RNAs (nv-exRNAs) constitute the majority of the extracellular RNAome, but little is known about their stability, function and potential use as disease biomarkers. Herein, we measured the stability of several naked RNAs when incubated in human serum, urine and cerebrospinal fluid (CSF). We identified extracellularly produced tRNA-derived small RNAs (tDRs) with half-lives of up to three hours in CSF. Contrary to widespread assumptions, these intrinsically stable small RNAs are full-length tRNAs containing broken phosphodiester bonds (i.e., nicked tRNAs). Standard molecular biology protocols, including phenol-based RNA extraction and heat, induce the artifactual denaturation of nicked tRNAs and the consequent in vitro production of tDRs. Broken bonds are roadblocks for reverse transcriptases, preventing amplification and/or sequencing of nicked tRNAs in their native state. To solve this, we performed enzymatic repair of nicked tRNAs purified under native conditions, harnessing the intrinsic activity of phage and bacterial tRNA repair systems. Enzymatic repair regenerated an RNase R-resistant tRNA-sized band in northern blot and enabled RT-PCR amplification of full-length tRNAs. We also separated nicked tRNAs from tDRs by chromatographic methods under native conditions, identifying nicked tRNAs inside stressed cells and in vesicle-depleted human biofluids. Dissociation of nicked tRNAs produces single-stranded tDRs that can be spontaneously taken up by human epithelial cells, positioning stable nv-exRNAs as potentially relevant players in intercellular communication pathways.

molecular biology↗

bioRxiv2022

A Standardized Ontology for Naming tRNA-derived RNAs Based on Molecular Origin

Small RNAs processed from transfer RNA are recognized to have regulatory functions distinct from protein synthesis. This rapidly advancing field has led to a constellation of transcript nomenclatures. Building upon the accepted tRNA naming system and linking tRNA-derived small RNAs to their molecular sources, we propose an improved nomenclature. Facilitated by the tDRnamer system, it will promote inter-study comparisons leveraging a biologically-rooted nomenclature for this emerging class of intriguing regulators.

bioinformatics↗

bioRxiv2022

Cytoplasmic processing of human transfer RNAs

Biogenesis of different classes of eukaryotic RNAs proceeds via different pathways that require strict spatiotemporal resolution. The intracellular organization has evolved to provide order for RNA processing to coordinate different maturation steps with specific enzymatic reaction. In higher eukaryotes, processing of transfer RNAs (tRNAs) is postulated to be almost entirely intranuclear, while in lower eukaryotes like yeast, tRNA maturation is both nuclear and cytoplasmic. Here, we show that tRNA processing is largely cytosolic event in human cells. After transcription, unprocessed precursors of tRNAs (pre-tRNAs) bound by La protein are exported from the nucleus into the cytoplasm. Using cell fractionation analysis and pre-tRNA-specific fluorescence in situ hybridization (FISH) protocol, we show tRNA splicing/ligation and end-processing takes place in the cytoplasm where majority of processing enzymes is also located. We propose here a model where processing of intron-less and intron-containing pre-tRNAs is cytoplasmic similarly to the observed in lower eukaryotes, although tRNA splicing precedes 5- and 3-end processing in human cells unlike in yeast.

molecular biology↗

bioRxiv2022

Stress promotes RNA G-quadruplex folding in human cells

Guanine-rich nucleic acids can fold into G-quadruplex (G4) structures. Although endogenous RNAs contain sequences that can fold into RNA G4s (rG4s) in vitro, their folding and functions in vivo are not well understood. We show that the folding of putative rG4s in human cells into bona fide rG4 structures is dynamically regulated by stress. By using a high-throughput approach based on differential reactivity of dimethyl sulfate (DMS) towards Gs within folded vs unfolded rG4s, we identified hundreds of endogenous rG4s whose folding is promoted by cellular stress and validated them using a newly developed rG4-specific ligand. Stress-dependent rG4s are enriched in mRNA 3'-untranslated regions, suggesting their role in regulating mRNA stability under stress. Lastly, rG4 folding is reversible upon stress removal or adaptation. Our study show that rG4s function as regulatory elements in regulating mRNA stability and cellular stress response. One-Sentence SummaryRNA G-quadruplexes assemble under stress in human cells

molecular biology↗

bioRxiv2021

Fast and Optimal Sequence-to-Graph Alignment Guided by Seeds

We present a novel A[*] seed heuristic that enables fast and optimal sequence-to-graph alignment, guaranteed to minimize the edit distance of the alignment assuming non-negative edit costs. We phrase optimal alignment as a shortest path problem and solve it by instantiating the A[*] algorithm with our seed heuristic. The seed heuristic first extracts non-overlapping substrings (seeds) from the read, finds exact seed matches in the reference, marks preceding reference positions by crumbs, and uses the crumbs to direct the A[*] search. The key idea is to punish paths for the absence of foreseeable seed matches. We prove admissibility of the seed heuristic, thus guaranteeing alignment optimality. Our implementation extends the free and open source aligner and demonstrates that the seed heuristic outperforms all state-of-the-art optimal aligners including GO_SCPLOWRAPHC_SCPLOWAO_SCPLOWLIGNERC_SCPLOW, VO_SCPLOWARGASC_SCPLOW, PO_SCPLOWAC_SCPLOWSGAL, and the prefix heuristic previously employed by ASO_SCPLOWTARIXC_SCPLOW. Specifically, we achieve a consistent speedup of >60x on both short Illumina reads and long HiFi reads (up to 25kbp), on both the E. coli linear reference genome (1Mbp) and the MHC variant graph (5Mbp). Our speedup is enabled by the seed heuristic consistently skipping >99.99% of the table cells that optimal aligners based on dynamic programming compute. ASO_SCPLOWTARIXC_SCPLOW aligner and evaluations: https://github.com/eth-sri/astarix Full paper: https://www.biorxiv.org/content/10.1101/2021.11.05.467453

bioinformatics↗