Biology subjects

Babaian, A.

Publications and source records attributed to Babaian, A..

15 recordsLinked to original sources

bioRxiv2026

An ancestral mitochondrial DNA insertion disrupts RNAi and enables persistence of a novel mycovirus in Cryptococcus neoformans

RNA interference (RNAi) is a widely conserved genome-defense mechanism that protects eukaryotes against viruses and transposable elements. We previously showed that RNAi loss can lead to hypermutation and antifungal drug resistance in the human fungal pathogen Cryptococcus neoformans, illuminating the potential clinical relevance of this pathway. In this study, we identified another function of RNAi in C. neoformans: mycovirus restriction. By screening known RNAi-deficient C. neoformans isolates, we identified a novel dsRNA mycovirus of the Orthototiviridae family, which we named CnTV1. We subsequently detected CnTV1 in three additional RNAi-deficient isolates. All CnTV1-positive isolates shared an ancestral nuclear mitochondrial DNA segment (NUMT) insertion that disrupts the gene encoding Argonaute (Ago1). Restoration of RNAi in sexually produced zygotes efficiently eliminated CnTV1. RNAi rescue by CRISPR-Cas9-mediated allele exchange eliminated CnTV1 during vegetative growth, further demonstrating RNAi is sufficient for mycoviral control. Loss of the RNA helicase Ski2 or the exoribonuclease Xrn1 increased CnTV1 abundance, revealing RNAi-independent restriction of the virus. Restoration of RNAi cleared the virus even in the absence of Ski2 or Xrn1, indicating a dominant role for RNAi in antiviral defense. To investigate the biological implications of CnTV1 infection, we developed a cytoplasmic-mixing approach and generated isogenic strain pairs in an RNAi-deficient background that differ only in viral infection status. Leveraging these strains, we show that CnTV1 infection leads to coordinated, low-magnitude transcriptomic changes and that strains lacking the mycovirus were moderately less virulent in a murine infection model. Our findings reveal that RNAi serves as a dominant antiviral defense system in C. neoformans and suggest that naturally occurring RNAi deficiency may be more prevalent than previously appreciated. This work highlights mycovirus persistence as an important consequence of RNAi loss in this WHO-designated critical priority fungal pathogen.

genetics↗

bioRxiv2026

Resolving human neuronal herpesvirus reactivation via petabase-scale association studies

Mounting evidence implicates herpesvirus reactivation in the etiology of Alzheimers disease, yet we lack a refined molecular characterization of pathogenesis in neurodegeneration. Here, we mine over 10 petabytes of human sequencing data for viral transcripts, identifying recurrent herpes simplex virus 1 (HSV-1) reactivation in healthy but not pathological post-mortem human brain tissue. Integrative single-nucleus analyses resolve direct evidence of HSV-1 expression in RORB+ glutamatergic neurons, implicating viral reactivation in a neuronal population progressively lost during dementia.

genomics↗

bioRxiv2026

Petabase-scale Papillomavirus Discovery

Freely available nucleic acid sequencing databases have accumulated to a vast archive of genetic diversity, in excess of 50 petabase-pairs from tens of millions of experiments. Together, these data constitute a digital survey of Earths genome. However, the richness of biological information contained within these repositories remains largely unexplored, in large part owing to the technical challenges of analyzing petabytes of data. Recently, Logan completed the sequence-assembly and compression of 27 million sequencing libraries from the Sequence Read Archive (SRA), and here, we systematically search Logan-SRA to reveal the global diversity of the DNA-based Papillomaviruses (PVs). In a single [~]10-hour alignment-based search against the Logan assemblage, we independently re-identified 65% of the 992 PVs recorded within the NCBI Virus database, a body of work representing over five decades of PV characterization. We further expand the diversity of PVs by 34%, identifying 383 novel PV types spanning 105 associated host species, including taxa with no previously associated PVs, such as rhinoceros, voles, and grey foxes. Through integration of virus phylogeny, sample geography, and ecological metadata, we show that novel PV discovery is not directly proportional to sampling effort, and there are significant hotspots of PV biodiversity in East Africa and South America, and that undersampled biomes can yield disproportionately more novel PVs. Public sequencing repositories contain vast, unrealized biological information that is now accessible through advanced computational infrastructure. Here we lay the foundations for the efficient analysis of petabase-scale datasets for DNA virus discovery, with applications to uncovering all genetic diversity.

bioinformatics↗

bioRxiv2024

Logan: Planetary-Scale Genome Assembly Surveys Life's Diversity

The breadth of lifes diversity is unfathomable, but public nucleic acid sequencing data offers a window into the dispersion and evolution of genetic diversity across Earth. However the rapid growth and accumulation of sequence data have outpaced efficient analysis capabilities. The largest collection of freely available sequencing data is the Sequence Read Archive (SRA), comprising 27.3 million datasets or 5 x 1016 basepairs. To realize the potential of the SRA, we constructed Logan, a massive sequence assembly transforming short reads into long contigs and compressing the data over 100-fold, enabling highly efficient petabase-scale analysis. We created Logan-Search, a k-mer index of Logan for free planetary-scale sequence search, returning matches in minutes. We used Logan contigs to identify >200 million plastic-degrading enzyme homologs, and validate novel enzymes with catalytic activities exceeding current reference standards. Further, we vastly expand the known diversity of proteins (30-fold over UniRef50), plasmids (22-fold over PLSDB), P4 satellites (4.5-fold), and the recently described Obelisk RNA elements (3.7-fold). Logan also enables ecological and biomedical data mining, such as global tracking of antimicrobial resistance genes and the characterization of viral reactivation across millions of human BioSamples. By transforming the SRA, Logan democratizes access to the worlds public genetic data and opens frontiers in biotechnology, molecular ecology, and global health.

bioinformatics↗

bioRxiv2024

Self-cleaving ribozymes conserved in RNA viruses unveil a new role in protein translation

Small self-cleaving ribozymes are catalytic RNAs originally discovered in viroid-like agents, which are replicating circular RNAs (circRNAs) postulated as relics of a prebiotic RNA world. In the last decade, however, small ribozymes have also been detected across the tree of life, from bacterial to human genomes, and more recently, in unusual circRNA viruses. Here we report the conserved occurrence of diverse small ribozymes within the linear genomes of typical double- and single-stranded RNA virus families from fungi and plants. Type I hammerhead ribozyme motifs occur in the 5-UTR regions of chrysovirids and fusarivirids, displaying self-cleaving activity in vitro and in vivo. Similar hammerhead, as well as hepatitis delta and twister ribozymes, are also found in diverse megabirna-, hypo-, fusagra-, toti-or tombus-like viruses among others. The ribozymes occur not only as isolated motifs within UTRs but also as tandem pairs that encompass small RNA segments (186-399 nt) resembling Zetavirus-like sequences. In vivo characterization of the 5-UTR with a ribozyme from a chrysovirid revealed that the RNA-cleaving activity is essential for protein translation initiation in fungi. Analogous experiments in plants with diverse ribozyme motifs indicated that just the presence of a self-cleaving activity can induce cap-independent translation. We conclude that RNA self-cleaving activity, historically linked to the rolling circle replication of viroid-like circRNAs, appears to be co-opted by linear RNA viruses for translational roles.

microbiology↗

bioRxiv2024

Viroid-like colonists of human microbiomes

Here, we describe the "Obelisks," a previously unrecognised class of viroid-like elements that we first identified in human gut metatranscriptomic data. "Obelisks" share several properties: (i) apparently circular RNA [~]1kb genome assemblies, (ii) predicted rod-like secondary structures encompassing the entire genome, and (iii) open reading frames coding for a novel protein superfamily, which we call the "Oblins". We find that Obelisks form their own distinct phylogenetic group with no detectable sequence or structural similarity to known biological agents. Further, Obelisks are prevalent in tested human microbiome metatranscriptomes with representatives detected in [~]7% of analysed stool metatranscriptomes (29/440) and in [~]50% of analysed oral metatranscriptomes (17/32). Obelisk compositions appear to differ between the anatomic sites and are capable of persisting in individuals, with continued presence over >300 days observed in one case. Large scale searches identified 29,959 Obelisks (clustered at 90% nucleotide identity), with examples from all seven continents and in diverse ecological niches. From this search, a subset of Obelisks are identified to code for Obelisk-specific variants of the hammerhead type-III self-cleaving ribozyme. Lastly, we identified one case of a bacterial species (Streptococcus sanguinis) in which a subset of defined laboratory strains harboured a specific Obelisk RNA population. As such, Obelisks comprise a class of diverse RNAs that have colonised, and gone unnoticed in, human, and global microbiomes.

microbiology↗

bioRxiv2023

A Parasite Odyssey: An RNA virus concealed in Toxoplasma gondii

We are entering a "Platinum Age of Virus Discovery", an era marked by exponential growth in the discovery of virus biodiversity, and driven by advances in metagenomics and computational analysis. In the ecosystem of a human (or any animal) there are more species of viruses than simply those directly infecting the animal cells. Viruses can infect all organisms constituting the microbiome, including bacteria, fungi, and unicellular parasites. Thus the complexity of possible interactions between host, microbe, and viruses is unfathomable. To understand this interaction network we must employ computationally-assisted virology as a means of analyzing and interpreting the millions of available samples to make inferences about the ways in which viruses may intersect human health. From a computational viral screen of human neuronal datasets, we identified a novel narnavirus Apocryptovirus odysseus (Ao) which likely infects the neurotropic parasite Toxoplasma gondii. Previously, several parasitic protozoan viruses (PPVs) have been mechanistically established as triggers of host innate responses, and here we present in silico evidence that Ao is a plausible pro-inflammatory factor in human and mouse cells infected by T. gondii. T. gondii infects billions of people worldwide, yet the prognosis of toxoplasmosis disease is highly variable, and PPVs like Ao could function as a hitherto undescribed hypervirulence factor. In a broader screen of over 7.6 million samples, we explored phylogenetically-proximal viruses to Ao and discovered 19 Apocryptovirus species, all found in libraries annotated as vertebrate transcriptome or metatranscriptomes. While the Narnavirus samples making up this genus-like clade are derived from sheep, goat, bat, rabbit, chicken, and pigeon samples, the presence of virus is strongly predictive of parasitic (Apicomplexa) nucleic acid co-occurrence, supporting that these are a clade of parasite-infecting viruses. This is a computational proof-of-concept study in which we rapidly analyze millions of datasets from which we distilled a mechanistically, ecologically, and phylogenetically refined hypothesis. We predict this highly diverged Ao RNA virus is biologically a T. gondii infection, and that Ao, and other viruses like it, will modulate this disease which afflicts billions worldwide.

microbiology↗

bioRxiv2023

Petascale Homology Search for Structure Prediction

The recent CASP15 competition highlighted the critical role of multiple sequence alignments (MSAs) in protein structure prediction, as demonstrated by the success of the top AlphaFold2-based prediction methods. To push the boundaries of MSA utilization, we conducted a petabase-scale search of the Sequence Read Archive (SRA), resulting in gigabytes of aligned homologs for CASP15 targets. These were merged with default MSAs produced by ColabFold-search and provided to ColabFold-predict. By using SRA data, we achieved highly accurate predictions (GDT_TS > 70) for 66% of the non-easy targets, whereas using ColabFold-search default MSAs scored highly in only 52%. Next, we tested the effect of deep homology search and ColabFolds advanced features, such as more recycles, on prediction accuracy. While SRA homologs were most significant for improving ColabFolds CASP15 ranking from 11th to 3rd place, other strategies contributed too. We analyze these in the context of existing strategies to improve prediction.

bioinformatics↗

bioRxiv2022

Extant hybrids of RNA viruses and viroid-like elements

Earths life may have originated as self-replicating RNA. Some of the simplest current RNA replicators are RNA viruses, defined by linear RNA genomes encoding an RNA-dependent RNA polymerase (RdRP), and subviral agents with single-stranded, circular RNA genomes, such as viroids encoding paired self-cleaving ribozymes. Amongst a massive expansion of candidate viroid and viroid-like elements, we report that fungal pathogens, ambiviruses, are viroid-like elements which undergo rolling circle replication and encode their own viral RdRP, thus they are a distinct hybrid infectious agent. These findings point to a deep evolutionary history between modern RNA viruses and sub-viral elements and offer new perspectives on the evolution of primordial infectious agents, and RNA life. One-Sentence SummaryNovel infectious agents resembling self-cleaving viroid-like RNAs whilst encoding a viral RNA-dependent RNA polymerase.

microbiology↗

bioRxiv2021

Ribovirus classification by a polymerase barcode sequence

RNA viruses encoding a polymerase gene (riboviruses) dominate the known eukaryotic virome. Next-generation sequencing is revealing a wealth of new riboviruses with uncharacterised phenotypes, precluding classification by traditional taxonomic methods. These are often classified on the basis of polymerase sequence identity, but standardised methods to support this approach are currently lacking. To address this need, we describe the polymerase palmprint, a well-defined segment of the palm sub-domain delineated by well-conserved catalytic motifs. We present a novel algorithm, Palmscan, which identifies palmprints in nucleotide and amino acid sequences. We describe PALMdb, a reference database of palmprints derived from public sequence databases. Palmscan source code and PALMdb data are deposited at https://github.com/rcedgar/palmscan and https://github.com/rcedgar/palmdb, respectively.

bioinformatics↗

bioRxiv2020

Petabase-scale sequence alignment catalyses viral discovery

Public databases contain a planetary collection of nucleic acid sequences, but their systematic exploration has been inhibited by a lack of efficient methods for searching this corpus, now exceeding multiple petabases and growing exponentially [1, 2]. We developed a cloud computing infrastructure, Serratus, to enable ultra-high throughput sequence alignment at the petabase scale. We searched 5.7 million biologically diverse samples (10.2 petabases) for the hallmark gene RNA dependent RNA polymerase, identifying well over 105 novel RNA viruses and thereby expanding the number of known species by roughly an order of magnitude. We characterised novel viruses related to coronaviruses and to hepatitis{delta} virus, respectively and explored their environmental reservoirs. To catalyse a new era of viral discovery, we established a free and comprehensive database of these data and tools. Expanding the known sequence diversity of viruses can reveal the evolutionary origins of emerging pathogens and improve pathogen surveillance for the anticipation and mitigation of future pandemics.

bioinformatics↗

bioRxiv2019

Loss of macp{Psi} ribosomal RNA modification is a major feature of cancer

The ribosome is an RNA-protein complex essential for translation in all domains of life. The structural and catalytic core of the ribosome is its ribosomal RNA (rRNA). While mutations in ribosomal protein (RP) genes are known drivers of oncogenesis, oncogenic rRNA variants have remained elusive. We discovered a cancer-specific single nucleotide variation in 18S rRNA at nucleotide 1248.U in up to 45.9% of colorectal carcinoma (CRC) patients and present across >22 cancer types. This is the site of a unique hyper-modified base, 1-methyl-3--amino--carboxyl-propyl pseudouridine (m1acp3{Psi}), a >1 billion years conserved RNA modification at the ribosomes peptidyl decoding-site. A sub-set of CRC tumors we term hypo-m1acp3{Psi}, show sub-stoichiometric m1acp3{Psi}-modification unlike normal control tissues. A m1acp3{Psi} knockout model and hypo-m1acp3{Psi} patient tumors share a translational signature, characterized by highly abundant ribosomal proteins. Thus, m1acp3{Psi}-deficient rRNA forms an uncharacterized class of onco-ribosome which may serve as a chemotherapeutic target for treating cancer patients.

cancer biology↗

bioRxiv2017

bioSyntax: Syntax Highlighting For Computational Biology

Computational biology requires the reading and comprehension of biological data files. Plain-text formats such as SAM, VCF, GTF, PDB and FASTA, often contain critical information that is obfuscated by the complexity of the data structures. bioSyntax (http://bioSyntax.org) is a freely available suite of syntax highlighting packages for vim, gedit, Sublime, and less, which aids computational scientists to parse and work with their data more efficiently.

bioinformatics↗

bioRxiv2017

LIONS: Analysis Suite for Detecting and Quantifying Transposable Element Initiated Transcription from RNA-seq

SummaryTransposable Elements (TEs) influence the evolution of novel transcriptional networks yet the specific and meaningful interpretation of how TE-initiation events contribute to the transcriptome has been marred by computational and methodological deficiencies. We developed LIONS for the analysis of paired-end RNA-seq data to specifically detect and quantify TE-initiated transcripts.\n\nAvailabilitySource code, container, test data and instruction manual are freely available at www.github.com/ababaian/LIONS.\n\nContactababaian@bccrc.ca or mahdi.karimi@lms.mrc.ac.uk or dmager@bccrc.ca.\n\nSupplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2017

Intra- and Inter-individual genetic variation in human ribosomal RNAs

The ribosome is an ancient RNA-protein complex essential for translating DNA to protein. At its core are the ribosomal RNAs (rRNAs), the most abundant RNA in the cell. To support high levels of transcription, repetitive arrays of ribosomal DNA (rDNA) are necessary and the long-standing hypothesis is that they undergo sequence homogenization towards rDNA uniformity.\n\nHere I present evidence of the rich genetic diversity in human rDNA, both within and between individuals. Using state-of-the-art genome sequencing data revealed an average of 192.7 intra-individual variants, including some deeply penetrating the rDNA copies, such as the bi-allelically expressed 28S.59A>G. From 104 diverse genomes, 947 high-confidence variants were identified and unmask a hidden genetic diversity of humans.\n\nThese findings support the emerging concept that ribosomes are heterogeneous within cells and extends the heterogeneity into the realm of population genetics. Fundamentally, do our ribosomal variants determine how our cells interpret the genome?

genomics↗