About

Todd M. Lowe is a faculty member at the Baskin School of Engineering at UC Santa Cruz. The school emphasizes socially responsible innovation across various engineering disciplines, including health engineering, climate and sustainability, machine learning, artificial intelligence, games, and human computer interaction. The university fosters a collaborative environment where faculty and students work together to create technology with a positive societal impact, leveraging top-tier research resources and interdisciplinary approaches. While the page highlights the school's research areas, community engagement, and institutional achievements, it does not provide specific details about Todd M. Lowe's individual research focus, background, or key contributions.

Research topics

• Biology
• Genetics
• Computational biology
• Evolutionary biology
• Biochemistry

Selected publications

• The regulation, function and disease relevance of cytoplasmic tRNAs

  Nature Reviews Molecular Cell Biology · 2026-04-21

  articleOpen access
  PublisherOA PDFDOI

• Mistranslation from an endogenous tRNA variant in human pan-genome cell lines

  Nucleic Acids Research · 2026-02-24

  articleOpen access

  Human transfer RNA (tRNA) anticodon variants are a source of translation error. The tRNASerAGA-2-3 variant (G35A) occurs in 2% of the human population and causes mis-incorporation of serine at phenylalanine codons. Here, we developed a dual fluorescent reporter to quantify mis-incorporation levels in live human and murine cells and validated mistranslation by mass spectrometry. In β-lymphocytes from individuals in the 1000 genomes project, we confirmed the anticipated genotype of cells with A35 minor alleles, and tRNA sequencing demonstrated expression, C32 hypo-modification, and partial 5'-fragmentation of the endogenous mutant tRNASerAAA. Nanoparticle delivery of the fluorescent reporter confirmed serine mis-incorporation in the pan-genome cell lines. The data demonstrate that a natural genome-encoded human tRNA mutant causes mistranslation in cells derived from healthy individuals. Our findings have important implications for translation fidelity in humans and the application of missense suppressor tRNAs to medicine.

  PublisherDOI

• The diploid reference genome of a human embryonic stem cell line

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-30 · 1 citations

  articleOpen access

  Advances in DNA sequencing and assembly technologies are spurring a shift from haploid reference genomes to sample-specific diploid assemblies. Here, we generated the first telomere-to-telomere (T2T) diploid reference for the widely used human embryonic stem cell (hESC) line, H9 (WAe009-A). This haplotype-resolved assembly is highly accurate with comprehensive annotation of genes, segmental duplications, methylation, and chromatin conformation. Pangenomic and phased-locus inference point to H9's mixed ancestry with a predominant European component. H9-specific genomic features include near-perfect telomeres ∼1.65-fold longer than other T2T assemblies, consistent with telomerase activity during pluripotency; chromosome 17 inversions that can predispose offspring to neurological syndromes; and expansions of ncRNA clusters, with overall genomic stability maintained despite extensive culturing. Mapping multi-omic datasets to the genome, we demonstrate the power of this resource for allele-specific, high-precision transcriptomic, genetic, and epigenetic analyses, with far-reaching implications for human development and disease.

  PublisherDOI

• Key RNA-binding domains in the La protein establish tRNA modification levels in <i>Trypanosoma brucei</i>

  Nucleic Acids Research · 2025-07-08 · 4 citations

  articleOpen access

  The RNA-binding protein La is found in most eukaryotes, and despite being essential in many organisms, its function is not completely clear. Trypanosoma brucei, the causative agent of human African trypanosomiasis, encodes a 'classical' La protein (TbLa) composed of a La-motif, two RNA recognition motifs (RRM1 and RRM2α), a C-terminal short basic motif (SBM), and a nuclear localization signal (NLS). In T. brucei, like in most eukaryotes, position 34 of tRNATyr, -Asp, -Asn and -His is modified with queuosine (Q34). The steady-state levels of queuosine-modified tRNA in the insect form (procyclic) of T. brucei can fluctuate dynamically depending on growth conditions, but the mechanism(s) controlling Q34 levels are not well understood. A well-established function of La is in precursor-tRNA 3'-end metabolism, but in this work, we demonstrate that La also controls Q34-tRNA levels. Individual domain deletions showed that while deletion of La motif or RRM1 causes dysregulation of Q34-tRNA levels, no other domain plays a similar role. We also show that La is important for the normal balance of several additional tRNA modifications. These findings are discussed in the context of substrate competition between La and modification enzymes, also highlighting subcellular localization as a key determinant of tRNA function.

  PublisherOA PDFDOI

• Analyzing, visualizing, and annotating tRNA-derived RNAs using tRAX and tDRnamer

  Methods in enzymology on CD-ROM/Methods in enzymology · 2025-01-01 · 4 citations

  articleOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• RNAcentral in 2026: Genes and literature integration

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-24

  preprintOpen access

  Abstract RNAcentral was founded in 2014 to serve as a comprehensive database of non-coding RNA sequences. It began by providing a single unified interface to more specialised resources, and now contains 45 million sequences. It has grown beyond providing a single interface to many specialised resources and now provides several services and analyses. These include secondary structure prediction with R2DT, sequence search, and analysis with Rfam. Since its last publication in 2021, RNAcentral has developed two major features. First, literature integration with the development of LitScan and LitSumm. LitScan automatically identifies and links relevant publications to RNA entries, while LitSumm uses natural language processing to generate functional summaries from the literature. Together, these tools address the critical challenge of connecting sequence data with scattered functional knowledge across thousands of publications. Secondly, RNAcentral has created gene level entries. Gene level entries represent a large structural change to RNAcentral. While RNAcentral previously organized data exclusively at the sequence level, we now group related transcripts into gene-centric views. This allows researchers to explore all isoforms, splice variants, and related sequences for a gene in a unified interface, better reflecting biological organization and facilitating comparative analyses. RNAcentral is freely available at: https://rnacentral.org .

  PublisherOA PDFDOI

• The Landscape of tRNA Modifications in Archaea

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-07 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Transfer RNA (tRNA) modifications are essential for structural integrity, decoding fidelity, and stress adaptation, yet their evolutionary dynamics remain poorly understood. Here, we apply Ordered Two-Template Relay sequencing (OTTR-seq) to comprehensively profile tRNA modifications across nine archaeal species spanning diverse ecological niches. We uncover coordinated and mutually exclusive methylation at acceptor stem positions 6 and 67 in hyperthermophiles, as well as clade-specific co-modification at positions 10 and 26, which are typically known for their importance as tRNA modification anti-determinants. Comparative analyses also reveal lineage-specific divergence in the domain architectures of tRNA methyltransferases, including Trm14, Trm10, Trm11, and Trm1. We further refine known identity elements such as the G10oU25 pairing, and highlight novel structural contexts that facilitate or prevent modification. These findings exemplify the co-evolution of tRNAs and their modifying enzymes, providing new insights into how archaea may fine-tune translation in extreme environments. The scope of these data and comparative analyses establish a multispecies framework for future biochemical, mechanistic, and predictive modeling efforts.

  PublisherOA PDFDOI

• Gammaherpesvirus infection triggers the formation of tRNA fragments from premature tRNAs

  mBio · 2025-05-30 · 2 citations

  articleOpen access

  Transfer RNAs (tRNAs) are fundamental for both cellular and viral gene expression during viral infection. In addition, mounting evidence supports the biological function for tRNA cleavage products, including the control of gene expression during conditions of stress and infection. We previously reported that infection with the model murine gammaherpesvirus 68, MHV68, leads to enhanced tRNA transcription. However, whether this has any influence on tRNA transcript processing, viral replication, or the host response is not known. Here, we combined two new approaches, sequencing library preparation by ordered two template relay (OTTR) and tRNA bioinformatic analysis by tRAX, to quantitatively profile full-length tRNAs and tRNA fragment (tRF) identities during MHV68 infection. We find that MHV68 infection triggers both pre-tRNA and mature tRNA cleavage, resulting in the accumulation of specific tRFs. OTTR-tRAX revealed not only host tRNAome changes, but also the expression patterns of virally encoded tRNAs (virtRNAs) and virtRFs made from the MHV68 genome. Because the transcript ends of several host tRFs matched tRNA splice junctions, we tested and confirmed the role of tRNA splicing factors TSEN2 and CLP1 in MHV68-induced tRF biogenesis. Further, we show that CLP1 kinase, which regulates tRNA splicing among other RNA processing events, is required for efficient MHV68 replication. Our findings provide new insight into how gammaherpesvirus infection both impacts and relies on tRNA transcription and processing.IMPORTANCEDiverse conditions of infection and cellular stress incite the cleavage of transfer RNAs (tRNAs), leading to the formation of tRNA fragments (tRFs) that can directly regulate gene expression. In our study of gammaherpesviruses, such as murine herpesvirus 68 and human oncogenic Kaposi sarcoma-associated herpesvirus, we discovered that tRNA regulation and cleavage are key components of gene reprogramming during infection. We present the first in-depth profile of tRF generation in response to DNA virus infection, using state-of-the-art sequencing techniques that overcome several challenges with tRNA sequencing. We present several lines of evidence that tRFs are made from newly transcribed premature tRNAs and propose that this may be a defining characteristic of tRNA cleavage during infection. Finally, we show that tRNA splicing machinery is involved with the formation of some MHV68-induced tRFs, with a key regulator of splicing, CLP1, required for maximal viral titer. Taken together, we posit that tRNA processing may be integral to the elegant shift in gene expression that occurs during viral takeover of the host cell.

  PublisherDOI

• A hypoxia-responsive tRNA-derived small RNA confers renal protection through RNA autophagy

  Science · 2025-07-17 · 17 citations

  articleOpen access

  Transfer RNA-derived small RNAs (tsRNAs or tDRs) perform a range of cellular functions. Here, we showed that tRNA-Asp-GTC-3'tDR, a hypoxia-induced tDR derived from the 3' end of tRNA-Asp-GTC, activated autophagic flux in kidney cells and its silencing blocked autophagic flux. Functional gain-/loss-of-function studies in murine kidney disease models demonstrated a substantial renoprotective function of tRNA-Asp-GTC-3'tDR. Mechanistically, tRNA-Asp-GTC-3'tDR assembled stable G-quadruplex structures and sequestered pseudouridine synthase 7 (PUS7), preventing catalytic pseudouridylation of histone mRNAs. The resulting pseudouridylation deficiency directed histone mRNAs to the autophagosome-lysosome pathway, triggering RNA autophagy. This tDR-induced RNA autophagy pathway was activated during murine and human kidney diseases, suggesting clinical relevance. Thus, tRNA-Asp-GTC-3'tDR plays a role in regulating RNA autophagy, which helps to maintain homeostasis in kidney cells and protects against kidney injury.

  PublisherOA PDFDOI

• High-fidelity and differential nonsense suppression in live cells and a frontotemporal dementia allele with human transfer RNAs

  Nucleic Acids Research · 2025-07-19 · 4 citations

  articleOpen access

  Nonsense mutations generate premature termination codons (PTCs) that are responsible for 11% of genetic disease alleles. The arginine (Arg, CGA) to stop (UGA) mutation is the most common PTC. Humans encode >600 transfer RNA (tRNA) genes with many identical and similar copies. We developed a dual fluorescent reporter to quantify PTC readthrough in live cells and found single nucleotide mutations of human tRNAArg gene variants enabled differential nonsense suppression that depended on the tRNA sequence and the cell type. We investigated G36A variants of all six human tRNAArgUCG isodecoders, and only the TCG-6-1 tRNA, where G36A occurs in 0.01% of human genomes, was unable to translate nonsense codons. With tRNA sequencing, we showed that a suppressor tRNA derived from the TCG-3-1 gene was expressed 2.1-fold higher and generated 1.8-fold more nonsense suppression than a tRNA derived from the TCG-4-1 gene. In a neuroblastoma model of frontotemporal dementia, we observed >70% readthrough of progranulin R493X with a suppressor tRNA that represented 5%-18% of the total tRNAArg pool. The tRNAs outperformed aminoglycoside-induced nonsense suppression in efficacy, tolerability to the cells, and translation fidelity according to mass spectrometry. Our studies show that human nonsense suppressor tRNAs can correct genetic defects that cause disease.

  PublisherDOI

Recent grants

• High-Throughput Small RNA Sequencing in Archaea

  NSF · $809k · 2008–2012

• Community Center for Archaeal and Extremophile Genome Research

  NSF · $810k · 2007–2012

• A Unified Atlas of Dynamic tRNA Function

  NIH · $4.6M · 2012–2024

Frequent coauthors

• Patricia P. Chan

  37 shared

• Patrick P. Dennis

  31 shared

• Leroy Hood

  Institute for Systems Biology

  25 shared

• Young Ah Goo

  James S. McDonnell Foundation

  24 shared

• Stephen R. Lasky

  24 shared

• Gregory G. Mahairas

  24 shared

• Vésteinn Thórsson

  24 shared

• Min Pan

  Guangzhou Medical University

  24 shared

Education

• Ph.D., Genetics

  Washington University in St. Louis

  1999

Awards & honors

• Richard E. Green, Lifetime Achievement Award (2025)
• Mike Beck, Innovator of the Year (2025)
• NeuroSWARM3, developed by the Yanik Lab led by Ahmet A. Yani…
• Bud Colligan, Community Changemaker (2025)
• XR Experience Jury Award at SXSW (2026)