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PubMed2026

Ferroptosis as a mediator of gut microbiota-driven inflammatory bowel disease: Evidence from genetic analyses.

Gut microbiota dysbiosis is increasingly recognized as a contributor to inflammatory bowel disease (IBD), yet causal relationships and underlying mechanisms remain unclear. Ferroptosis, an iron-dependent form of regulated cell death, plays a key role in epithelial barrier damage and inflammation. This study aimed to determine whether specific gut microbial taxa are causally associated with IBD and whether ferroptosis-related genes mediate this association using Mendelian randomization (MR). Two-sample MR and mediation MR analyses were performed using genome-wide association study summary data from the FinnGen consortium (IBD), the genome-wide association study catalog (473 gut microbial taxa), and the deCODE database (ferroptosis-related genes). Instrumental variables were selected with thresholds of P < 1 × 10-6 for microbes and P < 5 × 10-8 for traits, and linkage disequilibrium clumping (r2 < 0.001) was applied. Twenty-three microbial taxa showed significant causal associations with IBD (e.g., Chromatiales, OR = 0.51; Acetobacterales, OR = 2.61). Several ferroptosis-related genes were linked to IBD risk (e.g., GPX4, STAT3, IDO1). Mediation MR revealed that genes such as MUC1, IDO1, and ADAM23 partially mediated microbial effects on IBD, with mediation proportions up to 7.6%. This study provides novel genetic evidence supporting a gut microbiota-ferroptosis-IBD axis. Ferroptosis-related pathways may partially mediate microbial effects on IBD pathogenesis and represent promising targets for future therapeutic interventions.

Ferroptosis↗

PubMed1994

Toxicity of a heterologous leucyl-tRNA (anticodon CAG) in the pathogen Candida albicans: in vivo evidence for non-standard decoding of CUG codons.

Plasmids containing derivatives of the Saccharomyces cerevisiae leucyl-tRNA (tRNA(3Leu)) gene that vary in anticodon sequence were constructed and transformed into the pathogen Candida albicans and S. cerevisiae. C. albicans could readily be transformed with plasmids encoding leucyl-tRNA genes with the anticodons CAA and UAA (recognizing the codons UUG and UUA) and expression of the heterologous tRNALeu could be demonstrated by Northern RNA blotting. In contrast, no transformants were obtained if the anticodons were UAG (codons recognized CUN, UUR) and CAG (codon CUG), indicating that the insertion of leucine at CUG codons is toxic for C. albicans. All tRNALeu-encoding plasmids transformed S. cerevisiae with equally high efficiencies. These results provide in vivo evidence that non-standard decoding of CUG codons is essential for the viability of C. albicans.

Anticodon↗

PubMed1998

The hypotrichous ciliate Euplotes octocarinatus has only one type of tRNACys with GCA anticodon encoded on a single macronuclear DNA molecule.

Deviations from the universal genetic code have evolved independently several times in ciliated protozoa. Thus, in some species UAA and UAG are no longer used as termination codons, but are read as glutamine, whereas in the genus Euplotes , UGA is translated as cysteine. We have investigated the nature of the tRNACys isoacceptor responsible for decoding UGA in Euplotes cells. Southern hybridization analyses indicated that a single DNA molecule of 630 bp encoding tRNACys exists in the macronucleus of Euplotes octocarinatus . Cloning and sequencing of this fragment revealed that it contains only one copy of a tRNACys gene, which codes for a normal tRNACys with GCA anticodon. This is the first report of the characterization of a tRNA gene in any hypotrichous ciliate. It contains putative signals for initiation and termination of transcription by RNA polymerase III and can be transcribed efficiently in vitro in HeLa cell nuclear extract. Intensive studies on the DNA and tRNA level involving PCR analyses have not disclosed the existence of any tRNA Cys isoacceptor with UCA or ICA anticodons. Translation of the UGA codon by tRNA sub GCA sup Cys necessitates a G:A mispairing in the first anticodon position. We discuss a number of aspects which might contribute to the finding that a near-cognate tRNA isoacceptor efficiently translates the UGA stop codon.

Animals↗

PubMed2003

Prokaryotic-style frameshifting in a plant translation system: conservation of an unusual single-tRNA slippage event.

Ribosomal frameshifting signals are found in mobile genetic elements, viruses and cellular genes of prokaryotes and eukaryotes. Typically they comprise a slippery sequence, X XXY YYZ, where the frameshift occurs, and a stimulatory mRNA element. Here we studied the influence of host translational environment and the identity of slippery sequence-decoding tRNAs on the frameshift mechanism. By expressing candidate signals in Escherichia coli, and in wheatgerm extracts depleted of endogenous tRNAs and supplemented with prokaryotic or eukaryotic tRNA populations, we show that when decoding AAG in the ribosomal A-site, E.coli tRNA(Lys) promotes a highly unusual single-tRNA slippage event in both prokaryotic and eukaryotic ribosomes. This event does not appear to require slippage of the adjacent P-site tRNA, although its identity is influential. Conversely, asparaginyl-tRNA promoted a dual slippage event in either system. Thus, the tRNAs themselves are the main determinants in the selection of single- or dual-tRNA slippage mechanisms. We also show for the first time that prokaryotic tRNA(Asn) is not inherently 'unslippery' and induces efficient frameshifting when in the context of a eukaryotic translation system.

Base Sequence↗

PubMed1994

Direct recognition of mRNA stop signals by Escherichia coli polypeptide chain release factor two.

The interaction between the translational stop signal and the polypeptide chain release factor protein (RF) within complexes of Escherichia coli ribosomes has been investigated by site-directed photochemical cross-linking experiments. Twelve mRNA analogues containing 4-thiouridine residues as part of stop signals were synthesized. Highly efficient cross-linking to RF-2 from 4-thiouridine (sU) residues of sUGAN-containing mRNAs was observed, and cross-linking from those of sUAAN was observed at a lower efficiency. This indicates that RF-2 is in close physical contact with the stop signal on the ribosome. The yield of the RF-2-mRNA cross-link depended on the identity of the fourth base for the sUGAN set of signals, suggesting that the fourth base of the stop signal affects the interaction between RF-2 and the stop codon. A region previously implicated as part of the decoding site of the small ribosomal subunit, 1385-1420 of the 16 S rRNA, was also cross-linked with these mRNAs. No new cross-links were obtained in the presence of the release factor. The data are consistent with models in which the RF has an anticodon-like domain that contacts the stop signal directly at or near the ribosomal site in which sense codons are decoded.

Bacterial Proteins↗

PubMed1994

The decoding region of 16S RNA; a cross-linking study of the ribosomal A, P and E sites using tRNA derivatized at position 32 in the anticodon loop.

A photo-reactive diazirine derivative was attached to the 2-thiocytidine residue at position 32 of tRNA(Arg)I from Escherichia coli. This modified tRNA was bound under suitable conditions to the A, P or E site of E.coli ribosomes. After photo-activation of the diazirine label, the sites of cross-linking to 16S rRNA were identified by our standard procedures. Each of the three tRNA binding sites showed a characteristic pattern of cross-linking. From tRNA at the A site, a major cross-link was observed to position 1378 of the 16S RNA, and a minor one to position 936. From the P site, there were major cross-links to positions 693 and to 957 and/or 966, as well as a minor cross-link to position 1338. The E site bound tRNA showed major cross-links to position 693 (identical to that from the P site) and to positions 1376/1378 (similar, but not identical, to the cross-link observed from the A site). Immunological analysis of the concomitantly cross-linked ribosomal proteins indicated that S7 was the major target of cross-linking from all three tRNA sites, with S11 as a minor product. The results are discussed in terms of the overall topography of the decoding region of the 30S ribosomal subunit.

Anticodon↗

PubMed1997

Gene expression evidence indicates that nucleotides 507-513 and 1434-1440 in 16S rRNA are organized in close proximity on the Escherichia coli 30S ribosomal subunit.

A non-Shine-Dalgamo translational initiator is identified in Escherichia coli. The nucleotide sequence ACCUACUCGAGUUAG, designated as PL, is capable of initiating translation of pokeweed antiviral protein (PAP) and human calcitonin (hCT) mRNAs in E. coli cells. The yield of recombinant protein was double that obtained with the consensus Shine-Dalgarno-sequence-(SD)-driven translation. The PL sequence is composed of two heptanucleotides (ACCUACU, box I and GAGUUAG, box II) which are complementary to nucleotides 1434-1440 and 507-513, respectively, in 16S rRNA. Mutational analysis shows that the translation initiation efficiency with either box alone is much lower than that obtained with the entire PL sequence, indicating that the boxes interact simultaneously with both complementary regions in 16S rRNA during the translation initiation step. Based on these results, we propose that the two widely separated regions 507-513 (part of helical domain 18) and 1434-1440 (belonging to helical domain 44) are organized in close proximity to each other and to the ribosome decoding center on the surface of the E. coli 30S ribosomal subunit.

Base Sequence↗

PubMed1996

The downstream box: an efficient and independent translation initiation signal in Escherichia coli.

The downstream box (DB) was originally described as a translational enhancer of several Escherichia coli and bacteriophage mRNAs located just downstream of the initiation codon. Here, we introduced nucleotide substitutions into the DB and Shine-Dalgarno (SD) region of the highly active bacteriophage T7 gene 10 ribosome binding site (RBS) to examine the possibility that the DB has an independent and functionally important role. Eradication of the SD sequence in the absence of a DB abolished the translational activity of RBS fragments that were fused to a dihydrofolate reductase reporter gene. In contrast, an optimized DB at various positions downstream of the initiation codon promoted highly efficient protein synthesis despite the lack of a SD region. The DB was not functional when shifted upstream of the initiation codon to the position of the SD sequence. Nucleotides 1469-1483 of 16S rRNA ('anti-downstream box') are complementary to the DB, and optimizing this complementarity strongly enhanced translation in the absence and presence of a SD region. We propose that the stimulatory interaction between the DB and the anti-DB places the start codon in close contact with the decoding region of 16S rRNA, thereby mediating independent and efficient initiation of translation.

Bacteriophage T7↗

PubMed1994

Characterization of serine and leucine tRNAs in an asporogenic yeast Candida cylindracea and evolutionary implications of genes for tRNA(Ser)CAG responsible for translation of a non-universal genetic code.

Five serine and three leucine isoaceptor tRNAs were purified from the asporogenic yeast Candida cylindracea, in which codon CUG is translated as serine instead of leucine, and their primary structures were determined. From the wobble hypothesis, it was assumed that one of the tRNA(Leu) species (Leu1), with the anticodon CmAA, corresponded to the UUG leucine codon, and that the remaining two leucine tRNAs (Leu2 and Leu3), with the same IAG anticodon sequence would decode the CUU, CUC and CUA codons as leucine, but not the CUG codon; this was clarified by an in vitro translation experiment with C.cylindracea using synthetic mRNAs containing the CUA or CUG codons. One of the serine tRNAs (Ser1) has already been demonstrated to have the anticodon CAG and to be responsible for translation of the codon CUG in C.cylindracea. Three of the other species of tRNA(Ser) (Ser2,3 and 4), with the anticodon sequences cm5UGA, IGA and CGA, can translate all four codons in the UCN codon box, while the remaining species (Ser5), with the anticodon GCU, corresponds to AGU and AGC serine codons. The gene sequences for these five serine and three leucine tRNAs were also determined, with the finding that only tRNA(Ser)CAG (Ser1) has an intron. At least five different types of tRNA(Ser)CAG genes exist in the genome of C.cylindracea. The nucleotide sequences of the flanking regions of these tRNA(Ser)CAG genes indicated that the tRNA(Ser)CAG gene has duplicated at least three times on the genome. The existence of multiple genes for tRNA(Ser)CAG on the genome may account for the observation that codon CUG is used very frequently in C.cylindracea. All of these tRNASerCAG genes contain the CCA sequence in their 3' termini, suggesting the possibility that during their multiplication process in the evolution of the C.cylindracea genome, the tRNA(Ser)CAG molecule was integrated into DNA via reverse transcription.

Base Sequence↗

PubMed1991

Genetic evidence that genes fdhD and fdhE do not control synthesis of formate dehydrogenase-N in Escherichia coli K-12.

Enterobacteria synthesize two formate dehydrogenases, formate dehydrogenase-N (encoded by fdnGHI) and formate dehydrogenase H (encoded by fdhF). Previous work has identified two rha-linked Salmonella typhimurium genes, fdnB and fdnC, which are required primarily for formate dehydrogenase-N activity. Analogous mutants, termed fdhD and fdhE, have been isolated in Escherichia coli. We used gene fusions between fdnG, the structural gene for the large subunit of formate dehydrogenase-N, and lacZ, the structural gene for beta-galactosidase, to examine E. coli fdnGHI operon expression in fdhD and fdhE insertion mutants. Expression of the phi (fdnG-lacZ) gene fusions was little affected by these insertions, suggesting that fdhD and fdhE do not control transcription or UGA decoding of the formate dehydrogenase-N structural genes. Our complementation tests, with cloned E. coli fdhD and fdhE genes, indicate that the S. typhimurium fdnC and fdnB genes are functionally homologous to the E. coli fdhD and fdhE genes, respectively.

Cloning, Molecular↗

PubMed2003

Continuing the search for dyslexia genes on 6p.

This study is a continuation and extension of the work with Orton Developmental Dyslexia (DD) pedigrees [Grigorenko et al., 1997; 2000, Grigorenko et al., 2001]. This study utilized an extended sample (N = 176) and a well-saturated map of chromosome 6p (30 markers). Six phenotypes were constructed to span a range of dyslexia-related cognitive processes. These phenotypes were: (1) Phonemic Awareness (of spoken words); (2) Phonological Decoding (of printed nonwords); (3) Rapid Automatized Naming (of colored squares or object drawings); (4) Single Word Reading (orally, of printed real words); (5) Phonemic Awareness/Decoding/Single-Word Reading pathway; and (6) Phonemic Awareness/Rapid Naming/Single-Word Reading pathway. The study resulted in two major findings. First, considering the distributions of the genetic linkage indicators across all phenotypes examined, there appear to be three regions of interest (around markers D6S109, D6S1261, and in the D6S105-D6S265 region). Any of these regions could serve as a starting point in the search for specific gene candidates contributing to the manifestation of DD, yet they all might be echo peaks of a single peak, the boundary of which is difficult to establish due to the limited power of this sample. Second, the DD-related linkage in 6p21.3 appears to be most closely related to the manifestations of DD through phonemic awareness and single-word reading deficits.

Adolescent↗

PubMed1998

Dependence of the 16S rRNA decoding region structure on Mg2+, subunit association, and temperature.

The effects of Mg2+ concentration, subunit association, and temperature on the structure of 16S rRNA in the Escherichia coli ribosome were investigated using UV cross-linking and gel electrophoresis analysis. Mg2+ concentrations between 1 and 20 mM and temperatures between 5 and 55 degreesC had little effect on the frequency of 12 of the 14 cross-links in 30S subunits and modest effects on the same cross-links in 70S ribosomes. In contrast, two cross-links, C967 x C1400 and C1402 x C1501, involving rRNA in the decoding region are present in 30S subunits only above 3 mM Mg2+, increase in frequency at higher Mg2+ concentration, and are both more frequent when 50S subunits are included in the reactions. In 70S ribosomes, the cross-link C1402 x C1501 increases but the cross-link C967 x C1400 decreases at higher Mg2+ concentrations. One cross-link, C1397 x U1495, is detected only in 70S ribosomes and decreases in frequency as Mg2+ concentration is increased. An additional cross-link, A1093 x C1182, decreases upon subunit association. The cross-link frequency differences indicate that the arrangement of the decoding region of the 16S rRNA, but not in the rest of the subunit, is readily altered by Mg2+ ions and subunit association.

Base Sequence↗

PubMed2002

The role of neuroscience in the remediation of students with dyslexia.

Dyslexia is a specific learning disability that is neurobiological in origin. It is characterized by difficulties with accurate and/or fluent word recognition, spelling and decoding abilities. Research findings agree that these and other observed behavioral manifestations largely result from a deficit in the phonological component of language. However, conflicting theories on the exact nature of the phonological deficit have given rise to divergent treatment approaches. Recent advances in functional brain imaging and genetics have allowed these theories to be examined more closely. If implemented appropriately, commercial programs can be effective in identifying dyslexia. Treatment of dyslexia has been advanced through neuroscience, yet further study is needed to provide rigorous, reproducible findings that will sustain commercial approaches.

Brain↗

PubMed2026

DNA-aware evaluation and debiasing of sequence-to-function models.

MOTIVATION: Genome sequence-to-function (S2F) models are widely used to interpret base-resolution functional genomics assays. Most S2F models are trained and evaluated against observed counts and profile-shapes using statistical objectives and fidelity metrics. These choices are well motivated, but they are DNA-independent. At the same time, experimental measurements arise from DNA-dependent assays with distinct characteristics. This mismatch motivates a complementary DNA-aware evaluation of S2F-predicted and experimental functional genomic tracks. RESULTS: We study DNA-dependency of experimental and S2F-predicted tracks using track-conditional genome language models (cgLMs). cgLMs predict masked nucleotides from a conditioning track under controlled DNA visibility. Across ATAC-seq and TF ChIP-seq peaks from GM12878 and K562, cgLM-probing reveals a consistent masked DNA-decodability gap between many experimental and S2F-predicted tracks. In particular, single-task (e.g. BPNet) and multi-task (e.g. AlphaGenome) S2F-predicted tracks enabled cgLMs to recover masked nucleotides with significantly higher accuracy and confidence than matched experimental tracks. Analyses of nonpeak and dinucleotide-shuffled sequences show that this gap is not confined to peaks and is not captured by standard DNA-agnostic profile-shape fidelity metrics alone. ChromBPNet Tn5-denoised predictions were an exception and behaved closer to the experimental regime, suggesting that staged training may reduce the gap. We then convert this diagnostic into a critic-derived objective, DNA-dependency matching (DDM), using a frozen multi-headed cgLM critic. We introduce Critic-Guided Profile-Shape Editing (CGPSE), a preliminary post hoc debiasing framework for frozen S2F models. In GM12878 ATAC-seq, CGPSE partially reduces the masked DNA-decodability gap for AlphaGenome and BPNet predictions, while exposing a tradeoff with profile-shape fidelity. AVAILABILITY AND IMPLEMENTATION: https://github.com/li-lab-mcgill/dna-aware-s2f-eval.

DNA↗

PubMed2026

Towards efficient perturbation for the noncoding genome.

Deciphering the functionality of the noncoding genome, which includes important cis-regulatory elements (CREs) and transcribed noncoding RNA genes, remains technically challenging. Here, using massively parallel genetic screening, we systematically benchmark the performance of five representative loss-of-function perturbation tools, including single-guide RNA (gRNA) mediated SpCas9 cleavage or CRISPR interference, and paired gRNA (pgRNA) involved dual-SpCas9, Big Papi (paired SpCas9 and SaCas9) or dual-enAsCas12a fragment deletion methods, in decoding the roles of the noncoding genome. For targeting CREs such as enhancers, dual-SpCas9 outperforms other methods with superior efficiency in destroying functional genomic regions. For perturbing noncoding RNA genes, in addition to dual-SpCas9, other RNA-targeting methods such as RNA interference are recommended to discriminate transcript-dependent or -independent roles. A deep learning model, DeepDC, with an associated web server, is built to facilitate optimal dual-SpCas9 pgRNA design for efficiently deleting a genomic fragment. Together, our work provides practical guidance on selecting appropriate loss-of-function tools to resolve the functional complexity of the noncoding genome.

CRISPR-Cas Systems↗

PubMed1998

The Human Genome Project: applications in the diagnosis and treatment of neurologic disease.

The Human Genome Project (HGP), an international program to decode the entire DNA sequence of the human genome in 15 years, represents the largest biological experiment ever conducted. This set of information will contain the blueprint for the construction and operation of a human being. While the primary driving force behind the genome project is the potential to vastly expand the amount of genetic information available for biomedical research, the ramifications for other fields of study in biological research, the biotechnology and pharmaceutical industry, our understanding of evolution, effects on agriculture, and implications for bioethics are likely to be profound.

Brain Diseases↗

PubMed1989

Suppression of a -1 frameshift mutation by a recessive tRNA suppressor which causes doublet decoding.

sufS was found to suppress the only known suppressible-1 frameshift mutation, trpE91, at a site identified as GGA and mapped within the single gene of the only tRNA that can decode GGA in Escherichia coli. It mapped to the same gene in Salmonella typhimurium. sufS alleles were recessive, and dominant alleles could not be isolated. This is in contrast to all other tRNA structural gene mutations identified thus far that cause frameshift suppression. The recessiveness implies that all sufS alleles are poor competitors against their wild-type tRNA(Gly2) counterparts. The base G immediately 5' of the GGA suppression site influenced the level but was not critical for suppression by sufS601. From this result, it is inferred that sufS601 causes frameshifting by doublet decoding.

Alleles↗

PubMed1998

Rabbit beta-globin is extended beyond its UGA stop codon by multiple suppressions and translational reading gaps.

Translational reading gaps occur when genetic information encoded in mRNA is not translated during the normal course of protein synthesis. This phenomenon has been observed thus far only in prokaryotes and is a mechanism for extending the reading frame by circumventing the normal stop codon. Reading frames of proteins may also be extended by suppression of the stop codon mediated by a suppressor tRNA. The rabbit beta-globin read-through protein, the only known, naturally occurring read-through protein in eukaryotes, was sequenced by ion trap mass spectrometry to determine how the reading frame is extended. Seven different proteolytic peptide fragments decoded by the same sequence that spans the UGA stop codon of rabbit beta-globin mRNA were detected. Three of these peptides contain translational reading gaps of one to three amino acids that correspond to the UGA stop codon site and/or one or two of the immediate downstream codons. To our knowledge, this is the first reported example of the occurrence of reading gaps in protein synthesis in eukaryotes. This event is unique in that it is associated with bypasses involving staggered lengths of untranslated information. Four of the seven peptides contain serine, tryptophan, cysteine, and arginine decoded by UGA and thus arise by suppression. Serine is donated by selenocysteine tRNA, and it, like the other tRNAs, has previously been shown to suppress UGA in vitro in mammals, but not in vivo.

Amino Acid Sequence↗