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PubMed2006

Genomewide scan for real-word reading subphenotypes of dyslexia: novel chromosome 13 locus and genetic complexity.

Dyslexia is a common learning disability exhibited as a delay in acquiring reading skills despite adequate intelligence and instruction. Reading single real words (real-word reading, RWR) is especially impaired in many dyslexics. We performed a genome scan, using variance components (VC) linkage analysis and Bayesian Markov chain Monte Carlo (MCMC) joint segregation and linkage analysis, for three quantitative measures of RWR in 108 multigenerational families, with follow up of the strongest signals with parametric LOD score analyses. We used single-word reading efficiency (SWE) to assess speed and accuracy of RWR, and word identification (WID) to assess accuracy alone. Adjusting SWE for WID provided a third measure of RWR efficiency. All three methods of analysis identified a strong linkage signal for SWE on chromosome 13q. Based on multipoint analysis with 13 markers we obtained a MCMC intensity ratio (IR) of 53.2 (chromosome-wide P < 0.004), a VC LOD score of 2.29, and a parametric LOD score of 2.94, based on a quantitative-trait model from MCMC segregation analysis (SA). A weaker signal for SWE on chromosome 2q occurred in the same location as a significant linkage peak seen previously in a scan for phonological decoding. MCMC oligogenic SA identified three models of transmission for WID, which could be assigned to two distinct linkage peaks on chromosomes 12 and 15. Taken together, these results indicate a locus for efficiency and accuracy of RWR on chromosome 13, and a complex model for inheritance of RWR accuracy with loci on chromosomes 12 and 15.

Adolescent↗
PubMed1995

UGA suppression by a mutant RNA of the large ribosomal subunit.

A role for rRNA in peptide chain termination was indicated several years ago by isolation of a 168 rRNA (small subunit) mutant of Escherichia coli that suppressed UGA mutations. In this paper, we describe another interesting rRNA mutant, selected as a translational suppressor of the chain-terminating mutant trpA (UGA211) of E. coli. The finding that it suppresses UGA at two positions in trpA and does not suppress the other two termination codons, UAA and UAG, at the same codon positions (or several missense mutations, including UGG, available at one of the two positions) suggests a defect in UGA-specific termination. The suppressor mutation was mapped by plasmid fragment exchanges and in vivo suppression to domain II of the 23S rRNA gene of the rrnB operon. Sequence analysis revealed a single base change of G to A at residue 1093, an almost universally conserved base in a highly conserved region known to have specific interactions with ribosomal proteins, elongation factor G, tRNA in the A-site, and the peptidyltransferase region of 23S rRNA. Several avenues of action of the suppressor mutation are suggested, including altered interactions with release factors, ribosomal protein L11, or 16S rRNA. Regardless of the mechanism, the results indicate that a particular residue in 23S rRNA affects peptide chain termination, specifically in decoding of the UGA termination codon.

Base Sequence↗
PubMed2004

MAP-O-MAT: internet-based linkage mapping.

UNLABELLED: MAP-O-MAT is a web-based server for automated linkage mapping of human polymorphic DNA markers. MAP-O-MAT facilitates the verification of order and map distances for custom mapping sets using genotype data from the CEPH database, and from the Marshfield, SNP Consortium and Rutgers linkage maps (exclusive to the deCODE genotyping data). The CRI-MAP program is used for likelihood calculations and some mapping algorithms, and physical map positions are provided from the human genome assembly. AVAILABILITY: MAP-O-MAT is located at http://compgen.rutgers.edu/mapomat/ CONTACT: matise@biology.rutgers.edu.

Chromosome Mapping↗
PubMed1995

tRNA genes transcribed from the plastid-like DNA of Plasmodium falciparum.

Besides their mitochondrial genome, malarial parasites contain a second organellar DNA. This 35 kb circular molecule has a number of features reminiscent of plastid DNAs. Sequence analysis shows that along with other genes the circle codes for 25 different tRNAs all of which are transcribed. Six of the tRNAs have some unusual features, and one has an intron, the only one found so far on the circle. Comparison of codon and anticodon usage indicates that the 25 tRNAs are sufficient to decode all the protein genes present on the circle. The maintenance of such a parsimonious but complete translation system is further evidence for the functionality of the circle.

Animals↗
PubMed1995

The CUG codon is decoded in vivo as serine and not leucine in Candida albicans.

Previous studies have shown that the yeast Candida albicans encodes a unique seryl-tRNA(CAG) that should decode the leucine codon CUG as serine. However, in vitro translation of several different CUG-containing mRNAs in the presence of this unusual seryl-tRNA(CAG) result in an apparent increase in the molecular weight of the encoded polypeptides as judged by SDS-PAGE even though the molecular weight of serine is lower than that of leucine. A possible explanation for this altered electrophoretic mobility is that the CUG codon is decoded as modified serine in vitro. To elucidate the nature of CUG decoding in vivo, a reporter system based on the C. albicans gene (RBP1) encoding rapamycin-binding protein (RBP), coupled to the promoter of the C. albicans TEF3 gene, was utilized. Sequencing and mass-spectrometry analysis of the recombinant RBP expressed in C. albicans demonstrated that the CUG codon was decoded exclusively as serine while the related CUU codon was translated as leucine. A database search revealed that 32 out of the 65 C. albicans gene sequences available have CUG codons in their open reading frames. The CUG-containing genes do not belong to any particular gene family. Thus the amino acid specified by the CUG codon has been reassigned within the mRNAs of C. albicans. We argue here that this unique genetic code change in cellular mRNAs cannot be explained by the 'Codon Reassignment Theory'.

Amino Acid Sequence↗
PubMed2005

Single nucleotide +1 frameshifts in an apparently functional mitochondrial cytochrome b gene in ants of the genus Polyrhachis.

Twelve of 30 species examined in the ant genus Polyrhachis carry single nucleotide insertions at one or two positions within the mitochondrial cytochrome b (cytb) gene. Two of the sites are present in more than one species. Nucleotide substitutions in taxa carrying insertions show the strong codon position bias expected of functional protein coding genes, with substitutions concentrated in the third positions of the original reading frame. This pattern of evolution of the sequences strongly suggests that they are functional cytb sequences. This result is not the first report of +1 frameshift insertions in animal mitochondrial genes. A similar site was discovered in vertebrates, where single nucleotide frameshift insertions in many birds and a turtle were reported by Mindell et al. (Mol Biol Evol 15:1568, 1998). They hypothesized that the genes are correctly decoded by a programmed frameshift during translation. The discovery of four additional sites gives us the opportunity to look for common features that may explain how programmed frameshifts can arise. The common feature appears to be the presence of two consecutive rare codons at the insertion site. We hypothesize that the second of these codons is not efficiently translated, causing a pause in the translation process. During the stall the weak wobble pairing of the tRNA bound in the peptidyl site of the ribosome, together with an exact Watson-Crick codon-anticodon pairing in the +1 position, allows translation to continue in the +1 reading frame. The result of these events is an adequate level of translation of a full-length and fully functional protein. A model is presented for decoding of these mitochondrial genes, consistent with known features of programmed translational frameshifting in the yeast TY1 and TY3 retrotransposons.

Amino Acid Sequence↗
PubMed2002

The transorientation hypothesis for codon recognition during protein synthesis.

During decoding, a codon of messenger RNA is matched with its cognate aminoacyl-transfer RNA and the amino acid carried by the tRNA is added to the growing protein chain. Here we propose a molecular mechanism for the decoding phase of translation: the transorientation hypothesis. The model incorporates a newly identified tRNA binding site and utilizes a flip between two tRNA anticodon loop structures, the 5'-stacked and the 3'-stacked conformations. The anticodon loop acts as a three-dimensional hinge permitting rotation of the tRNA about a relatively fixed codon-anticodon pair. This rotation, driven by a conformational change in elongation factor Tu involving GTP hydrolysis, transorients the incoming tRNA into the A site from the D site of initial binding and decoding, where it can be proofread and accommodated. The proposed mechanisms are compatible with the known structures, conformations and functions of the ribosome and its component parts including tRNAs and EF-Tu, in both the GTP and GDP states.

Anticodon↗
PubMed2001

Regulation of gene expression by action potentials: dependence on complexity in cellular information processing.

Nervous system development and plasticity are regulated by neural impulse activity, but it is not well understood how the pattern of action potential firing could regulate the expression of genes responsible for long-term adaptive responses in the nervous system. Studies on mouse sensory neurons in cell cultures equipped with stimulating electrodes show that specific genes can be regulated by different patterns of action potentials, and that the temporal dynamics of intracellular signalling cascades are critical in decoding and integrating information contained in the pattern of neural impulse activity. Functional consequences include effects on neurite outgrowth, cell adhesion, synaptic plasticity and axon-glial interactions. Signalling pathways involving Ca2+, CaM KII, MAPK and CREB are particularly important in coupling action potential firing to the transcriptional regulation of both neurons and glia, and in the conversion of short-term to long-term memory. Action potentials activate multiple convergent and divergent pathways, and the complex network properties of intracellular signalling and transcriptional regulatory mechanisms contribute to spike frequency decoding.

Action Potentials↗
PubMed2001

Seryl-tRNA synthetase is not responsible for the evolution of CUG codon reassignment in Candida albicans.

A number of Candida species translate the standard leucine-CUG codon as serine using a novel ser-tRNA(CAG). This tRNA, which has an unusual anticodon stem-loop structure, has been implicated in the evolution of this codon reassignment. However, such a sense codon reassignment might also require a change in the specificity of the cognate aminoacyl tRNA-synthetase, in this case the ser-tRNA synthetase. Here we describe the cloning and sequence analysis of the C. albicans seryl aminoacyl-tRNA synthetase (CaSerRS) gene (CaSES1). The predicted CaSerRS sequence shows a significant level of amino acid identity to SerRs from other organisms and fully complements a S. cerevisiae SerRS null strain without any apparent defect in growth rate. This suggests that the SerRS recognizes and charges S. cerevisiae ser-tRNAs with similar efficiency to that of the S. cerevisiae SerRS. Using an antibody raised against CaSerRS, we also demonstrate the presence of SerRS in a range of Candida spp. showing CUG codon reassignment. We conclude that the key element in CUG reassigment in Candida spp. is the tRNA that decodes the CUG codon rather than a SerRS structural change. The nucleotide sequence of the CaSES1 gene has been deposited at GenBank under Accession No. AF290915.

Amino Acid Sequence↗
PubMed2000

Inhibition of selenoprotein synthesis by selenocysteine tRNA[Ser]Sec lacking isopentenyladenosine.

A common posttranscriptional modification of tRNA is the isopentenylation of adenosine at position 37, creating isopentenyladenosine (i(6)A). The role of this modified nucleoside in protein synthesis of higher eukaryotes is not well understood. Selenocysteyl (Sec) tRNA (tRNA([Ser]Sec)) decodes specific UGA codons and contains i(6)A. To address the role of the modified nucleoside in this tRNA, we constructed a site-specific mutation, which eliminates the site of isopentenylation, in the Xenopus tRNA([Ser]Sec) gene. Transfection of the mutant tRNA([Ser]Sec) gene resulted in 80% and 95% reduction in the expression of co-transfected selenoprotein genes encoding type I and II iodothyronine deiodinases, respectively. A similar decrease in type I deiodinase synthesis was observed when transfected cells were treated with lovastatin, an inhibitor of the biosynthesis of the isopentenyl moiety. Neither co-transfection with the mutant tRNA gene nor lovastatin treatment reduced type I deiodinase mRNA levels. Also, mutant tRNA expression did not alter initiation of translation or degradation of the type I deiodinase protein. Furthermore, isopentenylation of tRNA([Ser]Sec) was not required for synthesis of Sec on the tRNA. We conclude that isopentenylation of tRNA([Ser]Sec) is required for efficient translational decoding of UGA and synthesis of selenoproteins.

Animals↗
PubMed2004

Imminent approaches towards molecular interventions in ageing.

Ageing is an innate feature of living organisms. Sensational progress in its molecular understanding in the last decade has culminated into a highly complex picture. Emerging from this complexity are the distinctive roles of some of the tumor suppressor pathways including p53 and pRB in maintenance of senescence phenotype, and telomere maintaining pathways in its escape. We discuss here the current scenario of molecular ageing and the use of modern approaches for its intervention in culture system, at least. Many of the tools we describe here are the newly emergent functional RNA tools that are proved to be fruitful in decoding the human genome. These post-genomic technologies will help us in the discovery of gene targets for interventions aiming to improve the quality at later years of life beyond their mere algebraic extension.

Aging↗
PubMed1983

Anticodon shift in tRNA: a novel mechanism in missense and nonsense suppression.

In a previous publication, an unusual UGG-reading missense suppressor caused by insertion of an extra adenylate residue in the anticodon loop of an Escherichia coli glycine tRNA was described. In this study, we provide in vivo evidence that the additional nucleotide causes an "anticodon shift" by one nucleotide in the 3' direction and that the "new" anticodon can explain the unanticipated coding properties of the suppressor. We converted the UGG suppressor with ethyl methanesulfonate, a base-substitution mutagen, to suppressors that read codons related to UGG by a single base change. Sequence analysis of each mutant tRNA revealed that its mutational alteration was an anticipated base change in one of the three nucleotides of the "new" anticodon. Although the new suppressors read codons beginning with A or U, the mutant tRNAs lack the customary hypermodified nucleosides on the 3' side of the anticodon. As determined on the basis of their in vivo coding specificities, the new mutant tRNAs do not continue to utilize the original anticodon triplet for decoding. Furthermore, the failure of the UGG suppressor to correct frameshift mutations throughout each of three genes of the trp operon suggests that the addition of a nucleotide to the anticodon loop of a tRNA does not necessarily result in out-of-frame decoding by the tRNA. Therefore, a "frameshift" mutation in a tRNA has principally changed the triplet codon recognition properties of the molecule.

Anticodon↗
PubMed2025

Integrating advanced analytical methods to assess epigenetic marks affecting response to hypomethylating agents in higher risk myelodysplastic syndrome.

BACKGROUND: Patients with higher-risk (HR) myelodysplastic syndrome (MDS), ineligible for allogeneic hematopoietic stem cell transplantation (alloHSCT), require prompt therapeutic interventions, such as treatment with hypomethylating agents (HMAs) to restore normal DNA methylation patterns, mainly of oncosuppressor genes, and consequently to delay disease progression and increase overall survival (OS). However, response assessment to HMA treatment relies on conventional methods with limited capacity to uncover a wide spectrum of underlying molecular events. METHODS: We implemented liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess 5' methyl-2' deoxycytidine (5mdC), 5' hydroxy-methyl-2'-deoxycytidine (5hmdC) levels and global adenosine/thymidine ([dA]/[T]) ratio in bone marrow aspirates from twenty-one HR MDS patients, pre- and post-HMA treatment. Additionally, targeted methylation analysis was performed by interpretation of NGS-methylation (MeD-seq) data obtained from the same patient cohort. RESULTS: LC/MS-MS analysis revealed a significant hypomethylation status in responders (Rs), already established at baseline and a trend for further DNA methylation reduction post-HMA treatment. Non-responders (NRs) reached statistical significance for DNA hypomethylation only post-HMA treatment. The 5hmdC epigenetic mark was approximately detected at 37.5-40% among NRs and Rs, implying the impairment of the natural active demethylation pathway, mediated by the ten-eleven (TET) 5mdC dioxygenases. R and NR subgroups displayed a [dA]/[T] ratio&#x2009;<&#x2009;1 (0.727&#x2009;-&#x2009;0.633), supporting high frequences of 5mdC transition to thymidine. Response to treatment, according to whole genome MeD-seq data analysis, was associated with specific, scattered hypomethylated DMRs, rather than presenting a global effect across genome. MeD-seq analysis identified divergent epigenetic effects along chromosomes 7, 9, 12, 16, 18, 21, 22, X and Y. Within statistically significant selected chromosomal bins, genes encoding for proteins and non-coding RNAs with reversed methylation profiles between Rs and NRs, were highlighted. CONCLUSIONS: Implementation of powerful analytical tools to identify the dynamic DNA methylation changes in HR MDS patients undergoing HMA therapy demonstrated that LC-MS/MS exerts high efficiency as a broad-based but rapid and cost-effective methodology (compared to MeD-seq) to decode different perspectives of the epigenetic background of HR MDS patients and possess discriminative efficacy of the response phenotype to HMA treatment.

Humans↗
PubMed2000

Neuropsychological deficits in pediatric patients with childhood-onset schizophrenia and psychotic disorder not otherwise specified.

OBJECTIVE: Children with transient psychotic symptoms and serious emotional disturbances who do not meet current criteria for schizophrenia or other presently recognized diagnostic categories commonly present diagnostic and treatment problems. Clarifying the connections between children with narrowly defined schizophrenia and children with a more broadly defined phenotype (i.e., Psychotic Disorder Not Otherwise Specified, PD-NOS) has implications for understanding the pathophysiology of schizophrenia. In this study, the neuropsychological test performance of a subgroup of children with atypical psychosis was compared with that of patients with childhood-onset schizophrenia (COS). METHOD: Cognitive function was assessed with neuropsychological test battery regimens in 51 neuroleptic-nonresponsive patients within the first 270 at NIMH testing (24 PD-NOS, 27 COS) were included in this analysis. Seventeen (39%) of 44 COS subjects were unavailable for this study as their IQ tested <70. The PD-NOS patients were younger than the COS patients at the time of testing (12.0+/-2.8 vs 14.4+/-1.8years, respectively, p<0.004). The test levels of these groups were compared with each other. RESULTS: The neuropsychological test results for the PD-NOS and COS patients were 1-2standard deviations below normative data across a broad array of cognitive functions. There were no overall differences in the test levels for the six summary scales (F=2.82, df=1, 36, p=0.10) or in the profile shape (F=1.70, df=5, 180, p=0.14) between the PD-NOS and COS groups. For the COS patients, there was a significant difference between their mean full-scale WISC IQ (84.7+/-16.2) and their average standard scores for both the spelling (97.7+/-16.1, n=23, t=4.0, p=0.001) and reading decoding subtests (97.7+/-13.7, n=23, t=3.7, p=0.001) of the Kaufman Test of Educational Achievement. CONCLUSIONS: Treatment-refractory PD-NOS and COS patients share a similar pattern of generalized cognitive deficits, including deficits in attention, learning and abstraction which are commonly observed in adult patients with schizophrenia. These data support a hypothesis that at least some of the PD-NOS cases belong within the schizophrenic spectrum, which is of importance for future genetic studies planned for this cohort.

Adolescent↗
PubMed2026

Decoding Primary Open-Angle Glaucoma: A Multi-Omics Approach to Identify Druggable Effector Genes.

PURPOSE: Genomewide association studies (GWAS) have identified numerous primary open angle glaucoma (POAG) risk loci, yet most reside in non-coding regions with unclear function. Mapping these loci to effector genes can elucidate disease mechanisms, identify functionally conserved variants, improve cross-ancestry risk prediction by reducing population-specific noise, and uncover shared therapeutic targets. METHODS: Here, we integrate European POAG GWAS with six types of multi-omics molecular Quantitative Trait Locis (xQTLs) using multi-trait colocalization to identify candidate effector variants and evaluate their cross-population relevance using genetic risk score (GRS) analysis, and their therapeutic potential through drug target prioritization. RESULTS: We identified 25 POAG effector variants colocalized with at least one xQTLs. In non-European populations, effector variants showed stronger effect size correlations with Europeans than non-colocalized variants (Pearson r2 = African 0.85 vs. 0.71; East Asian 0.81 vs. 0.69; and Latin American 0.91 vs. 0.75). Effector variants also had smaller allele frequency variations across populations (average interquartile range [IQR] = 0.15 vs. 0.20). The genetic risk score based on effector variants performed comparably to the genome-wide significant single-nucleotide polymorphism (SNP)-based GRS in non-European populations. Drug prioritization identified zinc, copper, sunitinib, probucol, and astemizole as potential common therapeutic agents for POAG and its subtypes. CONCLUSIONS: Our findings offer deeper insight into the molecular mechanisms underlying glaucoma and effector variants for developing more robust GRS models and broadly effective therapeutic strategies for POAG.

Humans↗
PubMed2002

A cytosolic tRNA with an unmodified adenosine in the wobble position reads a codon ending with the non-complementary nucleoside cytidine.

Out of more than 500 sequenced cytosolic tRNAs, there is only one with an unmodified adenosine in the wobble position (position 34). The reason for this rare occurrence of A34 is that it is mostly deaminated to inosine-34 (I34). I34 is a common constituent in the wobble position of tRNAs and has a decoding capacity different from that of A34. We have isolated a mutant (proL207) of Salmonella typhimurium, in which the wobble nucleoside G34 has been replaced by an unmodified A in tRNA(Pro)(GGG), which is the only tRNA that normally reads the CCC codon. Thus, this mutant apparently has no tRNA that is considered cognate for the codon CCC. Despite this, the mutant grows normally. As expected, Pro-tRNA selection at the CCC codon in the A-site in a mutant deleted for the proL gene, which encodes the tRNA(Pro)(GGG), was severely reduced. However, in comparison this rate of selection was only slightly reduced in the proL207 mutant with its A34 containing tRNA(Pro)(AGG) suggesting that this tRNA reads CCC. Moreover, measurements of the interference by a tRNA residing in the P-site on the apparent termination efficiency at the A-site indicated that indeed the A34 containing tRNA reads the CCC codon. We conclude that A34 in a cytosolic tRNA is not detrimental to the cell and that the mutant tRNA(Pro)(AGG) is able to read the CCC codon like its wild-type counterpart tRNA(Pro)(GGG). We suggest that the decoding of the CCC codon by a 5'-AGG-3' anticodon occurs by a wobble base-pair between a protonated A34 and a C in the mRNA.

Adenosine↗
PubMed2006

Acquisition of the wobble modification in mitochondrial tRNALeu(CUN) bearing the G12300A mutation suppresses the MELAS molecular defect.

The A3243G mutation in the mitochondrial gene for human mitochondrial (mt) tRNA(Leu(UUR)), responsible for decoding of UUR codons, is associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). We previously demonstrated that this mutation causes defects in 5-taurinomethyluridine (taum(5)U) modification at the anticodon first (wobble) position of the mutant mt tRNA(Leu(UUR)), leading to a UUG decoding deficiency and entraining severe respiratory defects. In addition, we previously identified a heteroplasmic mutation, G12300A, in the other mt leucine tRNA gene, mt tRNA(Leu(CUN)), which functions as a suppressor of the A3243G respiratory defect in cybrid cells containing A3243G mutant mtDNA. Although the G12300A mutation converts the anticodon sequence of mt tRNA(Leu(CUN)) from UAG to UAA, this tRNA carrying an unmodified wobble uridine still cannot decode the UUG codon. Mass spectrometric analysis of the suppressor mt tRNA(Leu(CUN)) carrying the G12300A mutation from the phenotypically revertant cells revealed that the wobble uridine acquires de novo taum(5)U modification. In vitro translation confirmed the functionality of the suppressor tRNA for decoding UUG codons. These results demonstrate that the acquisition of the wobble modification in another isoacceptor tRNA is critical for suppressing the MELAS mutation, and they highlight the primary role of the UUG decoding deficiency in the molecular pathogenesis of MELAS syndrome.

Adenosine↗