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Results for “human tRNA genetic variance”

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8 recordsLinked to original sources
PubMed2025

MapID-based quantitative mapping of chemical modifications and expression of human transfer RNA.

Detection and quantification of tRNA chemical modifications are critical for understanding their regulatory functions in biology and diseases. However, tRNA-seq-based methods for modification mapping encountered challenges both experimentally (poor processivity of heavily modified tRNAs during reverse transcription or RT) and bioinformatically (frequent reads misalignment to highly similar tRNA genes). Here, we report "MapID-tRNA-seq" where we deployed an evolved reverse transcriptase (RT-1306) into tRNA-seq and developed "MapIDs" that reduce redundancy of the human tRNA genome and explicitly annotate genetic variances. RT-1306 generated robust mutations against m1A and m3C, and RT stops against multiple bulky roadblock modifications. MapID-assisted data processing enabled systematic exclusion of false-positive discoveries of modifications which arise from reads misalignment onto similar genes. We applied MapID-tRNA-seq into mapping m1A, m3C and expression levels of tRNAs in three mammary cell lines, which revealed cell-type dependent modification sites and potential translational regulation of the reduced mitochondrial activities in breast cancer.

Humans↗
PubMed2005

Sequence variation in the tRNA genes of human mitochondrial DNA.

Recent analyses have shown that nonsynonymous variation in human mitochondrial DNA (mtDNA) contains nonneutral variants, suggesting the presence of mildly deleterious mutations. Many of the disease-causing mutations in mtDNA occur in the genes encoding the tRNAs. Nucleotide sequence variation in these genes has not been studied in human populations, nor have the structural consequences of nucleotide substitutions in tRNA molecules been examined. We therefore determined the nucleotide sequences of the 22 tRNA genes in the mtDNA of 477 Finns and, also, obtained 435 European sequences from the MitoKor database. No differences in population polymorphism indices were found between the two data sets. We assessed selective constraints against various tRNA domains by comparing allele frequencies between these domains and the synonymous and nonsynonymous sites, respectively. All tRNA domains except the variable loop were more conserved than synonymous sites, and T stem and D stem were more conserved than the respective loops. We also analyzed the energetic consequences of the 96 polymorphisms recovered in the two data sets or in the Mitomap database. The minimum free energy (DeltaG) was calculated using the free energy rules as implemented in mfold version 3.1. The DeltaG's were normally distributed among the 22 wild-type tRNA genes, whereas the 96 polymorphic tRNAs departed significantly from a normal distribution. The largest differences in DeltaG between the wild-type and the polymorphic tRNAs in the Finnish population tended to be in the polymorphisms that were present at low frequencies. Allele frequency distributions and minimum free energy calculations both suggested that some polymorphisms in tRNA genes are nonneutral.

Analysis of Variance↗
PubMed1998

Genetic studies of polymorphisms in ten non-insulin-dependent diabetes mellitus candidate genes in Tamil Indians from Pondichery.

We report a study of 10 candidate genes presumably involved in diabetes or insulin resistance or obesity among Pondicherian Tamil Indians, an isolated population with a high prevalence of diabetes. Forty-nine families with at least two affected patients in the sibship (567 individuals) were selected and tested by PCR-RFLP techniques for reported mutations in 10 diabetes or obesity candidate genes: glucagon receptor, insulin receptor substrate 1, insulin receptor, human beta 3 adrenergic receptor, fatty acid binding protein 2, mitochondrial tRNA(Leu(UUR)), sulphonylurea receptor, human uncoupling protein and the glycogen-associated regulatory subunit of protein phosphatase-1. Glucokinase gene was also screened for mutations. No mutations were found in glucokinase, glucagon receptor and mitochondrial genes in any of the 49 probands. Frequencies of polymorphisms at other loci were similar to those reported in Caucasian populations, except for 4 of the loci at which a higher frequency of variants was observed: human beta 3 adrenergic receptor, human uncoupling type 1 protein, fatty acid binding protein 2 and the glycogen-associated regulatory subunit of protein phosphatase-1. However, no evidence of association between any of these gene variants and non-insulin-dependent diabetes mellitus (NIDDM) or quantitative traits related to NIDDM (including body mass index, waist/hip ratio, insulinaemia, glycaemia, triglycerides and total cholesterol) was found in our sample. These results suggest that none of these gene variants commonly found in the Pondicherian Tamil population of South India is a major NIDDM predisposing locus, although it cannot be excluded that they may contribute to the polygenic background of the metabolic syndrome in Pondichery.

Adult↗
PubMed2003

Executive and visuospatial deficits in patients with chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome.

Although neuropsychological deficits have been reported in mitochondrial cytopathies, patients with chronic progressive external ophthalmoplegia (CPEO) or Kearns-Sayre syndrome (KSS) have not been studied systematically using a comprehensive test battery. The aim of our study was to assess the range and extent of putative cognitive dysfunction in 22 patients with CPEO or KSS, and to compare cognitive performance of patients with healthy control subjects matched for age, sex and years of education. Genetic analysis of skeletal muscle tissue from 22 patients with CPEO or KSS included screening for mitochondrial DNA (mtDNA) point mutations (3243/8344) and mtDNA deletions. All patients were examined by a neuropsychological test battery covering verbal skills, verbal and visual memory, visuo-spatial perception, visual construction, attention, abstraction and flexibility, and Quality of Life. Molecular genetic analysis of mtDNA revealed single large-scale deletions in 15 out of 22 patients and the tRNA (Leu) A3243G point mutation in two out of 22 patients. In five out of 22 patients none of the frequently encountered mtDNA mutations could be detected. Neuropsychological testing did not reveal general intellectual deterioration, but specific cognitive deficits, particularly in visual construction, attention and abstraction/flexibility. Subgroup analysis of 15 patients with mtDNA deletions showed similar results when compared with the full group. In our series of patients with CPEO or KSS neuropsychological testing did not reveal signs that would suggest general intellectual decline or dementia, but provided evidence of specific focal neuropsychological deficits, suggesting particular impairment of visuospatial perception associated to parieto-occipital lobes and executive deficits associated to the prefrontal cortex.

Adult↗
PubMedDate not supplied

Codon usage and tRNA genes in eukaryotes: correlation of codon usage diversity with translation efficiency and with CG-dinucleotide usage as assessed by multivariate analysis.

The species-specific diversity of codon usage in five eukaryotes (Schizosaccharomyces pombe, Caenorhabditis elegans, Drosophila melanogaster, Xenopus laevis, and Homo sapiens) was investigated with principal component analysis. Optimal codons for translation were predicted on the basis of tRNA-gene copy numbers. Highly expressed genes, such as those encoding ribosomal proteins and histones in S. pombe, C. elegans, and D. melanogaster, have biased patterns of codon usage which have been observed in a wide range of unicellular organisms. In S. pombe and C. elegans, codons contributing positively to the principal component with the largest variance (Z1-parameter) corresponded to the optimal codons which were predicted on the basis of tRNA gene numbers. In D. melanogaster, this correlation was less evident, and the codons contributing positively to the Z1-parameter corresponded primarily to codons with a C or G in the codon third position. In X. laevis and H. sapiens, codon usage in the genes encoding ribosomal proteins and histones was not significantly biased, suggesting that the primary factor influencing codon-usage diversity in these species is not translation efficiency. Codon-usage diversity in these species is known to reflect primarily isochore structures. In the present study, the second additional factor was explained by the level of use of codons containing CG-dinucleotides, and this is discussed with respect to transcription regulation via methylation of CG-dinucleotides, which is observed in mammalian genomes.

Animals↗
PubMed1994

P1 and cosmid clones define the organization of 280 kb of the mouse H-2 complex containing the Cps-1 and Hsp70 loci.

A 280 kilobase (kb) contig was isolated from mouse genomic P1 and cosmid libraries, using as probes human cDNA and genomic DNA fragments that map in the interval between the second component of complement and tumor necrosis factor genes of the HLA complex. The clone contig demonstrates synteny of eleven mouse genes that are homologous to genes initially mapped within the human major histocompatibility complex. These include the mouse homologs of BAT2 (HLA-B-associated transcript 2) through BAT9 and also three HSP70-related genes. Five P1 clones form a contig of 240 kb that spans from BAT9 through BAT3. Twelve cosmid clones are arranged in three contigs that confirm most of the structure of the P1 contig and link the mouse BAT3 homolog to the BAT2 homolog approximately 15 kb farther telomeric. Polymorphic DNA markers within the cloned region were used to map the cleft palate susceptibility-1 (Cps-1) locus to the interval between Hsp70.1 and BAT6 (valyl-tRNA synthetase). This refines the location of the Cps-1 locus to a 45 kb region contained in the H2-124 P1 insert.

Adenosine Triphosphatases↗
PubMed2005

Sequence context effects on oligo(dT) termination signal recognition by Saccharomyces cerevisiae RNA polymerase III.

Eukaryotic RNA polymerase (Pol) III terminates transcription at short runs of T residues in the coding DNA strand. By genomic analysis, we found that T(5) and T(4) are the shortest Pol III termination signals in yeasts and mammals, respectively, and that, at variance with yeast, oligo(dT) terminators longer than T(5) are very rare in mammals. In Saccharomyces cerevisiae, the strength of T(5) as a terminator was found to be largely influenced by both the upstream and the downstream sequence context. In particular, the CT sequence, which is naturally present downstream of T(5) in the 3'-flank of some tDNAs, was found to act as a terminator-weakening element that facilitates translocation by reducing Pol III pausing at T(5). In contrast, tDNA transcription termination was highly efficient when T(5) was followed by an A or G residue. Surprisingly, however, when a termination-proficient T(5) signal was taken out from the tDNA context and placed downstream of a fragment of the SCR1 gene, its termination activity was compromised, both in vitro and in vivo. Even the T(6) sequence, acting as a strong terminator in tRNA gene contexts, was unexpectedly weak within the SNR52 transcription unit, where it naturally occurs. The observed sequence context effects reflect intrinsic recognition properties of Pol III, because they were still observed in a simplified in vitro transcription system only consisting of purified RNA polymerase and template DNA. Our findings strengthen the notion that termination signal recognition by Pol III is influenced in a complex way by the region surrounding the T cluster and suggest that read-through transcription beyond T clusters might play a significant role in the biogenesis of class III gene products.

Animals↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗