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PubMed2026

The paradoxical extinction: Exploring signatures of assortative mating as a possible mechanism that maintains canonical Red Wolf genetic ancestry in the American Gulf Coast canids.

Admixed genomes, particularly those with an evolutionary history of genetic exchange with an endangered or extinct species, are valued for innovative and unconventional conservation actions. Here, we show the substantial conservation value that the admixed canids of the Gulf Coast have as they retain high amounts of contemporary Red Wolf ancestry and unique genetic variation of past Red Wolf lineages (e.g. ghost ancestry). We analyzed 54,439 loci genotyped across the genome of 413 North American canids and investigated the role that assortative mating with respect to ancestry proportions played in the retention of endangered genetic variation. We report high correlations of inter-chromosomal ancestry proportions that varied with geographic location along Texas and Louisiana Gulf Coast populations, with the stronger signatures reported in the latter. We found that models of assortative mating promoted greater ancestry variance compared with random mating leading to increased efficiency of selection for Red Wolf and ghost alleles. Despite the Red Wolf being extinct in the wild, original, and ghost genomic variation persists in Gulf Coast admixed canids. We suggest two conservation strategies that value and preserve this unique and endangered genomic variation through designed breeding programs. Ultimately the incorporation of this ghost genetic variation would be valuable to boost the genetic viability of the ex situ Red Wolf breeding program, create in situ redundancy, and avoid extinction for this endemic American wolf species.

Animals↗
PubMed2004

Codon bias signatures, organization of microorganisms in codon space, and lifestyle.

New and simple numerical criteria based on a codon adaptation index are applied to the complete genomic sequences of 80 Eubacteria and 16 Archaea, to infer weak and strong genome tendencies toward content bias, translational bias, and strand bias. These criteria can be applied to all microbial genomes, even those for which little biological information is known, and a codon bias signature, that is the collection of strong biases displayed by a genome, can be automatically derived. A codon bias space, where genomes are identified by their preferred codons, is proposed as a novel formal framework to interpret genomic relationships. Principal component analysis confirms that although GC content has a dominant effect on codon bias space, thermophilic and mesophilic species can be identified and separated by codon preferences. Two more examples concerning lifestyle are studied with linear discriminant analysis: suitable separating functions characterized by sets of preferred codons are provided to discriminate: translationally biased (hyper)thermophiles from mesophiles, and organisms with different respiratory characteristics, aerobic, anaerobic, facultative aerobic and facultative anaerobic. These results suggest that codon bias space might reflect the geometry of a prokaryotic "physiology space." Evolutionary perspectives are noted, numerical criteria and distances among organisms are validated on known cases, and various results and predictions are discussed both on methodological and biological grounds.

Adaptation, Biological↗
PubMed2005

Expressed sequence tag-linked microsatellites as a source of gene-associated polymorphisms for detecting signatures of divergent selection in atlantic salmon (Salmo salar L.).

The prediction that selection affects the genome in a locus-specific way also affecting flanking neutral variation, known as genetic hitchhiking, enables the use of polymorphic markers in noncoding regions to detect the footprints of selection. However, as the strength of the selective footprint on a locus depends on the distance from the selected site and will decay with time due to recombination, the utilization of polymorphic markers closely linked to coding regions of the genome should increase the probability of detecting the footprints of selection as more gene-containing regions are covered. The occurrence of highly polymorphic microsatellites in the untranslated regions of expressed sequence tags (ESTs) is a potentially useful source of gene-associated polymorphisms which has thus far not been utilized for genome screens in natural populations. In this study, we searched for the genetic signatures of divergent selection by screening 95 genomic and EST-derived mini- and microsatellites in eight natural Atlantic salmon, Salmo salar L., populations from different spatial scales inhabiting contrasting natural environments (salt-, brackish, and freshwater habitat). Altogether, we identified nine EST-associated microsatellites, which exhibited highly significant deviations from the neutral expectations using different statistical methods at various spatial scales and showed similar trends in separate population samples from different environments (salt-, brackish, and freshwater habitats) and sea areas (Barents vs. White Sea). We consider these ESTs as the best candidate loci affected by divergent selection, and hence, they serve as promising genes associated with adaptive divergence in Atlantic salmon. Our results demonstrate that EST-linked microsatellite genome scans provide an efficient strategy for discovering functional polymorphisms, especially in nonmodel organisms.

Animals↗
PubMed1992

Human histidyl-tRNA synthetase: recognition of amino acid signature regions in class 2a aminoacyl-tRNA synthetases.

We have determined the sequence of cDNA for the human histidyl-tRNA synthetase (HRS) in a hepatoma cell line and confirmed it in fetal myoblast and fibroblast cell lines. The newly determined sequence differs in 48 places, including insertions and deletions, from a previously published sequence. By sequence specific probing and by direct sequencing, we have established that only the newly determined sequence is present in genomic DNA and we have sequenced 500 hundred bases upstream of the translation start site. The predicted amino acid sequence now clearly demonstrates all three motifs recognized in class 2 aminoacyl-tRNA synthetases. Alignment of E. coli, yeast, and when available, mammalian predicted amino acid sequences for three of the four members of the class 2a subgroup (his, pro, ser, and thr) shows strong preservation of amino acid specific signature regions proximal to motif 2 and proximal to motif 3. These probably represent the active site binding regions for the proximal acceptor stem and for the amino acid. The first two exons of human HRS contain a 32 amino acid helical motif, first described in human QRS, a class 1 synthetase, which is found also in a yeast RNA polymerase, a rabbit termination factor, and both bovine and human WRS, suggesting that it may be an RNA binding motif.

Amino Acid Sequence↗
PubMed1994

Radiolytic signature of Z-DNA.

Ionizing radiations induce various damages in DNA via the hydroxyl radical OH. generated by the radiolysis of water. We compare here the radiosensitivity of B- and Z-DNA, by using a Z-prone stretch included in a plasmid. In the supercoiled plasmid, the stretch is in the Z-form, whereas it is in the B-form when the plasmid is relaxed. Frank strand breaks (FSB) and alkali-revealed breaks (ARB) were located and quantified using sequencing gel electrophoresis. We show that B- and Z-DNA have the same mean sensitivity towards radiolytic attack, for both FSB and ARB. Nevertheless, the guanine sites are more sensitive, and the cytosine sites less sensitive in Z- than in B-DNA, leading to a characteristic signature of the Z-form. The comparison of experiments with the outcome of a Monte Carlo simulation of OH. radical attack suggests that transfer of initial damage from a guanine base to its attached sugar or the adjacent 3' cytosine is more important in Z-DNA than in B-DNA.

Base Sequence↗
PubMed1996

Transcriptional repression by the orphan steroid receptor RVR/Rev-erb beta is dependent on the signature motif and helix 5 in the E region: functional evidence for a biological role of RVR in myogenesis.

RVR/Rev-erb beta/BD73 is an orphan steroid receptor that has no known ligand in the "classical' sense. RVR binds as a monomer to an element which consists of an A/T-rich sequence upstream of the consensus hexameric half-site. However, RVR does not activate transcription and blocks transactivation of this element by ROR/RZR. The mechanism of RVR action remains obscure, hence we used the GAL4 hybrid system to identify and characterize an active transcriptional silencer in the ligand binding domain (LBD) of RVR. Rigorous deletion and mutational analysis demonstrated that this repressor domain is encoded by amino acids 416-449 of RVR. Furthermore, we demonstrated that efficient repression is dependent on the so-called LBD-specific signature motif, (F/W)AKxxxxFxxLxxxDQxxLL (which spans loop3-4 and helix 4) and helix 5 (H5; identified in the crystal structures of the steroid receptor LBDs). Although RVR is expressed in many adult tissues, including skeletal muscle, and during embryogenesis, its physiological function in differentiation and mammalian development remains unknown. Since other 'orphans', e.g. COUP-TF II and Rev-erbA alpha, have been demonstrated to regulate muscle and adipocyte differentiation, we investigated the expression and functional role of RVR during mouse myogenesis. In C2C12 myogenic cells, RVR mRNA was detected in proliferating myoblasts and was suppressed when the cells were induced to differentiate into post-mitotic, multinucleated myotubes by serum withdrawal. This decrease in RVR mRNA correlated with the appearance of muscle-specific markers (e.g. myogenin mRNA). RVR 'loss of function' studies by constitutive over-expression of a dominant negative RVR delta E resulted in increased levels of p21Cip1/Waf1 and myogenin mRNAs after serum withdrawal. Time course studies indicated that expression of RVR delta E mRNA results in the precocious induction and accumulation of myogenin and p21 mRNAs after serum withdrawal. In addition, we demonstrated that over-expression of the COUP-TF II and Rev-erbA alpha receptors in C2C12 cells completely blocked induction of p21 mRNA after serum withdrawal. In conclusion, our studies identified a potent transcriptional repression domain in RVR, characterized critical amino acids within the silencing region and provide evidence for the physiological role of RVR during myogenesis.

Amino Acid Sequence↗
PubMed2004

Thirteen-exon-motif signature for vertebrate nuclear and mitochondrial type IB topoisomerases.

DNA topoisomerases contribute to various cellular activities that involve DNA. We previously identified a human nuclear gene that encodes a mitochondrial DNA topoisomerase. Here we show that genes for mitochondrial DNA topoisomerases (type IB) exist only in vertebrates. A 13-exon topoisomerase motif was identified as a characteristic of genes for both nuclear and mitochondrial type IB topoisomerases. The presence of this signature motif is thus an indicator of the coexistence of nuclear and mitochondrial type IB DNA topoisomerases. We hypothesize that the prototype topoisomerase IB with the 13-exon structure formed first, and then duplicated. One topoisomerase specialized for nuclear DNA and the other for mitochondrial DNA.

Amino Acid Motifs↗
PubMed2006

Plant MPSS databases: signature-based transcriptional resources for analyses of mRNA and small RNA.

MPSS (massively parallel signature sequencing) is a sequencing-based technology that uses a unique method to quantify gene expression level, generating millions of short sequence tags per library. We have created a series of databases for four species (Arabidopsis, rice, grape and Magnaporthe grisea, the rice blast fungus). Our MPSS databases measure the expression level of most genes under defined conditions and provide information about potentially novel transcripts (antisense transcripts, alternative splice isoforms and regulatory intergenic transcripts). A modified version of MPSS has been used to perform deep profiling of small RNAs from Arabidopsis, and we have recently adapted our database to display these data. Interpretation of the small RNA MPSS data is facilitated by the inclusion of extensive repeat data in our genome viewer. All the data and the tools introduced in this article are available at http://mpss.udel.edu.

Arabidopsis↗
PubMed2006

More complete gene silencing by fewer siRNAs: transparent optimized design and biophysical signature.

Highly accurate knockdown functional analyses based on RNA interference (RNAi) require the possible most complete hydrolysis of the targeted mRNA while avoiding the degradation of untargeted genes (off-target effects). This in turn requires significant improvements to target selection for two reasons. First, the average silencing activity of randomly selected siRNAs is as low as 62%. Second, applying more than five different siRNAs may lead to saturation of the RNA-induced silencing complex (RISC) and to the degradation of untargeted genes. Therefore, selecting a small number of highly active siRNAs is critical for maximizing knockdown and minimizing off-target effects. To satisfy these needs, a publicly available and transparent machine learning tool is presented that ranks all possible siRNAs for each targeted gene. Support vector machines (SVMs) with polynomial kernels and constrained optimization models select and utilize the most predictive effective combinations from 572 sequence, thermodynamic, accessibility and self-hairpin features over 2200 published siRNAs. This tool reaches an accuracy of 92.3% in cross-validation experiments. We fully present the underlying biophysical signature that involves free energy, accessibility and dinucleotide characteristics. We show that while complete silencing is possible at certain structured target sites, accessibility information improves the prediction of the 90% active siRNA target sites. Fast siRNA activity predictions can be performed on our web server at http://optirna.unl.edu/.

Artificial Intelligence↗
PubMed2006

Capturing genomic signatures of DNA sequence variation using a standard anonymous microarray platform.

Comparative genomics, using the model organism approach, has provided powerful insights into the structure and evolution of whole genomes. Unfortunately, only a small fraction of Earth's biodiversity will have its genome sequenced in the foreseeable future. Most wild organisms have radically different life histories and evolutionary genomics than current model systems. A novel technique is needed to expand comparative genomics to a wider range of organisms. Here, we describe a novel approach using an anonymous DNA microarray platform that gathers genomic samples of sequence variation from any organism. Oligonucleotide probe sequences placed on a custom 44 K array were 25 bp long and designed using a simple set of criteria to maximize their complexity and dispersion in sequence probability space. Using whole genomic samples from three known genomes (mouse, rat and human) and one unknown (Gonystylus bancanus), we demonstrate and validate its power, reliability, transitivity and sensitivity. Using two separate statistical analyses, a large numbers of genomic 'indicator' probes were discovered. The construction of a genomic signature database based upon this technique would allow virtual comparisons and simple queries could generate optimal subsets of markers to be used in large-scale assays, using simple downstream techniques. Biologists from a wide range of fields, studying almost any organism, could efficiently perform genomic comparisons, at potentially any phylogenetic level after performing a small number of standardized DNA microarray hybridizations. Possibilities for refining and expanding the approach are discussed.

Animals↗
PubMed2006

Hematopoietic gene promoters subjected to a group-combinatorial study of DNA samples: identification of a megakaryocytic selective DNA signature.

Identification of common sub-sequences for a group of functionally related DNA sequences can shed light on the role of such elements in cell-specific gene expression. In the megakaryocytic lineage, no one single unique transcription factor was described as linage specific, raising the possibility that a cluster of gene promoter sequences presents a unique signature. Here, the megakaryocytic gene promoter group, which consists of both human and mouse 5' non-coding regions, served as a case study. A methodology for group-combinatorial search has been implemented as a customized software platform. It extracts the longest common sequences for a group of related DNA sequences and allows for single gaps of varying length, as well as double- and multiple-gap sequences. The results point to common DNA sequences in a group of genes that is selectively expressed in megakaryocytes, and which does not appear in a large group of control, random and specific sequences. This suggests a role for a combination of these sequences in cell-specific gene expression in the megakaryocytic lineage. The data also point to an intrinsic cross-species difference in the organization of 5' non-coding sequences within the mammalian genomes. This methodology may be used for the identification of regulatory sequences in other lineages.

Animals↗
PubMed2004

Generation of longer 3' cDNA fragments from massively parallel signature sequencing tags.

Massively Parallel Signature Sequencing (MPSS) is a powerful technique for genome-wide gene expression analysis, which, similar to SAGE, relies on the production of short tags proximal to the 3'end of transcripts. A single MPSS experiment can generate over 10(7) tags, providing a 10-fold coverage of the transcripts expressed in a human cell. A significant fraction of MPSS tags cannot be assigned to known transcripts (orphan tags) and are likely to be derived from transcripts expressed at very low levels (approximately 1 copy per cell). In order to explore the potential of MPSS for the characterization of the human transcriptome, we have adapted the GLGI protocol (Generation of Longer cDNA fragments from SAGE tags for Gene Identification) to convert MPSS tags into their corresponding 3' cDNA fragments. GLGI-MPSS was applied to 83 orphan tags and 41 cDNA fragments were obtained. The analysis of these 41 fragments allowed the identification of novel transcripts, alternative tags generated from polymorphic and alternatively spliced transcripts, as well as the detection of artefactual MPSS tags. A systematic large-scale analysis of the genome by MPSS, in combination with the use of GLGI-MPSS protocol, will certainly provide a complementary approach to generate the complete catalog of human transcripts.

Alternative Splicing↗
PubMed2001

HIV-1 and HIV-2 LTR nucleotide sequences: assessment of the alignment by N-block presentation, "retroviral signatures" of overrepeated oligonucleotides, and a probable important role of scrambled stepwise duplications/deletions in molecular evolution.

Previous analyses of retroviral nucleotide sequences, suggest a so-called "scrambled duplicative stepwise molecular evolution" (many sectors with successive duplications/deletions of short and longer motifs) that could have stemmed from one or several starter tandemly repeated short sequence(s). In the present report, we tested this hypothesis by focusing on the long terminal repeats (LTRs) (and flanking sequences) of 24 human and 3 simian immunodeficiency viruses. By using a calculation strategy applicable to short sequences, we found consensus overrepresented motifs (often containing CTG or CAG) that were congruent with the previously defined "retroviral signature." We also show many local repetition patterns that are significant when compared with simply shuffled sequences. First- and second-order Markov chain analyses demonstrate that a major portion of the overrepresented oligonucleotides can be predicted from the dinucleotide compositions of the sequences, but by no means can biological mechanisms be deduced from these results: some of the listed local repetitions remain significant against dinucleotide-conserving shuffled sequences; together with previous results, this suggests that interspersed and/or local mononucleotide and oligonucleotide repetitions could have biased the dinucleotide compositions of the sequences. We searched for suggestive evolutionary patterns by scrutinizing a reliable multiple alignment of the 27 sequences. A manually constructed alignment based on homology blocks was in good agreement with the polypeptide alignment in the coding sectors and has been exhaustively assessed by using a multiplied alphabet obtained by the promising mathematical strategy called the N-block presentation (taking into account the environment of each nucleotide in a sequence). Sector by sector, we hypothesize many successive duplication/deletion scenarios that fit our previous evolutionary hypotheses. This suggests an important duplication/deletion role for the reverse transcriptase, particularly in inducing stuttering cryptic simplicity patterns.

Algorithms↗
PubMed1999

Genomic signature: characterization and classification of species assessed by chaos game representation of sequences.

We explored DNA structures of genomes by means of a new tool derived from the "chaotic dynamical systems" theory (the so-called chaos game representation [CGR]), which allows the depiction of frequencies of oligonucleotides in the form of images. Using CGR, we observe that subsequences of a genome exhibit the main characteristics of the whole genome, attesting to the validity of the genomic signature concept. Base concentrations, stretches (runs of complementary bases or purines/pyrimidines), and patches (over- or underexpressed words of various lengths) are the main factors explaining the variability observed among sequences. The distance between images may be considered a measure of phylogenetic proximity. Eukaryotes and prokaryotes can be identified merely on the basis of their DNA structures.

Algorithms↗
PubMed2026

Interferon-driven gene signature identifies two distinct subgroups in rheumatoid factor-positive polyarticular juvenile idiopathic arthritis.

OBJECTIVE: To characterize the demographic, clinical, serological, genetic background, course and value of the interferon (IFN)-score in a cohort of patients with rheumatoid factor (RF)-positive polyarticular juvenile idiopathic arthritis (pJIA). METHODS: Monocentric retrospective study of patients with RF-positive pJIA. Demographic, clinical and laboratory data were collected. The IFN-score was calculated based on the expression levels of 24 IFN stimulated genes. Whole exome sequencing was performed in 22 patients. RESULTS: Thirty-two patients were included. The IFN score was positive in 18 patients (56.2%) and negative in 14 patients (43.7%). An increased IFN score was associated with a significantly higher family history of autoimmunity (p = 0.0004), parental first-degree consanguinity (p = 0.05) and prevalence of antibodies to anti-cyclic citrullinated peptide (ACPA) (p = 0.01). Three patients with interstitial lung disease exhibited a positive IFN score. Conversely, demographic features and characteristics of polyarthritis did not differ between the two groups. Clinically inactive disease was achieved in 21/32 (66%) patients, with no significant difference according to the IFN score. Remission was never achieved with methotrexate alone. We identified one patient with a pathogenic de novo mutation in COPA. Additionally, ultra-rare variants in genes related to IFN and/or innate immunity were found in 21/22 (95.5%) patients. CONCLUSION: The IFN signature identified two distinct subgroups in RF-positive pJIA according to family history and immunological features. Our study suggests that patients with an elevated IFN score should be screened for pulmonary involvement. Future prospective studies are required to validate the use of the IFN score as a biomarker in RF-positive pJIA.

Rheumatoid factor↗
PubMed2025

Odd-Chain Dicarboxylic Acid Feeding Produces a Glutaric Aciduria Type 1-Like Metabolic Signature in Mice.

Glutaric aciduria type-1 (GA1) is an inherited mitochondrial neurometabolic disorder with a poorly understood pathogenesis and unmet medical needs. GA1 can be diagnosed via its hallmark biochemical signature consisting of glutaric aciduria, 3-hydroxyglutaric aciduria, and increased plasma glutarylcarnitine. These glutaryl-CoA-derived metabolites are thought to originate solely in the mitochondria. Here, we demonstrate that wild-type mice fed an 11-carbon odd-chain dicarboxylic acid (undecanedioic acid, DC11) recreate the biochemical phenotype of GA1. Odd-chain dicarboxylic acids like DC11 are not present in food but can arise from several endogenous processes, such as lipid peroxidation and fatty acid ω-oxidation. DC11 is chain-shortened in peroxisomes to glutaryl (DC5)-CoA, which then gives rise to the GA1-like pattern of DC5 metabolites in urine, tissues, and blood. Glutaric acid released from peroxisomes during DC11 chain-shortening can enter mitochondria for reactivation by the enzyme succinyl-CoA:glutarate-CoA transferase (SUGCT) and become substrate for glutaryl-CoA dehydrogenase (GCDH), the enzyme that is deficient in GA1. Our data provide proof-of-concept that the generation of dicarboxylic acids by ω-oxidation, which is stimulated during the same catabolic states known to trigger acute encephalopathy in GA1, may exacerbate disease by increasing the glutaryl-CoA substrate load in mitochondria.

Animals↗
PubMedDate not supplied

Evaluation of platelet and coagulation function in different animal species using the xylum clot signature analyzer.

Platelet and coagulation function were evaluated in four different animal species with a newly developed clot signature analyzer (CSA). CSA is unique in that it simultaneously measures global platelet and coagulation function under flow using whole blood. No anticoagulant, chemical, or immunologic agent is required. Three CSA parameters are measurable: platelet mediated hemostasis time (PHT), collagen induced thrombus formation time (CITF), and clotting time (CT). Bovine, ovine, and canine species were chosen because these are the animal models most frequently used in in vivo testing of cardiovascular implants. These parameters, as well as data from whole blood platelet aggregometry (commonly used for platelet function studies because of the response to exogenous agonists), and platelet counts from these animals, were measured and compared with those in humans. In all three parameters, the canine species showed distinctively shorter time values than other species, including humans, suggesting that the dog is not an ideal animal model for the evaluation of blood-surface interactions. Ovine and human blood showed similar PHT and CT values, but CITF time values were significantly shorter in sheep than in humans. With bovine blood, PHT was most prolonged among the four species compared. CT and CITF times in calves were shorter than those in humans, although the difference in CITF time was not statistically significant. Adenosine diphosphate induced platelet aggregation showed the same order of responsiveness in four species as did CITF. It was noted that the intermeasurement variation was rather high for CSA parameters, especially in PHT, warranting caution when this parameter is used to study time-dependent changes after device implantation.

Animals↗
PubMed2004

Diagnosis of pneumonia with an electronic nose: correlation of vapor signature with chest computed tomography scan findings.

OBJECTIVES/HYPOTHESIS: The electronic nose is a sensor of volatile molecules that is useful in the analysis of expired gases. The device is well suited to testing the breath of patients receiving mechanical ventilation and is a potential diagnostic adjunct that can aid in the detection of patients with ventilator-associated pneumonia. STUDY DESIGN: A prospective study. METHODS: We performed a prospective study of patients receiving mechanical ventilation in a surgical intensive care unit who underwent chest computed tomography (CT) scanning. A single attending radiologist reviewed the chest CT scans, and imaging features were recorded on a standardized form. Within 48 hours of chest CT scan, five sets of exhaled gas were sampled from the expiratory limb of the ventilator circuit. The gases were assayed with a commercially available electronic nose. Both linear and nonlinear analyses were performed to identify correlations between imaging features and the assayed gas signatures. RESULTS: Twenty-five patients were identified, 13 of whom were diagnosed with pneumonia by CT scan. Support vector machine analysis was performed in two separate analyses. In the first analysis, in which a training set was identical to a prediction set, the accuracy of prediction results was greater than 91.6%. In the second analysis, in which the training set and the prediction set were different, the accuracy of prediction results was at least 80%, with higher accuracy depending on the specific parameters and models being used. CONCLUSION: The electronic nose is a new technology that continues to show promise as a potential diagnostic adjunct in the diagnosis of pneumonia and other infectious diseases.

Adult↗