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PubMed1998

Genomic structure of the human RBP56/hTAFII68 and FUS/TLS genes.

We previously isolated RBP56 cDNA by PCR using mixed primers designed from the conserved sequences of the RNA binding domain of FUS/TLS and EWS proteins. RBP56 protein turned out to be hTAFII68 which was isolated as a TATA-binding protein associated factor (TAF) from a sub-population of TFIID complexes (Bertolotti A., Lutz, Y., Heard, D.J., Chambon, P., Tora, L., 1996. hTAFII68, a novel RNA/ssDNA-binding protein with homology to the proto-oncoproteins TLS/FUS and EWS is associated with both TFIID and RNA polymerase II. EMBO J. 15, 5022-5031). The RBP56/hTAFII68, FUS/TLS and EWS proteins comprise a sub-family of RNA binding proteins, which consist of an N-terminal Ser, Gly, Gln and Tyr-rich region, an RNA binding domain, a Cys2/Cys2 zinc finger motif and a C-terminal RGG-containing region. Rearrangement of the FUS/TLS gene and the EWS gene has been found in several types of malignant tumors, and the resultant fusion proteins play an important role in the pathogenesis of these tumors. In the present study, we determined the genomic structure of the RBP56/hTAFII68 gene. The RBP56/hTAFII68 gene spans about 37kb and consists of 16 exons from 33bp to 562bp. The longest exon, exon 15, encodes the C-terminal region containing 19 repeats of a degenerate DR(S)GG(G)YGG sequence. While the structure of the FUS/TLS gene has been reported previously, we determined the total DNA sequence of the FUS/TLS gene, consisting of 12kb. The RBP56/hTAFII68, FUS/TLS and EWS genes consist of similar numbers of exons. Comparison of the structures of these three genes showed that the organization of exons in the central part encoding a homologous RNA binding domain and a cysteine finger motif is highly conserved, and other exon boundaries are also located at similar sites, indicating that these three genes most likely originate from the same ancestor gene.

Base Sequence↗

PubMed1997

Genomic structure of a novel chloride channel gene, CLIC2, in Xq28.

A transcript map was previously constructed in the 1200-kb telomeric region of Xq28. One of the cDNAs, XAP121, displayed homology to a p64 bovine chloride channel and to a human chloride channel (p64CLCP, NCC27) at both the nucleotide and the peptide levels. In addition, all three sequences exhibited homologies to numerous ESTs derived from human, mouse, rat and pig. While the human NCC27 and XAP121 homologs encode small peptides of 241 and 243 amino acids, respectively, the bovine peptide has a length of 437 amino acids. This suggests that the human genes represent a novel and separate class of small chloride channels. Unlike other chloride channels, the NCC27 peptide was recently shown to localize intracellularly in the cytoplasm and nucleus. The NCC27 and XAP121 genes have thus been designated CLIC1 and CLIC2 for chloride intracellular channel genes 1 and 2, respectively. Since a direct association exists between a number of human chloride channel genes and a range of hereditary diseases, CLIC2 possibly represents a candidate for one of the many diseases linked to Xq28. To facilitate defined mutation analyses, we determined the genomic structure of the CLIC2 gene.

Amino Acid Sequence↗

PubMed1998

Genomic structure of TBX2 indicates conservation with distantly related T-box genes.

TBX2 is a member of a recently discovered gene family of transcription factors, named T-box genes after the Brachyury or T gene. Mutations in two of these family members, TBX5 and TBX3, have recently been shown to be responsible for the congenital abnormalities associated with Holt Oram syndrome and ulnar-mammary syndrome respectively, while mutations in T-box genes in other species also result in developmental abnormalities in the tissues where the gene is normally expressed. Thus, it likely that other T-box genes are responsible for additional human developmental anomalies. Here we report the exon/intron boundaries of TBX2 and a polymorphism within intron 2 of TBX2 that should be useful for exploring the involvement of this gene in human genetic disease. We further note that the exon/intron boundaries of TBX2 are highly conserved within the T-box domain with those of both T and TBX5, as well as with a new human T-box gene and more distantly related genes from Caenorhabditis elegans and Drosophila. This observation should facilitate the analysis of the genomic structure of other members of this gene family. It is also of interest that several members of this gene family have an additional intron that is variably present within members of at least two different lineages of the T-box family. This observation has implications regarding the evolution of T-box genes.

Animals↗

PubMed2001

Identification, mapping, and genomic structural analysis of an immunoreceptor tyrosine-based inhibition motif-bearing C-type lectin from homozygous clones of rainbow trout (Oncorhynchus mykiss).

Utilizing a spleen-derived cDNA library and rapid amplification of cDNA 5' ends, we cloned a novel type II C-type lectin from two homozygous clones of rainbow trout. The cDNA is 2535 bp in length, and contains a 1017-bp open reading frame. From this sequence, a protein containing 339 amino acids (aa) was deduced. Using PSI-BLAST to search the GenBank database, the deduced protein is a C-type lectin, belonging to the type II membrane receptors. The protein contains four domains: an 87-aa N-terminal cytoplasmic domain, a 21-aa transmembrane domain, an 82-aa neck domain, and a 149-aa C-terminal C-type lectin domain. Two immunoreceptor tyrosine-based inhibition motifs (ITIMs) were located in the N-terminal cytoplasmic domain. RT-PCR results indicated that this gene is transcribed mainly in peripheral blood lymphocytes, spleen, kidney, and gill, and its expression in liver and intestine is weak. Monoclonal antibody 1.14 was used to isolate B cells from peripheral blood lymphocytes. Analysis revealed that this gene is highly expressed in B cells. Genomic DNA was amplified with long-template PCR and sequenced. The gDNA is 12.0 kb in length and contains nine exons and eight introns. The first intron of the genes from the OSU and AR clones differed in length. Based on this difference, the genotype of 69 doubled-haploid offspring of OSU and AR were screened. Subsequently, this gene was mapped on the rainbow trout linkage map to group XXI. Results of a Southern blot indicated that the gene ( TCL-2) exists as a single copy in the rainbow trout genome. The genomic structure, the deduced protein structure, the tissue expression pattern, as well as the phylogenetic analysis of the carbohydrate recognition domain based on the deduced amino acid sequence indicate that TCL-2 resembles CD72; however, the carbohydrate recognition domain sequences of TCL-2 and CD72 are highly diverged.

Amino Acid Motifs↗

PubMed2000

Sequence, genomic structure and tissue expression of carp (Cyprinus carpio L.) vertebrate ancient (VA) opsin.

We report the isolation and characterisation of a novel opsin cDNA from the retina and pineal of the common carp (Cyprinus carpio L.). When a comparison of the amino acid sequences of salmon vertebrate ancient opsin (sVA) and the novel carp opsin are made, and the carboxyl terminus is omitted, the level of identity between these two opsins is 81% and represents the second example of the VA opsin family. We have therefore termed this C. carpio opsin as carp VA opsin (cVA opsin). We show that members of the VA opsin family may exist in two variants or isoforms based upon the length of the carboxyl terminus and propose that the mechanism of production of the short VA opsin isoform is alternative splicing of intron 4 of the VA opsin gene. The VA opsin gene consists of five exons, with intron 2 significantly shifted in a 3' direction relative to the corresponding intron in rod and cone opsins. The position (or lack) of intron 2 appears to be a diagnostic feature which separates the image forming rod and cone opsin families from the more recently discovered non-visual opsin families (pin-opsins (P), vertebrate ancient (VA), parapinopsin (PP)). Finally, we suggest that lamprey P opsin should be reassigned to the VA opsin family based upon its level of amino acid identity, genomic structure with respect to the position of intron 2 and nucleotide phylogeny.

Amino Acid Sequence↗

PubMed2004

Structural genomics of membrane proteins.

Improvements in the fields of membrane-protein molecular biology and biochemistry, technical advances in structural data collection and processing, and the availability of numerous sequenced genomes have paved the way for membrane-protein structural genomics efforts. There has been significant recent progress, but various issues essential for high-throughput membrane-protein structure determination remain to be resolved.

Animals↗

PubMed2006

The potential impact of structural genomics on tuberculosis drug discovery.

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB) in humans, is a devastating infectious organism that kills approximately two million people annually. The current suite of antibiotics used to treat TB faces two main difficulties: (i) the emergence of multidrug-resistant (MDR) strains of M. tuberculosis, and (ii) the persistent state of the bacterium, which is less susceptible to antibiotics and causes very long antibiotic treatment regimes. The complete genome sequences of a laboratory strain (H37Rv) and a clinical strain (CDC1551) of M. tuberculosis and the concurrent identification of all the open reading frames that encode proteins within this organism, present structural biologists with a wide array of protein targets for structure determination. Comparative genomics of the species that make up the M. tuberculosis complex has also added an array of genomic information to our understanding of these organisms. In response to this, structural genomics consortia have been established for targeting proteins from M. tuberculosis. This review looks at the progress of these major initiatives and the potential impact of large scale structure determination efforts on the development of inhibitors to many proteins. Increasing sophistication in structure-based drug design approaches, in combination with increasing numbers of protein structures and inhibitors for TB proteins, will have a significant impact on the downstream development of TB antibiotics.

Animals↗

PubMed1997

Genome structure of the Lactobacillus temperate phage phi g1e: the whole genome sequence and the putative promoter/repressor system.

The complete genome sequence of a Lactobacillus temperate phage phi g1e was established. The double-stranded DNA is composed of 42,259 bp, and encodes for sixty-two possible open reading frames (ORF) as well as several potential regulatory sequences. Based on comparative analysis with other related proteins of the Lactobacillus and Lactococcus phages as well as the Escherichia coli phages (such as lambda), functions were putatively assigned to several phi g1e ORFs: cng and cpg (encoding for repressors), hel (helicase), ntp (NTPase), and several ORFs (e.g., minor capsid proteins). An about 1000-bp DNA region of phi g1e containing cpg and cng was inferred to function as a promoter/repressor system for the phi g1e lysogenic and lytic pathway.

Amino Acid Sequence↗

PubMed1992

Class-level relationships in the phylum Cnidaria: evidence from mitochondrial genome structure.

The phylogenetic relationships of the Recent cnidarian classes remain one of the classic problems in invertebrate zoology. We survey the structure of the mitochondrial genome in representatives of the four extant cnidarian classes and in the phylum Ctenophora. We find that all anthozoan species tested possess mtDNA in the form of circular molecules, whereas all scyphozoan, cubozoan, and hydrozoan species tested display mtDNA in the form of linear molecules. Because ctenophore and all other known metazoan mtDNA is circular, the shared occurrence of linear mtDNA in three of the four cnidarian classes suggests a basal position for the Anthozoa within the phylum.

Animals↗

PubMed2001

Functional and structural genomics using PEDANT.

MOTIVATION: Enormous demand for fast and accurate analysis of biological sequences is fuelled by the pace of genome analysis efforts. There is also an acute need in reliable up-to-date genomic databases integrating both functional and structural information. Here we describe the current status of the PEDANT software system for high-throughput analysis of large biological sequence sets and the genome analysis server associated with it. RESULTS: The principal features of PEDANT are: (i) completely automatic processing of data using a wide range of bioinformatics methods, (ii) manual refinement of annotation, (iii) automatic and manual assignment of gene products to a number of functional and structural categories, (iv) extensive hyperlinked protein reports, and (v) advanced DNA and protein viewers. The system is easily extensible and allows to include custom methods, databases, and categories with minimal or no programming effort. PEDANT is actively used as a collaborative environment to support several on-going genome sequencing projects. The main purpose of the PEDANT genome database is to quickly disseminate well-organized information on completely sequenced and unfinished genomes. It currently includes 80 genomic sequences and in many cases serves as the only source of exhaustive information on a given genome. The database also acts as a vehicle for a number of research projects in bioinformatics. Using SQL queries, it is possible to correlate a large variety of pre-computed properties of gene products encoded in complete genomes with each other and compare them with data sets of special scientific interest. In particular, the availability of structural predictions for over 300 000 genomic proteins makes PEDANT the most extensive structural genomics resource available on the web.

Arabidopsis↗

PubMed2005

Structural genomics of the severe acute respiratory syndrome coronavirus: nuclear magnetic resonance structure of the protein nsP7.

Here, we report the three-dimensional structure of severe acute respiratory syndrome coronavirus (SARS-CoV) nsP7, a component of the SARS-CoV replicase polyprotein. The coronavirus replicase carries out regulatory tasks involved in the maintenance, transcription, and replication of the coronavirus genome. nsP7 was found to assume a compact architecture in solution, which is comprised primarily of helical secondary structures. Three helices (alpha2 to alpha4) form a flat up-down-up antiparallel alpha-helix sheet. The N-terminal segment of residues 1 to 22, containing two turns of alpha-helix and one turn of 3(10)-helix, is packed across the surface of alpha2 and alpha3 in the helix sheet, with the alpha-helical region oriented at a 60 degrees angle relative to alpha2 and alpha3. The surface charge distribution is pronouncedly asymmetrical, with the flat surface of the helical sheet showing a large negatively charged region adjacent to a large hydrophobic patch and the opposite side containing a positively charged groove that extends along the helix alpha1. Each of these three areas is thus implicated as a potential site for protein-protein interactions.

Amino Acid Sequence↗

PubMed1991

The human ETS1 gene: genomic structure, promoter characterization and alternative splicing.

Genomic clones encompassing the human ETS1 gene were isolated and utilized to define its molecular organization. This gene consists of eight exons spanning over 60 kb. The 5' end of the human ETS1 gene was subcloned and characterized. S1 nuclease, primer extension and RNAase protection analyses of human mRNAs showed multiple transcription initiation sites. DNA sequence analysis indicated a high G + C content in the promoter region and the absence of either a 'TATA' box or a 'CAAT' box. Six consensus recognition sequences for the transcription factor SP1, two AP1 consensus sequences and one consensus AP2 recognition sequence were identified, as well as two GC elements with dyad symmetry. A palindromic region similar to the serum response element of the c-fos gene and two octamer consensus recognition sequences were located upstream of the promoter region. A series of promoter deletion constructs positioned upstream from the bacterial chloramphenicol acetyl transferase gene were transfected into HeLa cells and their functional promoter activity assayed. The deletion constructs identified the 5' boundary for maximum promoter activity at 486 bp upstream of the first initiation site and suggest possible positive and negative regulatory regions. Polymerase chain reaction analysis of ETS1 cDNA identified several amplified products, indicating alternative splicing. In addition to the presence of mRNA products lacking exon VII, products lacking exon IV, as well as ones lacking both exons IV and VII, were found.

Base Sequence↗

PubMed1983

Genome structure and virion polypeptides of the primate herpesviruses Herpesvirus aotus types 1 and 3: comparison with human cytomegalovirus.

Two serologically distinguishable primate herpesviruses, Herpesvirus aotus type 1 and type 3, were examined with regard to their genomes and structural polypeptides. The duplex DNA genomes of these two viruses were found to be essentially identical in molecular weight (Mr approximately equal to 145 X 10(6)) and guanine plus cytosine composition (55%). Both contained unique and inverted repeat nucleotide sequences of the same size and arrangement, which, as judged by DNA-DNA hybridization and restriction enzyme analyses, were at least 95% homologous. In addition, no differences were observed in electrophoretic profiles of virion polypeptides. Because of their great similarity with respect to these criteria, the two viruses ought to be considered independent isolates (or strains) of a single virus, which should be designated H. aotus type 1. The elevated molecular weight and presence of two sets of inverted repeat sequences closely resemble the structure of the human cytomegalovirus genome. However, no sequence homology (less than 5%) nor similarity in virion polypeptides was detected between H. aotus type 1 and human cytomegalovirus.

Cytomegalovirus↗

PubMed2006

TAR cloning: insights into gene function, long-range haplotypes and genome structure and evolution.

The structural and functional analysis of mammalian genomes would benefit from the ability to isolate from multiple DNA samples any targeted chromosomal segment that is the size of an average human gene. A cloning technique that is based on transformation-associated recombination (TAR) in the yeast Saccharomyces cerevisiae satisfies this need. It is a unique tool to selectively recover chromosome segments that are up to 250 kb in length from complex genomes. In addition, TAR cloning can be used to characterize gene function and genome variation, including polymorphic structural rearrangements, mutations and the evolution of gene families, and for long-range haplotyping.

Animals↗

PubMed2000

Deoxyribonuclease II: structure and chromosomal localization of the murine gene, and comparison with the genomic structure of the human and three C. elegans homologs.

Deoxyribonuclease II (DNase II) has been implicated in diverse functions including degradation of foreign DNA, genomic instability, and in mediating the DNA digestion associated with apoptosis. The production of a mouse deleted for DNase II would clearly help to discriminate these functions. We have cloned and sequenced the mouse gene encoding DNase II. It was found to have a similar intron/exon structure to the human gene, although introns 3 and 5 are considerably shorter. The gene is located on mouse chromosome 8. The order of genes at this locus is mGCDH, mEKLF, mDNase II, mSAST, which is the same order that these genes are found on human chromosome 19. The GenBank database contains incorrect expressed sequence tags (ESTs) for the 3' end of the mouse mRNA. Furthermore, the gene structure of two of the three homologs in C. elegans is also incorrectly predicted in the database. We have established the correct intron/exon structure for these genes and show the conserved sequence and structure of the C. elegans, murine and human genes.

Amino Acid Sequence↗

PubMed2025

Generating three-dimensional genome structures with a variational quantum algorithm.

Chromosome conformation capture experiments have revealed the underlying spatial interactions that govern three-dimensional (3D) genome organization and topology. Detecting 3D contacts between genomic loci considerably enhances our understanding of fundamental regulatory processes. Modeling 3D structures from experimental contact matrices can further contextualize the relationship between 3D genome organization and regulation. While classical algorithms have been successful in reconstructing genomic conformations, we investigate the prospect of quantum computation to aid in modeling the conformational space. In this context, we propose a novel variational quantum algorithm (VQA) to model the distribution of 3D genomic structures from experimental contact data. Through rigorous evaluations, we demonstrate the capability of our algorithm to sample ensembles of viable 3D conformations that agree well with experimental and simulated contact data. Furthermore, we extend our methodology to model the conformational space of a single cell or a population of cells. In the advent of sufficient quantum utility, the insights gained from this study can serve as a foundation for investigating high-resolution, large-scale ensembles of genomic conformations through generative VQAs.

Algorithms↗

PubMed2026

Hidden genomic structure and widespread structural polymorphism across environmental gradients in the spiny sea star Marthasterias glacialis.

Genomic regions of reduced recombination can preserve linkage among co-adapted alleles, facilitating local adaptation despite high connectivity. Such regions-often generated by chromosomal inversions-may be especially important in highly dispersive marine taxa yet remain poorly documented in echinoderms. Here, we combined a chromosome-level reference genome with genome-wide ddRAD-seq from 296 Marthasterias glacialis individuals across 19 Atlantic-Mediterranean locations to quantify population structure and scan for recombination-suppressed haploblocks. Genome-wide neutral markers showed significant population differentiation together with evidence of high connectivity, revealed by the presence of inter-ecoregion migrants. Additionally, we identified 16 polymorphic haploblocks with patterns consistent with putative chromosomal inversions spanning 18.6% of the genome. Haploblock haplotypes were strongly environmentally and geographically structured and contained genes with key functions in stress response, osmoregulation and thermal tolerance. Haplotype distributions also paralleled previously described mitochondrial lineages despite nuclear gene flow, consistent with a model of ancient divergence followed by secondary contact. Overall, our results suggest a role for widespread structural polymorphism in adaptive differentiation in Echinodermata, providing a framework for linking echinoderm genome rearrangements to ecological divergence. Marthasterias glacialis thus emerges as a promising system to explore how structural variation contributes to adaptation and genome evolution in highly dispersive organisms.

Animals↗

PubMed2024

Chromosome-scale assembly with improved annotation provides insights into breed-wide genomic structure and diversity in domestic cats.

INTRODUCTION: Comprehensive genomic resources offer insights into biological features, including traits/disease-related genetic loci. The current reference genome assembly for the domestic cat (Felis catus), Felis_Catus_9.0 (felCat9), derived from sequences of the Abyssinian cat, may inadequately represent the general cat population, limiting the extent of deducible genetic variations. OBJECTIVES: The goal was to develop Anicom American Shorthair 1.0 (AnAms1.0), a reference-grade chromosome-scale cat genome assembly. METHODS: In contrast to prior assemblies relying on Abyssinian cat sequences, AnAms1.0 was constructed from the sequences of more popular American Shorthair breed, which is related to more breeds than the Abyssinian cat. By combining advanced genomics technologies, including PacBio long-read sequencing and Hi-C- and optical mapping data-based sequence scaffolding, we compared AnAms1.0 to existing Felidae genome assemblies (20 scaffolds, scaffolds N50 > 150 Mbp). Homology-based and ab initio gene annotation through Iso-Seq and RNA-Seq was used to identify new coding genes and splice variants. RESULTS: AnAms1.0 demonstrated superior contiguity and accuracy than existing Felidae genome assemblies. Using AnAms1.0, we identified over 1.5 thousand structural variants and 29 million repetitions compared to felCat9. Additionally, we identified > 1,600 novel protein-coding genes. Notably, olfactory receptor structural variants and cardiomyopathy-related variants were identified. CONCLUSION: AnAms1.0 facilitates the discovery of novel genes related to normal and disease phenotypes in domestic cats. The analyzed data are publicly accessible on Cats-I (https://cat.annotation.jp/), which we established as a platform for accumulating and sharing genomic resources to discover novel genetic traits and advance veterinary medicine.

Animals↗