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PubMed2006

No evidence for maternal-fetal microchimerism in infantile hemangioma: a molecular genetic investigation.

In this study, using the placental origin theory as a basis, we set out to explore whether hemangioma endothelial cells (HEC) were maternal in origin. We rigorously addressed this hypothesis using several molecular genetic techniques. Fluorescent in situ hybridization on surgical specimens of proliferating hemangiomas (n=8) demonstrated no XX-labeled HEC from resected tumors of male infants. This analysis was followed by PCR genotyping of HEC (n=11) using microsatellite markers where cellular components were genotyped and compared to genomic DNA of corresponding mother-child pairs. In the seven informative mother-child pairs, HEC matched the genotype of the child and not the maternal genotype. Concerned that HEC represented a mixed population of cells, we subsequently enriched for cells using the placental-specific endothelial cell (EC) marker, Fc gammaRII. Three informative mother-child pairs exhibited only the genotype of the child in our enriched cell population. Using sequence analysis, we identified an informative single nucleotide polymorphism in an exon of the placental-EC-specific protein, GLUT1. When comparing GLUT1 complementary DNA (cDNA) with mother-child DNA, the genotype of the cDNA matched the constitutional DNA of the child. Our results indicate that hemangiomas are not microchimeric in origin. This study provides further insight into the origin of a tumor whose pathogenesis remains elusive.

Chimerism↗

PubMed2004

Linkage analysis for autism in a subset families with obsessive-compulsive behaviors: evidence for an autism susceptibility gene on chromosome 1 and further support for susceptibility genes on chromosome 6 and 19.

Although there is considerable evidence for a strong genetic component to idiopathic autism, several genome-wide screens for susceptibility genes have been carried out with limited concordance of linked loci, reflecting numerous genes of weak effect and/or sample heterogeneity. In the current study, linkage analysis was carried out in a sample of 62 autism-affected relative pairs with more severe obsessive-compulsive behaviors, selected from a larger (n=115) set of autism-affected relative pairs as a means of reducing sample heterogeneity. Obsessive-compulsive behaviors were assessed using the Autism Diagnostic Interview-Revised (ADI-R). In the sample with more severe obsessive-compulsive behaviors, multipoint NPL scores above 2 were observed on chromosomes 1, 4, 5, 6, 10, 11 and 19, with the strongest evidence for linkage on chromosome 1 at the marker D1S1656, where the multipoint NPL score was 3.06, and the two-point NPL score was 3.21. In follow-up analyses, analyzing the subset of families (n=35) where the patients had the most severe obsessive-compulsive behaviors generated a multipoint NPL score of 2.76, and a two-point NPL score of 2.79, indicating that the bulk of evidence for linkage was derived from the families most severely affected with obsessive-compulsive behaviors. The data suggest that there is an autism susceptibility gene on chromosome 1 and provide further support for the presence of autism susceptibility genes on chromosomes 6 and 19.

Autistic Disorder↗

PubMed2005

Evidence for linkage on 21q and 7q in a subset of autism characterized by developmental regression.

Autism is a pervasive developmental disorder with a strong genetic component. While candidate regions of the genome have been identified, location of genes conferring susceptibility to autism has been hindered by the heterogeneity within this clinically defined disorder, and the likely contribution of many genes of weak effect. Subsetting samples on the basis of distinct, nondiagnostic clinical features has been recommended to decrease sample heterogeneity. In this study, linkage analysis was performed on a subset of families in the database of the Autism Genetic Resource Exchange (AGRE). This set of autism-affected relative pairs (n=34) was also concordant for a history of developmental regression as measured by the Autism Diagnostic Interview-Revised (ADI-R). In this sample, a maximum multipoint LOD score of 3.4 under the dominant mode of inheritance and an NPL score of 3.0 (P=1.3 x 10(-3)) were observed on chromosome 21 near D21S1437. On chromosome 7 near D7S483 a LOD score of 2.0 under the dominant mode of inheritance and an NPL score of 3.7 (P=7.9 x 10(-5)) were observed. Genetic elements in these regions of 21q and 7q are likely to confer susceptibility to autism or modify the disease presentation in a subgroup of children characterized by a history of developmental regression.

Autistic Disorder↗

PubMed2004

Global gene repression by KaiC as a master process of prokaryotic circadian system.

A kaiABC clock gene cluster was previously identified from cyanobacterium Synechococcus elongatus PCC 7942, and the feedback regulation of kai genes was proposed as the core mechanism generating circadian oscillation. In this study, we confirmed that the Kai-based oscillator is the dominant circadian oscillator functioning in cyanobacteria. We probed the nature of this regulation and found that excess KaiC represses not only kaiBC but also the rhythmic components of all genes in the genome. This result strongly suggests that the KaiC protein primarily coordinates genomewide gene expression, including its own expression. We also found that a promoter derived from E. coli is feedback controlled by KaiC and restores the complete circadian rhythm in kaiBC-inactivated arrhythmic mutants, provided it can express kaiB and kaiC genes at an appropriate level. Unlike eukaryotic models, specific regulation of the kaiBC promoter is not essential for cyanobacterial circadian oscillations.

Bacterial Proteins↗

PubMed1983

Cloned genomic DNA sequences from Mycoplasma hyorhinis encoding antigens expressed in Escherichia coli.

A library of cloned Mycoplasma hyorhinis genomic sequences was constructed by incorporation of EcoRI digestion fragments of mycoplasma DNA into the lambda Charon 4A bacteriophage vector. Immunological screening of recombinant phage plaques identified clones containing genes encoding mycoplasma antigenic structures expressed in an Escherichia coli host. Two such recombinant phage isolates, lambda Ch4A-MhrG1 and lambda Ch4A-MhrG28, were defined and found to contain distinct genomic sequences by analysis of restriction endonuclease fragments. Inoculation of mice with recombinant gene products from lambda Ch4A-MhrG1 yielded antiserum selectively recognizing a Mr 29,500 trypsin-sensitive mycoplasma constituent. This established a means for producing selected immunogenic mycoplasma component in a bacterial host. The cloned genomic sequences of M. hyorhinis encoding expressed mycoplasma antigens represent molecular probes that can be characterized both by specific DNA sequences and by the antigenic structure of corresponding gene products. These genomic fragments define initial physical markers of the M. hyorhinis genome and may be useful in assessing antigenic and molecular genetic relationships within the genus Mycoplasma and among other members of the class Mollicutes.

Antibodies↗

PubMed1988

Gene sharing by delta-crystallin and argininosuccinate lyase.

The lens structural protein delta-crystallin and the metabolic enzyme argininosuccinate lyase (ASL; L-argininosuccinate arginine-lyase, EC 4.3.2.1) have striking sequence similarity. We have demonstrated that duck delta-crystallin has enormously high ASL activity, while chicken delta-crystallin has lower but significant activity. The lenses of these birds had much greater ASL activity than other tissues, suggesting that ASL is being expressed at unusually high levels as a structural component. In Southern blots of human genomic DNA, chicken delta 1-crystallin cDNA hybridized only to the human ASL gene; moreover, the two chicken delta-crystallin genes accounted for all the sequences in the chicken genome able to cross-hybridize with a human ASL cDNA, with preferential hybridization to the delta 2 gene. Correlations of enzymatic activity and recent data on mRNA levels in the chicken lens suggest that ASL activity depends on expression of the delta 2-crystallin gene. The data indicate that the same gene, at least in ducks, encodes two different functions, an enzyme (ASL) and a structural protein (delta-crystallin), although in chickens specialization and separation of functions may have occurred.

Amino Acid Sequence↗

PubMed1998

A viral suppressor of gene silencing in plants.

Gene silencing is an important but little understood regulatory mechanism in plants. Here we report that a viral sequence, initially identified as a mediator of synergistic viral disease, acts to suppress the establishment of both transgene-induced and virus-induced posttranscriptional gene silencing. The viral suppressor of silencing comprises the 5'-proximal region of the tobacco etch potyviral genomic RNA encoding P1, helper component-proteinase (HC-Pro) and a small part of P3, and is termed the P1/HC-Pro sequence. A reversal of silencing assay was used to assess the effect of the P1/HC-Pro sequence on transgenic tobacco plants (line T4) that are posttranscriptionally silenced for the uidA reporter gene. Silencing was lifted in offspring of T4 crosses with four independent transgenic lines expressing P1/HC-Pro, but not in offspring of control crosses. Viral vectors were used to assess the effect of P1/HC-Pro expression on virus-induced gene silencing (VIGS). The ability of a potato virus X vector expressing green fluorescent protein to induce silencing of a green fluorescent protein transgene was eliminated or greatly reduced when P1/HC-Pro was expressed from the same vector or from coinfecting potato virus X vectors. Expression of the HC-Pro coding sequence alone was sufficient to suppress virus-induced gene silencing, and the HC-Pro protein product was required for the suppression. This discovery points to the role of gene silencing as a natural antiviral defense system in plants and offers different approaches to elucidate the molecular basis of gene silencing.

Journal Article↗

PubMed2003

Molecular design and functional organization of the RecA protein.

The bacterial RecA protein participates in a remarkably diverse set of functions, all of which are involved in the maintenance of genomic integrity. RecA is a central component in both the catalysis of recombinational DNA repair and the regulation of the cellular SOS response. Despite the mechanistic differences of its functions, all require formation of an active RecA/ATP/DNA complex. RecA is a classic allosterically regulated enzyme, and ATP binding results in a dramatic increase in DNA binding affinity and a cooperative assembly of RecA subunits to form an ordered, helical nucleoprotein filament. The molecular events that underlie this ATP-induced structural transition are becoming increasingly clear. This review focuses on descriptions of our current understanding of the molecular design and allosteric regulation of RecA. We present a comprehensive list of all published recA mutants and use the results of various genetic and biochemical studies, together with available structural information, to develop ideas regarding the design of RecA functional domains and their catalytic organization.

Allosteric Regulation↗

PubMed2001

Quantitative-trait loci influencing body-mass index reside on chromosomes 7 and 13: the National Heart, Lung, and Blood Institute Family Heart Study.

Obesity is a risk factor for many chronic diseases, including glucose intolerance, lipid disorders, hypertension, and coronary heart disease. Even though the body-mass index (BMI) is a heterogeneous phenotype reflecting the amount of fat, lean mass, and body build, several studies have provided evidence of one or two major loci contributing to the variation in this complex trait. We sought to identify loci with potential influence on BMI in the data obtained from National Heart, Lung, and Blood Institute Family Heart Study. Two complementary samples were studied: (a) 1,184 subjects in 317 sibships, with 243 markers typed by the Utah Molecular Genetics Laboratory (UMGL) and (b) 3,027 subjects distributed among 401 three-generation families, with 404 markers typed by the Mammalian Genotyping Service (MGS). A genome scan using a variance-components-based linkage approach was performed for each sample, as well as for the combined sample, in which the markers from each analysis were placed on a common genetic map. There was strong evidence for linkage on chromosome 7q32.3 in each sample: the maximum multipoint LOD scores were 4.7 (P<10-5) at marker GATA43C11 and 3.2 (P=.00007) at marker D7S1804, for the MGS and UMGL samples, respectively. The linkage result is replicated by the consistent evidence from these two complementary subsets. Furthermore, the evidence for linkage was maintained in the combined sample, with a LOD score of 4.9 (P<10-5) for both markers, which map to the same location. This signal is very near the published location for the leptin gene, which is the most prominent candidate gene in this region. For the combined-sample analysis, evidence of linkage was also found on chromosome 13q14, with D13S257 (LOD score 3.2, P=.00006), and other, weaker signals (LOD scores 1.5-1.9) were found on chromosomes 1, 2, 3, 5, 6, 14, and 15.

Body Mass Index↗

PubMed1989

CMER, an RNA encoded by human cytomegalovirus is most likely transcribed by RNA polymerase III.

Through computer analysis of a human cytomegalovirus (HCMV) genomic region, previously identified to be homologous to human genomic DNA, an element showing significant similarity to the 3'-internal control region (3'-ICR or B-block) of a eukaryotic RNA polymerase III promoter could be detected. This region-located on the EcoRI b fragment within the UL segment of the viral genome of HCMV strain AD 169-cannot be transcribed in vitro in an RNA polymerase III specific transcription system. However, this part of the viral genome is able to compete for components of the RNA polymerase III transcription complex as shown in template exclusion experiments and by gel retardation assays. Two different synthetic oligonucleotides complementary to the 3'-ICR and to nucleotides located immediately downstream of this promoter element can anneal specifically to a HCMV-encoded ribonucleic acid (termed CMER) synthesized in human foreskin fibroblasts (HFF) late in virus replication. As a consequence of identifying the transcription initiation point by primer extension analyses the position of the 5'-internal control region (5'-ICR or A-block) of the CMER gene could be uncovered. Both identified control regions (the A-block as well as the B-block) of the transcription unit exhibit significant similarities to corresponding regulatory elements of other class III genes, including virus encoded class III genes. Initiation of in vivo transcription occurs 15 nucleotides upstream of the 5'-border of the 5'-ICR and the two non-contiguous gene internal promoter elements are separated by 79 nucleotides.

Base Sequence↗

PubMed2004

SNP500Cancer: a public resource for sequence validation and assay development for genetic variation in candidate genes.

The SNP500Cancer Database provides sequence and genotype assay information for candidate single nucleotide polymorphisms (SNPs) useful in mapping complex diseases, such as cancer. The database is an integral component of the NCI's Cancer Genome Anatomy Project. SNP500Cancer provides bi-directional sequencing information on a set of control DNA samples derived from anonymized subjects (102 Coriell samples representing four self-described ethnic groups: African/African-American, Caucasian, Hispanic and Pacific Rim). All SNPs are chosen from public databases and reports, and the choice of genes includes a bias towards non-synonymous and promoter SNPs in genes that have been implicated in one or more cancers. The web site is searchable by gene, chromosome, gene ontology pathway and by known dbSNP ID. As of July 2003, the database contains over 3400 SNPs, 2490 of which have been sequenced in the SNP500Cancer population. For each analyzed SNP, gene location and over 200 bp of surrounding annotated sequence (including nearby SNPs) are provided, with frequency information in total and per subpopulation, and calculation of Hardy-Weinberg Equilibrium (HWE) for each subpopulation. Sequence validated SNPs with minor allele frequency > 5% are entered into a high-throughput pipeline for genotyping analysis to determine concordance for the same 102 samples. The website provides the conditions for validated genotyping assays. SNP500Cancer provides an invaluable resource for investigators to select SNPs for analysis, design genotyping assays using validated sequence data, choose selected assays already validated on one or more genotyping platforms, and select reference standards for genotyping assays. The SNP500Cancer Database is freely accessible via the web page at http://snp500cancer.nci.nih.gov/.

Computational Biology↗

PubMed1977

Nucleoside triphosphate phosphohydrolase associated with cytoplasmic polyhedrosis virus.

Nucleoside triphosphate phosphohydrolase [EC 3.6.1.15] activity was found to be included in silkworm cytoplasmic polyhedrosis (CP) virus, which synthesizes mRNA carrying the 5'-terminal modification. This enzyme releases orthophosphate from the gamma-position in a nucleoside triphosphate, leaving nucleoside diphosphate. The rate of hydrolysis of ATP is faster than that of any other ribonucleoside triphosphate. Deoxy ATP is hydrolyzed rather faster than ATP. However, polynucleotides carrying triphosphate at the 5'-terminus, that is, 4S RNA which was synthesized by E. coli RNA polymerase [EC 2.7.7.6] using calf thymus DNA as a template, and the phage Q beta RNA (30S), are not effective substrates for this enzyme. Although the CP virion loses the viral genome and one kind of protein component on proteolytic treatment with pronase, the partially degraded virion still retains phosphohydrolase activity. The phosphohydrolase must therefore be associated firmly with the virion. This enzyme does not require the presence of nucleic acid for its function. Phosphohydrolysis of ATP by this enzyme activity represents a first step in the synthesis of the 5'-terminal modified mRNA of CP virus.

Adenosine Triphosphate↗

PubMed2000

Recessive and dominant genes interfere with the vascular transport of Potato virus A in diploid potatoes.

Resistance to Potato virus A (PVA) was examined in a diploid cross involving Solanum tuberosum subsp. andigena as a resistance source. Hypersensitive resistance (HR) to PVA cosegregated with extreme resistance (ER) to Potato virus Y conferred by the dominant gene Ry(adg) on chromosome XI. Hence, HR to PVA was controlled by a novel, dominant resistance gene closely linked to Ry(adg), or Ry(adg) recognized both viruses but conferred a different type of resistance to each virus. The HR prevented systemic infection with PVA following mechanical inoculation but not following graft inoculation. Another, recessive gene, ra, that may be linked or even allelic with Ry(adg) fully blocked vascular transport of PVA in graft-inoculated plants. Hence, a possibility exists that the genes for the three types of resistance to potyviruses may reside at the same, resistance gene-rich chromosome region syntenic in solanaceous species and might be related. The gene ra acted against all of the three PVA strains tested and, therefore, the avirulence determinants could not be mapped. However, also, PVA strain-specific resistance was found in the progeny. It was overcome by mutations introduced into the viral genome-linked protein and the helper component proteinase and/or the coat protein.

Biological Transport↗

PubMed1989

Typing of human rhinoviruses based on sequence variations in the 5' non-coding region.

Unambiguous assignment of restriction enzyme patterns to six individual serotypes of human rhinovirus was accomplished after amplification of a 380 bp DNA fragment derived from the 5' non-coding region. This was possible even though serotypes 1A and 1B and serotypes 2 and 49 differed only at 10 and 15 positions respectively. The method utilizes the conserved and variable components of this part of the genome and provides the basis for a simple and rapid method for typing of human rhinoviruses.

Base Sequence↗

PubMed2001

Complete nucleotide sequence and host range of South African cassava mosaic virus: further evidence for recombination amongst begomoviruses.

Complete nucleotide sequences of the DNA-A (2800 nt) and DNA-B (2760 nt) components of a novel cassava-infecting begomovirus, South African cassava mosaic virus (SACMV), were determined and compared with various New World and Old World begomoviruses. SACMV is most closely related to East African cassava mosaic virus (EACMV) in both its DNA-A (85% with EACMV-MH and -MK) and -B (90% with EACMV-UG2-Mld and EACMV-UG3-Svr) components; however, percentage sequence similarities of less than 90% in the DNA-A component allowed SACMV to be considered a distinct virus. One significant recombination event spanning the entire AC4 open reading frame was identified; however, there was no evidence of recombination in the DNA-B component. Infectivity of the cloned SACMV genome was demonstrated by successful agroinoculation of cassava and three other plant species (Phaseolus vulgaris, Malva parviflora and Nicotiana benthamiana). This is the first description of successful infection of cassava with a geminivirus using Agrobacterium tumefaciens.

Agrobacterium tumefaciens↗

PubMed2004

A signaling mucin at the head of the Cdc42- and MAPK-dependent filamentous growth pathway in yeast.

Signaling molecules such as Cdc42 and mitogen-activated protein kinases (MAPKs) can function in multiple pathways in the same cell. Here, we propose one mechanism by which such factors may be directed to function in a particular pathway such that a specific response is elicited. Using genomic approaches, we identify a new component of the Cdc42- and MAPK-dependent signaling pathway that regulates filamentous growth (FG) in yeast. This factor, called Msb2, is a FG-pathway-specific factor that promotes differential activation of the MAPK for the FG pathway, Kss1. Msb2 is localized to polarized sites on the cell surface and interacts with Cdc42 and with the osmosensor for the high osmolarity glycerol response (HOG) pathway, Sho1. Msb2 is glycosylated and is a member of the mucin family, proteins that in mammalian cells promote disease resistance and contribute to metastasis in cancer cells. Remarkably, loss of the mucin domain of Msb2 causes hyperactivity of the FG pathway, demonstrating an inhibitory role for mucin domains in MAPK pathway activation. Taken together, our data suggest that Msb2 is a signaling mucin that interacts with general components, such as Cdc42 and Sho1, to promote their function in the FG pathway.

Amino Acid Sequence↗

PubMed2003

Identification and characterization of multi-species conserved sequences.

Comparative sequence analysis has become an essential component of studies aiming to elucidate genome function. The increasing availability of genomic sequences from multiple vertebrates is creating the need for computational methods that can detect highly conserved regions in a robust fashion. Towards that end, we are developing approaches for identifying sequences that are conserved across multiple species; we call these "Multi-species Conserved Sequences" (or MCSs). Here we report two strategies for MCS identification, demonstrating their ability to detect virtually all known actively conserved sequences (specifically, coding sequences) but very little neutrally evolving sequence (specifically, ancestral repeats). Importantly, we find that a substantial fraction of the bases within MCSs (approximately 70%) resides within non-coding regions; thus, the majority of sequences conserved across multiple vertebrate species has no known function. Initial characterization of these MCSs has revealed sequences that correspond to clusters of transcription factor-binding sites, non-coding RNA transcripts, and other candidate functional elements. Finally, the ability to detect MCSs represents a valuable metric for assessing the relative contribution of a species' sequence to identifying genomic regions of interest, and our results indicate that the currently available genome sequences are insufficient for the comprehensive identification of MCSs in the human genome.

Animals↗

PubMed2005

Genetically indistinguishable SNPs and their influence on inferring the location of disease-associated variants.

As part of a recent high-density linkage disequilibrium (LD) study of chromosome 20, we obtained genotypes for approximately 30,000 SNPs at a density of 1 SNP/2 kb on four different population samples (47 CEPH founders; 91 UK unrelateds [unrelated white individuals of western European ancestry]; 97 African Americans; 42 East Asians). We observed that approximately 50% of SNPs had at least one genetically indistinguishable partner; i.e., for every individual considered, their genotype at the first locus was identical to their genotype at the second locus, or in LD terms, the SNPs were in "perfect" LD (r2 = 1.0). These "genetically indistinguishable SNPs" (giSNPs) formed into clusters of varying size. The larger the cluster, the greater the tendency to be located within genes and to overlap with giSNP clusters in other population samples. As might be expected for this map density, many giSNPs were located close to one another, thus reflecting local regions of undetected recombination or haplotype blocks. However, approximately 1/3 of giSNP clusters had intermingled, non-indistinguishable SNPs with incomplete LD (D' and r2 <1), sometimes spanning hundreds of kilobases, comprising up to 70 indistinguishable markers and overlapping multiple haplotype blocks. These long-range, nonconsecutive giSNPs have implications for disease gene localization by allelic association as evidence for association at one locus will be indistinguishable from that at another locus, even though both loci may be situated far apart. We describe the distribution of giSNPs on this map of chromosome 20 and illustrate the potential impact they can have on association mapping.

Black or African American↗