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PubMed2004

Recombination in uveitis-causing enterovirus strains.

The complete nucleotide sequences of three human echovirus (EV) 11 strains and one EV19 strain, all of which caused outbreaks of enterovirus uveitis (EU), a new infant disease first identified in 1980 in Siberia, were determined. One EV11 strain which caused an outbreak of sepsis-like disease in Hungary was also sequenced. All four EV11 strains were mosaic recombinants of the prototype EV11 strain Gregory, with their non-structural coding regions and 5' NTRs being more similar to other prototype enteroviruses (EV1, EV9). However, this finding is probably a feature of all circulating enterovirus strains and may not be related to their altered virulence. A full genome sequence comparison of the three subtypes of EU-causing strains excludes the role of recent recombination in their emergence, and points to their independent emergence.

5' Untranslated Regions↗

PubMed2002

New insights into testicular germ cell tumorigenesis from gene expression profiling.

We have shown recently that about half of the human TGCTs(3) reveal DNA copy number increases affecting two distinct regions on chromosome arm 17q. To identify potential target genes with elevated expressions attributable to the extra copies, we constructed a cDNA microarray containing 636 genes and expressed sequence tags from chromosome 17. The expression patterns of 14 TGCTs, 1 carcinoma in situ, and 3 normal testis samples were examined, all with known chromosome 17 copy numbers. The growth factor receptor-bound protein 7 (GRB7) and junction plakoglobin (JUP) were the two most highly overexpressed genes in the TGCTs. GRB7 is tightly linked to ERBB2 and is coamplified and coexpressed with this gene in several cancer types. Interestingly, the expression levels of ERBB2 were not elevated in the TGCTs, suggesting that GRB7 might be the target for the increased DNA copy number in TGCTs. Because of the limited knowledge of altered gene expression in the development of TGCTs, we also examined the expression levels of 512 additional genes located throughout the genome. Several genes novel to testicular tumorigenesis were consistently up- or down-regulated, including POV1, MYCL1, MYBL2, MXI1, and DNMT2. Additionally, overexpression of the proto-oncogenes CCND2 and MYCN were confirmed from the literature. The overexpressions were for some of the target genes closely associated to either seminoma or nonseminoma TGCTs, and hierarchical cluster analysis of the gene expression data effectively distinguished among the known histological subtypes. In summary, this focused functional genomic characterization of TGCTs has lead to the identification of new gene targets associated with a common genomic rearrangement as well as other genes with potential importance to testicular tumorigenesis.

Chromosomes, Human, Pair 17↗

PubMed2002

Precise mapping of recombination breakpoints suggests a common parent of two BC recombinant HIV type 1 strains circulating in China.

Two different BC recombinant HIV-1 strains have arisen and begun to circulate among intravenous drug users in China. The recombinants are mostly subtype C with a few small subtype B segments. Additional full-genome sequences of the two recombinants, termed CRF07_BC and CRFO&_BC, are now available for analysis. Four CRF07_BC strains, including c54, 97CNU01, 98CN009, and a new strain CNGL-179, described here, and four CRF08_BC strains, including 97CNGX-6, 97CNGX-7, 97CNGX-9, and 98CN006, were compared for their recombination breakpoints by bootscanning and software for fine mapping of recombinants. The four CRF07_BC strains shared an identical recombination structure and the four CRF08_BC strains shared an identical, but different, recombination structure. The two CRFs share five precise subtype B/C boundaries, although although other segments differ between them, suggesting that they shared a common ancestor, itself a BC recombinant that separately "back-crossed" onto different subtype C strains. Both CRFs are broadly distributed from north to south in western China and have maintained low interpatient diversity.

China↗

PubMed2026

SWI/SNF Alterations Define a Chromatin-Dependent Subtype of Urothelial Carcinoma.

PURPOSE: SWI/SNF (BAF) chromatin remodeling complex alterations are common in urothelial carcinoma, yet no biomarker-directed therapeutic strategies have been established for this population. We investigated whether BAF alterations delineate a biologically distinct, therapeutically actionable urothelial carcinoma subtype. EXPERIMENTAL DESIGN: We performed integrative genomic and transcriptomic analyses of 792 urothelial carcinoma tumors from the Oncology Research Information Exchange Network (ORIEN) and validated findings in the TCGA-BLCA cohort. Mechanistic studies incorporated RNA sequencing and ATAC-seq following histone deacetylase (HDAC) inhibition. Functional dependencies were assessed using patient-derived xenograft organoids and cell line models. Clinical relevance was explored in a biomarker-enriched investigator-initiated trial. RESULTS: Approximately half of urothelial carcinoma tumors exhibited BAF alterations, defining a previously unrecognized chromatin-altered molecular subtype characterized by activation of proliferative programs, loss of lineage identity, and altered metabolic signaling. This subtype was enriched for transcriptomic programs associated with HDAC inhibitor sensitivity and depleted of HDAC inhibitor resistance signatures. Mechanistically, HDAC inhibition induced widespread chromatin remodeling with reduced accessibility at AP-1 and TEAD-associated regions, and downregulation of E2F- and MYC-driven transcriptional networks. Functional studies confirmed enhanced HDAC inhibition sensitivity in ARID1A -mutated cell lines and a patient-derived organoid model. Early clinical observations demonstrated a durable responder treated with HDAC inhibitors and immunotherapy. CONCLUSIONS: BAF alterations define a chromatin-dependent tumor state in urothelial carcinoma that is selectively vulnerable to HDAC inhibition. Integrating genomic, epigenomic, functional, and early clinical evidence, these findings provide a rationale for biomarker-enriched clinical trials and HDAC inhibitor-based combination strategies in urothelial carcinoma.

Journal Article↗

PubMed2002

Microarray-based copy number and expression profiling in dedifferentiated and pleomorphic liposarcoma.

Sixteen dedifferentiated and pleomorphic liposarcomas were analyzed by comparative genomic hybridization (CGH) to genomic microarrays (matrix-CGH), cDNA-derived microarrays for expression profiling, and by quantitative PCR. Matrix-CGH revealed copy number gains of numerous oncogenes, i.e., CCND1, MDM2, GLI, CDK4, MYB, ESR1, and AIB1, several of which correlate with a high level of transcripts from the respective gene. In addition, a number of genes were found differentially expressed in dedifferentiated and pleomorphic liposarcomas. Application of dedicated clustering algorithms revealed that both tumor subtypes are clearly separated by the genomic profiles but only with a lesser power by the expression profiles. Using a support vector machine, a subset of five clones was identified as "class discriminators." Thus, for the distinction of these types of liposarcomas, genomic profiling appears to be more advantageous than RNA expression analysis.

Algorithms↗

PubMed2004

Characterization of the complete genomic sequence of genotype II hepatitis A virus (CF53/Berne isolate).

The complete genomic sequence of hepatitis A virus (HAV) CF53/Berne strain was determined. Pairwise comparison with other complete HAV genomic sequences demonstrated that the CF53/Berne isolate is most closely related to the single genotype VII strain, SLF88. This close relationship was confirmed by phylogenetic analyses of different genomic regions, and was most pronounced within the capsid region. These data indicated that CF53/Berne and SLF88 isolates are related more closely to each other than are subtypes IA and IB. A histogram of the genetic differences between HAV strains revealed four separate peaks. The distance values for CF53/Berne and SLF88 isolates fell within the peak that contained strains of the same subtype, showing that they should be subtypes within a single genotype. The complete genomic data indicated that genotypes II and VII should be considered a single genotype, based upon the complete VP1 sequence, and it is proposed that the CF53/Berne isolate be classified as genotype IIA and strain SLF88 as genotype IIB. The CF53/Berne isolate is cell-adapted, and therefore its sequence was compared to that of two other strains adapted to cell culture, HM-175/7 grown in MK-5 and GBM grown in FRhK-4 cells. Mutations found at nucleotides 3889, 4087 and 4222 that were associated with HAV attenuation and cell adaptation in HM175/7 and GMB strains were not present in the CF53/Berne strain. Deletions found in the 5'UTR and P3A regions of the CF53/Berne isolate that are common to cell-adapted HAV isolates were identified, however.

Base Sequence↗

PubMed2001

One-tube real-time isothermal amplification assay to identify and distinguish human immunodeficiency virus type 1 subtypes A, B, and C and circulating recombinant forms AE and AG.

To halt the human immunodeficiency virus type 1 (HIV-1) epidemic requires interventions that can prevent transmission of numerous HIV-1 subtypes. The most frequently transmitted viruses belong to the subtypes A, B, and C and the circulating recombinant forms (CRFs) AE and AG. A fast one-tube assay that identifies and distinguishes among subtypes A, B, and C and CRFs AE and AG of HIV-1 was developed. The assay amplifies a part of the gag gene sequence of the genome of all currently known HIV-1 subtypes and can identify and distinguish among the targeted subtypes as the reaction proceeds, because of the addition of subtype-specific molecular beacons with multiple fluorophores. The combination of isothermal nucleic acid sequence-based amplification and molecular beacons is a new approach in the design of real-time assays. To obtain a sufficiently specific assay, we developed a new strategy in the design of molecular beacons, purposely introducing mismatches in the molecular beacons. The subtype A and CRF AG isolates reacted with the same molecular beacon. We tested the specificity and sensitivity of the assay on a panel of the culture supernatant of 34 viruses encompassing all HIV-1 subtypes: subtypes A through G, CRF AE and AG, a group O isolate, and a group N isolate. Assay sensitivity on this panel was 92%, with 89% correct subtype identification relative to sequence analysis. A linear relationship was found between the amount of input RNA in the reaction mixture and the time that the reaction became positive. The lower detection level of the assay was approximately 10(3) copies of HIV-1 RNA per reaction. In 38% of 50 serum samples from HIV-1-infected individuals with a detectable amount of virus, we could identify subtype sequences with a specificity of 94% by using sequencing and phylogenetic analysis as the "gold standard." In conclusion, we showed the feasibility of the approach of using multiple molecular beacons labeled with different fluorophores in combination with isothermal amplification to identify and distinguish subtypes A, B, and C and CRFs AE and AG of HIV-1. Because of the low sensitivity, the assay in this format would not be suited for clinical use but can possibly be used for epidemiological monitoring as well as vaccine research studies.

Base Sequence↗

PubMed2002

Molecular epidemiology of cystic fibrosis-linked Burkholderia cepacia complex isolates from three national referral centres in Ireland.

AIMS: Burkholderia cepacia is a Gram-negative bacterium associated with increasing morbidity and mortality and is readily transmitted among infected cystic fibrosis (CF) patients. The B. cepacia complex consists of five distinct subgroups, termed genomovars. A collection of 17 presumptive B. cepacia isolates, obtained from three national CF referral centres located in different geographical regions in Ireland, was studied. The aim of this study was to investigate these isolates using molecular subtyping protocols for evidence of genetic relationships and for the presence of antibiotic resistance-encoding class 1 integron structures. METHODS AND RESULTS: Genomovar classifications were assigned to each isolate based on HaeIII enzyme profiles of their recA locus. Genetic relationships among this collection were also assessed after restriction fragment length polymorphism (RFLP)-mediated analysis of the 16S rDNA locus and DNA amplification fingerprinting (DAF). The surface expression of the cable pilus gene (cblA) may facilitate an early step in the infection process. All isolates were tested by amplification strategies for this marker. Burkholderia cepacia is known to be resistant to several antimicrobial agents. Resistance typing showed that the majority were resistant to three or more common antimicrobial agents. Five of the 17 isolates were resistant to sulphonamide, a characteristic linked with the presence of class 1 integrons. Gene cassettes containing beta-lactamase (oxa) and aminoglycoside acetyltransferase (aac(6')-1a) encoding genes were identified by polymerase chain reaction amplification. CONCLUSIONS: Most of the isolates in this study were classified as genomovar III and were indistinguishable based on their corresponding 16S rDNA-RFLP profiles, whilst DAF further subtyped the collection. The cblA marker was identified in 47% of the isolates, many of which clustered in the genomovar III group. Class 1 integrons with recombined gene cassettes containing bla-OXA and aac(6')-1a genes were identified. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates the application of molecular methods to investigate B. cepacia, a well-recognized human pathogen, cultured from Irish CF patients. Genomovar III was the most common genomic type identified. DNA fingerprinting further subtyped the latter isolates, facilitating a more detailed description of the molecular epidemiology. Drug resistance in these organisms can be explained, at least in part, by the presence of class 1 integrons. Development of targeted infection control strategies could be facilitated using these applied methods.

Amino Acid Sequence↗

PubMed2001

Recombination in human herpesvirus-8 strains from Uganda and evolution of the K15 gene.

Human herpesvirus-8 (HHV-8) is believed to be the aetiological agent of Kaposi's sarcoma (KS). KS accounts for half the reported cancer cases in Uganda, and occurs in endemic and epidemic [human immunodeficiency virus (HIV)-associated] forms. We confirmed a high prevalence (74%) of HHV-8 antibodies in 114 HIV-negative Ugandan blood donors, and characterized the genomes of HHV-8 strains present in 30 adult Ugandan KS patients. Phylogenetic analysis of the uniquely variable K1 gene indicated that the majority of KS patients were infected by the B subtype of HHV-8, several by the A5 subtype, and one by a variant of the C subtype. Sequence analysis of nine strains at several other genome loci spaced out across the genome indicated that five are recombinants between subtypes when considered independently of previously published definitions of parental (unrecombined) genotypes. When previously published parental genotypes were taken into account, seven of the nine strains appeared to be recombinants. Analysis of the K15 gene, which exists in HHV-8 in two highly diverged alleles, indicated that the P allele predominates, with only a single strain bearing the M allele. Divergence between the M allele in the latter strain and that in the previously sequenced BC1 strain is at least as great as that between representatives of the P allele. This indicates that introduction of the M allele into extant HHV-8 subtypes did not occur by a single, relatively recent recombination event as was concluded from a previous study in which very limited variation in the M allele was reported.

Adolescent↗

PubMed2002

HIV-1 subtypes and circulating recombinant forms (CRFs) in Northern Greece.

In order to understand the genetic diversity of virus isolates associated with the human immunodeficiency virus type one (HIV-1) epidemic in Northern Greece, 51 specimens from HIV-1 infected individuals were classified into subtypes by sequence-based phylogenetic analysis of the polymerase (pol) region of the viral genome. Forty two (82.3%) specimens were identified as pol subtype B, three (5.9%) as A, and one (2%) as CRF01_AE, while the remaining five (9.8%) specimens appeared to be complex recombinants, belonging to the Cypriot/Greek form CRF04_cpx. The proportion of CRF04_cpx strains is larger than previously reported, suggesting that the CRF04_cpx is significantly contributing to the Greek HIV-1 epidemic.

Female↗

PubMed2004

Comparative genomic hybridization analysis of hereditary swine cutaneous melanoma revealed loss of the swine 13q36-49 chromosomal region in the nodular melanoma subtype.

Genetic alterations implicated in malignant melanoma are still poorly understood. Malignant melanomas present highly variable histologic and cytologic patterns. The aim of the present study is to define genomic imbalances associated with the development of 2 histologic types of swine hereditary cutaneous melanoma. We have investigated 11 swine tumors by comparative genomic hybridization (CGH), 4 superficial spreading melanomas (SSMs) and 7 nodular melanomas (NMs). Following laser capture microdissection and degenerate oligonucleotide primed-polymerase chain reaction, we were able to isolate and then amplify DNA from the 2 histologic subtypes. Consensus regions of chromosome gains were identified on both histologic subtypes, on swine chromosomes 3p13-p17 (75% of the SSMs and 71% of the NMs), 12q (100% of the SSMs and 57% of the NMs) and 14q11-q21 (75% of the SSMs and 42% of NMs). Chromosomal loss was restricted to NM lesions and the swine 13q36-49 region was lost in 100% of the NMs. Interphase fluorescence in situ hybridization with a probe mapping to the 13q41-q42 region indicates loss of the corresponding region on NM lesions. Taking into account this CGH analysis and the comparative genomic data between swine and human genomes, we suggest that a role for the human chromosomes 3p11-qter and chromosome 21 losses should be investigated in human nodular melanoma progression.

Animals↗

PubMed2006

Identification of a genomic subgroup of BK polyomavirus spread in European populations.

BK polyomavirus (BKV) is highly prevalent in the human population, infecting children without obvious symptoms and persisting in the kidney in a latent state. In immunosuppressed patients, BKV is reactivated and excreted in urine. BKV isolates worldwide are classified into four serologically distinct subtypes, I-IV, with subtype I being the most frequently detected. Furthermore, subtype I is subdivided into subgroups based on genomic variations. In this study, the distribution patterns of the subtypes and subgroups of BKV were compared among four patient populations with various immunosuppressive states and of various ethnic backgrounds: (A) Finnish renal-transplant recipients; (B) Irish/English haematopoietic stem-cell transplant recipients with and without haemorrhagic cystitis; (C) Japanese renal-transplant recipients; and (D) Japanese bone-marrow transplant recipients. The typing sequences (287 bp) of BKV in population A were determined in this study; those in populations B-D have been reported previously. These sequences were subjected to phylogenetic and single nucleotide polymorphism analyses. Based on the results of these analyses, the BKV isolates in the four patient populations were classified into subtypes and subgroups. The incidence of subtype IV varied significantly among patient populations. Furthermore, the incidence of subgroup Ib-2 within subtype I was high in populations A and B, whereas that of Ic was high in populations C and D (P<0.01). These results suggest that subgroup Ib-2 is widespread among Europeans, whereas Ic is unique to north-east Asians. Furthermore, a phylogenetic analysis based on complete BKV DNA sequences supported the hypothesis that there is geographical separation of European and Asian BKV strains.

Asian People↗

PubMed1993

[HCV subtypes and their clinical significance].

We immunologically isolated a clone with a 177-bp DNA fragment, designated as #2-22, that had homology to the NS-5 region of a HCV genome. To classify this HCV isolate, we sequenced several clones (2028 bases in total) from a cDNA library constructed from a #2-22-positive patient's blood. They showed distinct similarity to the HC-J8 genome (type II b), among the known HCV subtypes. Using this #2-22 sequence for PCR, we screened the HCV-positive blood samples from Southern Kyushu, we could identify 27% of them as type II b. In another cDNA library, from a single blood donor, who did not have multiple infections of HCV, we found two clones that might have arisen from an ancestral (or previous or historical) intergenomic recombination. They had reversed orders of similarity to different HCV subtypes, that is, the first 149-bp clone had 94% identical bases with a segment of HC-J8 and 78% with the corresponding sequence of HC-J6, but the second 814-bp clone had 85% identical bases with a segment of HC-J8 and 94% to the corresponding sequence of HC-J6. The importance of subtype analysis is discussed in relation to its clinical application, such as diagnostics development.

Amino Acid Sequence↗

PubMed1982

Viral etiology of juvenile- and adult-onset squamous papilloma of the larynx.

Juvenile- and adult-onset laryngeal papillomas were examined for the presence of a human papillomavirus (HPV) genome and capsid antigens. DNA was isolated from a portion of tissue removed for therapeutic purposes, and the presence of a papillomavirus genome was detected by Southern transfer analysis. The viral DNA found in the 12 juvenile-onset and the 8 adult-onset laryngeal papillomas examined was identified as HPV-6 on the basis of size, restriction endonuclease digestion patterns, and homology detected under stringent conditions. Restriction endonuclease analysis of the viral genomes revealed at least four different subtypes, designated HPV-6c through HPV-6f. The most common subtype, HPV-6c, was detected in over half of the papillomas studied, including both juvenile and adult types. The remaining tissue was fixed and processed for immunocytochemistry. The immunoperoxidase technique was used with an antiserum that reacts with capsid antigen(s) common to all HPV serotypes. HPV antigen was found in two of the juvenile-onset papillomas and two of the adult-onset papillomas. The antigen was localized to the nucleus and was distributed in the superficial layers of the epithelium. HPV capsid antigen had not previously been detected in cases of adult-onset papilloma, and the HPV genome in both juvenile- and adult-onset laryngeal papillomas had not been characterized. Despite the absence of detectable viral antigen in most of the specimens examined, the presence of the HPV genome provides strong evidence for the papillomavirus etiology of these tumors.

Adolescent↗

PubMed1992

[Influence of Epstein-Barr virus genome on patient survival in Hodgkin's disease].

In the literature EBV is considered a possible etiologic factor for Hodgkin's disease (HD). We investigated 187 cases of HD for the presence of Epstein Barr virus using the polymerase chain reaction (PCR) technique on formalin fixed, paraffin embedded lymph node tissue to clarify the clinical importance of the incidence of this genome. The 187 cases included all subtypes. 66 cases (35.2%) were positive for EBV DNA. The statistical analysis of follow-up data from 130 patients revealed no influence of EBV DNA on survival time. In our investigation detection of EBV DNA by PCR showed no prognostic relevance for patients with HD.

DNA, Neoplasm↗

PubMed2005

Characterization of five nearly full-length genomes of early HIV type 1 strains in Ruili city: implications for the genesis of CRF07_BC and CRF08_BC circulating in China.

To trace the genesis of HIV-1 CRF07_BC and CRF08_BC, two predominant circulating recombinants among intravenous drug users in China, a retrospective molecular epidemiological investigation (1996-1998) was conducted in Ruili city of Yunnan, where the first AIDS epidemic among IDUs was reported in 1989. Fifty-four HIV-1 env C2V3 sequences were determined and genotyped with 49 subtype B and only 5 subtype C strains. The nearly full-length genome analyses of these five env-based subtype C samples revealed that four of them were actually BC recombinants and only one was pure subtype C. The first identified nonrecombinant HIV-1 subtype C, genetically close to Indian C representatives, provided direct evidence for the hypothesis that subtype C in China was introduced from India. Interestingly, three BC recombinants with subtype B as backbones were identified; one BC recombinant that precisely shared a common subtype B segment (nef region) with CRF07_BC and CRF08_BC was described, which indicated a close evolutionary relationship to these two CRFs. The sequences undoubtedly lead us to a better understanding of the emergence of CRF07_BC and CRF08_BC.

China↗

PubMed1997

Coinfection and genetic recombination between HIV-1 strains: possible biological implications in Australia and South East Asia.

It has been recognised that human immunodeficiency virus (HIV) mutates rapidly and that nucleotide substitutions, deletions, insertions, and rearrangements resulting from recombination events are the main factors that result in variation of the HIV-1 genome. Together, these processes are actively contributing to the diversity and virulence of viral forms comprising the acquired immune deficiency syndrome (AIDS) pandemic. There are 9 HIV-1 subtypes recognised (A-H and O), based on the envelope region segments. Inter-subtype recombination has been already described, whereas intra-subtype recombination has been difficult to detect. In this study, we have identified in vivo genetic recombination between HIV-1 strains belonging to subtype B in a patient who presented both intravenous drug use (IVDU) and homosexual sex as risk factors. Genetic analysis of viral strains in the hypervariable V3 region of the envelope gene indicated the presence of three distinct sequence groups categorized according to their respective tetrapeptide motifs-GPGR, GLGR and GPGK. Detailed genetic and phylogenetic analyses suggested the recombination occurring only between sequence groups with GPGR and GPGK tetrapeptide motifs. These data suggest that coinfection with closely related strains can occur in vivo, and the generation of hybrid HIV-1 genomes via genetic recombination between subtype B strains can result in further antigenic diversity which may thwart diagnosis and future vaccine efforts. Since HIV-1 subtype B is still the most commonly found subtype around the globe, the hybrid genomes between different subtype B strains may result in epidemiologic shifts and altered pathogenesis.

AIDS-Related Opportunistic Infections↗

PubMed1999

[A mutation specific polymerase chain reaction for detecting hepatitis B virus genome with A-to-C mutation at nt585].

OBJECTIVE: To investigate the prevalence of hepatitis B virus (HBV) nt585 A-to-C mutants in China. METHODS: A mutation specific polymerase chain reaction (msPCR) was established for amplifying HBV DNAs with A-to-C mutation at nt585. Two sets of primer pairs with same sequences except for one base at 3' terminus were designed and synthesized according to 48 of the known HBV genome sequences and the popular HBV subtypes, adr and adw, in China. RESULTS: 57 of HBV S gene fragments amplified by a nested PCR from different and child adult hepatitis B patients were characterized by using the msPCR. It was shown that HBV mutants with A-to-C mutation at nt585 could be confirmed. CONCLUSION: The msPCR is a specific and sensitive method for detecting the HBV nt585 A-to-C mutants.

Adult↗