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PubMed2006

An ordered, nonredundant library of Pseudomonas aeruginosa strain PA14 transposon insertion mutants.

Random transposon insertion libraries have proven invaluable in studying bacterial genomes. Libraries that approach saturation must be large, with multiple insertions per gene, making comprehensive genome-wide scanning difficult. To facilitate genome-scale study of the opportunistic human pathogen Pseudomonas aeruginosa strain PA14, we constructed a nonredundant library of PA14 transposon mutants (the PA14NR Set) in which nonessential PA14 genes are represented by a single transposon insertion chosen from a comprehensive library of insertion mutants. The parental library of PA14 transposon insertion mutants was generated by using MAR2xT7, a transposon compatible with transposon-site hybridization and based on mariner. The transposon-site hybridization genetic footprinting feature broadens the utility of the library by allowing pooled MAR2xT7 mutants to be individually tracked under different experimental conditions. A public, internet-accessible database (the PA14 Transposon Insertion Mutant Database, http://ausubellab.mgh.harvard.edu/cgi-bin/pa14/home.cgi) was developed to facilitate construction, distribution, and use of the PA14NR Set. The usefulness of the PA14NR Set in genome-wide scanning for phenotypic mutants was validated in a screen for attachment to abiotic surfaces. Comparison of the genes disrupted in the PA14 transposon insertion library with an independently constructed insertion library in P. aeruginosa strain PAO1 provides an estimate of the number of P. aeruginosa essential genes.

DNA Transposable Elements↗

PubMed2006

Genomic sequence of rhesus cytomegalovirus 180.92: insights into the coding potential of rhesus cytomegalovirus.

A pathogenic isolate of rhesus cytomegalovirus (rhCMV 180.92) was cloned, sequenced, and annotated. Comparisons with the published rhCMV 68.1 genome revealed 8 open reading frames (ORFs) in isolate 180.92 that are absent in 68.1, 10 ORFs in 68.1 that are absent in 180.92, and 34 additional ORFs that were not previously annotated. Most of the differences appear to be due to genetic rearrangements in both isolates from a region that is frequently altered in human CMV (hCMV) during in vitro passage. These results indicate that the rhCMV ORF repertoire is larger than previously recognized. Like hCMV, understanding of the complete coding capacity of rhCMV is complicated by genomic instability and may require comparisons with additional isolates in vitro and in vivo.

Animals↗

PubMed2004

Correlation of amino acid preference and mammalian viral genome type.

MOTIVATION: In the event of an outbreak of a disease caused by an initially unknown pathogen, the ability to characterize anonymous sequences prior to isolation and culturing of the pathogen will be helpful. We show that it is possible to classify viral sequences by genome type (dsDNA, ssDNA, ssRNA positive strand, ssRNA negative strand, retroid) using amino acid distribution. RESULTS: In this paper we describe the results of analysis of amino acid preference in mammalian viruses. The study was carried out at the genome level as well as two shorter sequence levels: short (300 amino acids) and medium length (660 amino acids). The analysis indicates a correlation between the viral genome types dsDNA, ssDNA, ssRNA positive strand, ssRNA negative strand and retroid and amino acid preference. We investigated three different models of amino acid preference. The simplest amino acid preference model, 1-AAP, is a normalized description of the frequency of amino acids in genomes of a viral genome type. A slightly more complex model is the ordered pair amino acid preference model (2-AAP), which characterizes genomes of different viral genome types by the frequency of ordered pairs of amino acids. The most complex and accurate model is the ordered triple amino acid preference model (3-AAP), which is based on ordered triples of amino acids. The results demonstrate that mammalian viral genome types differ in their amino acid preference. AVAILABILITY: The tools used to format and analyze data and supplementary material are available at http://www.cse.sc.edu/~rose/aminoPreference/index.html CONTACT: rose@cse.sc.edu.

Algorithms↗

PubMed2026

Perturbing H-NS function reveals roles in restricting virulence heterogeneity and pathogen adaptation.

Xenogeneic silencers, such as histone-like nucleoid structuring protein (H-NS), are critical for maintaining horizontally acquired genes in bacterial genomes and minimizing fitness costs associated with inappropriate expression. For bacterial pathogens, this has enabled the acquisition of costly virulence regulons, with H-NS balancing the need for tight silencing with rapid expression in host environments. For Salmonella enterica serovar Typhimurium (STm), survival in these environments relies on phenotypic heterogeneity in virulence gene expression and evolutionary adaptation. Although complete loss of hns is highly deleterious in STm, how subtle impairments to this global silencer disrupt heterogeneity in virulence gene expression and alter adaptation to host environments remains poorly understood. Here, we identify an STm hns hypomorph strain and find that its reduced H-NS DNA-binding affinity increases the proportion of virulence-expressing cells, resulting in enhanced epithelial cell infection in vitro. Furthermore, through experimental evolution in intracellular-like conditions in vitro, we demonstrate that both wild-type and mutant populations converge on disrupting the SPI-2 virulence regulon to improve fitness; however, the mutant population also acquires distinct adaptive mutations to resolve the underlying dysregulation in gene expression. These results suggest that H-NS sets single-cell virulence activation thresholds and that even minor disruptions to its silencing function impact pathogen adaptation, highlighting its role as a critical evolutionary buffer.

Salmonella typhimurium↗

PubMed2004

Variation suggestive of horizontal gene transfer at a lipopolysaccharide (lps) biosynthetic locus in Xanthomonas oryzae pv. oryzae, the bacterial leaf blight pathogen of rice.

BACKGROUND: In animal pathogenic bacteria, horizontal gene transfer events (HGT) have been frequently observed in genomic regions that encode functions involved in biosynthesis of the outer membrane located lipopolysaccharide (LPS). As a result, different strains of the same pathogen can have substantially different lps biosynthetic gene clusters. Since LPS is highly antigenic, the variation at lps loci is attributed to be of advantage in evading the host immune system. Although LPS has been suggested as a potentiator of plant defense responses, interstrain variation at lps biosynthetic gene clusters has not been reported for any plant pathogenic bacterium. RESULTS: We report here the complete sequence of a 12.2 kb virulence locus of Xanthomonas oryzae pv. oryzae (Xoo) encoding six genes whose products are homologous to functions involved in LPS biosynthesis and transport. All six open reading frames (ORFs) have atypical G+C content and altered codon usage, which are the hallmarks of genomic islands that are acquired by horizontal gene transfer. The lps locus is flanked by highly conserved genes, metB and etfA, respectively encoding cystathionine gamma lyase and electron transport flavoprotein. Interestingly, two different sets of lps genes are present at this locus in the plant pathogens, Xanthomonas campestris pv. campestris (Xcc) and Xanthomonas axonopodis pv. citri (Xac). The genomic island is present in a number of Xoo strains from India and other Asian countries but is not present in two strains, one from India (BXO8) and another from Nepal (Nepal624) as well as the closely related rice pathogen, Xanthomonas oryzae pv. oryzicola (Xoor). TAIL-PCR analysis indicates that sequences related to Xac are present at the lps locus in both BXO8 and Nepal624. The Xoor strain has a hybrid lps gene cluster, with sequences at the metB and etfA ends, being most closely related to sequences from Xac and the tomato pathogen, Pseudomonas syringae pv. tomato respectively. CONCLUSION: This is the first report of hypervariation at an lps locus between different strains of a plant pathogenic bacterium. Our results indicate that multiple HGT events have occurred at this locus in the xanthomonad group of plant pathogens.

Base Sequence↗

PubMed2005

Unraveling Brucella genomics and pathogenesis in immunocompromised IRF-1-/- mice.

PROBLEM: Brucellosis causes abortion in domestic animals and Malta fever in humans. Comparison of Brucella species genomes may reveal potential virulence mechanisms. Engineering bioluminescent Brucella would permit monitoring bacterial dissemination. METHOD OF STUDY: Microarray of the B. melitensis genome allowed comparison of gene content from six Brucella species. Bioluminescent B. melitensis strains were developed using transposon mutagenesis permitting the study of pathogenic Brucella in mice. Monitoring bacterial dissemination as well as organ localization permits evaluating the role of genes and genomic islands in mutant bacteria. RESULTS: Comparative genomic analysis revealed 217 ORFs altered in five Brucella species and were often found in islands. Bioluminescent bacteria disseminated from the injection site to liver, spleen, inguinal lymph nodes, testes and submanibular region. CONCLUSIONS: Genomic islands contribute to Brucella pathogenicity. Biophotonic imaging suggests that Brucella dissemination in mice parallels acute and chronic infections of humans.

Animals↗

PubMed1998

Preliminary description of biocidal (syringomycin) activity in fluorescent plant pathogenic Pseudomonas species.

Strains representing the fluorescent plant pathogenic Pseudomonas spp., Ps. agarici, Ps. asplenii, Ps. avellanae, Ps. beteli, Ps. caricapapayae, Ps. cichorii, Ps. corrugata, Ps. ficuserectae, Ps. flectens, Ps. fuscovaginae, Ps. marginalis, Ps. meliae, Ps. savastanoi, Ps. syringae, Ps. tolaasii and Ps. viridiflava were tested for biocidal activity using Aspergillus niger as assay organism. Inhibitory behaviour was found in strains of Ps. asplenii, Ps. blatchfordae, Ps. cichorii, Ps. corrugata, Ps. fuscovaginae, Ps. marginalis, Ps. marginalis pv. pastinacea, Ps. syringae pv. syringae, Ps. syringae pv. aptata, Ps. syringae pv. atrofaciens, Ps. syringae pv. lapsa, Ps. tolaasii, and strains of a Pseudomonas sp. pathogenic to Actinidia, in the Ps. savastanoi genomic sp. Antifungal activity could be identified with the production of members of the syringomycin family of toxins by strains in Ps. syringae, Ps. asplenii and Ps. fuscovaginae. These toxin reactions support suggestions made elsewhere of the synonym of the latter two species. In a preliminary characterization using tests for stability to heat, protease, acid and alkaline treatments, unknown toxins consistent with syringomycin-like toxins the strains from Actinidia species. The toxins from Ps. cichorii and from Ps. corrugata differed in their reactions from all other agents. Pseudomonas tolaasii produces the antifungal compound tolaasin. The white line reaction with Ps. reactions, a test for tolaasin production by strains of Ps. tolaasii, was confirmed as specific for this compound. Some of these low molecular weight toxins may be produced by some of these plant pathogenic strains.

Antifungal Agents↗

PubMed2002

Inducibility by pathogen attack and developmental regulation of the rice Ltp1 gene.

Using a genomic clone encoding a rice lipid transfer protein, LTP1, we analysed the activity of the 5' region of the Ltp1 gene in transgenic rice (Oryza sativa L.) during plant development and under pathogen attack. The -1176/+13, -556/+13 and -284/+13 regions of the promoter were fused upstream from the uidA reporter gene and nos 3' polyadenylation signal, resulting in the pdelta1176Gus, pdelta556Gus and pdelta284Gus constructs which were transferred to rice by microprojectile bombardment. Histochemical and fluorometric GUS assays and in situ detection of uidA transcripts in transgenic homozygous lines harbouring the pdelta1176Gus construct demonstrated that the Ltp1 promoter is preferentially active in aerial vegetative and reproductive organs and that both specificity and level of expression are regulated during organ development. In leaf sheath, GUS activity which is initially strictly localized in the epidermis of growing tissue, becomes restricted to the vascular system in mature tissues. In expanded leaf blade, expression of the uidA gene was restricted to the cutting level suggesting inducibility by wounding. Strong activity was detected in lemma and palea, sterile glumes, and immature anther walls and microspores but not in female reproductive organs. No GUS activity was detected during seed embryo maturation whereas the uidA gene was strongly expressed at early stages of somatic embryogenesis in scutellum tissue. The Ltp1 transcripts were found to strongly accumulate in response to inoculation with the fungal agent of the blast disease, Magnaporthe grisea, in two rice cultivars exhibiting compatible or incompatible host-pathogen interactions. Analysis of pdelta1176Gus leaf samples inoculated with the blast fungus demonstrated that the Ltp1 promoter is induced in all cell types of tissues surrounding the lesion and notably in stomata guard cells. In plants harbouring the Ltp1 promoter deletion construct pdelta556Gus, activity was solely detected in the vascular system of mature leaves whereas no uidA gene expression was observed in pdelta284Gus plants. These observations are consistent with the proposed role of LTP1 in strenghtening of structural barriers and organ protection against mechanical disruption and pathogen attack.

Antigens, Plant↗

PubMed2006

New findings on members of the family Anaplasmataceae of veterinary importance.

Members of the family Anaplasmataceae are obligate intracellular Gram-negative bacteria that naturally infect a variety of wild and domestic animal species, the spillover of which may lead to zoonosis. I discuss new findings on members of the family Anaplasmataceae of veterinary importance and therefore, I will describe the recent findings on Neorickettsia risticii in the trematode and related Neorickettsia species. I also will review the recent progress on Aegyptianella pullorum and other Aegyptianella sp., "Candidatus Neoehrlichia mikurensis" and Anaplasma phagocytophilum strains in various hosts. The whole genome sequences of two important veterinary pathogens-Anaplasma marginale, the bovine anaplasmosis agent, and Ehrlichia (formerly Cowdria) ruminantium, the agent of heartwater of ruminants-have been published. Taken together, these advances in research of the family Anaplasmataceae in the veterinary field provide us with insights into the evolution, reservoir, and transmission of these organisms in nature and their pathogenesis in natural and accidental hosts. It is through this work that surveillance, diagnosis, preventive measures, and treatment of ehrlichioses of both animals and humans can be improved.

Anaplasmataceae↗

PubMed2026

Multidrug resistance and genomic characteristics of nontypeable Haemophilus influenzae isolates from the respiratory tract of pediatric patients.

UNLABELLED: Nontypeable Haemophilus influenzae (NTHi) is a common colonizer of the human upper respiratory tract and one of the major pathogens responsible for pediatric respiratory tract infections. Given the increasing severity of its multidrug resistance (MDR), this study comprehensively investigated the genomic characteristics of circulating NTHi isolated from sputum and bronchoalveolar lavage fluid (BALF). A total of 104 H. influenzae isolates (69 from sputum; 35 from BALF) were collected from pediatric patients between January 2024 and January 2025. All isolates underwent whole-genome sequencing and antimicrobial susceptibility testing, followed by core/pan-genome phylogenetic analysis, multilocus sequence typing (MLST), and resistome profiling. Among them, 103 were identified as NTHi. We identified 29 known sequence types (STs) and 10 novel STs, with ST-107 (14.4%), ST-57 (10.6%), and ST-11 (8.7%) being the major circulating lineages. However, core-genome phylogenetic analysis provided a more granular view of the genetic variation within these identical STs. All the isolates showed high resistance to ampicillin (98.1%) and cefuroxime (84.6%). Genomically, the multidrug efflux pump gene hmrM was ubiquitous (100%). Ampicillin resistance was predominantly driven by blaTEM-1 carriage (77.9%), with minor contributions from chromosomal ftsI mutations. Fifteen plasmid replicons were predicted from 25 isolates, which highly coincided with the carriage of blaTEM-1 and other acquired resistance genes. This study demonstrates that MDR in pediatric NTHi is primarily driven by acquired resistance genes and chromosomal mutations, with specific resistant clones persisting and enriching under clinical antibiotic pressures. These findings underscore the importance of continuous high-resolution genomic surveillance in guiding rational antibiotic stewardship. IMPORTANCE: This study highlights the critical importance of high-resolution genomic surveillance in managing pediatric nontypeable Haemophilus influenzae (NTHi) infections. By utilizing whole-genome sequencing, we uncovered the pathogen's highly dynamic population structure and complex multidrug resistance (MDR) mechanisms. Crucially, our findings reveal a strong, non-random coupling between core genomic architectures, virulence factors, and MDR elements, driven by dual environmental and pharmacological pressures. This "virulence-MDR" co-evolutionary trend underscores the persistent clinical threat of locally adapted high-risk clones. These findings provide important insights for guiding rational clinical antibiotic stewardship, optimizing treatment strategies, and improving regional infection control.

Humans↗

PubMed1989

Identification of the major genetic determinant for neurovirulence of tick-borne orbiviruses.

Three members of the Great Island antigenic subgroup (Kemerovo serogroup) of tick-borne obiviruses produced fatal infections following intracerebral inculation of 2-day-old mice. The average survival times and PFU/LD50 ratios of mice inoculated with Wexford (WEX) virus were significantly greater than those of either Nugget (NUG) or Great Island (GI) virus. Reassortant viruses were isolated following dual infections of cell cultures with a spontaneous temperature-sensitive (ts) mutant of WEX virus, and either NUG wild-type virus or a ts mutant of GI virus. The neurovirulence for mice and derivation of the genomic RNA segments were determined for the reassortants. Analysis of this data revealed that the pathogenic phenotype of the reassortant viruses depended on the parental origin of genomic segment 4. The major genetic determinant of serotype specificity was not shown to influence neurovirulence in these investigations.

Animals↗

PubMed2005

Rapid directional shift of mitochondrial DNA heteroplasmy in animal tissues by a mitochondrially targeted restriction endonuclease.

Frequently, mtDNA with pathogenic mutations coexist with wild-type genomes (mtDNA heteroplasmy). Mitochondrial dysfunction and disease ensue only when the proportion of mutated mtDNAs is high, thus a reduction in this proportion should provide an effective therapy for these disorders. We developed a system to decrease specific mtDNA haplotypes by expressing a mitochondrially targeted restriction endonuclease, ApaLI, in cells of heteroplasmic mice. These mice have two mtDNA haplotypes, of which only one contains an ApaLI site. After transfection of cultured hepatocytes with mitochondrially targeted ApaLI, we found a rapid, directional, and complete shift in mtDNA heteroplasmy (2-6 h). We tested the efficacy of this approach in vivo, by using recombinant viral vectors expressing the mitochondrially targeted ApaLI. We observed a significant shift in mtDNA heteroplasmy in muscle and brain transduced with recombinant viruses. This strategy could prevent disease onset or reverse clinical symptoms in patients harboring certain heteroplasmic pathogenic mutations in mtDNA.

Adenoviridae↗

PubMed2026

Seqwin: ultrafast identification of signature sequences in microbial genomes.

MOTIVATION: Polymerase chain reaction (PCR) enables rapid, cost-effective diagnostics but requires prior identification of genomic regions that allow sensitive and specific detection of target microbial groups, herein referred to as microbial signature sequences. We introduce Seqwin, an open-source framework designed to automate microbial genome signature discovery. Tens of thousands of microbial genomes are now available for a single species, limiting the application of existing manual and automated approaches for identifying signatures. Modern approaches that are capable of leveraging all available microbial genomes will ensure sensitive and accurate DNA signature identification and enable robust pathogen detection for clinical, environmental, and public health applications. RESULTS: Seqwin builds weighted pan-genome minimizer graphs and uses a traversal algorithm to identify signature sequences that occur frequently in target genomes but remain rare in non-targets. Unlike earlier tools that depend on strict presence or absence of sequences, Seqwin accommodates natural sequence variation and scales to very large genome collections. When applied to genomes from C. difficile, M. tuberculosis, and S. enterica, Seqwin recovered more high-quality signatures than alternative methods with lower computational burden. Seqwin's analysis of nearly 15 000 S. enterica genomes yielded over 200 candidate signatures in three minutes. Seqwin provides an open-source solution for the long-standing need for scalable microbial signature discovery and diagnostic assay design. AVAILABILITY AND IMPLEMENTATION: Seqwin is available on GitHub (https://github.com/treangenlab/Seqwin) and can be installed via Bioconda (https://bioconda.github.io/recipes/seqwin/README.html). Benchmarking datasets, outputs, and scripts are available on Zenodo (https://doi.org/10.5281/zenodo.19874011).

Software↗

PubMed2003

Genome diversification in Staphylococcus aureus: Molecular evolution of a highly variable chromosomal region encoding the Staphylococcal exotoxin-like family of proteins.

Recent genomic studies have revealed extensive variation in natural populations of many pathogenic bacteria. However, the evolutionary processes which contribute to much of this variation remain unclear. A previous whole-genome DNA microarray study identified variation at a large chromosomal region (RD13) of Staphylococcus aureus which encodes a family of proteins with homology to staphylococcal and streptococcal superantigens, designated staphylococcal exotoxin-like (SET) proteins. In the present study, RD13 was found in all 63 S. aureus isolates of divergent clonal, geographic, and disease origins but contained a high level of variation in gene content in different strains. A central variable region which contained from 6 to 10 different set genes, depending on the strain, was identified, and DNA sequence analysis suggests that horizontal gene transfer and recombination have contributed to the diversification of RD13. Phylogenetic analysis based on the RD13 DNA sequence of 18 strains suggested that loss of various set genes has occurred independently several times, in separate lineages of pathogenic S. aureus, providing a model to explain the molecular variation of RD13 in extant strains. In spite of multiple episodes of set deletion, analysis of the ratio of silent substitutions in set genes to amino acid replacements in their products suggests that purifying selection (selective constraint) is acting to maintain SET function. Further, concurrent transcription in vitro of six of the seven set genes in strain COL was detected, indicating that the expression of set genes has been maintained in contemporary strains, and Western immunoblot analysis indicated that multiple SET proteins are expressed during the course of human infections. Overall, we have shown that the chromosomal region RD13 has diversified extensively through episodes of gene deletion and recombination. The coexpression of many set genes and the production of multiple SET proteins during human infection suggests an important role in host-pathogen interactions.

Animals↗

PubMed2004

Comparative whole-genome hybridization reveals genomic islands in Brucella species.

Brucella species are responsible for brucellosis, a worldwide zoonotic disease causing abortion in domestic animals and Malta fever in humans. Based on host preference, the genus is divided into six species. Brucella abortus, B. melitensis, and B. suis are pathogenic to humans, whereas B. ovis and B. neotomae are nonpathogenic to humans and B. canis human infections are rare. Limited genome diversity exists among Brucella species. Comparison of Brucella species whole genomes is, therefore, likely to identify factors responsible for differences in host preference and virulence restriction. To facilitate such studies, we used the complete genome sequence of B. melitensis 16M, the species highly pathogenic to humans, to construct a genomic microarray. Hybridization of labeled genomic DNA from Brucella species to this microarray revealed a total of 217 open reading frames (ORFs) altered in five Brucella species analyzed. These ORFs are often found in clusters (islands) in the 16M genome. Examination of the genomic context of these islands suggests that many are horizontally acquired. Deletions of genetic content identified in Brucella species are conserved in multiple strains of the same species, and genomic islands missing in a given species are often restricted to that particular species. These findings suggest that, whereas the loss or gain of genetic material may be related to the host range and virulence restriction of certain Brucella species for humans, independent mechanisms involving gene inactivation or altered expression of virulence determinants may also contribute to these differences.

Animals↗

PubMed2026

TUBA4A Pathogenic Variant Manifesting With Adulthood-Onset Genetic Myasthenic Syndrome, Myopathy, and Infertility.

OBJECTIVES: TUBA4A pathogenic variants are associated with ALS, frontotemporal dementia, spastic ataxia, spasticity, ataxia, Parkinson's disease, female infertility, macrothrombocytopenia, and myopathy. Four recently reported patients with TUBA4A neonatal/childhood onset myopathy had also a decrement on repetitive nerve stimulation (RNS), but such a finding was not further characterized. We describe a patient with a TUBA4A pathogenic variant with adulthood-onset genetic myasthenic syndrome accompanied by myopathy and infertility to highlight the neuromuscular junction defect as the main feature of the patient's phenotype. METHODS: We reviewed the patient's clinical and laboratory findings and performed transcriptomic analysis on the patient's muscle. RESULTS: A 53-year-old woman with infertility of unknown etiology manifested fatigability and proximal upper limb muscle weakness in her mid-30s, followed by lower limb involvement. Her examination showed proximal muscle weakness and fatigability but spared facial muscles. CK values were mildly elevated. Anti-AChR, MuSK, P/Q-type calcium channel, and LRP4 antibodies were absent. 2 Hz RNS showed decrement (-14% to -48%) in limb muscles that improved with 3,4-dyaminopyridine (3,4-DAP). Facilitation (231%) occurred in the trapezius. Muscle biopsy showed patchy loss of oxidative enzyme reactivity and no C5b9 or IgG at neuromuscular junctions. Whole genome sequencing identified a heterozygous known TUBA4A pathogenic variant (c.850G>A, p.Glu284Lys). Patient improved with 3,4-DAP and albuterol. DISCUSSION: TUBA4A p.Glu284Lys can lead to treatable myasthenic syndrome with postsynaptic and likely presynaptic involvement, as suggested by the patient's electrophysiological findings and response to therapy. This patient expands the TUBA4A-disorder spectrum to include overlapping myasthenic syndrome-myopathy and shows that neuromuscular disease and infertility can occur within the same patient.

Humans↗

PubMed2026

Histopathologic, Genomic, and Clinical Characteristics of Primary Cutaneous Melanocytic Tumors With Concomitant NRAS Q61 and IDH1 R132C Mutations.

Cutaneous melanocytic tumors with concomitant NRAS Q61 and IDH1 R132C mutations have been described as intermediate-grade melanocytomas with characteristic biphasic morphology, but the malignant end of this genotype-defined spectrum remains poorly characterized. We assessed histopathologic, immunohistochemical, molecular, and clinical features of 16 primary cutaneous melanocytic tumors harboring both mutations. Following integrated review, 7 tumors were classified as melanocytoma and 9 as melanoma. Melanocytomas showed reproducible biphasic architecture with congenital nevus-like features, a biphasic HMB-45 pattern, low Ki-67, PRAME negativity, retained p16, and minimal copy number variations (CNVs). Melanomas retained partial morphologic overlap in a subset but were distinguished by higher-grade cytology, immunohistochemical features supportive of malignancy, and progression-associated genomic alterations, including TERT promoter mutation (9/9), 9p21/CDKN2A loss (4/7), and higher CNV burden. NRAS and IDH1 variant allele frequencies were strongly concordant (r = 0.83, P < 0.001), supporting their presence in the same dominant clone. Clinically, two patients presented with stage IIIB disease, but no distant metastasis or melanoma-related death occurred during a median melanoma follow-up of 3.9 years (IQR, 2.5-5.1). In exploratory analyses, moderate-to-severe atypia (RR, 6.2; 95% CI, 1.0-38.8; P = .009), Ki-67 ≥10% (RR, 4.4; 95% CI, 1.1-18.4; P = .003), lymphocytic infiltrate (RR, 2.4; 95% CI, 1.1-5.3; P = .03), absence of the typical biphasic pattern (RR, 2.4; 95% CI, 1.1-5.3; P = .03), and complete p16 loss (RR, 2.4; 95% CI, 1.1-5.3; P = .03) were associated with molecular or clinical progression to melanoma, defined as the presence of at least one of the following: TERT promoter mutation, pathogenic CDKN2A mutation, 9p21/CDKN2A loss, ≥3 genome-wide segmental CNVs, or any metastasis. These findings support the existence of NRAS/IDH1 co-mutated melanoma as the malignant counterpart of NRAS/IDH1-mutated melanocytoma within a single genotype-defined spectrum.

IDH1 mutations↗

PubMed2006

PathogenMIPer: a tool for the design of molecular inversion probes to detect multiple pathogens.

BACKGROUND: Here we describe PathogenMIPer, a software program for designing molecular inversion probe (MIP) oligonucleotides for use in pathogen identification and detection. The software designs unique and specific oligonucleotide probes targeting microbial or other genomes. The tool tailors all probe sequence components (including target-specific sequences, barcode sequences, universal primers and restriction sites) and combines these components into ready-to-order probes for use in a MIP assay. The system can harness the genetic variability available in an entire genome in designing specific probes for the detection of multiple co-infections in a single tube using a MIP assay. RESULTS: PathogenMIPer can accept sequence data in FASTA file format, and other parameter inputs from the user through a graphical user interface. It can design MIPs not only for pathogens, but for any genome for use in parallel genomic analyses. The software was validated experimentally by applying it to the detection of human papilloma virus (HPV) as a model system, which is associated with various human malignancies including cervical and skin cancers. Initial tests of laboratory samples using the MIPs developed by the PathogenMIPer to recognize 24 different types of HPVs gave very promising results, detecting even a small viral load of single as well as multiple infections (Akhras et al, personal communication). CONCLUSION: PathogenMIPer is a software for designing molecular inversion probes for detection of multiple target DNAs in a sample using MIP assays. It enables broader use of MIP technology in the detection through genotyping of pathogens that are complex, difficult-to-amplify, or present in multiple subtypes in a sample.

Computational Biology↗