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PubMed2004

[Molecule based diagnosis].

Based on reviews of the concept of diagnostics and in general and in specific tumour areas it was clear that development of diagnostic procedures involving genomics will allow for much better targeted and tailored treatments in the future. This will result in better efficacy and better tolerability of cancer treatments, but will also allow for progress in prediction, diagnosis and dose selection. Large collaborative projects studying the efficacy and safety of drugs on the genome level is promising to bring important benefits to both patients and the national economy by reducing useless drug therapy. In colorectal cancer there are several genetic defects identified that can act as the target for directed therapy in the future. Expressions of tumour specific antigens open the way for immunological targeted therapies. Developments in the understanding of the genomic basis for resistance to anti-tumour therapy is promising to help targeting patients likely to respond and not develop resistance. A Japanese model is being developed to determine the relative risk of breast cancer of Japanese women. Based on this prevention therapies can be instigated. The last four years have seen the introduction of four novel targeted therapies. If this model should become a standard in the future, much stronger collaboration between academic research and pharmaceutical industry need to develop.

Antineoplastic Agents↗
PubMed2003

Array-based comparative genomic hybridization for the genomewide detection of submicroscopic chromosomal abnormalities.

Microdeletions and microduplications, not visible by routine chromosome analysis, are a major cause of human malformation and mental retardation. Novel high-resolution, whole-genome technologies can improve the diagnostic detection rate of these small chromosomal abnormalities. Array-based comparative genomic hybridization allows such a high-resolution screening by hybridizing differentially labeled test and reference DNAs to arrays consisting of thousands of genomic clones. In this study, we tested the diagnostic capacity of this technology using approximately 3,500 flourescent in situ hybridization-verified clones selected to cover the genome with an average of 1 clone per megabase (Mb). The sensitivity and specificity of the technology were tested in normal-versus-normal control experiments and through the screening of patients with known microdeletion syndromes. Subsequently, a series of 20 cytogenetically normal patients with mental retardation and dysmorphisms suggestive of a chromosomal abnormality were analyzed. In this series, three microdeletions and two microduplications were identified and validated. Two of these genomic changes were identified also in one of the parents, indicating that these are large-scale genomic polymorphisms. Deletions and duplications as small as 1 Mb could be reliably detected by our approach. The percentage of false-positive results was reduced to a minimum by use of a dye-swap-replicate analysis, all but eliminating the need for laborious validation experiments and facilitating implementation in a routine diagnostic setting. This high-resolution assay will facilitate the identification of novel genes involved in human mental retardation and/or malformation syndromes and will provide insight into the flexibility and plasticity of the human genome.

Chromosome Aberrations↗
PubMedDate not supplied

Panel One: marketing strategies and informing the patient/consumer. Infertility diagnostic techniques: the rush to market.

The human genome project will result in many new diagnostic techniques applicable to assisted reproduction. These may be directed both at infertile patients as well as at patients who seek ART because they carry a deleterious genetic disease. There are many potential advantages to the use of preprocedural testing as a means of obtaining additional preliminary information that might allow patients to make a more informed choice, either when deciding between ART and adoption or when comparing the benefits of various ART procedures. The cost of testing is relatively low when compared with the cost of additional IVF or ICSI cycles. In the case of genetic screening protocols, the results may be useful not only to the patient but also to the next generation. Genetic counseling should be made available in concert with expanded opportunities, both for diagnosing infertility and for making preimplantation genetic diagnoses. Already some of the genetic screening that has occurred because of discoveries made during the human genome initiative has become a regulatory concern with regard to insurance availability and other issues. When counseling patients, it is important to point out that certain tests hold far more prognostic value and/or serious health implications than others. A test to diagnose breast cancer susceptibility, for example, holds more serious ramifications than the less predictive test that detects the phenotype for Klinefelter's syndrome. Presymptomatic prognostic screening systems, such as the tests currently used to detect genetic mutations related to breast and prostate cancer and cystic fibrosis, provide diagnostic clues but also have serious societal implications. We are on a rather slippery slope when we attempt to determine which tests actually might prove beneficial to patients, both individually and collectively. Therefore, as part of patient counseling, cost-benefit ratios, in addition to clinical and preventive implications, should be weighed.

Female↗
PubMed2002

[From genetics to law, the jurist's point of view].

ONE MUST BEAR: In mind that science is not always beneficial for mankind. The primary objective of ethics must therefore be to awaken cause for concern, and a second objective should measure the stakes. Scientific texts do not always have to be adapted to scientific reality, since all progress does not necessarily require expression in terms of law. Law can be limited, with loopholes creating the well-known 'gap'. WITH GENETICS: Care must be taken in avoiding the free and wide use of genetic technology. Three principles must be applied: the refusal of eugenics, the non-use of the human body as a patrimony, and patients must give their informed consent. BIOETHICAL TEXTS: Cover the more selective applications of genetics: genetic fingerprints and the unresolved question of the status of the human body after death. Genetic diagnosis is distinctive. Genetic tests do not provide the certainty of a risk but its probability; and the results obtained also provide information on the family circle. Genetics reveal the identity of the human being. ACCORDING TO THE OVIEDO CONVENTION: (April 1997), the primary provisions concerning the ethical and legal protective measures with regard to genetics are as follows: the genetic heritage cannot be a factor of discrimination; genetic tests are qualified as predictive; the aim of interventions on the human genome can only preventive, diagnostic or therapeutic, and cannot be aimed at introducing a modification in the genome of descendants.

Bioethics↗
PubMed2004

Origin of intra-individual variation in PCR-amplified mitochondrial cytochrome oxidase I of Thrips tabaci (Thysanoptera: Thripidae): mitochondrial heteroplasmy or nuclear integration?

The mitochondrial genome is increasingly being used as a species diagnostic marker in insects. Typically, genomic DNA is PCR amplified and then analysed by restriction analyses or sequencing. This analysis system may cause some serious problems for molecular diagnosis. Besides the errors introduced by the PCR process, mtDNA sequence variation of amplified fragments may originate from mtDNA heteroplasmy or from nuclear integrations of mtDNA fragments, both of which have been shown to occur in insects. Here we document abundant variation in PCR-amplified sequences of the mitochondrial cytochrome oxidase I gene of Thrips tabaci. We confirm that the most common haplotype is of mitochondrial origin. Some of the observed mutations were introduced by the amplification process. However, the occurrence of some haplotypes at elevated frequencies indicates that within-individual variation of the respective fragment exists at low levels in T. tabaci. The frequencies of these sequences are too low to negatively affect mtDNA-based molecular diagnosis of T. tabaci. The possible origin of these variant haplotypes is discussed.

Animals↗
PubMed1998

Chromosomal gains and losses in primary cutaneous melanomas detected by comparative genomic hybridization.

The analysis of genetic changes in primary cutaneous melanoma has been limited by the need for fixation for diagnostic purposes. However, comparative genomic hybridization is able to analyze such specimens. We have applied comparative genomic hybridization to 32 primary melanomas to discover and map genomic regions with aberrant DNA copy numbers. The analysis was performed on native, nonamplified DNA extracted from manually dissected tumor sections. Loss of chromosome 9 was detected in 81% of the tumors, most commonly affecting the p arm. Additional common losses occurred on chromosomes 10 (63%), 6q (28%), and 8p (22%). Gains in copy number involved chromosomes 7 (50%), 8 (34%), 6p (28%), 1q (25%), 20 (13%), 17 (13%), and 2 (13%). Amplifications indicating areas harboring potential oncogenes were seen at 4q12, 5p14.3-pter, 7q33-qter, 8q12-13, 11q13.3-14.2, and 17q25. Correlations among the regions with copy number changes indicate that losses of chromosomes 9 and 10 occur early on in melanoma progression, whereas gains of chromosome 7 occur later. This sequence of events was further substantiated by an intratumoral comparison of copy number changes in areas with radial and vertical growth phase patterns. The overall pattern of regions affected by copy number changes is consistent with cytogenetic data from metastatic melanoma; however, the frequencies of involvement differ, providing further insight into the course of genetic events.

Age Factors↗
PubMed1989

Deviations from expected frequencies of CpG dinucleotides in herpesvirus DNAs may be diagnostic of differences in the states of their latent genomes.

The DNA sequences of genomes from G + C-rich and A + T-rich lymphotropic herpesviruses [i.e. gammaherpesviruses; Epstein-Barr virus and herpesvirus saimiri (HVS)] are deficient in CpG dinucleotides and contain an excess of TpG and CpA dinucleotides relative to frequencies predicted from their mononucleotide compositions. In contrast, for sequences from genomes of G + C-rich and A + T-rich neurotropic herpesviruses (i.e. alphaherpesviruses; herpes simplex virus and varicellazoster virus) and human cytomegalovirus (HCMV; a betaherpesvirus) the mean observed frequencies of these dinucleotides are close to those expected from their mononucleotide compositions. Comparisons between DNA sequences that encode proteins conserved in all these viruses also show that sequences of these lymphotropic viruses are CpG-deficient whereas the homologous genes from the neurotropic viruses and the HCMV are not. Analyses of local variations in dinucleotide frequencies reveal some occurrences of clustered CpG dinucleotides in generally deficient genomes (e.g. upstream of the thymidylate synthase gene of HVS) and locally CpG-deficient regions within some generally non-deficient genomes (e.g. the major immediate early genes of human, simian and murine CMVs). A relative deficiency in CpG and an excess of TpG and CpA dinucleotides is a diagnostic feature of higher eukaryotic DNA sequences that have been subjected to methylation of cytosine residues in CpG doublets with the resulting increase in mutations to give TpG (and thereby its complement, CpA). The available evidence implicates the latent genome as the site of methylation of these herpesviruses. We conclude that in the neurotropic herpesviruses the normal latent precursors to infectious progeny are not methylated whereas there is local methylation of the immediate early locus in the latent genomes of CMVs, and the latent genomes of these lymphotropic herpesviruses are extensively methylated.

Base Sequence↗
PubMed2026

Survey of diagnostic laboratories highlights need for improved standards in somatic genomic testing and reporting.

There is a growing international need to support somatic genomic testing, standardised variant curation and improved patient access to molecular profiling for somatic conditions, including cancer. We conducted a survey of scope, curation, reporting and sharing practices of diagnostic laboratories performing somatic testing in Australia and New Zealand. Laboratories with accreditation (n = 41) were invited in 2023 to complete a semi-structured, 25-question interview. Responses were received for 27 laboratories (66% response rate) offering solid tumour, haematological malignancy and non-cancer services. Only 36% of laboratories offered tests capturing the full breadth of variants, from single-nucleotide variants to gene fusions. Knowledge sharing was rare, with only one laboratory submitting variant classifications to a public knowledge base. Most laboratories (96%) conducted somatic testing in oncology. Of cancer laboratories, 35% offered testing considered capable of comprehensive genomic profiling (CGP). Almost half of cancer laboratories had already adopted the 2022 ClinGen/CGC/VICC oncogenicity guidelines, and 84% were using AMP/ASCO/CAP 2017 clinical significance guidelines. Only 47% of mixed discipline cancer laboratories reported biomarkers such as tumour mutational burden, with wide variation in reporting of matched therapy options. Our study has generated a unique overview of somatic laboratory practices in the region, and areas for global standardisation in somatic molecular testing and reporting. We also provide a model for practice and guideline uptake assessment, for application by other country-wide networks. This is particularly relevant in anticipation of CGP mainstreaming, with the increasing complexity of sequencing interpretation for laboratories and clinicians.

Humans↗
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↗
PubMed2002

Secretion and dynamics of herpes simplex virus in tears and saliva of patients with Bell's palsy.

OBJECTIVE: For clarification of the direct relationship between the reactivation of herpes simplex virus and the development of Bell's Palsy, a detection of the virus genome by deoxyribonucleic acid diagnostics and a quantitative analysis of its time-course change are both needed. The authors detected the HSV genome in specimens from patients with Bell's Palsy, quantified its number of copies, and examined time-course changes. SUBJECTS AND METHODS: The subjects were 16 patients with Bell's Palsy. The tear fluid and saliva from the submandibular gland and the parotid gland were separately collected from the affected and unaffected sides twice or more. A total of 244 specimens were subjected to extraction of deoxyribonucleic acid, polymerase chain reaction, and microplate hybridization. RESULTS: Herpes simplex virus-1 deoxyribonucleic acid was detected in 38 specimens (11.8%) from 5 patients (31%). The high detection (28.5%) was obtained within 2 weeks after onset. Detection at 3 weeks and later (2.8%) was significantly lower ( < 0.05). In three cases, deoxyribonucleic acid was also found on the unaffected side in the initial phase of the disease, but detection on that side (18.9%) was significantly lower than on the affected side (83.8%) ( < 0.01). The number of copies of the herpes simplex virus-1 genome was large on the affected side and early after the onset of the disease. CONCLUSIONS: The reactivation of herpes simplex virus-1 on the affected side is involved as a pathogenic factor of Bell's Palsy. A reactivation of herpes simplex virus-1 may be generated even on the unaffected side in the early phase of the disease. Herpes simplex virus deoxyribonucleic acid was not detected in any of the examined specimens collected from the remaining 11 cases. The need for constant study to clarify other causative factors of Bell's Palsy remains.

Adolescent↗
PubMed2006

Identification of diagnostic proteins in Mycobacterium avium subspecies paratuberculosis by a whole genome analysis approach.

Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) is an economically significant veterinary pathogen that causes Johne's disease in cattle and sheep. There is a critical need for improved diagnostic tests to detect M. paratuberculosis infection in these animals. As with many other animal diseases, efforts need to be concentrated on the development of simple, rapid, noninvasive tests that can be performed by veterinarians or animal producers without expensive laboratory equipment. With the genome sequence of M. paratuberculosis now complete, we have taken a different strategy to identify novel proteins that are present uniquely in M. paratuberculosis and are antigenic in the context of infected cattle. Through a whole genome comparison of M. paratuberculosis with other sequenced mycobacterial genomes, we identified a collection of more than 90 genes that are present uniquely in M. paratuberculosis. This list has been further trimmed to 39 after amplification using polymerase chain reaction of unique genes using the genomic deoxyribonucleic acid template from several mycobacterial species and isolates. A selection of the remaining genes has been cloned and expressed in Escherichia coli and purified by affinity chromatography. Successfully purified proteins were analyzed using sera from rabbits immunized with M. paratuberculosis. Furthermore, to identify antigens in the context of disease, sera from cattle with Johne's disease as well as healthy control cattle are used in immunoassays. Using this methodology, we identified the first protein antigens specific to M. paratuberculosis.

Animals↗
PubMed2005

Genomic and proteomic approaches for Chagas' disease: critical analysis of diagnostic methods.

Trypanosoma cruzi is the etiologic agent of Chagas' disease, a chronic inflammatory condition that results in heart and digestive complications. The first draft of the parasite genome is now complete and it is expected that, along with the published genomic and proteomic analyses discussed herein, it will lead to the identification of crucial genes and proteins directly associated with disease. This article reviews the current research trends addressing host-parasite interaction, parasite genetic variability and diagnosis. These advances will certainly bring about major developments not only in our understanding of Trypanosoma cruzi biology, but also in the application of new technologies to disease prevention and control.

Animals↗
PubMed2026

Schizophrenia and bipolar disorder: a comparative analysis of genetic and brain network connectivity.

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BD) are severe psychiatric conditions with overlapping clinical presentations, genetic risk factors, and brain network dysfunction. Whether alterations in large-scale intrinsic brain networks reflect shared or disorder-specific genetic influences remains poorly understood. Clarifying this distinction is essential for refining etiological models and improving diagnostic precision. METHODS: Genome-wide inferred statistics (GWIS) were applied to decompose the genetic architecture of SCZ and BD into shared and unique components. Using resting-state network (RSN) data from the UK Biobank, functional connectivity (FC) and structural connectivity (SC) were extracted as neuroimaging phenotypes. Causal inference approaches were subsequently employed to infer potential directional relationships between brain network connectivity and each disorder. RESULTS: Analyses revealed both common and distinct patterns of brain network connectivity associated with SCZ and BD. Notably, SC within the default mode network (DMN) exhibited opposing effects across the two disorders, suggesting divergent structural underpinnings despite clinical overlap. Additionally, SC within the limbic network (LN) and frontotemporal control network demonstrated potential causal relationships with both conditions, implicating these circuits astransdiagnostic neural substrates. CONCLUSION: These findings illuminate the shared and disorder-specific genetic and neural architecture underlying SCZ and BD. Integrating genome-wide genetic methods with large-scale neuroimaging data offers a powerful framework for disentangling psychiatric comorbidity and may inform more targeted diagnostic criteria and individualized treatment strategies.

Humans↗
PubMed2026

LAMBDA: a prophage detection benchmark for genomic language models.

Transformer-based genomic sequence models represent an emerging frontier in computational biology. Yet, their embeddings have not yet shown the same level of predictive power as natural and protein language models, highlighting a gap between current implementations and theoretical promise. Existing benchmarks for DNA language models primarily focus on classifying regulatory elements in eukaryotic genomes, leaving open the fundamental question of whether these models learn sequence-level features across whole genomes. We introduce LAMBDA, a benchmark designed to rigorously evaluate genome language model embeddings through phage-bacteria sequence discrimination across four categories of increasing complexity: probing tasks, fine-tuning assessments, diagnostic tests, and genome-wide prophage detection. Our comprehensive analysis of current genomic language models provides insight into the importance of training data selection relative to model size, the need for domain-specific training, and the capabilities and limitations of genomic language models for detecting prophage sequences. This benchmark represents a challenging genomic annotation task in the bacterial domain and addresses a key computational problem with direct relevance to microbiology and medicine.

Prophages↗
PubMed2026

LAMBDA: A Prophage Detection Benchmark for Genomic Language Models.

Transformer-based genomic sequence models represent an emerging frontier in computational biology. Yet, their embeddings have not yet shown the same level of predictive power as natural and protein language models, indicating a gap between current implementations and theoretical promise. Existing benchmarks for DNA language models primarily focus on classifying regulatory elements in eukaryotic genomes, leaving open the fundamental question of whether these models learn sequence-level features across whole genomes. We introduce LAMBDA, a benchmark designed to rigorously evaluate genome language model embeddings through phage-bacteria sequence discrimination across four categories of increasing complexity: probing tasks, fine-tuning assessments, diagnostic tests, and genome-wide prophage detection. Our comprehensive analysis of current genomic language models provides novel insights into the importance of training data quality relative to model size, the need for domain-specific training, and the application of genomic language models for detecting prophage sequences. This benchmark represents a challenging genomic annotation task in the bacterial domain and addresses a key computational problem with direct relevance to microbiology and medicine.

DNA language model↗
PubMed2004

Biotechnology and vaccines: application of functional genomics to Neisseria meningitidis and other bacterial pathogens.

Since its introduction, vaccinology has been very effective in preventing infectious diseases. However, in several cases, the conventional approach to identify protective antigens, based on biochemical, immunological and microbiological methods, has failed to deliver successful vaccine candidates against major bacterial pathogens. The recent development of powerful biotechnological tools applied to genome-based approaches has revolutionized vaccine development, biological research and clinical diagnostics. The availability of a genome provides an inclusive virtual catalogue of all the potential antigens from which it is possible to select the molecules that are likely to be more effective. Here, we describe the use of "reverse vaccinology", which has been successful in the identification of potential vaccines candidates against Neisseria meningitidis serogroup B and review the use of functional genomics approaches as DNA microarrays, proteomics and comparative genome analysis for the identification of virulence factors and novel vaccine candidates. In addition, we describe the potential of these powerful technologies in understanding the pathogenesis of various bacteria.

Bacterial Vaccines↗