Biomedical subjects

Genomics

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PubMed2004

Detection of low level genomic alterations by comparative genomic hybridization based on cDNA micro-arrays.

MOTIVATION: The accumulation of genomic alterations is an important process in tumor formation and progression. Comparative genomic hybridization performed on cDNA arrays (cDNA aCGH) is a common method to investigate the genomic alterations on a genome-wide scale. However, when detecting low-level DNA copy number changes this technology requires the use of noise reduction strategies due to a low signal to noise ratio. RESULTS: Currently a running average smoothing filter is the most frequently used noise reduction strategy. We analyzed this strategy theoretically and experimentally and found that it is not sensitive to very low level genomic alterations. The presence of systematic errors in the data is one of the main reasons for this failure. We developed a novel algorithm which efficiently reduces systematic noise and allows for the detection of low-level genomic alterations. The algorithm is based on comparison of the biological relevant data to data from so-called self-self hybridizations, additional experiments which contain no biological information but contain systematic errors. We find that with our algorithm the effective resolution for +/-1 DNA copy number changes is about 2 Mb. For copy number changes larger than three the effective resolution is on the level of single genes.

Algorithms↗

PubMed2026

Advances in genomics-driven genetic decoding and genomic design breeding in tomato.

Tomatoes are highly nutritious and represent one of the important vegetable fruits worldwide. Both historically and moving forward, genetic decoding and precision breeding remain fundamental to tomato improvement. Here, we summarize pivotal advances in decoding tomato genomes across domestication, improvement and evolution processes and provide a perspective on future breeding through precision design. In-depth population genetic studies have revealed how artificial selection systematically prioritized yield-related alleles at the cost of narrowing genetic diversity, especially at flavor-related loci-highlighting the urgent need to reconcile these trade-offs. Comparative genomics across species, viewed through an evolutionary lens, has uncovered critical insights into functional genes, deepening our understanding of the genetic architecture and regulatory mechanisms underlying key traits. Collectively, these advances have enabled precise identification and functional characterization of key genetic elements, paving the way for systematic redomestication of tomato through precision genomic design. Looking ahead, more efficient and precise breeding strategies will be required to accelerate genetic gains in tomato in the coming decades. The integration of recent genomic advances, coupled with genomic selection and artificial intelligence, into genomic design breeding offers a transformative framework, unlocking unprecedented opportunities for developing highly flavorful and consumer-customized tomato varieties.

Journal Article↗

PubMed2005

Evaluation of 3 methods of whole-genome amplification for subsequent metaphase comparative genomic hybridization.

A common aim in cancer research is to investigate mechanisms of malignant progression by genetic analysis of key stages, including pre-malignancy, microinvasion, and micrometastases. As such lesions are small and require microdissection from clinical samples, the amount of DNA that can be recovered is limited and frequently inadequate for commonly used techniques of genomic analysis, such as comparative genomic hybridization (CGH). There is a critical requirement for techniques of whole-genome amplification that minimize representation bias in the amplified sample. Several techniques have been described, although their relative suitability for CGH has not been examined adequately. Here we compare the abilities of degenerate oligonucleotide-primed PCR (DOP-PCR), multiple-strand displacement amplification (MDA), and balanced PCR accurately to amplify limited amounts of template DNA for use in CGH. Amplification by DOP-PCR and MDA, but not balanced PCR faithfully preserved the original genomic content following amplification, as evidenced by generally concordant CGH copy number karyograms. Whereas the amplification products of DOP-PCR were immediately available for labeling and hybridization, the products of MDA required a further digestion step to produce optimal-sized probes for CGH. Moreover, MDA was less reliable overall than DOP-PCR at the lowest starting amount of 10 pg of template DNA. We conclude that DOP-PCR is the method of choice for whole-genome amplification of minute quantities of DNA to enable global genomic analysis to be performed on limited clinical samples.

Metaphase↗

PubMed1984

A comparison of genomic homologies among the coxsackievirus B group: use of fragments of the cloned coxsackievirus B3 genome as probes.

Using fragments of the cloned coxsackievirus B3 (CB3) genome as hybridization probes, regions in the CB3 genome with widely varying homology to heterologous CB serotype genomes have been demonstrated. A region composed of about 3.2 to 3.5 kbp of the CB3 genome in the 5' half of the map is essentially unique to CB3 and exhibits little or no homology with heterologous CB serotype RNAs. The non-coding terminal 5' end of the CB3 genome is well-conserved among the CB serotype RNAs tested. A sequence in the P3 region of the CB3 genome is also well conserved among heterologous CB serotypes.

Cloning, Molecular↗

PubMed1990

The genome type of human parvovirus B19 strains isolated in Japan during 1981 differs from types detected in 1986 to 1987: a correlation between genome type and prevalence.

The genome DNAs of 12 strains of human parvovirus B19, isolated in Japan at two different times, 1981 and 1986 to 1987, were molecularly cloned in the plasmid pUC18. The cloned B19 DNAs were analysed by cleaving with restriction endonucleases, and were classified into several groups by genome type. The restriction endonuclease cutting patterns of B19 strains isolated during 1981 were similar to that of the group IV genome type, and the patterns of those isolated later were similar to that of group II, suggesting a correlation between the genome type and the prevalence. We conclude that the prevalences of B19 infection in Japan during 1981 and in 1986 to 1987 were caused by viruses differing in genome type, and that B19 viruses with similar genome types disseminated widely in Japan during each prevalence.

DNA, Viral↗

PubMed1991

The genome of human herpesvirus 6: maps of unit-length and concatemeric genomes for nine restriction endonucleases.

More than 50 fragments resulting from complete digestion of the DNA of human herpesvirus 6 (HHV-6, strain U1102) with BamHI, EcoRI, HindIII, KpnI, NruI, SalI or SmaI have been isolated as clones in M13, plasmid, cosmid and lambda vectors. Using these clones, maps have been constructed for the fragments produced by nine restriction enzymes from unit-length virus genomes and from their concatemeric precursors. The unit-length genome is a linear, double-stranded molecule of 161.5 kbp composed of a central segment of a largely unique sequence of 141 kbp (U) with a sequence of 10 kbp duplicated in the same orientation at both 'left' and 'right' genomic termini (i.e. 'left' and 'right' copies of the direct repeat; DRL and DRR). Adopting as standard an orientation in which the major capsid protein gene is 'left' of the gene for alkaline exonuclease, then the 'right' genome termini and DRL. U junctions occur close to or within repetitive (GGGTTA)n sequences. Repetitions of short sequence motifs are present in at least two other regions of the genome. One of these regions consists of a simple repeat (TC/G) of approximately 1.5 kbp in length and is unstable as clones in bacterial vectors. The second region is stably maintained in such vectors and consists of a tandem array of at least 25 copies of a 110 bp sequence containing a single KpnI site. Comparisons of fragments arising from unit-length DNA with those from virus DNA from the nuclei of infected cells have shown that the concatemeric junctions in intracellular DNA contain head-to-tail dimers of the terminal duplications (i.e. ...U1.DRR1.DRL2.U2...). The gross structure established here for the genome from the U1102 isolate of HHV-6 resembles closely that suggested by Pellett and his colleagues for the Z29 isolate and differs from that of the five previously characterized human herpesviruses. This structure of HHV-6 DNA bears a superficial resemblance to that proposed for DNA from channel catfish virus and equine cytomegalovirus.

Base Sequence↗

PubMed1997

Sequence-specific epigenetic effects of the maternal somatic genome on developmental rearrangements of the zygotic genome in Paramecium primaurelia.

In ciliates, the germ line genome is extensively rearranged during the development of the somatic macronucleus from a mitotic product of the zygotic nucleus. Germ line chromosomes are fragmented in specific regions, and a large number of internal sequence elements are eliminated. It was previously shown that transformation of the vegetative macronucleus of Paramecium primaurelia with a plasmid containing a subtelomeric surface antigen gene can affect the processing of the homologous germ line genomic region during development of a new macronucleus in sexual progeny of transformed clones. The gene and telomere-proximal flanking sequences are deleted from the new macronuclear genome, although the germ line genome remains wild type. Here we show that plasmids containing nonoverlapping segments of the same genomic region are able to induce similar terminal deletions; the locations of deletion end points depend on the particular sequence used. Transformation of the maternal macronucleus with a sequence internal to a macronuclear chromosome also causes the occurrence of internal deletions between short direct repeats composed of alternating thymines and adenines. The epigenetic influence of maternal macronuclear sequences on developmental rearrangements of the zygotic genome thus appears to be both sequence specific and general, suggesting that this trans-nucleus effect is mediated by pairing of homologous sequences.

Animals↗

PubMed2004

Genome-wide array-based comparative genomic hybridization of diffuse large B-cell lymphoma: comparison between CD5-positive and CD5-negative cases.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma and exhibits aggressive and heterogeneous clinical behavior. To genetically characterize DLBCL, we established our own array-based comparative genomic hybridization and analyzed a total of 70 cases [26 CD-positive (CD5+) DLBCL and 44 CD5-negative (CD5-) DLBCL cases]. Regions of genomic aberrations observed in >20% of cases of both the CD5+ and CD5- groups were gains of 1q21-q31, 1q32, 3p25-q29, 5p13, 6p21-p25, 7p22-q31, 8q24, 11q23-q24, 12q13-q21, 16p13, 18, and X and losses of 1p36, 3p14, 6q14-q25, 6q27, 9p21, and 17p11-p13. Because CD5 expression marks a subgroup with poor prognosis, we subsequently analyzed genomic gains and losses of CD5+ DLBCL compared with those of CD5-. Although both groups showed similar genomic patterns of gains and losses, gains of 10p14-p15 and 19q13 and losses of 1q43-q44 and 8p23 were found to be characteristic of CD5+ DLBCL. By focusing on the gain of 13q21-q34 and loss of 1p34-p36, we were also able to identify prognostically distinct subgroups among CD5+ DLBCL cases. These results suggest that array-based comparative genomic hybridization analysis provides a platform of genomic aberrations of DLBCL both common and specific to clinically distinct subgroups.

CD5 Antigens↗

PubMed2002

A whole-genome linkage scan suggests several genomic regions potentially containing quantitative trait Loci for osteoporosis.

Osteoporosis is an important health problem, particularly in the elderly women. Bone mineral density (BMD) is a major determinant of osteoporosis. For a sample of 53 pedigrees that contain 1249 sibling pairs, 1098 grandparent-grandchildren pairs, and 2589 first cousin pairs, we performed a whole- genome linkage scan using 380 microsatellite markers to identify genomic regions that may contain quantitative trait loci (QTL) of BMD. Each pedigree was ascertained through a proband with BMD values belonging to the bottom 10% of the population. We conducted two-point and multipoint linkage analyses. Several potentially important genomic regions were suggested. For example, the genomic region near the marker D10S1651 may contain a QTL for hip BMD variation (with two-point analysis LOD score of 1.97 and multipoint analysis LOD score of 2.29). The genomic regions near the markers D4S413 and D12S1723 may contain QTLs for spine BMD variation (with two-point analysis LOD score of 2.12 and 2.17 and multipoint analysis LOD score of 3.08 and 2.96, respectively). The genomic regions identified in this and some earlier reports are compared for exploration in extension studies with larger samples and/or denser markers for confirmation and fine mapping to eventually identify major functional genes involved in osteoporosis.

Bone Density↗

PubMed2003

[Genome-wide non-sequencing strategies for bacterial genome comparison: the necessity and an analysis of the variable bacterial world].

A tremendous success in bacterial genome sequencing has been achieved during the recent years; it resulted in making available, for analysis, multiple sequences of different bacterial genomes, including such pathogens as causative agents of syphilis, typhus, and tuberculosis as well as such organisms like archaebacterias living under extreme conditions. A comparative analysis of bacterial genomes leads to conclusions, which have a general biological value, and, in particular, to the conclusions about mechanisms and evolution rate as well as about the variability of genomes and interrelation between organisms and their habitat. On the other hand, the analysis reveals specific features of separate bacterial species responsible for their pathogenicity and ability to avoid the destruction of the host immune system as well as for adaptation to exist within a certain ecological niche. However, the variability of bacterial genomes is so high that methods, which enable to evaluate the variability without full genome sequencing, are needed to depict adequately the evolution and ecological characteristics of the prokaryotic world and to develop new effective therapeutics and diagnostic tools. The survey covers two approaches to such comparative analysis, i.e. DNA arrays and subtractive hybridization. The advantages and disadvantages of each approach are discussed and the necessity in a new approach combining the positive features of the two mentioned approaches is substantiated.

DNA, Bacterial↗

PubMed2001

Comparative genomics of lactococcal phages: insight from the complete genome sequence of Lactococcus lactis phage BK5-T.

Lactococcus lactis phage BK5-T and Streptococcus thermophilus phage Sfi21, two cos-site temperate Siphoviridae with 40-kb genomes, share an identical genome organization, sequence similarity at the amino acid level over about half of their genomes, and nucleotide sequence identity of 60% over the DNA packaging and head morphogenesis modules. Siphoviridae with similarly organized genomes and substantial protein sequence similarity were identified in several genera of low-GC-content Gram-positive bacteria. These phages demonstrated a gradient of relatedness ranging from nucleotide sequence similarity to protein sequence similarity to gene map similarity over the DNA packaging and head morphogenesis modules. Interestingly, the degree of relatedness was correlated with the evolutionary distance separating their bacterial hosts. These observations suggest elements of vertical evolution in phages. The structural genes from BK5-T shared no sequence relationships with corresponding genes/proteins from lactococcal phages belonging to distinct lactococcal phage species, including phage sk1 (phage species 936) that showed a closely related gene map. Despite a clearly distinct genome organization, lactococcal phages sk1 and c2 showed nine sequence-related proteins. Over the early gene cluster phage BK5-T shared nine regions of high nucleotide sequence similarity, covering at most two adjacent genes, with lactococcal phage r1t (phage species P335). Over the structural genes, the closest relatives of phage r1t were not lactococcal phages belonging to other phage species, but Siphoviridae from Mycobacteria (high-GC-content Gram-positive bacteria). Evidence for recent horizontal gene transfer between distinct phage species was obtained for dairy phages, but these transfers were limited to phages infecting the same bacterial host species.

Computational Biology↗

PubMed2004

Statistical evidence for a more than 800-million-year-old evolutionarily conserved genomic region in our genome.

Identification of conserved genomic regions between different species is crucial for the reconstruction of their last common ancestor. Indeed, such regions of conservation in today's species (if not due to chance) may either constitute stigmata of an ancestrally conserved region or result from a series of independent convergent events. The more phylogenetically distant the compared species are, the more we expect rearrangements and thus difficulties in finding regions of conservation. Here we decipher with strong evidence conserved genomic regions between vertebrates (human and zebrafish) and arthropods (Drosophila and Anopheles). This work includes a robust phylogenetic analysis in conjunction with a stringent statistical testing that allowed the significant rejection of a "by chance" conservation hypothesis. The conservation of gene clusters across four different species from two phylogenetically distant groups makes the hypothesis of an ancestral conservation more likely and parsimonious than the hypothesis of individual convergent events. This result shows that, in spite of more than 800 million years of divergence and evolution from their last common ancestor, we can still reveal stigmata of conservation between all these species. The last common ancestor of zebrafish, human, Drosophila, and Anopheles is the common ancestor of all protostomes and deuterostomes known as "Urbilateria." This study reveals clusters of probably ancestrally conserved genes and constitutes an advance toward the reconstruction of the genome of Urbilateria. Thus this work allows a better understanding of the evolutionary history of metazoan genomes, including our genome.

Animals↗

PubMed2004

Sugarcane bacilliform virus encapsidates genome concatamers and does not appear to integrate into the Saccharum officinarum genome.

Sugarcane bacilliform virus (SCBV) DNA molecules larger than the complete genome length of 7.6 kbp were detected in infected plants and in virions. We have confirmed that these high molecular weight nucleic acids were open circular DNA and viral in origin. Due to their open circular conformation, accurate size determination of the DNA molecules was not possible using conventional electrophoresis. Using field inversion gel electrophoresis (FIGE), however, the DNA appeared to increase in genome size increments, with sizes ranging from 1 to 4 genomes (31 kbp) detected. The DNA was packaged into virions, which may explain the observation of purified virions with lengths corresponding to one, two or three times the modal length of 130 nm. The DNA products were possibly concatamers formed during replication as a result of a terminal overlap on the sense strand, and were shown to be overlapped individual genome-length molecules and not covalently-bonded continuous DNA strands. Southern analysis indicated that SCBV sequences are not integrated into the sugarcane genome and that the high molecular weight DNA observed in the sugarcane accessions analysed represents SCBV concatamers.

Badnavirus↗

PubMed2004

Comparative map and trait viewer (CMTV): an integrated bioinformatic tool to construct consensus maps and compare QTL and functional genomics data across genomes and experiments.

In the past few decades, a wealth of genomic data has been produced in a wide variety of species using a diverse array of functional and molecular marker approaches. In order to unlock the full potential of the information contained in these independent experiments, researchers need efficient and intuitive means to identify common genomic regions and genes involved in the expression of target phenotypic traits across diverse conditions. To address this need, we have developed a Comparative Map and Trait Viewer (CMTV) tool that can be used to construct dynamic aggregations of a variety of types of genomic datasets. By algorithmically determining correspondences between sets of objects on multiple genomic maps, the CMTV can display syntenic regions across taxa, combine maps from separate experiments into a consensus map, or project data from different maps into a common coordinate framework using dynamic coordinate translations between source and target maps. We present a case study that illustrates the utility of the tool for managing large and varied datasets by integrating data collected by CIMMYT in maize drought tolerance research with data from public sources. This example will focus on one of the visualization features for Quantitative Trait Locus (QTL) data, using likelihood ratio (LR) files produced by generic QTL analysis software and displaying the data in a unique visual manner across different combinations of traits, environments and crosses. Once a genomic region of interest has been identified, the CMTV can search and display additional QTLs meeting a particular threshold for that region, or other functional data such as sets of differentially expressed genes located in the region; it thus provides an easily used means for organizing and manipulating data sets that have been dynamically integrated under the focus of the researcher's specific hypothesis.

Adaptation, Physiological↗

PubMed2006

GC content and genome length in Chargaff compliant genomes.

Musto et al. [H. Musto, H. Naya, A. Zavala, H. Romero, F. Alvarez-Valin, G. Bernardi, Genomic GC level, optimal growth temperature, and genome size in prokaryotes, Biochem. Biophys. Res. Commun. 347 (2006) 1-3] recently reported a linear correlation between GC content and genome length. The regression model was heteroscedactic which suggested that the relationship might be more clearly defined. Alternative regression models (R(2)>0.95) were fitted to a set of over 900 sequences compliant with Chargaff's second parity rule. The new models suggest that the relationship between GC content and genome length is more complex than was originally suggested. While similar models can be derived for non-Chargaff compliant genomes, their interpretation is likely to be more difficult.

Base Composition↗

PubMed2005

Comparative genome analysis of Bacillus cereus group genomes with Bacillus subtilis.

Genome features of the Bacillus cereus group genomes (representative strains of Bacillus cereus, Bacillus anthracis and Bacillus thuringiensis sub spp. israelensis) were analyzed and compared with the Bacillus subtilis genome. A core set of 1381 protein families among the four Bacillus genomes, with an additional set of 933 families common to the B. cereus group, was identified. Differences in signal transduction pathways, membrane transporters, cell surface structures, cell wall, and S-layer proteins suggesting differences in their phenotype were identified. The B. cereus group has signal transduction systems including a tyrosine kinase related to two-component system histidine kinases from B. subtilis. A model for regulation of the stress responsive sigma factor sigmaB in the B. cereus group different from the well studied regulation in B. subtilis has been proposed. Despite a high degree of chromosomal synteny among these genomes, significant differences in cell wall and spore coat proteins that contribute to the survival and adaptation in specific hosts has been identified.

Bacillus anthracis↗

PubMed2026

First nationwide full-genome characterisation of human-derived Andes virus in Chile: a retrospective genomic epidemiology study.

BACKGROUND: Andes virus (ANDV) is the only hantavirus known to transmit between humans and causes hantavirus cardiopulmonary syndrome in Chile and Argentina. In Chile, ANDV genomic diversity remains incompletely characterised. This study aimed to characterise the genetic diversity, geographical structure, and molecular signatures of ANDV using human clinical samples collected over a 13-year period (2011-24). METHODS: We conducted a retrospective genomic epidemiology study of ANDV infections in Chile. Clinical samples from patients with confirmed ANDV, collected between March 9, 2011, and June 27, 2024, were analysed and sequenced. Clinical and epidemiological data were obtained from diagnostic laboratories and surveillance programmes. Consensus sequences for the S, M, and L segments were generated, and genetic clustering and divergence were assessed using phylogenetic inference and variant calling. FINDINGS: We analysed clinical samples from 58 infected individuals and identified two major genomic variants of ANDV with distinct geographical distributions, defined by regionally structured patterns of nucleotide and amino acid substitutions across the S, M, and L segments: ANDV Chi-North (central Chile) and ANDV-South (southern Chile). No consistent clustering by clinical severity was observed, and no recurrent non-synonymous substitutions were uniquely associated with severe disease. Substitutions previously associated with person-to-person transmission in outbreaks in Argentina were not consistently observed in Chilean sequences, including in four person-to-person transmission cases. Although some substitutions described in ANDV-like viruses were present in the Chi-North lineage, this lineage remained phylogenetically distinct and geographically restricted to central Chile. INTERPRETATION: To our knowledge, this study provides the first nationwide genomic characterisation of human-derived ANDV in Chile. The identification of geographically structured variants indicates that ANDV diversity in Chile is driven by regional diversification rather than clinical outcome. The absence of consistent amino acid signatures associated with disease severity or person-to-person transmission suggests that these phenotypes are unlikely to be explained by viral genetic variation alone. These findings refine current understanding of ANDV evolution and highlight the need for continued integrated genomic surveillance in endemic regions. FUNDING: Agencia Nacional de Investigación y Desarrollo de Chile and National Institutes of Health.

Humans↗

PubMed2006

The ABC's of comparative genomics in the Brassicaceae: building blocks of crucifer genomes.

In this review we summarize recent advances in our understanding of phylogenetics, polyploidization and comparative genomics in the family Brassicaceae. These findings pave the way for a unified comparative genomic framework. We integrate several of these findings into a simple system of 24 conserved chromosomal blocks (labeled A-X). The naming, order, orientation and color-coding of these blocks are based on their positions in a proposed ancestral karyotype (n=8), rather than by their position in the reduced genome of Arabidopsis thaliana (n=5). We show how these crucifer building blocks can be rearranged to model the genome structures of A. thaliana, Arabidopsis lyrata, Capsella rubella and Brassica rapa. A framework for comparison between species is timely because several crucifer genome-sequencing projects are underway.

Brassicaceae↗