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PubMed2025

Chromosomal genome assembly resolves drug resistance loci in the parasitic nematode Teladorsagia circumcincta.

The parasitic nematode Teladorsagia circumcincta is one of the most important pathogens of sheep and goats in temperate climates worldwide and can rapidly evolve resistance to drugs used to control it. To understand the genetics of drug resistance, we have generated a highly contiguous genome assembly for the UK T. circumcincta isolate, MTci2. Assembly using PacBio long-reads and Hi-C long-molecule scaffolding together with manual curation resulted in a 573 Mb assembly (N50 = 84 Mb, total scaffolds = 1,286) with five autosomal and one sex-linked chromosomal-scale scaffolds consistent with its karyotype. The genome resource was further improved via annotation of 22,948 genes, with manual curation of over 3,200 of these, resulting in a robust and near complete resource (96.3% complete protein BUSCOs) to support basic and applied research on this important veterinary pathogen. Genome-wide analyses of drug resistance, combining evidence from three distinct experiments, identified selection around known candidate genes for benzimidazole, levamisole and ivermectin resistance, as well as novel regions associated with ivermectin and moxidectin resistance. These insights into contemporary and historic genetic selection further emphasise the importance of contiguous genome assemblies in interpreting genome-wide genetic variation associated with drug resistance and identifying key loci to prioritise in developing diagnostic markers of anthelmintic resistance to support parasite control.

Animals↗
PubMed1993

Use of an ordered cosmid library to deduce the genomic organization of Mycobacterium leprae.

In an attempt to unify the genetic and biological research on Mycobacterium leprae, the aetiological agent of leprosy, a cosmid library was constructed and then ordered by a combination of fingerprinting and hybridization techniques. The genome of M. leprae is represented by four contigs of overlapping clones which, together, account for nearly 2.8Mb of DNA. Several arguments suggest that the gaps between the contigs are small in size and that virtually complete coverage of the chromosome has been obtained. All of the cloned M. leprae genes have been positioned on the contig maps together with the 29 copies of the dispersed repetitive element, RLEP. These have been classified into four groups on the basis of differences in their organization. Several key housekeeping genes were identified and mapped by hybridization with heterologous probes, and the current genome map of this uncultivable pathogen comprises 72 loci.

Chromosome Mapping↗
PubMed2001

Genetic and physical mapping in mosquitoes: molecular approaches.

The genetic background of individual mosquito species and populations within those species influences the transmission of mosquito-borne pathogens to humans. Technical advances in contemporary genomics are contributing significantly to the detailed genetic analysis of this mosquito-pathogen interaction as well as all other aspects of mosquito biology, ecology, and evolution. A variety of DNA-based marker types are being used to develop genetic maps for a number of mosquito species. Complex phenotypic traits such as vector competence are being dissected into their discrete genetic components, with the intention of eventually using this information to develop new methods to prevent disease transmission. Both genetic- and physical-mapping techniques are being used to define and compare genome architecture among and within mosquito species. The integration of genetic- and physical-map information is providing a sound framework for map-based positional cloning of target genes of interest. This review focuses on advances in genome-based analysis and their specific applications to mosquitoes.

Animals↗
PubMed2006

The role of transposable element clusters in genome evolution and loss of synteny in the rice blast fungus Magnaporthe oryzae.

BACKGROUND: Transposable elements are abundant in the genomes of many filamentous fungi, and have been implicated as major contributors to genome rearrangements and as sources of genetic variation. Analyses of fungal genomes have also revealed that transposable elements are largely confined to distinct clusters within the genome. Their impact on fungal genome evolution is not well understood. Using the recently available genome sequence of the plant pathogenic fungus Magnaporthe oryzae, combined with additional bacterial artificial chromosome clone sequences, we performed a detailed analysis of the distribution of transposable elements, syntenic blocks, and other features of chromosome 7. RESULTS: We found significant levels of conserved synteny between chromosome 7 and the genomes of other filamentous fungi, despite more than 200 million years of divergent evolution. Transposable elements are largely restricted to three clusters located in chromosomal segments that lack conserved synteny. In contradiction to popular evolutionary models and observations from other model organism genomes, we found a positive correlation between recombination rate and the distribution of transposable element clusters on chromosome 7. In addition, the transposable element clusters are marked by more frequent gene duplications, and genes within the clusters have greater sequence diversity to orthologous genes from other fungi. CONCLUSION: Together, these data suggest that transposable elements have a profound impact on the M. oryzae genome by creating localized segments with increased rates of chromosomal rearrangements, gene duplications and gene evolution.

Base Sequence↗
PubMed2003

Discrimination among Listeria monocytogenes isolates using a mixed genome DNA microarray.

Listeria monocytogenes can cause serious illness in humans, usually following the ingestion of contaminated food. Epidemiologic investigation requires identification of specific isolates, usually done by a combination of serotyping and subtyping using pulsed-field gel electrophoresis (PFGE). DNA microarrays provide a new format to resolve genetic differences among isolates and, unlike PFGE, to identify specific genes associated with the infecting pathogen. A 585 probe, mixed genome microarray was constructed and 24 strains of L. monocytogenes were hybridized to the array. Microarray analysis allowed discrimination among L. monocytogenes isolates within a serotype and obtained from similar geographic and epidemiologic sources. Importantly, the microarray results preserved previously described phylogenetic relationships between major serogroups and, in a limited comparison, agreed with PFGE subtypes. The association of individual probes with isolates allowed identification of specific genes. Sequencing of 10 polymorphic probes identified nine matches with previously described bacterial genes including several suspected virulence factors. These results demonstrate that mixed genomic microarrays are useful for differentiating among closely related L. monocytogenes isolates and identifying genetic markers that can be used in epidemiologic and possibly pathogenesis studies.

Animals↗
PubMed1999

Sequence characterization of two new members of a multi-gene family in Serpulina hyodysenteriae (B204) with homology to a 39 kDa surface exposed protein: vspC and D.

Previous cloning and sequencing of clones from a genomic library constructed from Serpulina hyodysenteriae B204 had identified a tandem pair of open reading frames, identified as vspA and vspB (variable surface protein) expected to encode proteins with homology to ( but not identical with) a 39 kDa surface exposed membrane protein from this animal pathogen. Additional screening of the genomic library was performed to retrieve the remainder of the vspB gene using new oligonucleotide probes based upon the cloned gene sequences. Not only was this goal met but we also discovered two more adjacent and related vsp genes (vspC and vspD) and have completely sequenced them. They are all in a parallel orientation and appear to have a set of similar but distinct regulatory elements that may control separate expression of their open reading frames (ORFs). Thus, there are four contiguous vsp genes which are predicted to encode a family of structurally conserved proteins. The four adjacent open reading frames (ORFs) are of similar size (384-389 codons) and share from 83% to 90% identity in their amino acid sequence. Preliminary data suggests there may be yet another homologous gene copy in a distal location of S. hyodysenteriae that faithfully encodes the 39 kDa surface protein. The organization and homologies of these highly conserved multiple gene copies are discussed.

Amino Acid Sequence↗
PubMed2006

Host-pathogen systems biology.

Unlike traditional biological research that focuses on a small set of components, systems biology studies the complex interactions between a large number of genes, proteins and other elements of biological networks and systems. Host-pathogen systems biology examines the interactions between the components of two distinct organisms, either a microbial or viral pathogen and its animal host or two different microbial species in a community. With the availability of complete genomic sequences of various hosts and pathogens, together with breakthroughs in proteomics, metabolomics and other experimental areas, the investigation of host-pathogen systems on a multitude of levels of detail has come within reach.

Animals↗
PubMed2006

Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome.

Genomic disorders are characterized by the presence of flanking segmental duplications that predispose these regions to recurrent rearrangement. Based on the duplication architecture of the genome, we investigated 130 regions that we hypothesized as candidates for previously undescribed genomic disorders. We tested 290 individuals with mental retardation by BAC array comparative genomic hybridization and identified 16 pathogenic rearrangements, including de novo microdeletions of 17q21.31 found in four individuals. Using oligonucleotide arrays, we refined the breakpoints of this microdeletion, defining a 478-kb critical region containing six genes that were deleted in all four individuals. We mapped the breakpoints of this deletion and of four other pathogenic rearrangements in 1q21.1, 15q13, 15q24 and 17q12 to flanking segmental duplications, suggesting that these are also sites of recurrent rearrangement. In common with the 17q21.31 deletion, these breakpoint regions are sites of copy number polymorphism in controls, indicating that these may be inherently unstable genomic regions.

Chromosome Breakage↗
PubMed2003

Pathogen-induced systemic plant signal triggers DNA rearrangements.

Plant genome stability is known to be affected by various abiotic environmental conditions, but little is known about the effect of pathogens. For example, exposure of maize plants to barley stripe mosaic virus seems to activate transposable elements and to cause mutations in the non-infected progeny of infected plants. The induction by barley stripe mosaic virus of an inherited effect may mean that the virus has a non-cell-autonomous influence on genome stability. Infection with Peronospora parasitica results in an increase in the frequency of somatic recombination in Arabidopsis thaliana; however, it is unclear whether effects on recombination require the presence of the pathogen or represent a systemic plant response. It is also not clear whether the changes in the frequency of somatic recombination can be inherited. Here we report a threefold increase in homologous recombination frequency in both infected and non-infected tissue of tobacco plants infected with either tobacco mosaic virus or oilseed rape mosaic virus. These results indicate the existence of a systemic recombination signal that also results in an increased frequency of meiotic and/or inherited late somatic recombination.

Gene Expression Regulation, Plant↗
PubMed2004

The complete genome and proteome of Mycoplasma mobile.

Although often considered "minimal" organisms, mycoplasmas show a wide range of diversity with respect to host environment, phenotypic traits, and pathogenicity. Here we report the complete genomic sequence and proteogenomic map for the piscine mycoplasma Mycoplasma mobile, noted for its robust gliding motility. For the first time, proteomic data are used in the primary annotation of a new genome, providing validation of expression for many of the predicted proteins. Several novel features were discovered including a long repeating unit of DNA of approximately 2435 bp present in five complete copies that are shown to code for nearly identical yet uniquely expressed proteins. M. mobile has among the lowest DNA GC contents (24.9%) and most reduced set of tRNAs of any organism yet reported (28). Numerous instances of tandem duplication as well as lateral gene transfer are evident in the genome. The multiple available complete genome sequences for other motile and immotile mycoplasmas enabled us to use comparative genomic and phylogenetic methods to suggest several candidate genes that might be involved in motility. The results of these analyses leave open the possibility that gliding motility might have arisen independently more than once in the mycoplasma lineage.

Amino Acid Sequence↗
PubMed2000

New approaches for genotyping of Helicobacter pylori based on amplification of polymorphisms in intergenic DNA regions and at the insertion site of the cag pathogenicity island.

The population of the gastric pathogen Helicobacter pylori shows a high degree of genetic diversity. It is well established that heterogeneity at the isolate level is caused by nucleotide transitions within genes, differences in the gene order, and by genetic instability of single genes as well as of a large virulence-associated genomic DNA region, the cag pathogenicity island (PAI). Analysis of intergenic regions with specific PCR-assays developed in this study, revealed that DNA polymorphisms in the noncoding DNA localized in front of the genes ribA and vacA and at the insertion site of the cag PAI contribute to the genetic diversity of H. pylori and are useful for differentiation of individual isolates. Thirteen individual genotypes were identified by PCR analysis of these polymorphic loci in 487, 241, and 182 clinical H. pylori isolates. Sequence analysis revealed that genetic variability in front of genes ribA and vacA, and in the intergenic region at the PAI insertion site is caused by insertion and deletions of so-far-unknown DNA sequences as well as by parts of the H. pylori IS elements IS605 and IS606, respectively. The new genotypes identified could be used to differentiate antrum and corpus isolates from the same patients. Their combination with vacA allele subtypes and with the cagA status allowed to differentiate 140 isolates in 51 subtypes. In 36 cases the corresponding genotype patterns were isolate specific. In summary, the results confirm that DNA polymorphisms in intergenic regions contribute to the genetic diversity of H. pylori. Although individual H. pylori genotypes were not associated with peptic ulcer disease, the PCR-based approaches for their detection developed here should be of use for further investigation of genetic diversity in H. pylori and for epidemiological purposes.

Adult↗
PubMed1999

A random survey of the Cryptosporidium parvum genome.

Cryptosporidium parvum is an obligate intracellular pathogen responsible for widespread infections in humans and animals. The inability to obtain purified samples of this organism's various developmental stages has limited the understanding of the biochemical mechanisms important for C. parvum development or host-parasite interaction. To identify C. parvum genes independent of their developmental expression, a random sequence analysis of the 10.4-megabase genome of C. parvum was undertaken. Total genomic DNA was sheared by nebulization, and fragments between 800 and 1,500 bp were gel purified and cloned into a plasmid vector. A total of 442 clones were randomly selected and subjected to automated sequencing by using one or two primers flanking the cloning site. In this way, 654 genomic survey sequences (GSSs) were generated, corresponding to >320 kb of genomic sequence. These sequences were assembled into 408 contigs containing >250 kb of unique sequence, representing approximately 2.5% of the C. parvum genome. Comparison of the GSSs with sequences in the public DNA and protein databases revealed that 107 contigs (26%) displayed similarity to previously identified proteins and rRNA and tRNA genes. These included putative genes involved in the glycolytic pathway, DNA, RNA, and protein metabolism, and signal transduction pathways. The repetitive sequence elements identified included a telomere-like sequence containing hexamer repeats, 57 microsatellite-like elements composed of dinucleotide or trinucleotide repeats, and a direct repeat sequence. This study demonstrates that large-scale genomic sequencing is an efficient approach to analyze the organizational characteristics and information content of the C. parvum genome.

Amino Acid Sequence↗
PubMed2003

Genome-level evolution of resistance genes in Arabidopsis thaliana.

Pathogen resistance genes represent some of the most abundant and diverse gene families found within plant genomes. However, evolutionary mechanisms generating resistance gene diversity at the genome level are not well understood. We used the complete Arabidopsis thaliana genome sequence to show that most duplication of individual NBS-LRR sequences occurs at close physical proximity to the parent sequence and generates clusters of closely related NBS-LRR sequences. Deploying the statistical strength of phylogeographic approaches and using chromosomal location as a proxy for spatial location, we show that apparent duplication of NBS-LRR genes to ectopic chromosomal locations is largely the consequence of segmental chromosome duplication and rearrangement, rather than the independent duplication of individual sequences. Although accounting for a smaller fraction of NBS-LRR gene duplications, segmental chromosome duplication and rearrangement events have a large impact on the evolution of this multigene family. Intergenic exchange is dramatically lower between NBS-LRR sequences located in different chromosome regions as compared to exchange between sequences within the same chromosome region. Consequently, once translocated to new chromosome locations, NBS-LRR gene copies have a greater likelihood of escaping intergenic exchange and adopting new functions than do gene copies located within the same chromosomal region. We propose an evolutionary model that relates processes of genome evolution to mechanisms of evolution for the large, diverse, NBS-LRR gene family.

Arabidopsis↗
PubMed2005

The genome sequence of Salmonella enterica serovar Choleraesuis, a highly invasive and resistant zoonotic pathogen.

Salmonella enterica serovar Choleraesuis (S. Choleraesuis), a highly invasive serovar among non-typhoidal Salmonella, usually causes sepsis or extra-intestinal focal infections in humans. S. Choleraesuis infections have now become particularly difficult to treat because of the emergence of resistance to multiple antimicrobial agents. The 4.7 Mb genome sequence of a multidrug-resistant S. Choleraesuis strain SC-B67 was determined. Genome wide comparison of three sequenced Salmonella genomes revealed that more deletion events occurred in S. Choleraesuis SC-B67 and S.Typhi CT18 relative to S. Typhimurium LT2. S. Choleraesuis has 151 pseudogenes, which, among the three Salmonella genomes, include the highest percentage of pseudogenes arising from the genes involved in bacterial chemotaxis signal-transduction pathways. Mutations in these genes may increase smooth swimming of the bacteria, potentially allowing more effective interactions with and invasion of host cells to occur. A key regulatory gene of TetR/AcrR family, acrR, was inactivated through the introduction of an internal stop codon resulting in overexpression of AcrAB that appears to be associated with ciprofloxacin resistance. While lateral gene transfer providing basic functions to allow niche expansion in the host and environment is maintained during the evolution of different serovars of Salmonella, genes providing little overall selective benefit may be lost rapidly. Our findings suggest that the formation of pseudogenes may provide a simple evolutionary pathway that complements gene acquisition to enhance virulence and antimicrobial resistance in S. Choleraesuis.

Bacterial Proteins↗
PubMed1998

Selective generation of chromosomal cosmid libraries within the Trypanosoma cruzi genome project.

From a total genomic cosmid library of the pathogen Trypanosoma cruzi, specific sublibraries of the smallest four chromosomes were isolated by hybridization of the respective chromosomal bands obtained from pulsed-field gels. These libraries form the basis for initial mapping analyses that should provide information useful for both the ongoing physical mapping of the entire genome and eventual sequence analyses. Selectivity of the procedure was high with 75% to 92%, although cross-hybridization had to be expected from ubiquitous DNA features, such as centromeric and telomeric sequences, and other regions homologous between individual chromosomes. Overall, the number of identified clones was slightly higher than expected but well within the intrinsic experimental variation considering the uncertainty about the exact genome size, the variability in clonability and the higher frequency of repeat sequences in larger chromosomes. Chromosome III- and IV-specific cosmids were analyzed on Southern blots of chromosomal separations. For strain CL Brener, all clones tested exhibited cross-hybridization to a homologous chromosome larger than 1 Mbp, supporting the assumption of the respective chromosome couple being diploid pairs.

Animals↗
PubMed1995

The complete genome structure and phylogenetic relationship of infectious hematopoietic necrosis virus.

Infectious hematopoietic necrosis virus (IHNV), a member of the family Rhabdoviridae, causes a severe disease with high mortality in salmonid fish. The nucleotide sequence (11,131 bases) of the entire genome was determined for the pathogenic WRAC strain of IHNV from southern Idaho. This allowed detailed analysis of all 6 genes, the deduced amino acid sequences of their encoded proteins, and important control motifs including leader, trailer and gene junction regions. Sequence analysis revealed that the 6 virus genes are located along the genome in the 3' to 5' order: nucleocapsid (N), polymerase-associated phosphoprotein (P or M1), matrix protein (M or M2), surface glycoprotein (G), a unique non-virion protein (NV) and virus polymerase (L). The IHNV genome RNA was found to have highly complementary termini (15 of 16 nucleotides). The gene junction regions display the highly conserved sequence UCURUC(U)7RCCGUG(N)4CACR (in the vRNA sense), which includes the typical rhabdovirus transcription termination/polyadenylation signal and a novel putative transcription initiation signal. Phylogenetic analysis of M, G and L protein sequences allowed insights into the evolutionary and taxonomic relationship of rhabdoviruses of fish relative to those of insects or mammals, and a broader sense of the relationship of non-segmented negative-strand RNA viruses. Based on these data, a new genus, piscivirus, is proposed which will initially contain IHNV, viral hemorrhagic septicemia virus and Hirame rhabdovirus.

Animals↗
PubMed2024

Genomics-informed neuropsychiatric care for neurodevelopmental disorders: Results from a multidisciplinary clinic.

PURPOSE: Patients with neurodevelopmental disorders (NDDs) have high rates of neuropsychiatric comorbidities. Genomic medicine may help guide care because pathogenic variants are identified in up to 50% of patients with NDDs. We evaluate the impact of a genomics-informed, multidisciplinary, neuropsychiatric specialty clinic on the diagnosis and management of patients with NDDs. METHODS: We performed a retrospective study of 316 patients from the University of California, Los Angeles Care and Research in Neurogenetics Clinic, a genomics-informed multidisciplinary clinic. RESULTS: Among the 246 patients who underwent genetic testing, 41.8% had a pathogenic or likely pathogenic variant. Patients had 62 different genetic diagnoses, with 12 diagnoses shared by 2 or more patients, whereas 50 diagnoses were found in only single patients. Genetic diagnosis resulted in direct changes to clinical management in all patients with a pathogenic or likely pathogenic variant, including cascade testing (30.6%), family counseling (22.2%), medication changes (13.9%), clinical trial referral (2.8%), medical surveillance (30.6%), and specialty referrals (69.4%). CONCLUSIONS: A genomics-informed model can provide significant clinical benefits to patients with NDDs, directly affecting management across multiple domains for most diagnosed patients. As precision treatments advance, establishing a genetic diagnosis will be critical for proper management. With the growing number of rare neurogenetic disorders, clinician training should emphasize core principles of genomic medicine over individual syndromes.

Humans↗