Biomedical subjects

Genomics

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PubMed2005

Genome sequence of the non-pathogenic strain 15 of pneumonia virus of mice and comparison with the genome of the pathogenic strain J3666.

Pneumonia virus of mice (PVM) is a member of the subfamily Pneumovirinae and is the closest known relative of respiratory syncytial virus. Both viruses cause pneumonia in their respective hosts. Here, the genome sequences of two strains of PVM, non-pathogenic strain 15 and pathogenic strain J3666, are reported. Comparison of the genome sequences revealed 59 nucleotide differences between the two strains, 37 of which were coding. The nucleotide differences were spread throughout the genome, affecting cis-acting regulatory regions and seven of the ten genes. Development of a reverse-genetics system for PVM should allow further elucidation of the functional importance of the genetic differences between the two strains identified here.

Amino Acid Sequence↗

PubMed2003

Whole-genome shotgun optical mapping of Rhodobacter sphaeroides strain 2.4.1 and its use for whole-genome shotgun sequence assembly.

Rhodobacter sphaeroides 2.4.1 is a facultative photoheterotrophic bacterium with tremendous metabolic diversity, which has significantly contributed to our understanding of the molecular genetics of photosynthesis, photoheterotrophy, nitrogen fixation, hydrogen metabolism, carbon dioxide fixation, taxis, and tetrapyrrole biosynthesis. To further understand this remarkable bacterium, and to accelerate an ongoing sequencing project, two whole-genome restriction maps (EcoRI and HindIII) of R. sphaeroides strain 2.4.1 were constructed using shotgun optical mapping. The approach directly mapped genomic DNA by the random mapping of single molecules. The two maps were used to facilitate sequence assembly by providing an optical scaffold for high-resolution alignment and verification of sequence contigs. Our results show that such maps facilitated the closure of sequence gaps by the early detection of nascent sequence contigs during the course of the whole-genome shotgun sequencing process.

Chromosomes, Bacterial↗

PubMed2003

An appraisal of the potential for illegitimate recombination in bacterial genomes and its consequences: from duplications to genome reduction.

An exhaustive search for shortly spaced repeats in 74 bacterial chromosomes reveals that they are much more numerous than is usually acknowledged. These repeats were divided into five classes: close repeats (CRs), tandem repeats (TRs), simple sequence repeats (SSRs), spaced interspersed direct repeats, and "others." CRs are widespread and constitute the most abundant class, particularly in coding sequences. The other classes are less frequent, but each individual element shows a higher potential for recombination, when the number of repeats and their distances are taken into account. SSRs and TRs are more frequent in pathogens, as expected given their role in contingency loci, but are also widespread in the other bacteria. The analysis of CRs shows that they have an important role in the evolution of genomes, namely by generating duplications and deletions. Several cases compatible with a significant role of small CRs in the formation of large repeats were detected. Also, gene deletion in Buchnera correlates with repeat density, suggesting that CRs may lead to sequence deletion in general and genome reductive evolution of obligatory intracellular bacteria in particular. The assembly of these results indicates that shortly spaced repeats are key players in the dynamics of genome evolution.

Chromosome Mapping↗

PubMed2003

Rapid genome divergence at orthologous low molecular weight glutenin loci of the A and Am genomes of wheat.

To study genome evolution in wheat, we have sequenced and compared two large physical contigs of 285 and 142 kb covering orthologous low molecular weight (LMW) glutenin loci on chromosome 1AS of a diploid wheat species (Triticum monococcum subsp monococcum) and a tetraploid wheat species (Triticum turgidum subsp durum). Sequence conservation between the two species was restricted to small regions containing the orthologous LMW glutenin genes, whereas >90% of the compared sequences were not conserved. Dramatic sequence rearrangements occurred in the regions rich in repetitive elements. Dating of long terminal repeat retrotransposon insertions revealed different insertion events occurring during the last 5.5 million years in both species. These insertions are partially responsible for the lack of homology between the intergenic regions. In addition, the gene space was conserved only partially, because different predicted genes were identified on both contigs. Duplications and deletions of large fragments that might be attributable to illegitimate recombination also have contributed to the differentiation of this region in both species. The striking differences in the intergenic landscape between the A and A(m) genomes that diverged 1 to 3 million years ago provide evidence for a dynamic and rapid genome evolution in wheat species.

Base Sequence↗

PubMed1997

Mapping 28 erythrocyte antigen, plasma protein and enzyme polymorphisms using an efficient genomic scan of the porcine genome.

One hundred and fifty-four microsatellite markers were selected for genomic scanning of the porcine genome and were grouped into amplification sets to reduce the cost and labour required. Thirty amplification sets had two markers (duplex), 20 sets had three markers (triplex) and five sets had four markers (quadruplex) while 14 markers were analysed separately. The selection criteria for microsatellites were: ease of scoring, level of polymorphism, genetic location and ability to be genotyped in a multiplexed polymerase chain reaction (PCR). The selected microsatellites were chosen to span the entire genome flanked by the porcine linkage map with intervals between adjacent markers of 15-20 cM where possible. The utility of this set of markers was demonstrated by linkage analyses with loci controlling blood plasma protein and red cell enzyme polymorphisms (n = 13), erythrocyte antigens (n = 15), the S blood group, coat colour and ryanodine receptor from 174 backcross Meishan-White Composite pigs. These loci displayed various forms of inheritance and most (24 loci) have been placed in linkage groups. Significant two-point linkages (lod > 3.0) were detected for each polymorphic marker. These results provide the first linkage assignments for phosphoglucomutase (PGM2) and erythrocyte antigen F (EAF) to SSC8; and serum amylase (AMY) and erythrocyte antigen I (EAI) to SSC18. All of the remaining polymorphic loci (n = 24) mapped to previously identified regions confirming earlier results. Most of the markers used in this study should be useful in resource populations of various breed crosses as the number of alleles detected in a multibreed reference population was one of the selection criteria.

Animals↗

PubMed1993

The mitochondrial genome of the mosquito Anopheles gambiae: DNA sequence, genome organization, and comparisons with mitochondrial sequences of other insects.

The entire 15,363 bp mitochondrial genome was cloned and sequenced from the mosquito Anopheles gambiae. With respect to the protein-coding genes, rRNA genes and the control region, the gene order was identical to that reported for other insects. There were significant differences, however, in the position and orientation of specific tRNA loci. The overall nucleotide composition was heavily biased towards adenine and thymine, which accounted for 77.6% of all nucleotides. Comparisons were made with the mitochondrial genomes of other insects on the basis genome size and organization, DNA and putative amino acid sequence data, nucleotide substitutions, codon usage and bias, and patterns of AT enrichment.

Amino Acid Sequence↗

PubMed1995

The Mycobacterium leprae genome: systematic sequence analysis identifies key catabolic enzymes, ATP-dependent transport systems and a novel polA locus associated with genomic variability.

In the framework of the mycobacterial genome sequencing project, a continuous 37,049 bp sequence from the Mycobacterium leprae chromosome has been determined. Computer analysis revealed 10 complete open reading frames, and nine of their products show similarity to known proteins. Seven of these were identified as the enzyme isocitrate lyase, two P-type ATPase cation transporters, two AMP-binding proteins, the ribosomal protein S1, and DNA polymerase I. Interestingly, the polA gene, encoding DNA polymerase, is flanked by two inverted copies of a new class of the M. leprae specific repetitive sequence, RLEP, and this structure resembles a transposable element. A second copy of this element was found at another locus in the genome, but the two copies were not present in equal amounts and could not be found in all isolates of M. leprae. This is the first evidence for genomic variability in the leprosy bacillus and might ultimately be useful for developing a molecular test capable of distinguishing between strains of M. leprae.

Adenosine Triphosphatases↗

PubMed2006

The mitochondrial genome of the wine yeast Hanseniaspora uvarum: a unique genome organization among yeast/fungal counterparts.

The complete sequence of the apiculate wine yeast Hanseniaspora uvarum mtDNA has been determined and analysed. It is an extremely compact linear molecule containing the shortest functional region ever found in fungi (11 094 bp long), flanked by Type 2 telomeric inverted repeats. The latter contained a 2704-bp-long subterminal region and tandem repeats of 839-bp units. In consequence, a population of mtDNA molecules that differed at the number of their telomeric reiterations was detected. The functional region of the mitochondrial genome coded for 32 genes, which included seven subunits of respiratory complexes and ATP synthase (the genes encoding for NADH oxidoreductase subunits were absent), two rRNAs and 23 tRNA genes which recognized codons for all amino acids. A single intron interrupted the cytochrome oxidase subunit 1 gene. A number of reasons contributed towards its strikingly small size, namely: (1) the remarkable size reduction (by >40%) of the rns and rnl genes; (2) that most tRNA genes and five of the seven protein-coding genes were the shortest among known yeast homologs; and (3) that the noncoding regions were restricted to 5.1% of the genome. In addition, the genome showed multiple changes in the orientation of transcription and the gene order differed drastically from other yeasts. When all protein coding gene sequences were considered as one unit and were compared with the corresponding molecules from all other complete mtDNAs of yeasts, the phylogenetic trees constructed robustly supported its placement basal to the yeast species of the 'Saccharomyces complex', demonstrating the advantage of this approach over single-gene or multigene approaches of unlinked genes.

Base Sequence↗

PubMed1996

Genomic organization of purK and purE in Brevibacterium ammoniagenes ATCC 6872: purE locus provides a clue for genomic evolution.

From the genomic library of Brevibacterium ammoniagenes ATCC6872, the purE locus encoding 5'-phosphoribosyl-5-aminoimidazole (AIR) carboxylase (EC 4.1.1.21) was cloned and its nucleotide sequence was determined. From the sequence analysis, two distinct open reading frames (ORFs) in the sequence of the purE locus were identified as purK and purE genes (purK-purE). An in vivo translation experiment reconfirmed the purK and purE genes to be independent. The genomic organization in the purE locus of B. ammoniagenes is opposite to that of the bacteria Escherichia coli and Bacillus subtilis. However, it coincides with the fused genes (purKE) of higher organisms Saccharomyces cerevisiae, Schizosaccharomyces pombe and Vigna aconitifolia. This suggests that the purE locus might be an intermediate form for genomic evolution of bacteria to higher organisms.

Amino Acid Sequence↗

PubMed2004

The Ashbya gossypii genome as a tool for mapping the ancient Saccharomyces cerevisiae genome.

We have sequenced and annotated the genome of the filamentous ascomycete Ashbya gossypii. With a size of only 9.2 megabases, encoding 4718 protein-coding genes, it is the smallest genome of a free-living eukaryote yet characterized. More than 90% of A. gossypii genes show both homology and a particular pattern of synteny with Saccharomyces cerevisiae. Analysis of this pattern revealed 300 inversions and translocations that have occurred since divergence of these two species. It also provided compelling evidence that the evolution of S. cerevisiae included a whole genome duplication or fusion of two related species and showed, through inferred ancient gene orders, which of the duplicated genes lost one copy and which retained both copies.

Base Composition↗

PubMed2006

Comparative genomic analysis of three strains of Ehrlichia ruminantium reveals an active process of genome size plasticity.

Ehrlichia ruminantium is the causative agent of heartwater, a major tick-borne disease of livestock in Africa that has been introduced in the Caribbean and is threatening to emerge and spread on the American mainland. We sequenced the complete genomes of two strains of E. ruminantium of differing phenotypes, strains Gardel (Erga; 1,499,920 bp), from the island of Guadeloupe, and Welgevonden (Erwe; 1,512,977 bp), originating in South Africa and maintained in Guadeloupe in a different cell environment. Comparative genomic analysis of these two strains was performed with the recently published parent strain of Erwe (Erwo) and other Rickettsiales (Anaplasma, Wolbachia, and Rickettsia spp.). Gene order is highly conserved between the E. ruminantium strains and with A. marginale. In contrast, there is very little conservation of gene order with members of the Rickettsiaceae. However, gene order may be locally conserved, as illustrated by the tuf operons. Eighteen truncated protein-encoding sequences (CDSs) differentiate Erga from Erwe/Erwo, whereas four other truncated CDSs differentiate Erwe from Erwo. Moreover, E. ruminantium displays the lowest coding ratio observed among bacteria due to unusually long intergenic regions. This is related to an active process of genome expansion/contraction targeted at tandem repeats in noncoding regions and based on the addition or removal of ca. 150-bp tandem units. This process seems to be specific to E. ruminantium and is not observed in the other Rickettsiales.

Conserved Sequence↗

PubMed1996

Human papillomavirus type 70 genome cloned from overlapping PCR products: complete nucleotide sequence and genomic organization.

The genome of human papillomavirus (HPV) type 70 (HPV 70), isolated from a cervical condyloma, was obtained by cloning overlapping PCR products. By automated DNA sequence analysis, the genome was found to consist of 7,905 bp with a G + C content of 40%. The genomic organization showed the characteristic features shared by other sequenced HPVs. Nucleotide sequence comparison with previously known HPV types demonstrated the closest homology with HPV 68 (82%), HPV 39 (82%), HPV 18 (70%), HPV 45 (70%), and HPV 59 (70%). Comparison with seven other partially sequenced HPV 70 isolates showed homologies of between 100 and 99.5%. Cloning of overlapping PCR products and automated DNA sequence analysis was found to be a feasible method of obtaining full-length sequences of HPVs.

Base Composition↗

PubMed1992

The herpes simplex virus type 1 (HSV-1) a sequence serves as a cleavage/packaging signal but does not drive recombinational genome isomerization when it is inserted into the HSV-2 genome.

We inserted the terminal repeat (a sequence) of herpes simplex virus type 1 (HSV-1) strain KOS into the tk gene of HSV-2 strain HG52 in order to assess the ability of the HSV-1 a sequence to provoke genome isomerization events in an HSV-2 background. We found that the HSV-1 a sequence was cleaved by the HSV-2 cleavage/packaging machinery to give rise to novel genomic termini. However, the HSV-1 a sequence did not detectably recombine with the HSV-2 a sequence. These results demonstrate that the viral DNA cleavage/packaging system contributes to a subset of genome isomerization events and indicate that the additional recombinational inversion events that occur during infection require sequence homology between the recombination partners.

Base Sequence↗

PubMed2006

Mitochondrial genomics of gadine fishes: implications for taxonomy and biogeographic origins from whole-genome data sets.

Phylogenetic analysis of 13 substantially complete mitochondrial DNA genome sequences (14,036 bp) from 10 taxa of gadine codfishes and pollock provides highly corroborated resolution of outstanding questions on their biogeographic evolution. Of 6 resolvable nodes among species, 4 were supported by >95% of bootstrap replications in parsimony, distance, likelihood, and similarly high posterior probabilities in bayesian analyses, one by 85%-95% according to the method of analysis, and one by 99% by one method and a majority of the other two. The endemic Pacific species, walleye pollock (Theragra chalcogramma), is more closely related to the endemic Atlantic species, Atlantic cod (Gadus macrocephalus), than either is to a second Pacific endemic, Pacific cod (Gadus macrocephalus). The walleye pollock should thus be referred to the genus Gadus as originally described (Gadus chalcogrammus Pallas 1811). Arcto-Atlantic Greenland cod, previously regarded as a distinct species (G. ogac), are a genomically distinguishable subspecies within pan-Pacific G. macrocephalus. Of the 2 endemic Arctic Ocean genera, Polar cod (Boreogadus) as the outgroup to Arctic cod (Arctogadus) and Gadus sensu lato is more strongly supported than a pairing of Boreogadus and Arctogadus as sister taxa. Taking into consideration historical patterns of hydrogeography, we outline a hypothesis of the origin of the 2 endemic Pacific species as independent but simultaneous invasions through the Bering Strait from an Arcto-Atlantic ancestral lineage. In contrast to the genome data, the complete proteome sequence (3830 amino acids) resolved only 3 nodes with >95% confidence, and placed Alaska pollock outside the Gadus clade owing to reversal mutations in the ND5 locus that restore ancestral, non-Gadus, amino acid residues in that species.

Amino Acid Sequence↗

PubMed1999

Population genomics in Sardinia: a novel approach to hunt for genomic combinations underlying complex traits and diseases.

The availability of highly polymorphic markers permits testing whether complex traits and diseases result from genomic interactions between nonallelic normal variants at separate loci. Such variants may be identified by deviations from the expected distributions of alleles at a high number of polymorphic loci, when individuals with the phenotype of interest are compared to normal controls of the same breeding unit, provided that both groups share the same remote ancestry and had no ancestors in common for the last three to four generations. The circumstances needed for such studies are ideally met on the island of Sardinia. The recurrent finding of the same type of association in separate breeding units between the phenotype of interest and a given genotype should allow a distinction between true genetic identity by descent and randomly occurring identities, as these will be obviously different in separate breeding units. The availability of several breeding units located in sharply different ecological environments will permit assessment of the role of nature/nurture factors in the degree of manifestation of each newly discovered genotype/phenotype association. A pilot study to evaluate the proposed strategy has been carried out in the Sardinian village of Carloforte, a community of about 8,000 individuals who have remained genetically homogeneous. Fifty-five control samples have been genotyped with six tetranucleotide microsatellites and with a subset of the 400 markers contained in the ABI PRISM linkage mapping panel, version 2. The allele frequencies for these microsatellite markers have been determined for these 55 individuals and compared to those from a random sampling of subsets of these 55 persons. For the six tetranucleotide microsatellites, a subset of as few as 20 people displayed the same allele frequency distributions as observed with the original 55 unrelated individuals. In conclusion, when samples are chosen from the same breeding unit, the number of individuals sufficient to draw the genomic profile of an isolated population can be relatively small. Likewise, the number of probands with the phenotype of interest can be even smaller when they are ascertained with the same genealogical criteria as the normal controls. By comparing the genomic profile of the probands to a fraction of the control samples within each of several separate breeding units of common remote ancestry, the search for genotype/phenotype association for mono- and multifactorial traits and diseases should be simplified and yield unequivocal results.

Aged↗

PubMed2005

Intratumoral genomic heterogeneity in advanced head and neck cancer detected by comparative genomic hybridization.

OBJECTIVES: Little is known about the extent of intratumoral genetic heterogeneity in head and neck squamous cell carcinoma (HNSCC). MATERIAL: Therefore, we examined 79 stage III and IV primary HNSCCs and matched lymph node metastases for over- and underrepresentation of specific chromosome regions by comparative genomic hybridization. RESULTS: The overall ratio of gains and losses was higher in metastases (M) than in primary (P) tumors (4/1 vs. 2.5/1). Gains of 3q (78.1% P vs. 87.5% M) and 11q (78.1% P vs. 62.5% M), and deletions of 3p (43.8% P vs. 34.4% M) and 9p (31.3% P vs. 15.6% M) were most frequently detected. The highest rate of intratumoral discordance was observed for primary tumors and corresponding metastases (32.8%) compared to matched pairs of 2 metastases (26.5%), and of 2 anatomically distinct sides of 1 primary tumor (24.3%). Furthermore, the discordance rate was dependent on the primary tumor site (oral cavity 49.2%, oropharynx 31%, hypopharynx 30.3% and larynx 27.3%). In some tumors, the extent of genomic discordance argues against a monoclonal origin. CONCLUSION: We demonstrate a high individual variation of intratumoral genomic heterogeneity depending on the localization and selection of matched pairs. These findings are of specific importance in view of establishing prognostic markers.

Aged↗

PubMed2006

Microsatellite polymorphism across the M. tuberculosis and M. bovis genomes: implications on genome evolution and plasticity.

BACKGROUND: Microsatellites are the tandem repeats of nucleotide motifs of size 1-6 bp observed in all known genomes. These repeats show length polymorphism characterized by either insertion or deletion (indels) of the repeat units, which in and around the coding regions affect transcription and translation of genes. RESULTS: Systematic comparison of all the equivalent microsatellites in the coding regions of the three mycobacterial genomes, viz. Mycobacterium tuberculosis H37Rv, Mycobacterium tuberculosis CDC1551 and Mycobacterium bovis, revealed for the first time the presence of several polymorphic microsatellites. The coding regions affected by frame-shifts owing to microsatellite indels have undergone changes indicative of gene fission/fusion, premature termination and length variation. Interestingly, the genes affected by frame-shift mutations code for membrane proteins, transporters, PPE, PE_PGRS, cell-wall synthesis proteins and hypothetical proteins. CONCLUSION: This study has revealed the role of microsatellite indel mutations in imparting novel functions and a certain degree of plasticity to the mycobacterial genomes. There seems to be some correlation between microsatellite polymorphism and the variations in virulence, host-pathogen interactions mediated by surface antigen variations, and adaptation of the pathogens. Several of the polymorphic microsatellites reported in this study can be tested for their polymorphic nature by screening clinical isolates and various mycobacterial strains, for establishing correlations between microsatellite polymorphism and the phenotypic variations among these pathogens.

Bacterial Proteins↗

PubMed2002

Insights into cereal genomes from two draft genome sequences of rice.

Draft genome sequences have been reported for two subspecies of rice. The drafts include the sequences of an estimated 99% of all rice genes and provide major advances in our understanding of the content and complexity of cereal genomes in general and the rice genome in particular.

Computational Biology↗