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PubMed2003

Evidence for multiple hybrid groups in Trypanosoma cruzi.

A role for parasite genetic variability in the spectrum of Chagas disease is emerging but not yet evident, in part due to an incomplete understanding of the population structure of Trypanosoma cruzi. To investigate further the observed genotypic variation at the sequence and chromosomal levels in strains of standard and field-isolated T. cruzi we have undertaken a comparative analysis of 10 regions of the genome from two isolates representing T. cruzi I (Dm28c and Silvio X10) and two from T. cruzi II (CL Brener and Esmeraldo). Amplified regions contained intergenic (non-coding) sequences from tandemly repeated genes. Multiple nucleotide polymorphisms correlated with the T. cruzi I/T. cruzi II classification. Two intergenic regions had useful polymorphisms for the design of classification probes to test on genomic DNA from other known isolates. Two adjacent nucleotide polymorphisms in HSP 60 correlated with the T. cruzi I and T. cruzi II distinction. 1F8 nucleotide polymorphisms revealed multiple subdivisions of T. cruzi II: subgroups IIa and IIc displayed the T. cruzi I pattern; subgroups IId and IIe possessed both the I and II patterns. Furthermore, isolates from subgroups IId and IIe contained the 1F8 polymorphic markers on different chromosome bands supporting a genetic exchange event that resulted in chromosomes V and IX of T. cruzi strain CL Brener. Based on these analyses, T. cruzi I and subgroup IIb appear to be pure lines, while subgroups IIa/IIc and IId/IIe are hybrid lines. These data demonstrate for the first time that IIa/IIc are hybrid, consistent with the hypothesis that genetic recombination has occurred more than once within the T. cruzi lines.

Animals↗
PubMed2003

Compositional structure of repetitive elements is quantitatively related to co-expression of gene pairs.

A sequence similarity metric operating on 10 kb upstream regions of gene pairs quantitatively predicts a portion of co-variation of expression of gene pairs in large-scale gene expression studies in human tumors and tumor-derived cell lines. The signal on which the metric depends most strongly originates in the compositional structure of repetitive genomic sequences (particularly Alu elements) present in these upstream regions. This effect is completely separable from effects of isochore composition on gene expression. The results implicate repetitive elements with some functional role in transcriptional regulation of the specific genes in whose promoter regions they reside and lend credence to suggestions that the general phenomenon of repetitive element insertions may be a fundamental evolutionary mechanism for modulating gene transcription.

Base Composition↗
PubMedDate not supplied

Transient tachypnea of the newborn (TTN): a role for polymorphisms of surfactant protein B (SP-B) encoding gene?

BACKGROUND: Transient tachypnea of the newborn (TTN) is usually a benign self-limiting respiratory disorder in the immediate neonatal period. The lipophilic surfactant-associated protein B (SP-B) was demonstrated to be the most relevant structural component of the surfactant system for immediate postnatal pulmonary adaptation. We hypothesized genetic variations of surfactant protein B (heterozygous 121 ins 2 mutation er intron 4 polymorphisms) to be related to TTN. PATIENTS AND METHOD: We screened genomic DNA of 83 healthy term neonates (gestational age: 39 (37 - 41) completed weeks [median and range]; birth weight: 3325 +/- 541 grams [mean +/- SD]) and 75 infants presenting with TTN (gestational age: 38 (37 - 41) completed wecks [median and range]; birth weight: 3091 +/- 435 grams [mean +/- SD]) by means of PCR-amplification, fragment length and sequence analysis. TTN was diagnosed an the basis of the clinical signs with respiratory rate > 60 breaths/minute, fraction of inspired oxygen > 0.21, and characteristic radiographic findings within less than 24 hours after birth. Newborns with any infection, pulmonary or cardiac congenital malformations, postnatal asphyxia and infants born to diabetic mothers were excluded. RESULTS: In TTN-group the frequency of male infants (68.4 % versus 44.6 %, p < 0.05) and caeserian section were significantly higher (68.4 % versus 30.1 %, p < 0.05). We did not find any statistical difference in frequency of intron 4 variations between controls and TTN-group (8.4 % versus 10.7 %). None of the infants were heterozygous for the 121ins2 SP-B mutation. CONCLUSIONS: WC conclude polymorphisms of intron 4 and heterozygous 121 ins 2 mutation not to associated with TTN.

Age Factors↗
PubMed2002

A novel paralogous gene family involved in phase-variable flagella-mediated motility in Campylobacter jejuni.

Flagella-mediated motility is recognized to be one of the major factors contributing to virulence in Campylobacter jejuni. Motility of this bacterium is known to be phase variable, although the mechanism of such variation remains unknown. C. jejuni genome sequencing revealed a number of genes prone to phase variation via a slipped-strand mispairing mechanism. Many of these genes are hypothetical and are clustered in the regions involved in formation of three major cell surface structures: capsular polysaccharide, lipooligosaccharide and flagella. Among the genes of unknown function, the flagellar biosynthesis and modification region contains seven hypothetical paralogous genes designated as the motility accessory factor (maf) family. Remarkably, two of these genes (maf1 and maf4) were found to be identical and both contain homopolymeric G tracts. Using insertional mutagenesis it was demonstrated that one of the genes, maf5, is involved in formation of flagella. Phase variation of the maf1 gene via slipped-strand mispairing partially restored motility of the maf5 mutant. The maf family represents a new class of bacterial genes related to flagellar biosynthesis and phase variation. Reversible expression of flagella may be advantageous for the adaptation of C. jejunito the varied in vivo and ex vivo environments encountered during its life cycle, as well in evasion of the host immune response.

Amino Acid Sequence↗
PubMed2005

Prospects of manipulating diatom silica nanostructure.

A key to the development of nanotechnology will be the ability to make complex nanoscaled three-dimensional structures at low cost and in large numbers. The wide variety of structures in the silicified cell walls of diatoms offers a promising natural source of such materials. Diatom silica can be converted into other materials, with maintenance of detailed morphology. To facilitate the use of diatoms in nanotechnology, specific manipulation of the structure in vivo will be desirable. This article explores the possibilities of manipulating diatom silica structure, by nongenetic and genetic means. Nongenetic influences that affect silica structure include changes in environmental conditions and life cycle stages and the presence or absence of particular compounds. The genetically based natural variation in structure in different diatom species indicates that genetic manipulation is possible. To achieve this, however, several goals must be met. The first is to identify cell wall synthesis (CWS) genes involved in structure formation. The recently completed genome sequence of Thalassiosira pseudonana opens the door for genomic and proteomic approaches to accomplish this. An important method to determine the function of CWS genes will be to modify gene sequences or expression and monitor the effect on structure. Performing gene modifications is straightforward, and modified genes can be introduced into diatoms, but the current inability to replace native diatom genes with modified copies could be a problem. However, there are feasible approaches yet to be applied to achieve this goal. It is very likely that continued development and application of molecular genetic techniques will enable us to specifically modify diatom silicified structures and provide a detailed understanding of the underlying mechanism of their formation.

Biomimetics↗
PubMed2002

Structure and evolution of plant disease resistance genes.

This article reviews recent advances that shed light on plant disease resistance genes, beginning with a brief overview of their structure, followed by their genomic organization and evolution. Plant disease resistance genes have been exhaustively investigated in terms of their structural organization, sequence evolution and genome distribution. There are probably hundreds of NBS-LRR sequences and other types of R-gene-like sequences within a typical plant genome. Recent studies revealed positive selection and selective maintenance of variation in plant resistance and defence-related genes. Plant resistance genes are highly polymorphic and have diverse recognition specificities. R-genes occur as members of clustered gene families that have evolved through duplication and diversification. These genes appear to evolve more rapidly than other regions of the genome, and domains such as the leucine-rich repeat, are subject to adaptive selection

Evolution, Molecular↗
PubMed2006

Relaxing haplotype block models for association testing.

The arrival of publicly available genome-wide variation data is creating new opportunities for reconciling model-based methods for associating genotypes and phenotypes with the complexities of real genome data. Such data is particularly valuable for testing the utility of models of conserved haplotype structure to association studies. While there is much interest in "haplotype block" models that assume population-wide regions of low diversity, there is also evidence that such models eliminate correlations potentially useful to association studies. We investigate the value of relaxing the rigidity of block models by developing an association testing method using the previously developed "haplotype motif" model, which retains the notion of representing haploid sequences as concatenations of conserved haplotypes but abandons the assumption of population-wide block boundaries. We compare the effectiveness of motif, block, and single-variant models at finding association with simulated phenotypes using real and simulated data. We conclude that the benefits of haplotype models in any form are modest, but that haplotype models in general and block-free models in particular are useful in picking up correlations near the boundaries of the detectable level.

Chromosomes, Human, Pair 22↗
PubMed1997

Sequence analysis of SRSV in fecal specimens from an epidemic of infantile gastroenteritis, October to December 1995, Japan.

From October to December in 1995, an epidemic of infantile gastroenteritis occurred all over Japan except in Hokkaido and Okinawa prefectures. The number of infected infants and young children was estimated to be over 5 million cases [Editorial, IASR 1996]. The stool specimens from patients were examined for the presence of small round structured viruses (SRSVs) by reverse transcription-polymerase chain reaction (RT-PCR) and nucleotide sequencing of parts of the RNA-dependent RNA polymerase region. Thirty-five of 87 stool specimens examined gave positive results. Genomic variation was investigated by sequence analysis of a 327 bp cDNA region. The nucleotide and deduced amino acid sequences of the ten strains segregated into two distinct groups; one showed 96.0-100% nucleotide and 99.1-100% amino acid identity, the others showed 91.4-99.7% nucleotide and 93.5-100% identity. The main mechanism of transmission remains unknown. However, these data suggest the possibility of person-to-person spread by two or more kinds of SRSV.

Base Sequence↗
PubMed2006

Comparative genomics and concerted evolution of beta-tubulin paralogs in Leishmania spp.

BACKGROUND: Tubulin isotypes and expression patterns are highly regulated in diverse organisms. The genome sequence of the protozoan parasite Leishmania major contains three distinct beta-tubulin loci. To investigate the diversity of beta-tubulin genes, we have compared the published genome sequence to draft genome sequences of two further species L. infantum and L. braziliensis. Untranscribed regions and coding sequences for each isoform were compared within and between species in relation to the known diversity of beta-tubulin transcripts in Leishmania spp. RESULTS: All three beta-tubulin loci were present in L. infantum and L. braziliensis, showing conserved synteny with the L. major sequence, hence confirming that these loci are paralogous. Flanking regions suggested that the chromosome 21 locus is an amastigote-specific isoform and more closely related (either structurally or functionally) to the chromosome 33 'array' locus than the chromosome 8 locus. A phylogenetic network of all isoforms indicated that paralogs from L. braziliensis and L. mexicana were monophyletic, rather than clustering by locus. CONCLUSION: L. braziliensis and L. mexicana sequences appeared more similar to each other than each did to its closest relative in another species; this indicates that these sequences have evolved convergently in each species, perhaps through ectopic gene conversion; a process not yet evident among the more recently derived L. major and L. infantum isoforms. The distinctive non-coding regions of each beta-tubulin locus showed that it is the regulatory regions of these loci that have evolved most during the diversification of these genes in Leishmania, while the coding regions have been conserved and concerted. The various loci in Leishmania satisfy a need for innovative expression of beta-tubulin, rather than elaboration of its structural role.

3' Flanking Region↗
PubMed2005

Global divergence of microbial genome sequences mediated by propagating fronts.

We model the competition between homologous recombination and point mutation in microbial genomes, and present evidence for two distinct phases, one uniform, the other genetically diverse. Depending on the specifics of homologous recombination, we find that global sequence divergence can be mediated by fronts propagating along the genome, whose characteristic signature on genome structure is elucidated, and apparently observed in closely related Bacillus strains. Front propagation provides an emergent, generic mechanism for microbial "speciation," and suggests a classification of microorganisms on the basis of their propensity to support propagating fronts.

Bacillus↗
PubMedDate not supplied

Occurrence and structure-function relationship of pentameric short sequence repeats in microbial genomes.

It is suggested that genomes found in any form of cellular life contain potentially size-variable repetitive DNA moieties. In eukaryotes, large proportions of the multi-chromosomal genome consist of various classes of repetitive DNA. Also in archaeal genomes, repetitive DNA is encountered and, as is the case for the eukaryotes as well, little or no function is at present attributable to most of it. For prokaryotes, elegant experiments have highlighted so-called slipped strand nucleotide mispairing (SSM) as a basic and causal mechanism, giving rise to repeat unit number variation at a distinct locus. Illegitimate base pairing in regions of repetitive DNA during replication, in association with defective DNA repair and enhanced nuclease susceptibility of replication intermediates, in the end gives rise to deletion or addition of repeat units. Prokaryotic short sequence repeats (SSRs) harbour arrays of short repeat units, between one and approximately 20 nucleotides in length. SSRs are involved in various mechanisms of microbial gene expression regulation. Promoter strength can be affected by altering the spacing between important structural domains as can the integrity of open reading frames. In the present communication the literature on microbial SSRs harbouring repeat units that are five nucleotides in length will be briefly reviewed. Examples of these SSRs with discrete functionality are encountered in bacterial species such as Haemophilus influenzae, Neisseria gonorrhoeae, and Pasteurella haemolytica. In addition, several of the currently known bacterial and archaeal whole genome sequences were scanned for the presence of novel examples of potential five-nucleotide SSRs (and others) in order to gather additional knowledge on the propensity and putative functions of this type of potential genetic switch.

Base Sequence↗
PubMed2003

Human inter-individual DNA sequence variation in candidate genes, drug targets, the importance of haplotypes and pharmacogenomics.

The identification of genes predisposing to human diseases is of paramount importance for understanding the molecular basis of the disease and individually different drug response, and will establish new routes to diagnosis and therapeutic advances of immense medical benefit. A key step common to all strategies for disease gene identification is the systematic analysis of candidate gene sequences to identify specific sequence variations associated with disease or any other phenotype of pharmaceutical relevance. In this article, current concepts and approaches to haplotype-based candidate gene analysis are reviewed. Moreover, a comprehensive summary of recent studies and data on the amount, nature, pattern and structure of genetic variation in candidate genes is given. These data demonstrate altogether remarkable gene sequence and haplotype diversity. Numerous individually different forms of a gene may exist. This presents challenges to the traditional views of the concept of "a" gene with far-reaching implications on the functional analysis of candidate gene variation, on the establishment of "sequence"-"structure"-"function" and complex haplotype/genotype-phenotype relationships, on the identification, evaluation and prioritization of drug targets and the concept of a "personalized medicine" in general. Moreover, present and future approaches to the identification of candidate and disease genes will be addressed. These include whole genome-based approaches such as integrative genomics as well as functional genomics-based approaches to analyze and model complex biological and medical processes. The analysis of whole complex systems in particular will provide the basis to make "maximally informed" guesses on candidate genes and address complex variability patterns in genes as well as complex genotype-phenotype relationships comprehensively at an advanced level.

Base Sequence↗
PubMed2006

Variation in the human genome and the inherited basis of common disease.

The availability of a reference human genome sequence-an increasingly dense catalog-knowledge of common genetic variation, and new developments in technology present an unprecedented opportunity to systematically explore the genetic basis of complex human diseases such as cancer. An understanding of the common mutations that can cause distinct human cancers will be critical for identifying new targets for drug discovery, patient stratification for clinical trials, and analysis of drug response data to delineate classes of patients that respond to therapy. The genome structure of cancer can be investigated in several ways. Germline mutations can be investigated in large-scale, case-control, or family studies. Somatic alternations can be identified using state-of-the-art genomic technologies such as high-density oligonucleotide arrays and targeted resequencing. Combined, these approaches will lead to a better understanding of the cancer genome.

Gene Expression Profiling↗
PubMed2003

Diversity in coding tandem repeats in related Neisseria spp.

BACKGROUND: Tandem repeats contained within coding regions can mediate phase variation when the repeated units change the reading frame of the coding sequence in a copy number dependent manner. Coding tandem repeats are those which do not alter the reading frame with copy number, and the changes in copy number of these repeats may then potentially alter the function or antigenicity of the protein encoded. Three complete neisserial genomes were analyzed and compared to identify coding tandem repeats where the number of copies of the repeat will have some structural consequence for the protein. This is the first study to address coding tandem repeats that may affect protein structures using comparative genomics, combined with a population survey to investigate which show interstrain variability. RESULTS: A total of 28 genes were identified. Of these, 22 contain coding tandem repeats that vary in copy number between the three sequenced strains, three strain specific genes were included for investigation on the basis of having >90% identity between repeated units, and three genes with repeated elements of >250 bp were included although no length variations were seen in the genomes. Amplification, and sequencing of repeats showing altered copy number, of these 28 coding tandem repeat containing regions, from a set of largely unrelated strains, revealed further repeat length variation in several cases. CONCLUSION: Eighteen genes were identified which have variation in repeat copy number between strains of the same species, twelve of which show greater diversity in repeat copy number than is present in the sequenced genomes. In some cases, this may reflect a mechanism for the generation of antigenic variation, as previously described in other species. However, some of the genes identified encode proteins with cytoplasmic functions, including sugar metabolism, DNA repair, and protein production, in which repeat length variation may have other functions. Coding tandem repeats appear to represent a largely unexplored mechanism of generating diversity in the Neisseria spp.

Adhesins, Bacterial↗
PubMed2004

Fine-scale geographical structure, intra-individual polymorphism and recombination in nuclear ribosomal internal transcribed spacers in Armeria (Plumbaginaceae).

BACKGROUND AND AIMS: Isolation and drift are the main causes for geographic structure of molecular variation. In contrast, the one found in a previous survey in Armeria (Plumbaginaceae) for nuclear ribosomal ITS multicopy regions was species-independent and has been hypothesized to be due to extensive gene-flow and biased concerted evolution. Since this was inferred from a genus-level phylogenetic analysis, the aim of this study was to check for the occurrence of such structure and the validity of the proposed model at a local scale, in a southern Spanish massif (Sierra Nevada), as well as to examine the evolutionary implications at the organism level. METHODS: In addition to 117 sequences of direct PCR products from genomic DNA, 50 sequences of PCR products from cloned DNA were obtained to analyse cases of intragenomic polymorphisms for the ITS regions. KEY RESULTS: Sequence data confirm the occurrence of a species-independent structure at a local scale and reveal insights through the analysis of contact areas between different ITS copies (ribotypes). A comparison between cloned and direct sequences (a) confirms that, within these contact areas, ITS copies co-occur both in different individuals and within single genomes; and (b) reveals recombination between different copies. CONCLUSIONS: This study supports the utility of direct sequences for detecting intra-individual polymorphism and for partially inferring the ITS copies involved, given previous knowledge of the variability. The main evolutionary implication at the organism level is that gene-flow and concerted evolution shape the geographic structure of ITS variation.

Base Sequence↗
PubMed1998

Beyond complete genomes: from sequence to structure and function.

Computer analysis of complete prokaryotic genomes shows that microbial proteins are in general highly conserved--approximately 70% of them contain ancient conserved regions. This allows us to delineate families of orthologs across a wide phylogenetic range and, in many cases, predict protein functions with considerable precision. Sequence database searches using newly developed, sensitive algorithms result in the unification of such orthologous families into larger superfamilies sharing common sequence motifs. For many of these superfamilies, prediction of the structural fold and specific amino acid residues involved in enzymatic catalysis is possible. Taken together, sequence and structure comparisons provide a powerful methodology that can successfully complement traditional experimental approaches.

Animals↗
PubMed2005

Unique organisation of tRNA genes in Entamoeba histolytica.

The genome sequence of the protistan parasite Entamoeba histolytica HM-1:IMSS has been completed recently. Among the findings has been a unique organisation for the tRNA genes in this organism. Forty-two of the tRNA isoacceptor types are encoded in tandem arrays that vary in unit length from 490 to 1775 basepairs and contain from 1 to 5 tRNA genes. In three cases a 5S RNA gene is also present in the unit. An estimated 10% of the genome is made up of these arrays. Interspersed between RNA-encoding sequences are short tandem repeats that are polymorphic between isolates and, in some cases, within isolates. The number and organisation of tRNA genes in E. histolytica is unprecedented. In addition to encoding the tRNAs of the organism we propose that the arrays may fulfil a structural role in the genome.

Animals↗
PubMed2003

Enrichment of segmental duplications in regions of breaks of synteny between the human and mouse genomes suggest their involvement in evolutionary rearrangements.

The sequence of the mouse genome allows one to compare the conservation of synteny between the human and mouse genome and exploration of regions that might have been involved in major rearrangements during the evolution of these two species (evolutionary genome rearrangements). Recent segmental duplications (or duplicons) are paralogous DNA sequences with high sequence identity that account for about 3.5-5% of the human genome and have emerged during the past approximately 35 million years of evolution. These regions are susceptible to illegitimate recombination leading to rearrangements that result in genomic disorders or genomic mutations. A catalogue of several hundred segmental duplications potentially leading to genomic rearrangements has been reported. The authors and others have observed that some chromosome regions involved in genomic disorders are shuffled in orientation and order in the mouse genome and that regions flanked by segmental duplications are often polymorphic. We have compared the human and mouse genome sequences and demonstrate here that recent segmental duplications correlate with breaks of synteny between these two species. We also observed that nine primary regions involved in human genomic disorders show changes in the order or the orientation of mouse/human synteny segments, were often flanked by segmental duplications in the human sequence. We found that 53% of all evolutionary rearrangement breakpoints associate with segmental duplications, as compared with 18% expected in a random location of breaks along the chromosome (P<0.0001). Our data suggest that segmental duplications have participated in the recent evolution of the human genome, as driving forces for evolutionary rearrangements, chromosome structure polymorphisms and genomic disorders.

Animals↗