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PubMed1992

Advances in the detection of ploidy differences in cancer by in situ hybridization.

Three main techniques allow the detection of changes in the cellular genomic content. The karyotyping procedure on metaphase spreads can give specific information on chromosome number and structural chromosome changes, but analyses are restricted to a limited number of chromosome spreads. Furthermore, cell culturing of (in particular solid) cancer specimens can result in selection of a minor tumour cell population with a high proliferative capacity. On the other hand, flow cytometry allows the analyses of large numbers of cells, but does not detect small variations in the DNA content or structural changes. The fluorescent in situ hybridization (FISH) procedure combines the advantages of the two former procedures, in that relatively large numbers of cells can be analysed easily and specific chromosomal changes can be detected.

DNA Probes↗
PubMed2003

[The effect of rye chromosomes on callus induction and regeneration in callus cultures of immature embryos of wheat-rye substitution lines, Triticum aestivum L. cultivar Saratovskaia 29/Secale cereale L. cultivar Onokhoiskaia].

The effect of individual rye chromosomes on the induction of callus and the character of its regenerating capacity was studied with cultured immature embryos of wheat-rye (Triticum aestivum L. cv. Saratovskaya 29-Secale cereale L. cv. Onokhoiskaya) substitution lines. The genotypic diversity of the substitution lines proved to significantly affect variation of parameters characterizing the major types of callus cultures, that is, frequencies of embryogenic calli, which are capable of shoot regeneration, and of morphogenic calli, which produce root structures. Functioning in the genotypic background of common wheat cultivar Saratovskaya, chromosomes 2R and 3R of rye cultivar Onokhoiskaya stimulated significantly the induction of embryogenic callus highly capable of shoot regeneration. Rye chromosome 2R present in place of chromosome 2D in the common wheat genome suppressed the induction of callus producing root structures. Rye chromosomes 1R and 6R suppressed the induction of embryogenic callus capable of shoot regeneration.

Chromosomes, Plant↗
PubMed2006

Human population genetic structure and diversity inferred from polymorphic L1(LINE-1) and Alu insertions.

BACKGROUND/AIMS: The L1 retrotransposable element family is the most successful self-replicating genomic parasite of the human genome. L1 elements drive replication of Alu elements, and both have had far-reaching impacts on the human genome. We use L1 and Alu insertion polymorphisms to analyze human population structure. METHODS: We genotyped 75 recent, polymorphic L1 insertions in 317 individuals from 21 populations in sub-Saharan Africa, East Asia, Europe and the Indian subcontinent. This is the first sample of L1 loci large enough to support detailed population genetic inference. We analyzed these data in parallel with a set of 100 polymorphic Alu insertion loci previously genotyped in the same individuals. RESULTS AND CONCLUSION: The data sets yield congruent results that support the recent African origin model of human ancestry. A genetic clustering algorithm detects clusters of individuals corresponding to continental regions. The number of loci sampled is critical: with fewer than 50 typical loci, structure cannot be reliably discerned in these populations. The inclusion of geographically intermediate populations (from India) reduces the distinctness of clustering. Our results indicate that human genetic variation is neither perfectly correlated with geographic distance (purely clinal) nor independent of distance (purely clustered), but a combination of both: stepped clinal.

Alu Elements↗
PubMed2001

Genome wide oscillations in expression. Wavelet analysis of time series data from yeast expression arrays uncovers the dynamic architecture of phenotype.

A reanalysis of expression arrays in yeast cells synchronized by alpha factor blockade or through the use of temperature sensitive mutants uncovered a genome wide pattern of oscillations in mRNA concentrations. Using wavelet decomposition as a signal processing technique and enhancement strategies borrowed from image processing, noise and trends in the Stanford yeast cell cycle data were partitioned away from time series profiles to uncover genome-wide oscillations in expression. These oscillations which were typically of cell cycle or half cell cycle duration, 40 and 80 minutes in the Stanford data set suggest that there are large-scale temporal structures and high frequency oscillations in mRNA levels through the cell cycle. Wavelet decomposition, which acts like a band pass filter bank, was used to determine where most of the power appeared in the decomposition. The approximately 40-min oscillation is mirrored in continuous chemostat cultures. In these cultures, metabolic synchrony involving an unknown proportion of the transcriptome can be monitored by measurement of oxygen consumption and can be sustained for weeks. These 40-min oscillations are stable and precise with coefficients of variation less than 1% for both period and amplitude. The hypothesis that high and low amplitude oscillations are a ubiquitous property of the genetic regulatory circuitry was supported by the observation of period doubling bifurcations in the distribution of population doubling times in yeast.

Cell Cycle↗
PubMed2002

Expression of major surface protein 2 variants with conserved T-cell epitopes in Anaplasma centrale vaccinates.

Major surface protein 2 (MSP-2), identified as a protection-inducing immunogen against Anaplasma marginale challenge, is an immunodominant outer membrane protein with orthologues in all examined Anaplasma species. Although immunization with live Anaplasma centrale has long been used to induce protection against acute disease upon challenge with virulent A. marginale, its MSP-2 structure and whether MSP-2 variants are generated during persistence of the vaccine strain was unknown. In this study, we showed that the A. centrale vaccine strain persisted for a minimum of 4 years postvaccination and generated sequential MSP-2 variants. Comparison of amino acid sequences encoded by A. centrale msp-2 transcripts from the initial postimmunization period and from sequential time points during persistence of the vaccine strain revealed a central hypervariable domain flanked by conserved amino and carboxy-terminal regions. This structure corresponded to that shown in A. marginale MSP-2, where the central hypervariable region encodes variant B-cell epitopes in the extracellular domain and the flanking transmembrane domains are rich in CD4(+)-T-cell epitopes. Importantly, at least four CD4(+)-T-cell epitopes are conserved between the two species, a finding consistent with A. marginale challenge triggering a recall response of CD4(+) T cells induced by A. centrale vaccination. The genomic arrangement is conserved between A. centrale and A. marginale with multiple msp-2 pseudogenes and a single operon-linked expression site for the full-length msp-2. This conservation of both genomic structure for generating MSP-2 variants and the CD4(+)-T-cell epitopes between these two genetically distinct Anaplasma species indicates that they present a similar repertoire of MSP-2 epitopes to the immune system and that this similarity may be responsible for all or part of the A. centrale vaccine efficacy.

Amino Acid Sequence↗
PubMed2005

Comparative phylogenetic analysis of cystatin gene families from arabidopsis, rice and barley.

The plant cystatins or phytocystatins comprise a family of specific inhibitors of cysteine proteinases. Such inhibitors are thought to be involved in the regulation of several endogenous processes and in defence against pests and pathogens. Extensive searches in the complete rice and Arabidopsis genomes and in barley EST collections have allowed us to predict the presence of twelve different cystatin genes in rice, seven in Arabidopsis, and at least seven in barley. Structural comparisons based on alignments of all the protein sequences using the CLUSTALW program and searches for conserved motifs using the MEME program have revealed broad conservation of the main motifs characteristic of the plant cystatins. Phylogenetic analyses based on their deduced amino acid sequences have allowed us to identify groups of orthologous cystatins, and to establish homologies and define examples of gene duplications mainly among the rice and barley cystatin genes. Moreover, the absence of a counterpart between the two monocots, as well as strong variations in the motifs that interact with the cysteine proteinases, may be related to a species-specific evolutionary process. This cystatin classification should facilitate the assignment of proteinase specificities and functions to other cystatins as new information is obtained.

Amino Acid Motifs↗
PubMed1997

Polymorphism and structure of the gene coding for the alpha 1 subunit of the Artemia franciscana Na/K-ATPase.

Genomic clones coding for one of the two identified Artemia franciscana Na/K-ATPase alpha subunits, the alpha 1 subunit, have been isolated. Several overlapping clones were obtained, although their restriction maps showed a large heterogeneity. Sequencing of their exons showed that they differ in up to 3.46% of their nucleotides in translated regions and 8.18% in untranslated regions. Southern blot analysis of DNA purified from different lots of A. franciscana cysts and from isolated individuals suggests that the variation is due to the existence of multiple Na/K-ATPase alpha 1 subunit alleles in A. franciscana. The Na/K-ATPase alpha 1 subunit gene is divided into 15 exons. Ten of the 14 introns are located in identical positions in this gene as in the human Na/K-ATPase alpha 3 subunit gene. Analysis of the 5' flanking region of the gene has allowed identification of the transcription-initiation sites. The adjacent upstream region has been shown to have functional promoter activity in cultured mammalian cells, suggesting the evolutionary conservation of some of the promoter regulatory sequences.

Amino Acid Sequence↗
PubMed2003

Evolution and development of mammalian limb integumentary structures.

The adaptive radiation of mammalian clades has involved marked changes in limb morphology that have affected not only the skeleton but also the integumentary structures. For example, didelphid marsupials show distinct differences in nail and claw morphology that are functionally related to the evolution of arboreal, terrestrial, and aquatic foraging behaviors. Vespertilionoid bats have evolved different volar pad structures such as adhesive discs, scales, and skin folds, whereas didelphid marsupials have apical pads covered either with scales, ridges, or small cones. Comparative analysis of pad and claw development reveals subtle differences in mesenchymal and ectodermal patterning underlying interspecific variation in morphology. Analysis of gene expression during pad and claw development reveals that signaling molecules such as Msx1 and Hoxc13 play important roles in the morphogenesis of these integumentary structures. These findings suggest that evolutionary change in the expression of these molecules, and in the response of mesenchymal and ectodermal cells to these signaling factors, may underlie interspecific differences in nail, claw, and volar pad morphology. Evidence from comparative morphology, development, and functional genomics therefore sheds new light on both the patterns and mechanisms of evolutionary change in mammalian limb integumentary structures.

Animals↗
PubMed2000

The human ribosomal protein L6 gene in a critical region for Noonan syndrome.

We have determined the genomic structure of the human ribosomal protein L6 gene (RPL6) and assigned it to the interval containing the Noonan syndrome locus. RPL6 spans 4415bp and consists of seven exons and six introns. The first exon is only 19bp in length, containing a 5' non-coding region and a polypyrimidine tract. The second exon starts with the initiator ATG. Although the overall structure of the protein is highly conserved among mammalian species, there is significant variation in the N-terminal portion. We have refined the position of RPL6, using two different radiation hybrid panels. RPL6 was mapped to chromosome 12q24.1 between the markers D12S84 and D12S861, which is in the critical region for Noonan syndrome.

Amino Acid Sequence↗
PubMed2005

Evidence for diversifying selection at the pyoverdine locus of Pseudomonas aeruginosa.

Pyoverdine is the primary siderophore of the gram-negative bacterium Pseudomonas aeruginosa. The pyoverdine region was recently identified as the most divergent locus alignable between strains in the P. aeruginosa genome. Here we report the nucleotide sequence and analysis of more than 50 kb in the pyoverdine region from nine strains of P. aeruginosa. There are three divergent sequence types in the pyoverdine region, which correspond to the three structural types of pyoverdine. The pyoverdine outer membrane receptor fpvA may be driving diversity at the locus: it is the most divergent alignable gene in the region, is the only gene that showed substantial intratype variation that did not appear to be generated by recombination, and shows evidence of positive selection. The hypothetical membrane protein PA2403 also shows evidence of positive selection; residues on one side of the membrane after protein folding are under positive selection. R', previously identified as a type IV strain, is clearly derived from a type III strain via a 3.4-kb deletion which removes one amino acid from the pyoverdine side chain peptide. This deletion represents a natural modification of the product of a nonribosomal peptide synthetase enzyme, whose consequences are predictive from the DNA sequence. There is also linkage disequilibrium between the pyoverdine region and pvdY, a pyoverdine gene separated by 30 kb from the pyoverdine region. The pyoverdine region shows evidence of horizontal transfer; we propose that some alleles in the region were introduced from other soil bacteria and have been subsequently maintained by diversifying selection.

Bacterial Outer Membrane Proteins↗
PubMed2000

Nucleotide sequences and mutations of the 5'-nontranslated region (5'NTR) of natural isolates of an epidemic echovirus 11' (prime).

An echovirus 11' (prime) virus caused an epidemic in Hungary in 1989. The leading clinical form of the diseases was myocarditis. Hemorrhagic hepatitis syndroms were also caused, however, with lethal outcome in 13 newborn babies. Altogether 386 children suffered from registered clinical disease. No accumulation of serous meningitis cases and intrauterine death were observed during the epidemic, and the monovalent oral poliovirus vaccination campaign has prevented the further circulation of the virus. The 5'-nontranslated region (5'-NTR) of 12 natural isolates were sequenced (nucleotides: 260-577). The 5'-NTR was found to be different from that of the prototype Gregory strain (X80059) of EV11 (less than 90% identity), but related to the swine vesicular disease virus (D16364) SVDV and EV9 (X92886) as indicated by the best fitting dendogram. The examination of the variable nucleotides in the internal ribosomal entry site (IRES) revealed, that the nucleotide sequence of a region of the epidemic 5'-NTR was identical to that of coxsackievirus B2. Five of the epidemic isolates were found to carry mutations. Seven EV11' IRES elements possessed identical sequences indicating, that the virus has evolved before its arrival to Hungary. The comparative examination of the suboptimal secondary structures revealed, that no one of the mutations affected the secondary structure of stem-loop structures IV and V in the IRES elements. Although it has been shown previously, that the echovirus group is genetically coherent and related to coxsackie B viruses the sequence differences in the epidemic isolates resulted in profound modification of the central stem (residues 477-529) of stem-loop structure No.V known to be affecting neurovirulence of polioviruses. Two alternate cloverleaf (stem-loop) structures were also recognised (nucleotides 376 to 460 and 540 to 565) which seem to mask both regions of the IRES element complementary to the 3'-end of the 18 S rRNA (460 to 466 and 561 to 570), thus probably diminishing initiation of translation. The possible biological importance of the alternative cloverleaf structures is supported by the fact that neither the 17 variable nucleotides nor the two mutations of epidemic isolates within the regions seem to modify the predicted alternative secondary structures in EV11, SVDV and CBV1-4.

5' Untranslated Regions↗
PubMed1984

Nucleotide sequence of the VP1 gene of the foot-and-mouth disease virus strain A Venceslau.

The VP1 coat protein of FMDV strain A Venceslau (Aven) consists of 213 amino acid residues. Serum neutralization tests demonstrated that strain Aven is closely related to strain A Argentina/79 (A79) but significantly different from strain A24Cruzeiro (A24). There is a strong correlation between the amino acid sequences and the serological data. Nucleotide and amino acid sequence analyses of VP1 showed that serologically related viruses (Aven and A79) differ less in this region of the genome than those of serologically distinct viruses (Aven vs. A24). The most significant variation between Aven and A24 occurs at amino acid positions 43 to 46, in which all four residues are different.

Amino Acid Sequence↗
PubMed2002

Sugarcane genomics: depicting the complex genome of an important tropical crop.

In the past few years, approaches such as molecular cytogenetics and the use of molecular markers have permitted significant advances in the establishment of the evolutionary origin and genome structure of sugarcane, an important polyploid crop. The availability of new resources, such as a bacterial artificial chromosome library and a huge collection of expressed sequence tags, has opened the gateway to promising functional analyses on a genomic scale.

Chromosome Mapping↗
PubMed1991

Genomic structure of the human prototype strain H of hepatitis C virus: comparison with American and Japanese isolates.

Genomic RNA from the human prototype strain H of the hepatitis C virus (HCV-H) has been molecularly cloned and sequenced. The HCV-H sequence reported consists of 9416 nucleotides including the 5' and 3' untranslated regions. HCV-H shows 96% amino acid identity with the American isolate HCV-1 but only 84.9% with the Japanese isolates HCV-J and HCV-BK. In addition to the hypervariable region (region V) previously identified in the putative E2 domain, three other variable domains were identified: region V1 (putative E1), region V2 (putative E2), and region V3 (putative NS5). These regions appear rather conserved (86-100%) among the American isolates (HCV-1 and HC-J1) or among various Japanese isolates (HCV-J, HCV-BK, HCV-JH, and HC-J4) but show striking heterogeneity when the two subgroups are compared (42-87.5% amino acid difference). A structural similarity between the 5'-terminal hairpin structure of HCV and of poliovirus was observed. This study further suggests the existence of at least two genomic subtypes of HCV and confirms a distant relationship between HCV and pestiviruses.

Amino Acid Sequence↗
PubMed2002

Direct detection of insertion/deletion polymorphisms in an autosomal region by analyzing high-density markers in individual spermatozoa.

Direct polymerase chain reaction (PCR) detection of insertion/deletion (indel) polymorphisms requires sample homozygosity. For the indel polymorphisms that have the deletion allele with a relatively low frequency in the autosomal regions, direct PCR detection becomes difficult or impossible. The present study is, to our knowledge, the first designed to directly detect indel polymorphisms in a human autosomal region (i.e., the immunoglobulin V(H) region), through use of single haploid sperm cells as subjects. Unique marker sequences (n=32), spaced at approximately 5-kb intervals, were selected near the 3' end of the V(H) region. A two-round multiplex PCR protocol was used to amplify these sequences from single sperm samples from nine unrelated healthy donors. The parental haplotypes of the donors were determined by examining the presence or absence of these markers. Seven clustered markers in 6 of the 18 haplotypes were missing and likely represented a 35-40-kb indel polymorphism. The genotypes of the donors, with respect to this polymorphism, perfectly matched the expectation under Hardy-Weinberg equilibrium. Three V(H) gene segments, of which two are functional, are affected by this polymorphism. According to these results, >10% of individuals in the human population may not have these gene segments in their genome, and approximately 44% may have only one copy of these gene segments. The biological impact of this polymorphism would be very interesting to study. The approach used in the present study could be applied to understand the physical structure and diversity of all other autosomal regions.

Genes, Immunoglobulin↗
PubMed2006

Prioritizing regions of candidate genes for efficient mutation screening.

The availability of the complete sequence of the human genome has dramatically facilitated the search for disease-causing sequence variations. In fact, the rate-limiting step has shifted from the discovery and characterization of candidate genes to the actual screening of human populations and the subsequent interpretation of observed variations. In this study we tested the hypothesis that some segments of candidate genes are more likely than others to contain disease-causing variations and that these segments can be predicted bioinformatically. A bioinformatic technique, prioritization of annotated regions (PAR), was developed to predict the likelihood that a specific coding region of a gene will harbor a disease-causing mutation based on conserved protein functional domains and protein secondary structures. This method was evaluated by using it to analyze 710 genes that collectively harbor 4,498 previously identified mutations. Nearly 50% of the genes were recognized as disease-associated after screening only 9% of the complete coding sequence. The PAR technique identified 90% of the genes as containing at least one mutation, with less than 40% of the screening resources that traditional approaches would require. These results suggest that prioritization strategies such as PAR can accelerate disease-gene identification through more efficient use of screening resources.

Computational Biology↗
PubMed1993

A phenotypically neutral dimorphism of protein S: the substitution of Lys155 by Glu in the second EGF domain predicted by an A to G base exchange in the gene.

During the course of structural gene analysis of a family with type III protein S deficiency, we found a novel DNA polymorphism: an A or G variation at nucleotide 732 in exon 6 of the PS-alpha gene. This A to G mutation would lead to a substitution of Lys155 by Glu in the second EGF domain. Linkage study with restriction enzyme analysis using mutagenic PCR strategy showed that the same mutation was also present in three other members of the patient's family and two individuals from an unrelated kindred, while they all had normal amounts of both immunological and functional PS levels. Restriction enzyme analysis of 182 normal Japanese genomic samples showed that 1.65% of normal population were heterozygotes for this variant allele. These findings suggest that this substitution in exon 6 is not responsible for the type III protein S deficiency but a phenotypically neutral polymorphism. Hereby we designate this polymorphism as PS-732.

Adolescent↗
PubMed2002

Comparative genetics and evolution of annexin A13 as the founder gene of vertebrate annexins.

Annexin A13 (ANXA13) is believed to be the original founder gene of the 12-member vertebrate annexin A family, and it has acquired an intestine-specific expression associated with a highly differentiated intracellular transport function. Molecular characterization of this subfamily in a range of vertebrate species was undertaken to assess coding region conservation, gene organization, chromosomal linkage, and phylogenetic relationships relevant to its progenitor role in the structure-function evolution of the annexin gene superfamily. Protein diagnostic features peculiar to this subfamily include an alternate isoform containing a KGD motif, an elevated basic amino acid content with polyhistidine expansion in the 5'-translated region, and the conservation of 15% core tetrad residues specific to annexin A13 members. The 12 coding exons comprising the 58-kb human ANXA13 gene were deduced from BAC clone sequencing, whereas internal repetitive elements and neighboring genes in chromosome 8q24.12 were identified by contig analysis of the draft sequence from the human genome project. A unique exon splicing pattern in the annexin A13 gene was corroborated by coanalysis of mouse, rat, zebrafish, and pufferfish genomic DNA and determined to be the most distinct of all vertebrate annexins. The putative promoter region was identified by phylogenetic footprinting of potential binding sites for intestine-specific transcription factors. Mouse annexin A13 cDNA was used to map the gene to an orthologous linkage group in mouse chromosome 15 (between Sdc2 and Myc by backcross analysis), and the zebrafish cDNA permitted its localization to linkage group 24. Comparative analysis of annexin A13 from nine species traced this gene's speciation history and assessed coding region variation, whereas phylogenetic analysis showed it to be the deepest-branching vertebrate annexin, and computational analysis estimated the gene age and divergence rate. The unique, conserved aspects of annexin A13 primary structure, gene organization, and genetic maps identify it as the probable common ancestor of all vertebrate annexins, beginning with the sequential duplication to annexins A7 and A11 approximately 700 MYA, before the emergence of chordates.

Alternative Splicing↗