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PubMed1999

Gene organization and sequence of the region containing the ribosomal protein genes RPL13A and RPS11 in the human genome and conserved features in the mouse genome.

We have determined the organization and sequence of the region containing two ribosomal protein (rp) genes in the human and mouse genomes. The two genes, human RPL13A and RPS11, and mouse Rpl13a and Rps11, are tandemly located in both genomes with an interval of only 4.6kb in the case of the human genes and 1.6kb in the case of the mouse genes. The human RPL13A and RPS11 are 4236bp and 3254bp in length and comprise eight and five exons respectively, whereas the mouse Rps11 is 1951bp long and has five exons. Structural comparison of these genes, including previously reported mouse Rpl13a, revealed a significant conservation of sequences in the promoter regions. Although most rp genes are dispersed throughout the human genome, the conserved features and adjacent localization indicate possible coordinate transcription of the two genes. Furthermore, we have found that four small nucleolar RNA (snoRNA) genes are located in the introns of the two rp genes, both human and mouse. U32, U33, and U34 snoRNAs are encoded in introns 2, 4, and 5 of RPL13A respectively, and U35 in the sixth intron of RPL13A and the third intron of RPS11. The same organization of these snoRNA genes was also observed in the case of the mouse genes.

Animals↗
PubMed2003

Comparing bacterial genomes through conservation profiles.

We constructed two-dimensional representations of profiles of gene conservation across different genomes using the genome of Escherichia coli as a model. These profiles permit both the visualization at the genome level of different traits in the organism studied and, at the same time, reveal features related to the genomes analyzed (such as defective genomes or genomes that lack a particular system). Conserved genes are not uniformly distributed along the E. coli genome but tend to cluster together. The study of gene distribution patterns across genomes is important for the understanding of how sets of genes seem to be dependent on each other, probably having some functional link. This provides additional evidence that can be used for the elucidation of the function of unannotated genes. Clustering these patterns produces families of genes which can be arranged in a hierarchy of closeness. In this way, functions can be defined at different levels of generality depending on the level of the hierarchy that is studied. The combined study of conservation and phenotypic traits opens up the possibility of defining phenotype/genotype associations, and ultimately inferring the gene or genes responsible for a particular trait.

Chromosome Mapping↗
PubMed1979

Incomplete genomes of the parvovirus minute virus of mice: selective conservation of genome termini, including the origin for DNA replication.

Deletion mutants of minute virus of mice arising during a single high-multiplicity passage and after serial undiluted passage have been isolated, and the incomplete viral genomes contained therein have been analyzed. The DNA isolated from incomplete virions derived from a single high-multiplicity passage was heterogeneous, ranging in size from 15 to 70% of the intact viral genome, with an average molecular length of approximately, 2,000 nucleotides. Two distinct types of molecules, designated as type I D-DNA and type II D-DNA, could be distinguished on the basis of their degree of secondary structure, and these were present in roughly equal amounts. Type I D-DNAs were predominantly single-stranded, recombinant molecules in which the self-complementary sequences derived from both genomic termini were conserved. The 5' terminus was modified relative to the analogous wild-type structure. Although virtually all of the wild-type genome sequence was seen in the total type I D-DNA population, sequences which map between coordinates 47.3 and 87.1 were clearly underrepresented. However, the extent and position of the deletions in individual molecules varied significantly. The shortest molecules in the population lacked between 90 and 95% of the internal wild-type genome sequence and consisted of sequences derived almost exclusively from within 5.0 map units (250 nucleotides) at both ends of the viral genome. Moreover, these miniature recombinant molecules were selectively amplified during serial undiluted passage and were therefore believed to contain all of the critical recognition sites necessary for the replication of minute virus of mice viral DNA. Type II D-DNAs were virus-specific, double-stranded hairpin molecules whose complementary strands were covalently continuous at variable sites distal to the 5' end of the viral minus strand. In sharp contrast to the type I genomes, these hairpin molecules consisted of sequences which mapped entirely at the 5' end of the viral genome between positions 85.0 and 100. Furthermore, type II molecules were gradually lost from the total D-DNA population during serial undiluted passage, suggesting that these molecules are not competent for DNA Replication but arise as the result of fatal replication errors. Deletion mutants of the type described here for minute virus of mice should be valuable generally as aids to future studies on parvovirus DNA replication, transcription, and cell-virus interactions.

Base Sequence↗
PubMed2000

Estimation of synteny conservation and genome compaction between pufferfish (Fugu) and human.

BACKGROUND: Knowledge of the amount of gene order and synteny conservation between two species gives insights to the extent and mechanisms of divergence. The vertebrate Fugu rubripes (pufferfish) has a small genome with little repetitive sequence which makes it attractive as a model genome. Genome compaction and synteny conservation between human and Fugu were studied using data from public databases. METHODS: Intron length and map positions of human and Fugu orthologues were compared to analyse relative genome compaction and synteny conservation respectively. The divergence of these two genomes by genome rearrangement was simulated and the results were compared to the real data. RESULTS: Analysis of 199 introns in 22 orthologous genes showed an eight-fold average size reduction in Fugu, consistent with the ratio of total genome sizes. There was no consistent pattern relating the size reduction in individual introns or genes to gene base composition in either species. For genes that are neighbours in Fugu (genes from the same cosmid or GenBank entry), 40-50% have conserved synteny with a human chromosome. This figure may be underestimated by as much as two-fold, due to problems caused by incomplete human genome sequence data and the existence of dispersed gene families. Some genes that are neighbours in Fugu have human orthologues that are several megabases and tens of genes apart. This is probably caused by small inversions or other intrachromosomal rearrangements. CONCLUSIONS: Comparison of observed data to computer simulations suggests that 4000-16 000 chromosomal rearrangements have occurred since Fugu and human shared a common ancestor, implying a faster rate of rearrangement than seen in human/mouse comparisons.

Animals↗
PubMed2003

Conservation of genome content and virulence determinants among clinical and environmental isolates of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a ubiquitous environmental bacterium capable of causing a variety of life-threatening human infections. The genetic basis for preferential infection of certain immunocompromised patients or individuals with cystic fibrosis by P. aeruginosa is not understood. To establish whether variation in the genomic repertoire of P. aeruginosa strains can be associated with a particular type of infection, we used a whole-genome DNA microarray to determine the genome content of 18 strains isolated from the most common human infections and environmental sources. A remarkable conservation of genes including those encoding nearly all known virulence factors was observed. Phylogenetic analysis of strain-specific genes revealed no correlation between genome content and infection type. Clusters of strain-specific genes in the P. aeruginosa genome, termed variable segments, appear to be preferential sites for the integration of novel genetic material. A specialized cloning vector was developed for capture and analysis of these genomic segments. With this capture system a site associated with the strain-specific ExoU cytotoxin-encoding gene was interrogated and an 80-kb genomic island carrying exoU was identified. These studies demonstrate that P. aeruginosa strains possess a highly conserved genome that encodes genes important for survival in numerous environments and allows it to cause a variety of human infections. The acquisition of novel genetic material, such as the exoU genomic island, through horizontal gene transfer may enhance colonization and survival in different host environments.

Bacterial Proteins↗
PubMed1984

A frequent restriction fragment length polymorphism in the human metallothionein-II processed gene region is evolutionarily conserved.

Genomic blot analysis of human DNA indicated that metallothioneins are represented by a multi-gene family. Clones containing metallothionein sequences have been isolated and two of these have been identified as metallothionein-I and metallothionein-II processed genes by sequence analysis. The metallothionein-II processed gene in humans shows two restriction fragment length polymorphisms of 4.5 and 4.8 kb (10(3) bases) when EcoRI-digested genomic DNA from various individuals was analysed by Southern blotting. All the three genotypes are found at a high frequency and thus the metallothionein-II processed gene represents a true polymorphic marker. Familial studies also indicate that these restriction fragment length polymorphisms follow the classical Mendelian inheritance. Detailed Southern blot analyses show that this restriction fragment length polymorphism is due to a restriction site polymorphism and is localized at the 5'-flanking region of the metallothionein-II processed gene. Sequence analysis of the suspected region in the 4.8 kb fragment shows that the sequence G*GATTC, which is found 371 nucleotides downstream from the EcoRI site on the 5' end of the 4.8 kb fragment, makes a HinfI site. A transition of *G to A in this sequence in the 4.5 kb allele has resulted in loss of the HinfI site and created an EcoRI site. Thus, this mutation has given rise to this restriction fragment length polymorphism.

Alleles↗
PubMed2001

Characterization of the genomic Xist locus in rodents reveals conservation of overall gene structure and tandem repeats but rapid evolution of unique sequence.

The Xist locus plays a central role in the regulation of X chromosome inactivation in mammals, although its exact mode of action remains to be elucidated. Evolutionary studies are important in identifying conserved genomic regions and defining their possible function. Here we report cloning, sequence analysis, and detailed characterization of the Xist gene from four closely related species of common vole (field mouse), Microtus arvalis. Our analysis reveals that there is overall conservation of Xist gene structure both between different vole species and relative to mouse and human Xist/XIST. Within transcribed sequence, there is significant conservation over five short regions of unique sequence and also over Xist-specific tandem repeats. The majority of unique sequences, however, are evolving at an unexpectedly high rate. This is also evident from analysis of flanking sequences, which reveals a very high rate of rearrangement and invasion of dispersed repeats. We discuss these results in the context of Xist gene function and evolution.

3' Untranslated Regions↗
PubMed2004

Conservation of genomic imprinting at the XIST, IGF2, and GTL2 loci in the bovine.

Genomic imprinting is theorized to exist in all placental mammals and some marsupials; however, extensive comparative analysis of animals aside from humans and mice remains incomplete. Here we report conservation of genomic imprinting in the bovine at the X chromosome inactivation-specific transcript (XIST), insulin-like growth factor 2 (IGF2), and gene trap locus 2 (GTL2) loci. Coding single nucleotide polymorphisms (SNPs) between Bos gaurus and Bos taurus were detected at the XIST, IGF2, and GTL2 loci, which have previously been identified as imprinted in either humans, mice, or sheep. Expression patterns of parental alleles in F1 hybrids indicated preferential paternal expression at the XIST locus solely in the chorion of females, whereas analysis of the IGF2 and GTL2 loci indicated preferential paternal and maternal expression of alleles, respectively, in both fetal and placental tissues. Comparative sequence analysis of the XIST locus and adjacent regions suggests that repression of the maternal allele in the bovine is controlled by a different mechanism than in mice, further reinforcing the importance of comparative analysis of imprinting.

Alleles↗
PubMed2025

Conservation Arks: Genomic Erosion and Inbreeding in an Abundant Island Population of Koalas.

The persistence of many threatened species depends on isolated habitat patches such as conservation parks, fenced reserves, and islands. While these 'conservation arks' provide refuge from many contemporary threats, they can also pose risks of genetic diversity loss and inbreeding depression, further exacerbating extinction risk. A pertinent example is the Kangaroo Island koala population in South Australia that originated from a few translocated founding individuals in the 1920s but now sustains a large population with a low prevalence of infectious disease. We investigated the extent and consequences of founder effects on genomic diversity, inbreeding, and adaptive potential in Kangaroo Island koalas by comparing them with mainland Australian populations using high-coverage whole genomes. Our findings support sharp, recent declines in effective population sizes (Ne) in both mainland and Kangaroo Island populations. However, Kangaroo Island koalas had much lower individual and population-level diversity. Together with longer and more numerous runs of homozygosity and an increased proportion of homozygous genetic load, these results support the hypothesis that a severe bottleneck has contributed to inbreeding and maladaptation in Kangaroo Island koalas. While Kangaroo Island has the potential to conserve a viable population of koalas, we recommend genetic rescue to restore diversity and mitigate inbreeding depression in this isolated population. Our results emphasise the need for longitudinal genomic monitoring and genetic management to maintain long-term viability and resilience in potential conservation arks. Understanding the demographic history of such populations will help inform future conservation aimed at preventing genetic erosion and preserving biodiversity.

Animals↗
PubMed2006

Post-transcriptional control of nuclear-encoded cytochrome oxidase subunits in Trypanosoma brucei: evidence for genome-wide conservation of life-cycle stage-specific regulatory elements.

Trypanosomes represent an excellent model for the post-transcriptional regulation of gene expression because their genome is organized into polycistronic transcription units. However, few signals governing developmental stage-specific expression have been identified, with there being no compelling evidence for widespread conservation of regulatory motifs. As a tool to search for common regulatory sequences we have used the nuclear-encoded components of the cytochrome oxidase (COX) complex of the trypanosome respiratory chain. Components of this complex represent a form of post-transcriptional operon because trypanosome mitochondrial activity is unusual in being developmentally programmed. By genome analysis we identified the genes for seven components of the COX complex. Each mRNA exhibits bloodstream stage-specific instability, which is not mediated by the RNA silencing pathway but which is alleviated by cycloheximide. Reporter assays have identified regulatory regions within the 3'-untranslated regions of three COX mRNAs operating principally at the translational level, but also via mRNA stability. Interrogation of the mapped regions via oligonucleotide frequency scoring provides evidence for genome-wide conservation of regulatory sequences among a large cohort of procyclic-enriched transcripts. Analysis of the co-regulated subunits of a stage-specific enzyme is therefore a novel approach to uncover cryptic regulatory sequences controlling gene expression at the post-transcriptional level.

3' Untranslated Regions↗
PubMed2003

Anaplastic thyroid cancer evolved from papillary carcinoma: demonstration of anaplastic transformation by means of the inter-simple sequence repeat polymerase chain reaction.

BACKGROUND: In thyroid tumors, the coexistence of well- and poorly differentiated tumor types has led to the hypothesis that poorly differentiated thyroid tumors develop from well-differentiated thyroid tumors. By evaluating the genomic instability of histologically distinct but coexisting tumor foci, this study aimed to develop an improved understanding of thyroid tumorigenesis and tumor evolution. DESIGN: Laser capture microdissection (LCM) was carried out on archival formalin-fixed, paraffin-embedded sections from a tumor containing foci of classic papillary thyroid cancer and anaplastic thyroid cancer. DNA was extracted from each microdissected tumor focus. In addition, cryopreserved bulk normal and neoplastic thyroid tissue underwent DNA extraction. All DNA samples were subsequently evaluated for genomic instability by means of inter-simple sequence repeat polymerase chain reaction. RESULTS: The LCM DNA from each archival paraffin-embedded tumor focus demonstrated unique patterns of banding as compared with the cryopreserved tumor and normal tissue DNA. Thus, intratumoral variability in genomic instability was observed. Comparison of inter-simple sequence repeat polymerase chain reaction patterns of LCM DNA from adjacent foci of papillary and anaplastic tumors showed conserved genome alterations. CONCLUSIONS: At the genome level, thyroid tumors may be highly heterogeneous. The intratumoral histologic heterogeneity observed in thyroid neoplasms reflects genetically heterogeneous underlying tumor cell populations that are demonstrated by the observed differences in their rates and extents of genomic instability. The conserved genomic alterations in the microdissected papillary and anaplastic foci suggest intratumoral evolution, with transformation of a preexisting papillary tumor to anaplastic carcinoma.

Aged↗
PubMed2006

Identification of Escherichia coli O157:H7 genomic regions conserved in strains with a genotype associated with human infection.

Beta-glucuronidase-negative, sorbitol-nonfermenting isolates of Shiga toxin-producing Escherichia coli O157 comprise part of a clone complex of related enterohemorrhagic E. coli isolates. High-resolution genotyping shows that the O157 populations have diverged into two different lineages that appear to have different ecologies. To identify genomic regions unique to the most common human-associated genotype, suppression subtractive hybridization was used to identify DNA sequences present in two clinical strains representing the human lineage I O157:H7 strains but absent from two bovine-derived lineage II strains. PCR assays were then used to test for the presence of these regions in 10 lineage I strains and 20 lineage II strains. Twelve conserved regions of genomic difference for lineage I (CRD(I)) were identified that were each present in at least seven of the lineage I strains but absent in most of the lineage II strains tested. The boundaries of the lineage I conserved regions were further delimited by PCR. Eleven of these CRD(I) were associated with E. coli Sakai S-loops 14, 16, 69, 72, 78, 82, 83, 91 to 93, 153, and 286, and the final CRD(I) was located on the pO157 virulence plasmid. Several potential virulence factors were identified within these regions, including a putative hemolysin-activating protein, an iron transport system, and several possible regulatory genes. Cluster analysis based on lineage I conserved regions showed that the presence/absence of these regions was congruent with the inferred phylogeny of the strains.

Animals↗
PubMed2006

Genomics and conservation genetics.

In large part, the relevance of genetics to conservation rests on the premise that neutral marker variation in populations reflects levels of detrimental and adaptive genetic variation. Despite its prominence, this tenet has been difficult to evaluate, until now. As we discuss here, genome sequence information and new technological and bioinformatics platforms now enable comprehensive surveys of neutral variation and more direct inferences of detrimental and adaptive variation in species with sequenced genomes and in 'genome-enabled' endangered taxa. Moreover, conservation schemes could begin to consider specific pathological genetic variants. A new conservation genetic agenda would utilize data from enhanced surveys of genomic variation in endangered species to better manage functional genetic variation.

Animals↗
PubMed2002

Genomic structure, conservation and FISH mapping of the Rattus norvegicus Adprt gene.

Poly(ADP-ribose) polymerase 1 (PARP-1) lies at the basis of a DNA-interacting protein family that maintains genome integrity. Here we describe the genomic organisation of rat PARP-1 gene (Adprt), refine its assignment to rat chromosome (RNO) 13q25-->q26 by FISH and compare its genomic organisation between rat, mouse and human. It appears that in human, mouse and rat Adprt consists of 23 similar-sized exons with well-conserved intron and exon borders. Adprt orthologs map to homologous chromosome regions at the termini of the q-arms of human and mouse chromosomes 1 and rat 13, with gene order being conserved between the rodents. Kimura protein distance comparison with human PARP-1 as reference revealed the bovine protein to be the least conserved with 10.3 substitutions per 100 amino acids, followed by rat (8.6) and mouse (8.4).

ADP Ribose Transferases↗
PubMed2004

Clusters of co-expressed genes in mammalian genomes are conserved by natural selection.

Genes that belong to the same functional pathways are often packaged into operons in prokaryotes. However, aside from examples in nematode genomes, this form of transcriptional regulation appears to be absent in eukaryotes. Nevertheless, a number of recent studies have shown that gene order in eukaryotic genomes is not completely random, and that genes with similar expression patterns tend to be clustered together. What remains unclear is whether co-expressed genes have been gathered together by natural selection to facilitate their regulation, or if the genes are co-expressed simply by virtue of their being close together in the genome. Here, we show that gene expression clusters tend to contain fewer chromosomal breakpoints between human and mouse than expected by chance, which indicates that they are being held together by natural selection. This conclusion applies to clusters defined on the basis of broad (housekeeping) expression, or on the basis of correlated transcription profiles across tissues. Contrary to previous reports, we find that genes with high expression are not clustered to a greater extent than expected by chance and are not conserved during evolution.

Animals↗
PubMed2005

Comparative functional genomics revealed conservation and diversification of three enhancers of the isl1 gene for motor and sensory neuron-specific expression.

Islet-1 (Isl1) is a member of the Isl1 family of LIM-homeodomain transcription factors (LIM-HD) that is expressed in a defined subset of motor and sensory neurons during vertebrate embryogenesis. To investigate how this specific expression of isl1 is regulated, we searched for enhancers of the isl1 gene that are conserved in vertebrate evolution. Initially, two enhancer elements, CREST1 and CREST2, were identified downstream of the isl1 locus in the genomes of fugu, chick, mouse, and human by BLAST searching for highly similar elements to those originally identified as motor and sensory neuron-specific enhancers in the zebrafish genome. The combined action of these elements is sufficient for completely recapitulating the subtype-specific expression of the isl1 gene in motor neurons of the mouse spinal cord. Furthermore, by direct comparison of the upstream flanking regions of the zebrafish and human isl1 genes, we identified another highly conserved noncoding element, CREST3, and subsequently C3R, a similar element to CREST3 with two CDP CR1 recognition motifs, in the upstream regions of all other isl1 family members. In mouse and human, CRESTs are located as far as more than 300 kb away from the isl1 locus, while they are much closer to the isl1 locus in zebrafish. Although all of zebrafish CREST2, CREST3, and C3R activate gene expression in the sensory neurons of zebrafish, CREST2 of mouse and human does not have the sequence necessary for sensory neuron-specific expression. Our results revealed both a remarkable conservation of the regulatory elements regulating subtype-specific gene expression in motor and sensory neurons and the dynamic process of reorganization of these elements whereby each element increases the level of cell-type specificity by losing redundant functions with the other elements during vertebrate evolution.

Animals↗
PubMed1997

The 5'-terminal 32 basepairs conserved between genome segments A and B contain a major promoter element of infectious bursal disease virus.

The regions of the infectious bursal disease virus (IBDV) genome with regulatory function are not known. In the present study, progressively deleted lengths of the 5' noncoding region of segment A were constructed in pGL3 vectors having SV40 enhancer or promoter, and a luciferase (LUC) reporter gene. Transient transfections of the constructs made in a promoter-less pGL3-Enhancer vector when transfected in Vero cells and the lysates assayed for LUC expression, allowed the localization of maximal activity to the 32-nucleotide stretch (precursor polyprotein ORF positions -131 to -100), which is highly conserved at the 5' end of both genome segments. This fragment, when evaluated in parallel in an enhancer-less pGL3-Promoter vector demonstrated no activity. To determine if this region is recognized by IBDV replicative proteins, we engineered modifications in an enhancer-less pGL3-Promoter vector where the terminal 32-bp fragment, the full-length noncoding region, or the noncoding region with the 32-bp fragment deleted was positioned in either the plus-sense or the minus-sense orientation immediately downstream of the SV40 promoter and upstream of the LUC gene. Transfections of these constructs in IBDV-infected and uninfected Vero cells resulted in the endogenous generation of recombinant viral-LUC RNAs containing the 5' terminal viral RNA sequences in either the plus-sense or the minus-sense orientation. LUC assays of the infected cell lysates showed up-regulated expression of LUC only with constructs containing the 32-bp fragment in the minus-sense orientation. Deletion of this 32-bp fragment abolished such LUC expression. We therefore conclude that the 5'-terminal 32 base pairs of genomic segment A contain a major promoter element in IBDV. In addition, our results show that IBDV replicative proteins recognize and transcribe single-stranded RNA in vivo.

Animals↗