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PubMed2003

Ancestral polymorphisms in genetic markers obscure detection of evolutionarily distinct populations in the endangered Florida grasshopper sparrow (Ammodramus savannarum floridanus).

Genetic analyses of bird subspecies designated as conservation units can address whether they represent units with independent evolutionary histories and provide insights into the evolutionary processes that determine the degree to which they are genetically distinct. Here we use mitochondrial DNA control region sequence and six microsatellite DNA loci to examine phylogeographical structure and genetic differentiation among five North American grasshopper sparrow (Ammodramus savannarum) populations representing three subspecies, including a population of the endangered Florida subspecies (A. s. floridanus). This federally listed taxon is of particular interest because it differs phenotypically from other subspecies in plumage and behaviour and has also undergone a drastic decline in population size over the past century. Despite this designation, we observed no phylogeographical structure among populations in either marker: mtDNA haplotypes and microsatellite genotypes from floridanus samples did not form clades that were phylogenetically distinct from variants found in other subspecies. However, there was low but significant differentiation between Florida and all other populations combined in both mtDNA (FST = 0.069) and in one measure of microsatellite differentiation (theta = 0.016), while the non-Florida populations were not different from each other. Based on analyses of mtDNA variation using a coalescent-based model, the effective sizes of these populations are large (approximately 80,000 females) and they have only recently diverged from each other (< 26,000 ybp). These populations are probably far from genetic equilibrium and therefore the lack of phylogenetic distinctiveness of the floridanus subspecies and minimal genetic differentiation is due most probably to retained ancestral polymorphism. Finally, levels of variation in Florida were similar to other populations supporting the idea that the drastic reduction in population size which has occurred within the last 100 years has not yet had an impact on levels of variation in floridanus. We argue that despite the lack of phylogenetic distinctiveness of floridanus genotypes the observed genetic differentiation and previously documented phenotypic differences justify continued designation of this subspecies as a protected population segment.

Animals↗
PubMed2002

Creutzfeldt-Jakob disease cluster in an Australian rural city.

Through the Australian National Creutzfeldt-Jakob Disease Registry, 6 pathologically confirmed sporadic cases were recognized over a 13-year period in persons who had been long-term residents of a moderate-sized rural city, whereas the expected number was 0.923. An extensive investigation could not find any point-source or case-to-case transmission links. This occurrence is highly statistically significant (p = 0.0027) when viewed in isolation and remains significant (p < 0.02) when only the cases that arose after the cluster was recognized were taken into account. However, a more conservative statistical analysis suggests that such a grouping could have arisen by chance in at least one population group of this size when the whole country is taken into consideration.

Aged↗
PubMed2002

Search for enhancers: teleost models in comparative genomic and transgenic analysis of cis regulatory elements.

Homology searches between DNA sequences of evolutionary distant species (phylogenetic footprinting) offer a fast detection method for regulatory sequences. Because of the small size of their genomes, tetraodontid species such as the Japanese pufferfish and green spotted pufferfish have become attractive models for comparative genomics. A disadvantage of the tetraodontid species is, however, that they cannot be bred and manipulated routinely under laboratory conditions, so these species are less attractive for developmental and genetic analysis. In contrast, an increasing arsenal of transgene techniques with the developmental model species zebrafish and medaka are being used for functional analysis of cis regulatory sequences. The main disadvantage is the much larger genome. While comparison between many loci proved the suitability of phylogenetic footprinting using fish and mammalian sequences, fast rate of change in enhancer structure and gene duplication within teleosts may obscure detection of homologies. Here we discuss the contribution and potentials provided by different teleost models for the detection and functional analysis of conserved cis-regulatory elements.

Animals↗
PubMed2005

The frequency of ipsilateral second tumors after breast-conserving surgery for DCIS: a population based analysis.

BACKGROUND: The diagnosis of ductal carcinoma in situ (DCIS) is increasing, although to the authors' knowledge there is no consensus regarding optimal treatment. This analysis of women treated with breast-conserving surgery (BCS) evaluated the impact of radiation therapy (RT) in patient outcomes. METHODS: The current study included a population-based sample of 1103 women residing in selected Surveillance, Epidemiology, and End Results (SEER) registries who were diagnosed with DCIS between 1991-1992. Data were obtained from the registry, physician follow-up, and pathology reports. Physicians were contacted in 1999 to determine whether the patient had developed a second event in the ipsilateral breast. For second events, pathology reports were reviewed to determine the presence of in situ or invasive disease. Registry data through 2001 were used to assess death rates and cause of death. Cox proportional hazards and logistic regression models were used to evaluate the rates of second events and breast carcinoma deaths between women treated with and without RT. RESULTS: Over an average of 91 months, 13.2% of women developed a second event. Rates of second events were 11% for women treated with BCS and RT compared with 15% for women treated with BCS only (adjusted hazards ratio, 0.64; 95% confidence interval, 0.44-0.92). Women receiving RT were significantly less likely to develop invasive breast carcinoma in the ipsilateral breast (adjusted odds ratio, 0.40). By 2001, the rate of death from breast carcinoma was 2.7%; in the group of women treated with BCS only compared with 0.8% in the group of women treated with BCS with RT. CONCLUSIONS: Among a population-based cohort, RT was found to significantly reduce the risk of second events in the ipsilateral breast, particularly invasive tumors, although not to the extent reported in clinical trials.

Aged↗
PubMed1990

Isolation and structure of a cDNA expressing a mammalian 3-methyladenine-DNA glycosylase.

A cDNA plasmid expression library was constructed from the poly(A)+ mRNA of H4 cells, a rat hepatoma cell line. The library was introduced into Escherichia coli strain BH290 deficient in the repair of 3-methyladenine (3-meAde) residues in DNA. This DNA repair deficiency renders the stain phenotypically sensitive to treatment with alkylating agents. The cDNA library was screened for survivors to methylmethane sulfonate. BH290 cells hosting one of the plasmids, pAPDG10 (Alkylated N-Purine-DNA Glycosylase), from surviving cells had a sensitivity to MMS equivalent to that of the wild type strain. Crude extracts of BH290 cells harboring the pAPDG10 plasmid released 3-meAde and 7-methylguanine residues from DNA methylated with [methyl-3H]dimethylsulfate. The cDNA sequence of 993 bp inserted in pAPDG10 has a single open reading frame greater than 85 amino acids in length. The derived APDG protein sequence of 253 amino acids and the 3-meAde-DNA glycosylase II of E. coli coded for by the alkA gene have regions of conserved sequences. Analysis of the genomic DNA using Southern hybridization suggests that the APDG gene has a minimal size of 6.5-12 kb. Northern blot analysis shows that the transcript produced in H4 cells is also present in normal rat liver cells.

Amino Acid Sequence↗
PubMed1994

The subunit interfaces of oligomeric enzymes are conserved to a similar extent to the overall protein sequences.

It is well established that, within families of homologous enzymes, amino acid residues that are involved in the chemistry of the reaction are highly conserved. To determine if residues at the subunit interface of oligomeric enzymes with shared active sites are also conserved, comparative analysis of five enzyme families was undertaken. For the chosen enzyme families, sequence data were available for a large number of proteins and a three-dimensional structure was known for at least two members of each family. The analysis indicates that the subunit interface and the hydrophobic core of proteins from all five families have diverged to a similar extent to the overall protein sequences.

Biological Evolution↗
PubMed2005

Hybrid native partitioning of interactions among nonconserved residues in chimeric proteins.

Given any operational criterion for pairwise interatomic interactions, for a pair of structurally homologous proteins there exists for both proteins a unique equivalent partitioning of the nonconserved residue positions into mutually non-interacting clusters. In the formation of a chimeric protein derived from these two parental sequences, if nonnative-like interactions are to be avoided in its tertiary structure, then all of the nonconserved residues of each cluster must necessarily be either maintained or interchanged simultaneously. This hybrid native partitioning criterion is applied to known gene shuffling results. When the degree of estimated disruption is modest, the HybNat algorithm provides an efficient predictor of structural integrity. This supports the expectation that a substantial fraction of sequences that conform to the hybrid native partitioning criterion will yield tertiary structures that largely preserve the native-like interactions of the parental proteins.

Algorithms↗
PubMed1995

Three-dimensional structure prediction of the NAD binding site of proton-pumping transhydrogenase from Escherichia coli.

A three-dimensional structure of the NAD site of Escherichia coli transhydrogenase has been predicted. The model is based on analysis of conserved residues among the transhydrogenases from five different sources, homologies with enzymes using NAD as cofactors or substrates, hydrophilicity profiles, and secondary structure predictions. The present model supports the hypothesis that there is one binding site, located relatively close to the N-terminus of the alpha-subunit. The proposed structure spans residues alpha 145 to alpha 287, and it includes five beta-strands and five alpha-helices oriented in a typical open twisted alpha/beta conformation. The amino acid sequence following the GXGXXG dinucleotide binding consensus sequence (residues alpha 172 to alpha 177) correlates exactly to a typical fingerprint region for ADP binding beta alpha beta folds in dinucleotide binding enzymes. In the model, aspartic acid alpha 195 forms hydrogen bonds to one or both hydroxyl groups on the adenosine ribose sugar moiety. Threonine alpha 196 and alanine alpha 256, located at the end of beta B and beta D, respectively, create a hydrophobic sandwich with the adenine part of NAD buried inside. The nicotinamide part is located in a hydrophobic cleft between alpha A and beta E. Mutagenesis work has been carried out in order to test the predicted model and to determine whether residues within this domain are important for proton pumping directly. All data support the predicted structure, and no residue crucial for proton pumping was detected. Since no three-dimensional structure of transhydrogenase has been solved, a well based tertiary structure prediction is of great value for further experimental design in trying to elucidate the mechanism of the energy-linked proton pump.

Amino Acid Sequence↗
PubMed1998

Molecular study and partial characterization of iron-only hydrogenase in Desulfovibrio fructosovorans.

An iron-only hydrogenase was partially purified and characterized from Desulfovibrio fructosovorans wild-type strain. The enzyme exhibits a molecular mass of 56 kDa and is composed of two distinct subunits HydA and HydB (46 and 13 kDa, respectively). The N-terminal amino acid sequences of the two subunits of the enzyme were determined with the aim of designing degenerate oligonucleotides. Direct and inverse polymerase chain reaction techniques were used to clone the hydrogenase encoding genes. A 9-nucleotide region located 75 bp upstream from the translational start codon of the D. fructosovorans hydA gene was found to be highly conserved. The analysis of the deduced amino acid sequence of these genes showed the presence of a signal sequence located in the small subunit, exhibiting the consensus sequence which is likely to be involved in the specific export mechanism of hydrogenases. Two ferredoxin-like motives involved in the coordination of [4Fe-4S] clusters were identified in the N-terminal domain of the large subunit. The amino acid sequence of the [Fe] hydrogenase from D. fructosovorans was compared with the amino acid sequences from eight other hydrogenases (cytoplasmic and periplasmic). These enzymes share an overall 18% identity and 28% similarity. The identity reached 73% and 69% when the D. fructosovorans hydrogenase sequence was compared with the hydrogenase sequences from Desulfovibrio vulgaris Hildenborough and Desulfovibrio vulgaris oxamicus Monticello, respectively.

Journal Article↗
PubMed2000

Analysis of the role of conserved cysteine residues in the bcl-2 oncoprotein.

The Bcl-2 oncoprotein is an integral membrane protein localized primarily to the outer membrane of the mitochondria. The precise molecular mechanism responsible for the antiapoptotic action of Bcl-2 remains unknown. Two cysteine residues are found in Bcl-2 and these residues are well-conserved across species. The first cysteine (cys(155)) is located in the alpha5 domain, a region important for the ion channel properties of Bcl-2, while the second cysteine (cys(226)) is located in the carboxyl-terminal membrane anchor domain. In this study, we found that replacement of both cysteines with serine residues generated a mutant protein that retained the ability to homodimerize and heterodimerize with proapoptotic Bax protein in vitro. In whole cells, the mutant protein efficiently heterodimerized with Bax, but exhibited impaired homodimerizationrelative to wild-type Bcl-2. The mutant protein was also less efficient than wild-type Bcl-2 at suppressing caspase activation, DNA fragmentation, and loss of viability during IL-3 withdrawal-induced apoptosis. Together, the data indicate that the cysteine residues in Bcl-2 contribute, but are not absolutely essential, to the ability of Bcl-2 to homodimerize, heterodimerize with Bax, and suppress apoptosis.

Amino Acid Substitution↗
PubMed1993

ZNF75: isolation of a cDNA clone of the KRAB zinc finger gene subfamily mapped in YACs 1 Mb telomeric of HPRT.

We have previously mapped a zinc finger genomic motif (ZNF75) to the Xq26 cytogenetic band by using a hybrid panel. Here, we report the isolation of the transcribed counterpart in a cDNA clone and its further localization. The cDNA clone, from a lung fibroblast library, is assembled from three exons, including a 289 amino acid (AA) long open reading frame containing a recently described motif, the Kruppel-associated box, 42 AA long, in exon 2. By comparison with other reported members of the subfamily, the exon-intron boundaries also appear to be very well conserved. Further analysis allowed us to map this gene 1 Mb downstream from the HPRT gene in the published YAC contig that extends across Xq26. Two other motifs, 87 and 78% homologous to ZNF75 at the amino acid level, were identified by PCR on total human DNA, but map outside Xq24-qter.

Amino Acid Sequence↗
PubMed1998

Structure and mapping of the G protein gamma3 subunit gene and a divergently transcribed novel gene, gng3lg.

The mammalian nervous system is rich in signaling mediated by heterotrimeric (alphabetagamma) G proteins. As an initial step to define the roles that particular gamma subunit types play in signaling, we have begun to clone and characterize those genes that encode gamma subunits enriched within neural tissue. In the present study, we have isolated and characterized the mouse gamma3 subunit gene (Gng3). The gamma3 subunit is expressed abundantly in the brain and at low levels in testes. Gng3 is composed of three exons spanning approximately 1.4 kb. A comparison of Gng3 with the gene structure for five other gamma subtypes indicates that although these proteins are diverse at the amino acid level, their exon-intron boundaries are conserved. Sequence analysis of the 5' flanking region of Gng3 revealed the presence of a novel gene, the gamma3 linked gene (Gng3lg). Gng3 and Gng3lg are organized in a head-to-head fashion with major transcription initiation sites separated by approximately 133 bp. Sequence analysis of a Gng3lg cDNA clone revealed an open reading frame encoding a 410-amino-acid protein of unknown function. Gng3lg transcripts are expressed in a variety of tissues including both brain and testes. Using an interspecific backcross panel, we localized both Gng3 and Gng3lg to the same locus on chromosome 19. The orientation, close proximity, and expression pattern of these two genes raise the distinct possibility that shared regulatory elements are used to control their expression.

Animals↗
PubMed2000

Canine heparan sulfate sulfamidase and the molecular pathology underlying Sanfilippo syndrome type A in Dachshunds.

Heparan sulfate sulfamidase (HSS) is a lysosomal exohydrolase that, when deficient, results in intralysosomal accumulation of heparan sulfate and the clinical phenotype of Sanfilippo syndrome type A. The first animal disease homolog of human Sanfilippo syndrome type A has been recently indentified in Dachshund littermates. To identify the molecular defect, the nucleotide sequences of the normal canine HSS gene and cDNA were determined using PCR-based approaches. The coding region showed 87% nucleotide homology, and 89% amino acid sequence homology, with human HSS. All exon-intron borders were conserved. Sequence analysis of the entire coding region with exon-intron boundaries was performed in the propositus, a healthy littermate, and six unrelated normal dogs. Comparison revealed a 3-bp deletion, 737-739delCCA, resulting in the loss of threonine at position 246 in both alleles of the propositus and in one allele of a healthy littermate. Prediction of the three-dimensional structure of canine HSS, based on homology with human arylsulfatases A and B, suggested the pathogenic effect of this deletion. Six other sequence variations in exons, and 10 in introns, appear to be benign polymorphisms. This study supports the potential development of a canine model of Sanfilippo syndrome type A to evaluate gene therapy for this disorder.

Amino Acid Sequence↗
PubMed1999

The descent of human herpesvirus 8.

Analysis of conserved herpesvirus genes shows that human herpesvirus 8 (HHV8) belongs to a clade of primate herpesviruses within the gamma2 sublineage. Overall, this clade has developed by cospeciation with host species. Seventeen genes of HHV8 and its nearest relatives lack simple homologues in other herpesviruses, and eight of these have known mammalian homologues, presumed to be the sources of the HHV8 versions. Comparative analyses yield further insights into the source or time of acquisition for several of these genes. All were acquired by the HHV8 lineage in the very distant past. Two unusual processes are manifest in the contemporary evolution of HHV8. First, the K1 gene is uniquely undergoing a process of extensive and positively selected substitution, of unknown significance. Secondly, the K15 gene has been substituted in some lineages by a distant homologue, presumably by recombination with an unknown herpesvirus. While available data are otherwise compatible with a cospeciational relationship between HHV8 and the human species, they do not exclude relatively recent transfer to humans from another primate host.

Chemokines, CC↗
PubMed2000

Apoptosis and the liver.

Regulation of the homeostatic balance between cell proliferation and programmed cell death, apoptosis, is essential for development and maintenance of multicellular organisms. Apoptosis is a genetically and evolutionarily highly conserved process. Analysis of the molecular mechanisms of apoptosis has led to a better understanding of many human diseases. Notably in cancer, but also in infectious or autoimmune disease, a deficiency in apoptosis is one of the key events in pathophysiology. On the other hand, overefficient apoptosis, as observed in fulminant liver failure, may be equally harmful for the organism indicating that a tight regulation of the apoptotic machinery is essential for survival. The execution of apoptosis may be initiated by many different signals, either from within or outside the cell involving ligand-receptor interactions, as has been shown for Fas/Fas-ligand, TNF-alpha/TNF-receptor or TGF-beta/TGF-receptor, or potentially by more unspecific signals such as ceramide or DNA damage. During the modulation phase of apoptosis many different genes such as p53, c-myc or Bcl-2/Bax have been shown to able to shift the balance either to cell survival or cell death.

Apoptosis↗
PubMed2026

Functional Prediction of Epitranscriptome.

N6-methyladenosine (m6A) is one of the most prevalent and well-studied RNA modifications, playing a pivotal role in many biological processes. With the recent advances in high-throughput sequencing technologies, tens of thousands of m6A sites have been reported. However, not all m6A sites are important or functionally significant, highlighting the need to distinguish biologically relevant m6As from non-functional or technically artefactual ones. Here, we describe ConsRM, which is a web-based resource that was designed to evaluate the importance of m6As from an evolutionary perspective. It introduced a novel scoring framework for quantifying the conservation degree of m6As in humans. Its web interface includes a database of 177998 distinct human m6A sites along with their calculated conservation score, and allows users to analyze their own data via the web server. ConsRM is freely accessible at: http://180.208.58.19/conservation/browser.html .

Humans↗
PubMed2006

The centrosome cycle.

Centrosomes are dynamic organelles involved in many aspects of cell function and growth. Centrosomes act as microtubule organizing centers, and provide a site for concerted regulation of cell cycle progression. While there is diversity in microtubule organizing center structure among eukaryotes, many centrosome components, such as centrin, are conserved. Experimental analysis has provided an outline to describe centrosome duplication, and numerous centrosome components have been identified. Even so, more work is needed to provide a detailed understanding of the interactions between centrosome components and their roles in centrosome function and duplication. Precise duplication of centrosomes once during each cell cycle ensures proper mitotic spindle formation and chromosome segregation. Defects in centrosome duplication or function are linked to human diseases including cancer. Here we provide a multifaceted look at centrosomes with a detailed summary of the centrosome cycle.

Animals↗
PubMed1992

T-cell receptor gamma/delta: comparison of gene configurations and function between humans and chimpanzees.

The human and chimpanzee T-cell receptor gamma-delta (TCR gamma delta) bearing cells represent a minor subset (3-8%) of T lymphocytes. In the periphery, the TCR gamma delta population has a restricted combinatorial repertoire. The TCRD-V1 and -V2 gene products are expressed in a mutually exclusive fashion, whereas, the TCRD-V2 and the TCRG-V9 encoded proteins show, in general, a coordinated expression. Restriction fragment length polymorphism analysis showed conservation of the restriction sites that identify the TCRG-V9 and TCRD-V2 rearrangements. The human TCRG-V9 locus has two alleles, TCRG-V9A1 and TCRG-V9A2 differing at codon position 31. The chimpanzee TCRG-V9 gene product differs from the products of the human TCRG-V9A1 and TCRG-V9A2 allele by two and three amino acid replacements, respectively. The human and the chimpanzee TCRG-V9-TCRD-V2 lymphocytes show a similar specific proliferative and cytolytic response to human Daudi Burkitt's lymphoma cells. Therefore, the amino acid replacements found in the chimpanzee TCRG-V9 gene product do not change the superantigen specificity across this species barrier.

Alleles↗