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PubMed1995

Compound mutants for the paralogous hoxa-4, hoxb-4, and hoxd-4 genes show more complete homeotic transformations and a dose-dependent increase in the number of vertebrae transformed.

The Hox gene products are transcription factors involved in specifying regional identity along the anteroposterior body axis. In the mouse, several single mutants for Hox genes show variably penetrant, partial homeotic transformations of vertebrae at their anterior limits of expression, suggesting that compound Hox mutants might show more complete transformations with greater penetrance than the single Hox mutants. Compound mutants for the paralogous group 3 genes, hoxa-3 and hoxd-3, show deletion of a cervical vertebrae, which is not readily interpretable in terms of an alteration in regional identity. Here, we report the skeletal phenotypes of compound mutants in the group 4 Hox genes, hoxa-4, hoxb-4, and hoxd-4. Mice mutant for each of these genes were intercrossed to generate the three possible double mutant combinations and the triple mutant. In contrast to the hoxa-3, hoxd-3 double mutants, group 4 Hox compound mutants displayed clear alterations in regional identity, including a nearly complete transformation of the second cervical vertebrae toward the morphology of the first cervical vertebra in one double mutant combination. In comparing the types of homeotic transformations observed, different double mutant combinations showed different degrees of synergism. These results suggest a certain degree of functional redundancy among paralogous genes in specifying regional identity. Furthermore, there was a remarkable dose-dependent increase in the number of vertebrae transformed to a first cervical vertebra identity, including the second through the fifth cervical vertebrae in the triple mutant. Thus, these genes are required in a larger anteroposterior domain than is revealed by the single mutant phenotypes alone, such that multiple mutations in these genes result in transformations of vertebrae that are not at their anterior limit of expression.

Animals↗
PubMed1995

Molecular evolution of the histidine biosynthetic pathway.

The available sequences of genes encoding the enzymes associated with histidine biosynthesis suggest that this is an ancient metabolic pathway that was assembled prior to the diversification of the Bacteria, Archaea, and Eucarya. Paralogous duplications, gene elongation, and fusion events involving different his genes have played a major role in shaping this biosynthetic route. Evidence that the hisA and the hisF genes and their homologous are the result of two successive duplication events that apparently took place before the separation of the three cellular lineages is extended. These two successive gene duplication events as well as the homology between the hisH genes and the sequences encoding the TrpG-type amidotransferases support the idea that during the early stages of metabolic evolution at least parts of the histidine biosynthetic pathway were mediated by enzymes of broader substrate specificities. Maximum likelihood trees calculated for the available sequences of genes encoding these enzymes have been obtained. Their topologies support the possibility of an evolutionary proximity of archaebacteria with low GC Gram-positive bacteria. This observation is consistent with those detected by other workers using the sequences of heat-shock proteins (HSP70), glutamine synthetases, glutamate dehydrogenases, and carbamoylphosphate synthetases.

Aldose-Ketose Isomerases↗
PubMed2006

Conserved co-regulation and promoter sharing of hoxb3a and hoxb4a in zebrafish.

The expression of zebrafish hoxb3a and hoxb4a has been found to be mediated through five transcripts, hoxb3a transcripts I-III and hoxb4a transcripts I-II, driven by four promoters. A "master" promoter, located about 2 kb downstream of hoxb5a, controls transcription of a pre-mRNA comprising exon sequences of both genes. This unique gene structure is proposed to provide a novel mechanism to ensure overlapping, tissue-specific expression of both genes in the posterior hindbrain and spinal cord. Transgenic approaches were used to analyze the functions of zebrafish hoxb3a/hoxb4a promoters and enhancer sequences containing regions of homology that were previously identified by comparative genomics. Two neural enhancers were shown to establish specific anterior expression borders within the hindbrain and mediate expression in defined neuronal populations derived from hindbrain rhombomeres (r) 5 to 8, suggesting a late role of the genes in neuronal cell lineage specification. Species comparison showed that the zebrafish hoxb3a r5 and r6 enhancer corresponded to a sequence within the mouse HoxA cluster controlling activity of Hoxa3 in r5 and r6, whereas a homologous region within the HoxB cluster activated Hoxb3 expression but limited to r5. We conclude that the similarity of hoxb3a/Hoxa3 regulatory mechanisms reflect the shared descent of both genes from a single ancestral paralog group 3 gene.

Animals↗
PubMed2000

Isolation and characterization of the human homeobox gene HOX D1.

Homeobox genes, first identified in Drosophila, encode transcription factors that regulate embryonic development along the anteroposterior axis of an organism. Vertebrate homeobox genes are described on the basis of their homology to the genes found within the Drosophila Antennapedia and Bithorax homeotic gene complexes. Mammals possess four paralogous homeobox (HOX) gene clusters, HOX A, HOX B, HOX C and HOX D, each located on different chromosomes, consisting of 9 to 11 genes arranged in tandem. We report the characterization of the human HOX D1 gene. This gene consists of two exons, encoding a 328 amino acid protein, separated by an intron of 354 bp. The human HOX D1 protein is one amino acid longer (328 amino acids) than the mouse protein (327 amino acids) and is 82% identical to the mouse HOX D1 homolog. The DNA binding homeodomain region of the human protein exhibits a 97% and 80% identity between mouse Hoxd1 and Drosophila labial homeodomains, respectively. The exon/intron and intron/exon splice junctions are conserved in position between human and mouse genes. Determination of the human HOX D1 gene structure permits the use of PCR based analysis of this gene for the assessment of mutations, for diseases that link to the HOXD cluster (such as Duanes Retraction Syndrome (DRS)), or polymorphisms associated with human variation. Molecular characterization of the HOXD1 gene may also permit analysis of the functional role of this gene in human neurogenisis.

Amino Acid Sequence↗
PubMed2004

Nonneutral evolution of the transcribed pseudogene Makorin1-p1 in mice.

Pseudogenes are nonfunctional relics of formerly functional genes and are thought to evolve neutrally. In some pseudogenes, however, the molecular evolutionary patterns are atypical of neutrally evolving sequences, exhibiting sequence conservation, codon-usage bias, and other features associated with functional genes. Makorin1-p1 is a transcribed pseudogene first identified in the mouse Mus musculus. The transcript of Makorin1-p1 can regulate the stability of the transcript of its paralogous functional gene Makorin1. Specifically, the half-life of Makorin1 mRNA increases significantly in the presence of Makorin1-p1 transcript, and targeted deletion of Makorin1-p1 is lethal in mice. Here, we show that Makorin1-p1 originated after the separation of Mus and Rattus but before the divergence of M. musculus and M. pahari. The transcribed region of Makorin1-p1 exhibits rates of point and indel substitutions that are two to four times lower than those in the untranscribed region, suggesting that the transcribed region is under functional constraint and is not evolving neutrally. Although the transcript of Makorin1-p1 likely functions by its sequence similarity to Makorin1, we find no evidence of gene conversion between them, indicating that functional conservation alone is sufficient to maintain their coordinated evolution. A duplication-degeneration model is proposed to explain how Makorin1-p1 was co-opted into the regulatory system of Makorin1. There are over 10,000 pseudogenes in a typical mammalian genome, and it is plausible that many functional but untranslatable pseudogenes exist. Our results illustrate the potential of using evolutionary analysis to identify such pseudogenes from genome sequences.

Animals↗
PubMed2006

Transcriptional coordination of the metabolic network in Arabidopsis.

Patterns of coexpression can reveal networks of functionally related genes and provide deeper understanding of processes requiring multiple gene products. We performed an analysis of coexpression networks for 1,330 genes from the AraCyc database of metabolic pathways in Arabidopsis (Arabidopsis thaliana). We found that genes associated with the same metabolic pathway are, on average, more highly coexpressed than genes from different pathways. Positively coexpressed genes within the same pathway tend to cluster close together in the pathway structure, while negatively correlated genes typically occupy more distant positions. The distribution of coexpression links per gene is highly skewed, with a small but significant number of genes having numerous coexpression partners but most having fewer than 10. Genes with multiple connections (hubs) tend to be single-copy genes, while genes with multiple paralogs are coexpressed with fewer genes, on average, than single-copy genes, suggesting that the network expands through gene duplication, followed by weakening of coexpression links involving duplicate nodes. Using a network-analysis algorithm based on coexpression with multiple pathway members (pathway-level coexpression), we identified and prioritized novel candidate pathway members, regulators, and cross pathway transcriptional control points for over 140 metabolic pathways. To facilitate exploration and analysis of the results, we provide a Web site (http://www.transvar.org/at_coexpress/analysis/web) listing analyzed pathways with links to regression and pathway-level coexpression results. These methods and results will aid in the prioritization of candidates for genetic analysis of metabolism in plants and contribute to the improvement of functional annotation of the Arabidopsis genome.

Arabidopsis↗
PubMed2006

Neofunctionalization in vertebrates: the example of retinoic acid receptors.

Understanding the role of gene duplications in establishing vertebrate innovations is one of the main challenges of Evo-Devo (evolution of development) studies. Data on evolutionary changes in gene expression (i.e., evolution of transcription factor-cis-regulatory elements relationships) tell only part of the story; protein function, best studied by biochemical and functional assays, can also change. In this study, we have investigated how gene duplication has affected both the expression and the ligand-binding specificity of retinoic acid receptors (RARs), which play a major role in chordate embryonic development. Mammals have three paralogous RAR genes--RAR alpha, beta, and gamma--which resulted from genome duplications at the origin of vertebrates. By using pharmacological ligands selective for specific paralogues, we have studied the ligand-binding capacities of RARs from diverse chordates species. We have found that RAR beta-like binding selectivity is a synapomorphy of all chordate RARs, including a reconstructed synthetic RAR representing the receptor present in the ancestor of chordates. Moreover, comparison of expression patterns of the cephalochordate amphioxus and the vertebrates suggests that, of all the RARs, RAR beta expression has remained most similar to that of the ancestral RAR. On the basis of these results together, we suggest that while RAR beta kept the ancestral RAR role, RAR alpha and RAR gamma diverged both in ligand-binding capacity and in expression patterns. We thus suggest that neofunctionalization occurred at both the expression and the functional levels to shape RAR roles during development in vertebrates.

Amino Acid Sequence↗
PubMed1994

The connexins and their family tree.

The connexins, gap junction forming proteins, are encoded by a gene family. Sequence comparisons reveal regions of conservation with functional implications for voltage dependence of junctional conductance, junction formation and regulation by phosphorylation. The best connexin tree shows that most gene duplications giving rise to the family occurred early in or before vertebrate divergence. The topology of most deep branches of the tree is uncertain. Evolutionary rates vary for different paralogous connexin genes.

Amino Acid Sequence↗
PubMed2004

Characterization of a novel postacrosomal perinuclear theca-specific protein, CYPT1.

The perinuclear theca (PT) is a unique cytoskeletal structure that surrounds the nucleus of the sperm. The posterior acrosome segment of the PT (postacrosomal PT) is thought to play roles in shaping the nucleus during differentiation of the spermatid and in activating the oocyte during fertilization. We isolated a cDNA clone that encoded a novel haploid germ cell-specific cysteine-rich perinuclear theca protein, CYPT1. The transcripts were expressed exclusively in testicular germ cells after meiotic division. Sequence analysis revealed that CYPT1 comprised 168 amino acids and that the N-terminal was rich in basic amino acids, including cysteine clusters. Immunohistochemical and biochemical analyses localized CYPT1 to the postacrosomal PT of elongated spermatids and mature sperm. The cypt1 had three paralogs that were expressed in adult testis. A comparison of genomic structure suggested that two of the three cypt1 paralogs were generated by gene triplication on the X chromosome, while one paralog was retrotransposed to an autosome. Interestingly, the 5'-flanking regions of these genes were highly homologous with the promoter region of the spermatid-specific gene Zfy-2. CYPT1 and the proteins of the paralogous genes constitute a novel, basic cysteine-rich sperm protein family that may contribute to the function of the postacrosomal PT during nuclear shaping.

Acrosome↗
PubMed2003

Two paralogous families of a two-gene subtilisin operon are widely distributed in oral treponemes.

Certain oral treponemes express a highly proteolytic phenotype and have been associated with periodontal diseases. The periodontal pathogen Treponema denticola produces dentilisin, a serine protease of the subtilisin family. The two-gene operon prcA-prtP is required for expression of active dentilisin (PrtP), a putative lipoprotein attached to the treponeme's outer membrane or sheath. The purpose of this study was to examine the diversity and structure of treponemal subtilisin-like proteases in order to better understand their distribution and function. The complete sequences of five prcA-prtP operons were determined for Treponema lecithinolyticum, "Treponema vincentii," and two canine species. Partial operon sequences were obtained for T. socranskii subsp. 04 as well as 450- to 1,000-base fragments of prtP genes from four additional treponeme strains. Phylogenetic analysis demonstrated that the sequences fall into two paralogous families. The first family includes the sequence from T. denticola. Treponemes possessing this operon family express chymotrypsin-like protease activity and can cleave the substrate N-succinyl-alanyl-alanyl-prolyl-phenylalanine-p-nitroanilide (SAAPFNA). Treponemes possessing the second paralog family do not possess chymotrypsin-like activity or cleave SAAPFNA. Despite examination of a range of protein and peptide substrates, the specificity of the second protease family remains unknown. Each of the fully sequenced prcA and prtP genes contains a 5' hydrophobic leader sequence with a treponeme lipobox. The two paralogous families of treponeme subtilisins represent a new subgroup within the subtilisin family of proteases and are the only subtilisin lipoprotein family. The present study demonstrated that the subtilisin paralogs comprising a two-gene operon are widely distributed among treponemes.

Amino Acid Sequence↗
PubMed1998

Transcription analysis of two disparate rRNA operons in the halophilic archaeon Haloarcula marismortui.

The genome of the halophilic archaeon Haloarcula marismortui contains two rRNA operons designated rrnA and rrnB. Genomic clones of the two operons and their flanking regions have been sequenced, and primary transcripts and processing intermediates derived from each operon have been characterized. The 16S, 23S, and 5S genes from the two operons were found to differ at 74 of 1,472 positions, 39 of 2,922 positions, and 2 of 122 positions, respectively. This degree of sequence divergence for multicopy (paralogous) rRNA genes was 10- to 50-fold or more higher than anticipated. The two operons exhibit other profound differences that include (i) the presence in rrnA and the absence in rrnB of tRNAAla and tRNACys genes in the intergenic and distal regions, respectively, (ii) divergent 5' flanking sequences, and (iii) distinct pathways for processing and maturation of 16S rRNA. Processing and maturation of 16S and 23S rRNA from rrnA operon transcripts and of 23S rRNA from rrnB operon transcripts follow the canonical halophilic pathway, whereas maturation of 16S rRNA from rrnB operon transcripts follows an unusual and different pathway that is apparently devoid of any 5' processing intermediate.

Base Sequence↗
PubMed2000

Annexin A11 (ANXA11) gene structure as the progenitor of paralogous annexins and source of orthologous cDNA isoforms.

The genomic organization of the annexin A11 gene was determined in mouse and human to assess its congruity with other family members and to examine the species variation in alternative splicing patterns. Mouse annexin A11 genomic clones were characterized by restriction analysis, Southern blotting, and DNA sequencing, and the homologous human gene (HGMW-approved gene symbol ANXA11) was deciphered from high-throughput genomic sequence with coanalysis of expressed sequence tags. Exons 6-15 of the tetrad core repeat region differ from annexins A7 and A13 but are spliced identically to other phylogenetic descendents, making annexin A11 the putative primary progenitor of up to nine paralogous human annexins. The 5' regions consist of untranslated exon 1, followed by an extensive intron 1 comprising almost half the total gene length of >40 kb, and additional GC-rich exons 2-5 encoding the proline- and glycine-rich amino-terminus. Distinct cDNA isoforms in cow and human were determined to be unique to each species and hence of dubious general significance for this gene's function. Multiple transcription start sites were revealed by primer extension analysis of the mouse gene, and transfection constructs containing the prospective promoter generated transcriptional activity comparable to that of the SV40 promoter. Internal repetitive elements and vicinal gene markers were mapped for the complete human annexin A11 gene sequence to characterize the surrounding genomic environment.

3T3 Cells↗
PubMed2005

Sensitivity to potassium tellurite of Escherichia coli cells deficient in CSD, CsdB and IscS cysteine desulfurases.

The csdA, csdB and iscS genes encoding for cysteine desulfurase enzymatic activities in Escherichia coli were independently inactivated and potassium tellurite sensitivity, determined for each of the resulting mutant clones, was found to be iscS > csdB > csdA. Structural genes encoding for each of the wild-type cysteine desulfurases were cloned into a vector containing the regulated ara promoter and further introduced into the mutant strains. Desulfurase-deficient cells transformed with homolog or paralog desulfurase genes and grown in arabinose-amended media restored their basal tellurite resistance. While csdB gene complemented the auxotrophy of csdB and iscS mutants for nicotinic acid, the iscS gene only complemented the auxotrophy of iscS cells for thiamine. Introduction of the csdA gene into the desulfurase-deficient strains did not change tellurite resistance or nutritional requirement patterns of the recipient cells. Complementation analysis could not be performed under anaerobic conditions because the three mutants did not show tellurite hypersensitivity. These results indicate that oxidative stress is involved in tellurite toxicity in E. coli.

Carbon-Sulfur Lyases↗
PubMed2002

Cryptosporidium parvum genes containing thrombospondin type 1 domains.

Cryptosporidium parvum is recognized as an enteropathogen of great worldwide medical and veterinary importance, yet understanding of its pathogenesis has been hampered in part by limited knowledge of the invasion machinery of this parasite. Recently, genes containing thrombospondin type 1 (TSP1) domains have been identified in several genera of apicomplexans, including thrombospondin-related adhesive proteins (TRAPs) that have been implicated as key molecules for parasite motility and adhesion onto host cell surfaces. Previously, a large-scale random survey of the C. parvum genome conducted in our laboratory revealed the presence of multiple genomic DNA sequences with a high degree of similarity to known apicomplexan TRAP genes. In the present study, TBLASTN screening of available C. parvum genomic sequences by using TSP1 domains as queries identified a total of 12 genes possessing TSP1-like domains. All genes have putative signal peptide sequences, one or more TSP1-like domains, plus additional extracellular protein modules such as Kringle, epidermal growth factor, and Apple domains. Two genes, putative paralogs CpTSP8 and CpTSP9, contain predicted introns near their amino termini, which were verified by comparing PCR products from cDNA versus genomic DNA templates. Reverse transcription-PCR analysis of transcript levels reveals that C. parvum TSP genes were developmentally regulated with distinct patterns of expression during in vitro infection. TRAPC1, CpTSP3, and CpTSP11 were expressed at high levels during both early and late stages of infection, whereas CpTSP2, CpTSP5, CpTSP6, CpTSP8, and CpTSP9 were maximally expressed during the late stages of infection. Only CpTSP4 was highly expressed solely at an early stage of infection.

Amino Acid Sequence↗
PubMed2006

Structure of Kluyveromyces lactis subtelomeres: duplications and gene content.

We have constructed a map of the duplicated regions of Kluyveromyces lactis subtelomeres. Seven out of 12 subtelomeres contain an almost identical 9 kb long segment starting from the end. This segment is bordered by a long terminal repeat element. Two of the subtelomeres share sequence similarity that extends over a total of 20 kb. The other subtelomeres also contain duplicated regions of 1-6 kb. Nonduplicated regions contain unique genes and genes from paralog families. All duplicated segments are in the same orientation with respect to the telomere, probably as a result of genetic exchange. We map the only two copies of retrotransposons in the genome, in subtelomeres. Low-complexity gene sequences that encode threonine- and serine-rich peptides are associated with the subtelomeres of K. lactis, as in Saccharomyces cerevisiae. The ubiquity of these sequences in hemiascomycete genomes, and the propensity they have to encode proteins with extracellular localization, make these genes ideal candidates for fast evolving 'contingency' genes involved in the adaptation of a species to its environment.

Amino Acid Sequence↗
PubMed1994

Functional analysis of mouse Hoxa-7 in Saccharomyces cerevisiae: sequences outside the homeodomain base contact zone influence binding and activation.

The murine developmental control gene product, Hoxa-7, was shown to function as a DNA-binding transactivator in Saccharomyces cerevisiae. The importance of the ATTA core, the preference for antp class flanking nucleotides, the importance of Asn-51 of the homeodomain (HD), and the synergism of multiple binding sites all reflect properties that have previously been described for HOM or Hox proteins in tissue culture systems. A comparison of contact positions among genes of paralog groups and classes of mammalian HDs points to a lack of diversity in positions that make base contact, suggesting that besides the combination of HD amino acid-base pair contacts, another means of recognizing differences between targets must exist if Hox genes select different targets. The HD of antennapedia is identical to the Hoxa-7 HD. The interaction of Hoxa-7 with the exact sequence used in the nuclear magnetic resonance three-dimensional structural analysis on the antennapedia HD was studied. Hoxa-7 binding and transactivation was influenced by sequences outside of the known base contact zone of this site. We conclude that Hoxa-7 protein has a second means to interact with DNA or/and that the sequences flanking the base contact zone influence HD interactions by distorting DNA within the contact zone (base or backbone). This result is discussed in terms of DNA flexure and two modes of transcription used in S. cerevisiae.

Animals↗
PubMed2004

Molecular pathology of filamin A: diverse phenotypes, many functions.

Defective cell signalling during embryonic development is a well-recognized modus operandi of mutations in genes that lead to congenital malformations. This signalling occurs within and around a dynamic cellular cytoskeleton that is continuously under modulating influences during morphogenesis. Evidence is accumulating to suggest that filamin A, an actin-binding protein and the product of one of three paralogous filamin genes in humans, represents a key molecule that connects such signalling events to modulation of the cellular cytoskeletal architecture. This review summarizes the clinical consequences of mutations in the gene encoding filamin A, FLNA. The molecular pathology of this gene suggests remarkable functional pleiotropy, indicative of diverse roles in embryonic, fetal and postnatal development.

Actins↗
PubMed1997

Homeoboxes in sea anemones (Cnidaria:Anthozoa): a PCR-based survey of Nematostella vectensis and Metridium senile.

Homeobox genes belong to a phylogenetically widespread family of regulatory genes that play important roles in pattern formation and cell-fate specification in several model systems (e.g., Drosophila, mouse, and C. elegans). Although the evolution of many classes of homeobox genes predates the diversification of the Bilateria, comparatively little is known about homeobox genes in outgroups to the Bilateria, such as the Cnidaria. We used the polymerase chain reaction to recover 12 partial homeoboxes from 2 species of sea anemones, Metridium senile and Nematostella vectensis (phylum Cnidaria; class Anthozoa). These homeoboxes appear to represent 9 distinct, mutually paralogous homeobox genes, 5 of which belong to previously identified cnidarian homeobox classes, and 4 of which appear to represent previously unidentified classes. The evolutionary relationships between the homeodomains of sea anemones and of bilaterian animals were assessed through database searches and phylogenetic analyses. As many as 5 of the anemone homeoboxes may belong to the Hox class, which suggests that the Hox gene complement of cnidarians is larger than previously expected. Homologs of the even-skipped gene of Drosophila were also identified in both Metridium and Nematostella.

Amino Acid Sequence↗