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PubMed2006

Dynamic expression of the LIM-homeodomain gene Lhx15 through larval brain development of the sea lamprey (Petromyzon marinus).

LIM-homeodomain genes encode a family of transcription factors with highly conserved roles in the patterning and regionalisation of the vertebrate brain. The expression of one of those genes, Lhx15, in the embryonic lamprey brain, characterises precise functional subdivisions. In order to analyse the non-embryonic development of the lamprey brain, we chose this gene to perform in situ hybridisations in Petromyzon marinus larvae of different ages. We demonstrate the usefulness of Lhx15 to follow the development and morphogenesis of brain structures and show the dynamical expression of this gene through time. Furthermore, we provide evidence for the evolutionary conservation of the expression of this gene in the spinal cord, notochord and urogenital system.

Animals↗
PubMed1987

[Evolution of RNA-dependent RNA polymerases of positive riboviruses].

A comparative analysis is presented of 24 known amino acid sequences of RNA-dependent RNA polymerases of positive strand RNA viruses infecting animals, plants and bacteria. Using a newly proposed methodology of group alignment for weakly similar sequences, evolutionary conserved fragments of all these proteins were unambiguously aligned. A unique pattern (consensus) of 7 invariant amino acid residues was revealed which is absent from the sequences of other RNA and DNA polymerases and is thought to unequivocally identify the RNA-dependent RNA polymerases of positive strand RNA viruses. Based on the obtained alignment a tentative phylogenetic tree of viral RNA polymerases was constructed for the first time. The RNA-dependent RNA polymerases of positive strand RNA viruses are concluded to comprise a distinct family of evolutionary related proteins.

Amino Acid Sequence↗
PubMed2003

Structural genomics of highly conserved microbial genes of unknown function in search of new antibacterial targets.

With more than 100 antibacterial drugs at our disposal in the 1980's, the problem of bacterial infection was considered solved. Today, however, most hospital infections are insensitive to several classes of antibacterial drugs, and deadly strains of Staphylococcus aureus resistant to vancomycin--the last resort antibiotic--have recently begin to appear. Other life-threatening microbes, such as Enterococcus faecalis and Mycobacterium tuberculosis are already able to resist every available antibiotic. There is thus an urgent, and continuous need for new, preferably large-spectrum, antibacterial molecules, ideally targeting new biochemical pathways. Here we report on the progress of our structural genomics program aiming at the discovery of new antibacterial gene targets among evolutionary conserved genes of uncharacterized function. A series of bioinformatic and comparative genomics analyses were used to identify a set of 221 candidate genes common to Gram-positive and Gram-negative bacteria. These genes were split between two laboratories. They are now submitted to a systematic 3-D structure determination protocol including cloning, protein expression and purification, crystallization, X-ray diffraction, structure interpretation, and function prediction. We describe here our strategies for the 111 genes processed in our laboratory. Bioinformatics is used at most stages of the production process and out of 111 genes processed--and 17 months into the project--108 have been successfully cloned, 103 have exhibited detectable expression, 84 have led to the production of soluble protein, 46 have been purified, 12 have led to usable crystals, and 7 structures have been determined.

Acid Anhydride Hydrolases↗
PubMed2000

The MADS-Box factor CeMEF2 is not essential for Caenorhabditis elegans myogenesis and development.

MEF2 is an evolutionarily conserved MADS (MCM1, Agamous, Deficiens, and serum response factor) box-type transcription factor that plays a critical role in vertebrate and Drosophila melanogaster myogenesis. We have addressed the developmental role of the single MEF2-like factor, CeMEF2, in Caenorhabditis elegans. Using expression assays and two mef-2 deletion alleles, we show that CeMEF2 is not required for proper myogenesis or development. Moreover, a putative null mef-2 allele fails to enhance or suppress the phenotypes of mutants in CeMyoD or CeTwist. Our results suggest that despite its evolutionary conservation of sequence and DNA binding properties, CeMEF2 has adopted a divergent role in development in the nematode compared with Drosophila and vertebrates.

Amino Acid Sequence↗
PubMed1997

The putative cell cycle gene, enhancer of rudimentary, encodes a highly conserved protein found in plants and animals.

The enhancer of rudimentary gene, e(r), in Drosophila melanogaster encodes a protein, ER, whose function has been implicated in pyrimidine biosynthesis and the cell cycle (Wojcik et al. (1994) Genetics 138, 1163-1170). In order to identify conserved regions of the protein and potentially important functional domains, the e(r) gene was cloned and sequenced from two other insects (Drosophila virilis and Aedes aegypti) and three vertebrates (Homo sapiens, Mus musculus, and Brachydanio rerio) and sequenced from a flowering plant (Arabidopsis thaliana). These sequences along with those of a nematode (Caenorhabditis elegans) exhibit a high degree of identity. ER of Drosophila melanogaster is 76% identical to the three vertebrate proteins, 49% identical to the nematode protein, and 40% identical to the plant protein. There is high evolutionary conservation among the vertebrates. The mouse and human proteins are identical and differ from that of the zebrafish by a single conservative amino-acid change (valine for isoleucine). A dramatic sequence conservation is seen in the position of the hydrophobic amino acids. Of the 27 positions occupied by hydrophobic amino acids in ER of Drosophila melanogaster, 25 of the corresponding positions in the human protein, 23 of the positions in Caenorhabditis elegans, and 20 of the positions in Arabidopsis thaliana have hydrophobic amino acids. Most of these residues are present in three conserved amphipathic alpha-helices, which are proposed to function in protein-protein interactions. Two phosphorylation sites for casein kinase II (CKII) have also been conserved within the animal groups. Purified ER from Drosophila melanogaster is phosphorylated in vitro by CKII, arguing that these two sites are functional in vivo. A putative shift in the secondary structure of ER caused by the phosphorylation of these sites suggests that CKII may be regulating the activity of the ER in vivo.

Aedes↗
PubMed1998

beta-D-glucosyl-hydroxymethyluracil is a conserved DNA modification in kinetoplastid protozoans and is abundant in their telomeres.

The unusual DNA base beta-D-glucosyl-hydroxymethyluracil, called "J, " replaces approximately 0.5-1% of Thy in DNA of African trypanosomes but has not been found in other organisms thus far. In Trypanosoma brucei, J is located predominantly in repetitive DNA, and its presence correlates with the silencing of telomeric genes. Using antibodies specific for J, we have developed sensitive assays to screen for J in a range of organisms and have found that J is not limited to trypanosomes that undergo antigenic variation but is conserved among Kinetoplastida. In all kinetoplastids tested, including the human pathogens Leishmania donovani and Trypanosoma cruzi, J was found to be abundantly present in the (GGGTTA)n telomere repeats. Outside Kinetoplastida, J was found only in Diplonema, a small phagotrophic marine flagellate, in which we also identified 5-MeCyt. Fractionation of Diplonema DNA showed that the two modifications are present in a common genome compartment, which suggests that they may have a similar function. Dinoflagellates appear to contain small amounts of modified bases that may be analogs of J. The evolutionary conservation of J in kinetoplastid protozoans suggests that it has a general function, repression of transcription or recombination, or a combination of both. T. brucei may have recruited J for the control of genes involved in antigenic variation.

Animals↗
PubMed1991

Evolution of mouse B1 repeats: 7SL RNA folding pattern conserved.

In a recent report mouse B1 genomic repeats were divided into six families representing different waves of fixation of B1 variants, consistent with the retroposition model of human Alu elements. These data are used to examine the distribution of nucleotide substitutions in individual genomic repeats with respect to family consensus sequences and to compare the minimal energy structures of the corresponding B1 RNAs. By an enzymatic approach the predicted structure of B1 RNAs is experimentally confirmed using as a model sequence an RNA of a young B1 family member transcribed in vitro by T7 RNA polymerase. B1 RNA preserves folding domains of the Alu fragment of 7SL RNA, its progenitor molecule. Our results reveal similarities among 7SL-like retroposons, human Alu, and rodent B1 repeats, and relate the evolutionary conservation of B1 family consensus sequences to selection at the RNA level.

Animals↗
PubMed2006

Genetic variation and the mitogen-activated protein kinase (MAPK) signaling pathway.

Non-synonymous single nucleotide polymorphisms (nsSNPs) are known to alter protein function, contributing to disease susceptibility. This report explores the nature of nsSNPs in the gene products of the highly conserved mitogen-activated protein kinase (MAPK) signaling pathways already implicated in cancer development. MAPK signaling pathways regulate cellular processes such as proliferation, differentiation, apoptosis, and survival mediated through interconnected signaling cascades. Using the dbSNP database, we have identified 25 nsSNPs in 17 out of 98 MAPK genes studied. Computational algorithms were used to predict whether the amino acid substitutions were evolutionarily tolerated, or affected putative functional units such as phosphorylation sites, protein motifs and domains. This study predicts that 36% of nsSNPs are likely to have functional consequences, based on evolutionary conservation analysis, and 36% based on phosphorylation prediction analysis. All such nsSNPs represent potentially functional and disease-causing/modifying alleles. More interestingly, the epistatic relationships discussed in this report represent potential synergistic/ antagonistic/additive effects of nsSNP combinations found within the same protein, or within members of the same protein complex and cascades. This strategy can effectively determine which nsSNPs potentially alter protein function, and can be utilized to study the genetic architecture and disease association of other biological protein complexes and networks.

Algorithms↗
PubMed1995

In vivo expression of alternatively spliced forms of integrin-associated protein (CD47).

Integrin-associated protein (IAP) is a 50 kDa plasma membrane protein physically and functionally associated with beta 3 integrins in a variety of cells. IAP has an extracellular immunoglobulin domain, five transmembrane domains and a short intracytoplasmic tail. IAP is recognized by anti-CD47 antibodies and is expressed on cells, such as erythrocytes and lymphocytes, which do not express beta 3 integrins. To learn more about potential functions of IAP we examined its expression in vivo. Using the polymerase chain reaction, we detected 4 alternatively splice forms of IAP which differ from each other only at their intracytoplasmic carboxy termini. These alternatively spliced forms are generated by inclusion or exclusion of three short exons within 5 kb in the genome and are highly conserved between mouse and man. There is tissue specificity of expression of the alternatively spliced forms of IAP mRNA, with bone marrow-derived cells expressing predominantly one form and neural tissue another. Using polyclonal antibodies which recognize the alternatively spliced bone marrow (form 2) and neural (form 4) forms of IAP, we found that in accord with the mRNA, form 2 protein was expressed in all tissues primarily on bone marrow-derived cells and endothelia, while form 4 was highly expressed in the brain and peripheral nervous system. The evolutionary conservation of IAP isoforms and their tissue-specific expression suggest an important role for these intracytoplasmic domains in IAP function.

Alternative Splicing↗
PubMed2006

Eleven ancestral gene families lost in mammals and vertebrates while otherwise universally conserved in animals.

BACKGROUND: Gene losses played a role which may have been as important as gene and genome duplications and rearrangements, in modelling today species' genomes from a common ancestral set of genes. The set and diversity of protein-coding genes in a species has direct output at the functional level. While gene losses have been reported in all the major lineages of the metazoan tree of life, none have proposed a focus on specific losses in the vertebrates and mammals lineages. In contrast, genes lost in protostomes (i.e. arthropods and nematodes) but still present in vertebrates have been reported and extensively detailed. This probable over-anthropocentric way of comparing genomes does not consider as an important phenomena, gene losses in species that are usually described as "higher". However reporting universally conserved genes throughout evolution that have recently been lost in vertebrates and mammals could reveal interesting features about the evolution of our genome, particularly if these losses can be related to losses of capability. RESULTS: We report 11 gene families conserved throughout eukaryotes from yeasts (such as Saccharomyces cerevisiae) to bilaterian animals (such as Drosophila melanogaster or Caenorhabditis elegans). This evolutionarily wide conservation suggests they were present in the last common ancestors of fungi and metazoan animals. None of these 11 gene families are found in human nor mouse genomes, and their absence generally extends to all vertebrates. A total of 8 out of these 11 gene families have orthologs in plants, suggesting they were present in the Last Eukaryotic Common Ancestor (LECA). We investigated known functional information for these 11 gene families. This allowed us to correlate some of the lost gene families to loss of capabilities. CONCLUSION: Mammalian and vertebrate genomes lost evolutionary conserved ancestral genes that are probably otherwise not dispensable in eukaryotes. Hence, the human genome, which is generally viewed as being the result of increased complexity and gene-content, has also evolved through simplification and gene losses. This acknowledgement confirms, as already suggested, that the genome of our far ancestor was probably more complex than ever considered.

Animals↗
PubMed2005

Primate chaperones Hsc70 (constitutive) and Hsp70 (induced) differ functionally in supporting growth and prion propagation in Saccharomyces cerevisiae.

Hsp70's are highly conserved essential protein chaperones that assist protein folding and prevent protein aggregation. They have modular structures consisting of ATPase, substrate-binding, and C-terminal domains. Substrate binding and release is regulated by ATP hydrolysis and nucleotide exchange, which in turn are regulated by cochaperones. Eukaryotes have constitutive (Hsc70) and stress-inducible (iHsp70) isoforms, but their functions have not been systematically compared. Using a yeast system to evaluate heterologous Hsp70's we find that primate Hsc70 supported growth but iHsp70 did not. Plant Hsc70 and iHsp70 counterparts behaved similarly, implying evolutionary conservation of this distinction. Swapping yeast and primate Hsp70 domains showed that (i) the Hsc70-iHsp70 distinction resided in the ATPase domain, (ii) substrate-binding domains of Hsp70's within and across species functioned similarly regarding growth, (iii) C-terminal domain function was important for growth, and (iv) Hsp70 functions important for cell growth and prion propagation were separable. Enzymatic analysis uncovered a correlation between substrate affinity and prion phenotype and showed that ATPase and protein-folding activities were generally similar. Our data support a view that intrinsic activities of Hsp70 isoforms are comparable, and functional differences in vivo lie mainly in complex interactions of Hsp70 with cochaperones.

Adenosine Triphosphatases↗
PubMed2004

The Bcl-2 protein family and its role in the development of neoplastic disease.

Programmed cell death is the physiological process responsible for shaping organs during embryogenesis, maintaining tissue homeostasis and allowing controlled deletion of potentially harmful cells within the adult organism. The genetics of apoptosis are well conserved in all metazoans and although the evolution of humans and worms separated more than 600 million years ago, basic signaling concepts in apoptosis are highly related in both species. More crucial to humans than worms is the fact that abnormalities in cell death control can contribute to the development of cancer. While C.elegans can easily survive with additional somatic cells that should normally be deleted during development humans may suffer pathological consequences, ranging from tumorigenesis to autoimmunity, as a result of mutations in cell death regulatory genes. Despite the high degree of evolutionary conservation in cell death control, apoptosis signaling in mammals is much more complex than in C.elegans. In mammalian cells, programmed cell death can be induced either by ligand-mediated activation of certain members of the tumor necrosis factor receptor family--so-called 'death receptors'--such as Fas (CD95/Apo-1) and TRAIL or it can be induced in a cell autonomous manner in response to certain stress signals by pro-apoptotic members of the Bcl-2 family. In this review, we focus on general concepts of how the Bcl-2 protein family regulates cell death and how deregulation of this 'intrinsic' apoptotic signaling pathway impinges on the pathogenesis of malignant disease, the major cause of death in the aging population.

Animals↗
PubMed2000

A conserved AU-rich element in the 3' untranslated region of bcl-2 mRNA is endowed with a destabilizing function that is involved in bcl-2 down-regulation during apoptosis.

The control of mRNA stability is becoming recognized as a crucial point of gene expression regulation. A common element responsible for mRNA decay modulation is the adenine- and uracil-rich element that is found in the 3' untranslated region of numerous mRNAs subjected to fast expression changes in response to various stimuli. Previously we identified a post-transcriptional regulation level for the antiapoptotic bcl-2 gene, which could be involved in t(14;18) lymphoma-associated bcl-2 overexpression. Here we demonstrate that bcl-2 mRNA is endowed with an adenine- and uracil-rich element (ARE) characterized by high evolutionary conservation not only among all chordates examined, but even between chordates and the nematode Caenorhabditis elegans (ced-9 gene). As for other well-established destabilizing AREs, the insertion of the bcl-2 ARE downstream from stable beta-globin mRNA causes an enhanced decay of the beta-globin transcript, which proves its functional role. This possibility is corroborated by the fact that the pathway leading to the modulating activity of bcl-2 ARE is influenced by PKC, since the addition of DAG and TPA markedly attenuated the bcl-2 ARE destabilizing potential. Conversely, it is noteworthy that when C(2)-ceramide is added to the culture medium as the apoptotic agent, the beta-globin transcript harboring the bcl-2 ARE undergoes a dramatic increase in decay. This observation clearly indicates that the destabilizing function of bcl-2 ARE is enhanced by apoptotic stimuli and suggests that this element could be involved in a post-transcriptional mechanism of bcl-2 down-regulation during apoptosis. The half-life of the mRNA of bcl-2 in Jurkat cells is prolonged by PKC stimulation and shortened by C(2)-ceramide addition, strongly supporting the view that bcl-2 mRNA stability plays a physiological role in modulating bcl-2 expression, particularly in its down-regulation during apoptosis. Thus, this element becomes a new candidate for mediating those bcl-2 gene expression changes-from apoptosis-associated down-regulation to tumor-associated overexpression-observed thus far that profoundly influence single cell fate and tissue homeostasis.

3' Untranslated Regions↗
PubMed2005

Comparative genomic analysis reveals a distant liver enhancer upstream of the COUP-TFII gene.

COUP-TFII is a central nuclear hormone receptor that tightly regulates the expression of numerous target lipid metabolism genes in vertebrates. However, it remains unclear how COUP-TFII itself is transcriptionally controlled since studies with its promoter and upstream region fail to recapitulate the gene's liver expression. In an attempt to identify liver enhancers in the vicinity of COUP-TFII, we employed a comparative genomic approach. Initial comparisons between humans and mice of the 3470-kb gene-poor region surrounding COUP-TFII revealed 2023 conserved noncoding elements. To prioritize a subset of these elements for functional studies, we performed further genomic comparisons with the orthologous pufferfish (Fugu rubripes) locus and uncovered two anciently conserved noncoding sequences (CNS) upstream of COUP-TFII (CNS-62kb and CNS-66kb). Testing these two elements using reporter constructs in liver cells (HepG2) revealed that CNS-66kb, but not CNS-62kb, yielded robust in vitro enhancer activity. In addition, an in vivo reporter assay using naked DNA transfer with CNS-66kb linked to luciferase displayed strong reproducible liver expression in adult mice, further supporting its role as a liver enhancer. Together, these studies further support the utility of comparative genomics to uncover gene regulatory sequences based on evolutionary conservation and provide the substrates to better understand the regulation and expression of COUP-TFII.

Animals↗
PubMed1998

Cloning of a novel member of the low-density lipoprotein receptor family.

A gene encoding a novel transmembrane protein was identified by DNA sequence analysis within the insulin-dependent diabetes mellitus (IDDM) locus IDDM4 on chromosome 11q13. Based on its chromosomal position, this gene is a candidate for conferring susceptibility to diabetes. The gene, termed low-density lipoprotein receptor related protein 5 (LRP5), encodes a protein of 1615 amino acids that contains conserved modules which are characteristic of the low-density lipoprotein (LDL) receptor family. These modules include a putative signal peptide for protein export, four epidermal growth factor (EGF) repeats with associated spacer domains, three LDL-receptor (LDLR) repeats, a single transmembrane spanning domain, and a cytoplasmic domain. The encoded protein has a unique organization of EGF and LDLR repeats; therefore, LRP5 likely represents a new category of the LDLR family. Both human and mouse LRP5 cDNAs have been isolated and the encoded mature proteins are 95% identical, indicating a high degree of evolutionary conservation.

Amino Acid Sequence↗
PubMed2006

Longin-like folds identified in CHiPS and DUF254 proteins: vesicle trafficking complexes conserved in eukaryotic evolution.

Eukaryotic protein trafficking pathways require specific transfer of cargo vesicles to different target organelles. A number of vesicle trafficking and membrane fusion components participate in this process, including various tethering factor complexes that interact with small GTPases prior to SNARE-mediated vesicle fusion. In Saccharomyces cerevisiae a protein complex of Mon1 and Ccz1 functions with the small GTPase Ypt7 to mediate vesicle trafficking to the vacuole. Mon1 belongs to DUF254 found in a diverse range of eukaryotic genomes, while Ccz1 includes a CHiPS domain that is also present in a known human protein trafficking disorder gene (HPS-4). The present work identifies the CHiPS domain and a sequence region from another trafficking disorder gene (HPS-1) as homologs of an N-terminal domain from DUF254. This link establishes the evolutionary conservation of a protein complex (HPS-1/HPS-4) that functions similarly to Mon1/Ccz1 in vesicle trafficking to lysosome-related organelles of diverse eukaryotic species. Furthermore, the newly identified DUF254 domain is a distant homolog of the mu-adaptin longin domain found in clathrin adapter protein (AP) complexes of known structure that function to localize cargo protein to specific organelles. In support of this fold assignment, known longin domains such as the AP complex sigma-adaptin, the synaptobrevin N-terminal domains sec22 and Ykt6, and the srx domain of the signal recognition particle receptor also regulate vesicle trafficking pathways by mediating SNARE fusion, recognizing specialized compartments, and interacting with small GTPases that resemble Ypt7.

Amino Acid Sequence↗
PubMed1988

Adenovirus transcriptional regulatory regions are conserved in mammalian cells and Saccharomyces cerevisiae.

The adenovirus early region 3 (E3) promoter is an early viral promoter which is strongly induced by the adenovirus transactivator protein E1A. DNase I footprinting with HeLa cell extracts has identified four factor-binding domains which appear to be involved in basal and E1A-induced transcriptional regulation. These binding domains may bind TATA region-binding factors (site I), the CREB/ATF protein (site II), the AP-1 protein (site III), and nuclear factor I/CTF (site IV). Recently, it has been shown that the DNA-binding domain of transcription factor AP-1 has homology with the yeast transcription factor GCN4 and that the yeast transactivator protein GAL4 is able to stimulate transcription in HeLa cells from promoters containing GAL4-binding sites. These results suggest an evolutionary conservation of both transcription factors and the mechanisms responsible for transcriptional activation in Saccharomyces cerevisiae and higher eucaryotic organisms. To determine whether similar patterns of transcriptional regulation were seen with the E3 promoter in HeLa and yeast cells, the E3 promoter fused to the chloramphenicol acetyltransferase (cat) gene was cloned into a high-copy-number plasmid and stably introduced into yeast cells. S1 analysis revealed that similar E3 promoter mRNA start sites were found in yeast and HeLa cells. DNase I footprinting with partially purified yeast extracts revealed that four regions of the E3 promoter were protected. Several of these regions were similar to binding sites determined by using HeLa cell extracts. Oligonucleotide mutagenesis of these binding domains indicated their importance in the transcriptional regulation of the E3 promoter in yeast cells. These results suggest that similar cellular transcription factor-binding sites may be involved in the regulation of promoters in both yeast and mammalian cells.

Adenoviridae↗
PubMed2005

Our chimpanzee mind.

Some might consider the title of this piece preposterous. Bishop Wilberforce would no doubt have shaken his fist at it, just as he disputed Huxley's championing of darwinian continuity. But the title of this essay is no more outrageous than one entitled 'The chimpanzee's bird brain', for there has been extensive evolutionary conservation of many neural and psychological functions across species. We share with chimpanzees some--but not all--mental functions, some of which are shared with other species as well. As the publication of the chimpanzee genome reveals, we also share a good deal of our DNA. Unfortunately, we are virtually in the dark when it comes to understanding how genes build minds. If comparative genomics is to enlighten our understanding of human origins, it must be accompanied by an equally rich description of animal psychology, both in terms of its underlying neural signatures and the evolutionary processes that led to convergence and divergence with other species.

Animals↗