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PubMed2006

HOX genes: seductive science, mysterious mechanisms.

HOX genes are evolutionarily highly conserved. The HOX proteins which they encode are master regulators of embryonic development and continue to be expressed throughout postnatal life. The 39 human HOX genes are located in four clusters (A-D) on different chromosomes at 7p15, 17q21 [corrected] 12q13, and 2q31 respectively and are assumed to have arisen by duplication and divergence from a primordial homeobox gene. Disorders of limb formation, such as hand-foot-genital syndrome, have been traced to mutations in HOXA13 and HOXD13. Evolutionary conservation provides unlimited scope for experimental investigation of the functional control of the Hox gene network which is providing important insights into human disease. Chromosomal translocations involving the MLL gene, the human homologue of the Drosophila gene trithorax, create fusion genes which exhibit gain of function and are associated with aggressive leukaemias in both adults and children. To date 39 partner genes for MLL have been cloned from patients with leukaemia. Models based on specific translocations of MLL and individual HOX genes are now the subject of intense research aimed at understanding the molecular programs involved, and ultimately the design of chemotherapeutic agents for leukaemia. Investigation of the role of HOX genes in cancer has led to the concept that oncology may recapitulate ontology, a challenging postulate for experimentalists in view of the functional redundancy implicit in the HOX gene network.

Animals↗
PubMed2004

Mutation of a highly conserved isoleucine disrupts hydrophobic interactions in the alpha beta spectrin self-association binding site.

We studied an infant with severe neonatal hemolytic anemia and hyperbilirubinemia that evolved into a partially compensated ellipto-poikilocytic anemia. His father had typical elliptocytosis. Their erythrocyte membranes demonstrated structural and functional defects in spectrin. Genetic studies revealed that the proband and his father were heterozygous for an alpha-spectrin mutation, Ile24Thr, in the alpha beta spectrin self-association binding site. The proband also carried the low expression allele alpha(LELY) in trans, influencing the clinical phenotype. The importance of isoleucine in this position of the proposed triple helical model of spectrin repeats is highlighted by its evolutionary conservation in all alpha spectrins from Drosophila to humans. Molecular modeling demonstrated that replacement of a hydrophobic isoleucine with a hydrophilic threonine disrupts highly conserved hydrophobic interactions in the interior of the spectrin triple helix critical for spectrin function.

Binding Sites↗
PubMed2003

Identification of SATB2 as the cleft palate gene on 2q32-q33.

Cytogenetic evidence, in the form of deletions and balanced translocations, points to the existence of a locus on 2q32-q33, for which haploinsufficiency results in isolated cleft palate (CPO). Here we show by high-resolution FISH mapping of two de novo CPO-associated translocations involving 2q32-q33 that one breakpoint interrupts the transcription unit of the gene encoding the DNA-binding protein SATB2 (formerly KIAA1034). The breakpoint in the other translocation is located 130 kb 3' to the SATB2 polyadenylation signal, within a conserved region of non-coding DNA. The SATB2 gene is transcribed in a telomeric to centromeric direction and lies in a gene-poor region of 2q32-q33; the nearest confirmed gene is 1.26 Mb centromeric to the SATB2 polyadenylation signal. SATB2-encoding transcripts are assembled from 11 exons that span 191 kb of genomic DNA. They encode a protein of 733 amino acids that has two CUT domains and a homeodomain and shows a remarkable degree of evolutionary conservation, with only three amino acid substitutions between mouse and human. This protein belongs to the same family as SATB1, a nuclear matrix-attachment region binding protein implicated in transcriptional control and control of chromatin remodelling. There are also sequence similarities to the Drosophila protein DVE. Whole mount in situ hybridization to mouse embryos shows site- and stage-specific expression of SATB2 in the developing palate. Despite the strong evidence supporting an important role for SATB2 in palate development, mutation analysis of 70 unrelated patients with CPO did not reveal any coding region variants.

Amino Acid Motifs↗
PubMed2000

Chromosomal mapping and genomic organization of an evolutionarily conserved zinc finger gene ZNF277.

A novel C2H2 zinc finger gene, ZNF277, has been localized to human chromosome 7q31.1. The gene is encoded by 12 exons in a genomic fragment of >100 kb between the microsatellite markers D7S523 and D7S471, deleted in a number of malignancies. The predicted open reading frame (ORF) of 438 amino acids shows an overall homology of 50% to the putative ORF F46B6.7 of Caenorhabditis elegans. The presence of a 30-amino-acid coiled-coil domain in both the C. elegans ORF F46B6.7 and ZNF277 is suggestive of functional similarities. ESTs for the murine orthologue ZFP277 are found in early embryonic stem cells, 16-cell stage embryo, and blastocysts. The evolutionary conservation and the expression profile suggest ZNF277 to be a critical regulator of development and differentiation.

Amino Acid Sequence↗
PubMed1987

Coenzyme binding ability of homologs of M4-lactate dehydrogenase in temperature adaptation.

Temperature effects on dissociation constants (Kd), binding enthalpies and apparent Michaelis constants (Km) for NADH, plus Arrhenius activation energies (Ea), substrate turnover numbers (kcat), and NADH 'on' constants (k1) were measured or calculated for M4-lactate dehydrogenase homologs from deep-sea, midwater, shallow-water temperate, and shallow-water tropical teleost fishes, and a mammal. At any single measurement temperature, Km and kcat values were significantly higher for groups adapted to lower temperatures. This pattern of Km values and temperature illustrates a strong evolutionary conservation of Km of NADH. When determined at the average body temperature of each species, the Km values are very similar, resulting in the preservation of the catalytic capacity and regulatory properties of these enzyme homologs at their in situ temperatures. In contrast, Kd values, while varying considerably among species, are not significantly different among the different groups at any one temperature. The ratio of Km to Kd tends to follow a phylogenetic pattern rather than a pattern of environmental adaptation. Thus, evolutionary adjustments in Km are not directly the result of changes in cofactor binding. All the rate constants involved in determining the Km and Kd of NADH (kcat, k1 and k-1) can be modified.

Adaptation, Physiological↗
PubMedDate not supplied

HIV infection of primate lymphocytes and conservation of the CD4 receptor.

The CD4 T-lymphocyte differentiation antigen is an essential component of the cell surface receptor for human immunodeficiency viruses (HIVs) causing AIDS (acquired immune deficiency syndrome) (refs 1-3). Peripheral blood lymphocytes of apes, New World and Old World monkeys express cell surface antigens homologous to CD4 of human T-helper lymphocytes. The cells of several of these species can be infected in short term culture with diverse strains of the type-1 or type-2 human immunodeficiency viruses (HIV-1 and HIV-2). HIV-1 is the prototype AIDS virus, and HIV-2 is the second type of AIDS virus, prevalent in West Africa. Infection of the primate cells correlates with evolutionary conservation on CD4 of one particular epitope cluster, and is inhibited by treatment of the cells with monoclonal antibodies to this epitope. The capacity of HIV to replicate in simian cells may provide a means for evaluating antiviral drugs and vaccines.

Animals↗
PubMed2004

Missense variations in the fibulin 5 gene and age-related macular degeneration.

BACKGROUND: Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the developed world. The study of a rare mendelian form of macular degeneration implicated fibulin genes in the pathogenesis of more common forms of this disease. We evaluated five fibulin genes in a large series of patients with AMD. METHODS: We studied 402 patients with AMD and 429 control subjects from the same clinic population. Patients were examined by means of indirect ophthalmoscopy, slit-lamp microscopy, and fundus photography to establish the presence and phenotypic pattern of AMD. DNA samples were screened for sequence variations in five members of the fibulin gene family. RESULTS: Amino acid-altering sequence variations were found in all five fibulin genes, many of which were observed only in patients with AMD. Several of the altered residues have been conserved during evolution. Seven of the 402 patients with AMD had amino acid-altering sequence variations in the fibulin 5 gene, whereas none were observed among 429 control subjects (P<0.01). In addition, these seven patients all had small, circular drusen, which are commonly referred to as basal laminar or cuticular drusen. CONCLUSIONS: Missense mutations in the fibulin 5 gene were found in 1.7 percent of patients with AMD. Many variations in other fibulin genes were also found in these patients, and the evolutionary conservation of the affected residues suggests that several of these variations may also be involved in AMD.

Aged↗
PubMed2005

Phenotype-genotype correlation in Hirschsprung disease is illuminated by comparative analysis of the RET protein sequence.

The ability to discriminate between deleterious and neutral amino acid substitutions in the genes of patients remains a significant challenge in human genetics. The increasing availability of genomic sequence data from multiple vertebrate species allows inclusion of sequence conservation and physicochemical properties of residues to be used for functional prediction. In this study, the RET receptor tyrosine kinase serves as a model disease gene in which a broad spectrum (> or = 116) of disease-associated mutations has been identified among patients with Hirschsprung disease and multiple endocrine neoplasia type 2. We report the alignment of the human RET protein sequence with the orthologous sequences of 12 non-human vertebrates (eight mammalian, one avian, and three teleost species), their comparative analysis, the evolutionary topology of the RET protein, and predicted tolerance for all published missense mutations. We show that, although evolutionary conservation alone provides significant information to predict the effect of a RET mutation, a model that combines comparative sequence data with analysis of physiochemical properties in a quantitative framework provides far greater accuracy. Although the ability to discern the impact of a mutation is imperfect, our analyses permit substantial discrimination between predicted functional classes of RET mutations and disease severity even for a multigenic disease such as Hirschsprung disease.

Amino Acid Sequence↗
PubMed2000

Multiple ISWI ATPase complexes from xenopus laevis. Functional conservation of an ACF/CHRAC homolog.

The nucleosomal ATPase ISWI is the catalytic subunit of several protein complexes that either organize or perturb chromatin structure in vitro. This work reports the cloning and biochemical characterization of a Xenopus ISWI homolog. Surprisingly, whereas we find four complex forms of ISWI in egg extracts, we find no functional homolog of NURF. One of these complexes, xACF, consists of ISWI, Acf1, and a previously uncharacterized protein of 175 kDa. Like both ACF and CHRAC, this complex organizes randomly deposited histones into a regularly spaced array. The remaining three forms include two novel ISWI complexes distinct from known ISWI complexes plus a histone-dependent ATPase complex. This comprehensive biochemical characterization of ISWI underscores the evolutionary conservation of the ACF/CHRAC family.

Adenosine Triphosphatases↗
PubMed2004

Detection of genome-scale ordered RNA structure (GORS) in genomes of positive-stranded RNA viruses: Implications for virus evolution and host persistence.

Discrete RNA secondary and higher-order structures, typically local in extent, play a fundamental role in RNA virus replication. Using new bioinformatics analysis methods, we have identified genome-scale ordered RNA structure (GORS) in many genera and families of positive-strand animal and plant RNA viruses. There was remarkably variability between genera that possess this characteristic; for example, hepaciviruses in the family Flaviviridae show evidence for extensive internal base-pairing throughout their coding sequences that was absent in both the related pestivirus and flavivirus genera. Similar genus-associated variability was observed in the Picornaviridae, the Caliciviridae, and many plant virus families. The similarity in replication strategies between genera in each of these families rules out a role for GORS in a fundamentally conserved aspect of this aspect of the virus life cycle. However, in the Picornaviridae, Flaviviridae, and Caliciviridae, the existence of GORS correlated strongly with the ability of each genus to persist in their natural hosts. This raises the intriguing possibility of a role for GORS in the modulation of innate intracellular defense mechanisms (and secondarily, the acquired immune system) triggered by double-stranded RNA, analogous in function to the expression of structured RNA transcripts by large DNA viruses. Irrespective of function, the observed evolutionary conservation of GORS in many viruses imposes a considerable constraint on genome plasticity and the consequent narrowing of sequence space in which neutral drift can occur. These findings potentially reconcile the rapid evolution of RNA viruses over short periods with the documented examples of extreme conservatism evident from their intimate coevolution with their hosts.

Animals↗
PubMed1986

Conservation of the cellular gene encoding the scrapie prion protein.

The major protein, PrP 27-30, in purified preparations of hamster scrapie prions is encoded within the genome of the experimental host. DNA sequences related to a PrP cDNA clone can be detected in a wide variety of organisms under relatively stringent conditions where the only signal generated by hamster or mouse DNA corresponds to the PrP gene. Three hosts for scrapie, goat, sheep and rat gave strong hybridization signals. In addition, three invertebrate DNAs reacted with the PrP probe, in the order nematode-Drosophila much greater than yeast. Thus, the sequences detected in goat, sheep, rat, nematode, Drosophila and possibly yeast DNA may arise from authentic PrP genes. This evolutionary conservation is consistent with the notion that PrP proteins participate in essential cellular processes.

Animals↗
PubMed1997

Current views on eye development.

Several genes involved in the regulation of eye development in different species have been identified. Structural and functional conservation have been found between some of these genes in organisms as diverse as Drosophila and mouse. One notable example is the relationship between the mouse Pax6 gene and eyeless of Drosophila. Ectopic expression of eyeless or mouse Pax6 in Drosophila results in the formation of additional eyes. Recently, another homeobox gene, Six3, was found to promote ectopic lens formation in fish embryos. The next step will be to unravel the associated regulatory pathways of these genes and assess the degree to which they display evolutionary conservation. This will be important in order to assimilate these findings with current anatomical and embryological models. It seems reasonable to believe that in the near future the characterization of the whole framework required for vertebrate eye development will be accomplished.

Animals↗
PubMed1991

Cooperation between CCAAT and octamer motifs in the distal sequence element of the rat U3 small nucleolar RNA promoter.

Mammalian U3 small nucleolar RNA promoters possess a highly conserved distal sequence element (DSE) consisting of CCAAT and octamer motifs separated by 11-12 base pairs. We show here that both motifs are required for transcription of a rat U3D gene in Xenopus oocytes. Deletion of the CCAAT motif leaves residual DSE activity, while removal of the octamer motif does not. Changing the conserved spacing between the two motifs generally inhibits transcription less than deletion of either motif, but increasing the spacing between the motifs by one helical turn of DNA preserves normal levels of transcription. We also show that the rat U3D DSE is functionally equivalent to the human U2 snRNA DSE, which consists of adjacent GC and octamer motifs, and that elements from the Herpes Simplex Virus thymidine kinase promoter can replace part or all of the U3D DSE. These data are apparently paradoxical; despite high evolutionary conservation, the U3 DSE is relatively insensitive to mutation, and other upstream motifs are also able to drive transcription from the U3 basal promoter. We suggest that the conserved structure of the U3 DSE may be required for regulation rather than efficiency of U3 transcription.

Animals↗
PubMed2004

Comparative analysis of cytokinesis in budding yeast, fission yeast and animal cells.

Cytokinesis is a temporally and spatially regulated process through which the cellular constituents of the mother cell are partitioned into two daughter cells, permitting an increase in cell number. When cytokinesis occurs in a polarized cell it can create daughters with distinct fates. In eukaryotes, cytokinesis is carried out by the coordinated action of a cortical actomyosin contractile ring and targeted membrane deposition. Recent use of model organisms with facile genetics and improved light-microscopy methods has led to the identification and functional characterization of many proteins involved in cytokinesis. To date, this analysis indicates that some of the basic components involved in cytokinesis are conserved from yeast to humans, although their organization into functional machinery that drives cytokinesis and the associated regulatory mechanisms bear species-specific features. Here, we briefly review the current status of knowledge of cytokinesis in the budding yeast Saccharomyces cerevisiae, the fission yeast Schizosaccharomyces pombe and animal cells, in an attempt to highlight both the common and the unique features. Although these organisms diverged from a common ancestor about a billion years ago, there are eukaryotes that are far more divergent. To evaluate the overall evolutionary conservation of cytokinesis, it will be necessary to include representatives of these divergent branches. Nevertheless, the three species discussed here provide substantial mechanistic diversity.

Animals↗
PubMed1994

A mammalian homologue of Drosophila heterochromatin protein 1 (HP1) is a component of constitutive heterochromatin.

The Drosophila HP1 gene contains a highly conserved sequence, the chromobox, which can be used to isolate HP1-like genes from both mouse (M31 and M32) and man (HSM1) (Singh et al., 1991). Here we report that a monoclonal antibody (MoAb) raised against the M31 protein recognises a 26-kDa protein in murine and human nuclear extracts and localises to large masses of condensed chromatin within murine interphase nuclei, some of which are associated with the nucleoli. At metaphase, the MoAb binds to the centromeres of both human and murine chromosomes. The evolutionary conservation of this chromosomal localisation indicates that the M31 protein is likely to be important in the packaging of mammalian chromosomal DNA into constitutive heterochromatin.

3T3 Cells↗
PubMed1989

Regional localization of the fibronectin and gamma-crystallin genes to bovine chromosome 8.

The genes for isocitrate dehydrogenase-1, fibronectin, and gamma-crystallin are syntenic in man, mouse, and cow. In an effort to assign this bovine syntenic group to a specific chromosome and to allow a cytological comparison of the conserved chromosomal region containing these genes in their respective species, we have localized the fibronectin and gamma-crystallin genes to bovine chromosome 8, region 1.1-1.4. This study incorporates the techniques of hybrid somatic cell analysis and in situ hybridization and the use of a Robertsonian-translocated marker chromosome from a related species for regional assignment of genes to a specific bovine chromosome. The regions on human chromosome 2q, mouse chromosome 1, and cow chromosome 8 that contain these genes are cytologically similar, perhaps representing evolutionary conservation at the cytogenetic level as well as at the gene level for this group of loci.

Animals↗
PubMed2003

Finding evolutionary relations beyond superfamilies: fold-based superfamilies.

Superfamily classifications are based variably on similarity of sequences, global folds, local structures, or functions. We have examined the possibility of defining superfamilies purely from the viewpoint of the global fold/function relationship. For this purpose, we first classified protein domains according to the beta-sheet topology. We then introduced the concept of kinship relations among the classified beta-sheet topology by assuming that the major elementary event leading to creation of a new beta-sheet topology is either an addition or deletion of one beta-strand at the edge of an existing beta-sheet during the molecular evolution. Based on this kinship relation, a network of protein domains was constructed so that the distance between a pair of domains represents the number of evolutionary events that lead one from the other domain. We then mapped on it all known domains with a specific core chemical function (here taken, as an example, that involving ATP or its analogs). Careful analyses revealed that the domains are found distributed on the network as >20 mutually disjointed clusters. The proteins in each cluster are defined to form a fold-based superfamily. The results indicate that >20 ATP-binding protein superfamilies have been invented independently in the process of molecular evolution, and the conservative evolutionary diffusion of global folds and functions is the origin of the relationship between them.

Adenosine Triphosphate↗
PubMed2006

Pumping RNA: nuclear bodybuilding along the RNP pipeline.

Cajal bodies (CBs) are nuclear subdomains involved in the biogenesis of several classes of small ribonucleoproteins (RNPs). A number of recent advances highlight progress in the understanding of the organization and dynamics of CB components. For example, a class of small Cajal body-specific (sca) RNPs has been discovered. Localization of scaRNPs to CBs was shown to depend on a conserved RNA motif. Intriguingly, this motif is also present in mammalian telomerase RNA and the evidence suggests that assembly of the active form of telomerase RNP occurs in and around CBs during S phase. Important steps in the assembly and modification of spliceosomal RNPs have also been shown to take place in CBs. Additional experiments have revealed the existence of kinetically distinct subclasses of CB components. Finally, the recent identification of novel markers for CBs in both Drosophila and Arabidopsis not only lays to rest questions about the evolutionary conservation of these nuclear suborganelles, but also should enable forward genetic screens for the identification of new components and pathways involved in their assembly, maintenance and function.

Animals↗