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PubMed1990

Highly conserved core domain and unique N terminus with presumptive regulatory motifs in a human TATA factor (TFIID).

The factor TFIID is one of several general factors that are necessary and sufficient for transcription initiation by mammalian RNA polymerase II. Stable interactions with the common TATA element lead both to template commitment and to the assembly of the other general factors into a functional preinitiation complex. Consistent with its key role in the promoter activation pathway, human TFIID also seems to be a target for some regulatory factors, as evidenced both by physical and functional studies of interactions between these components. The evolutionary conservation of functional properties led to the purification and cloning of yeast TFIID, the identification of presumptive structural motifs, and direct structure-function studies. Here we report the cloning of a complementary DNA encoding a functional human TFIID. This reveals an evolutionarily conserved core which corresponds precisely to the 180-residue DNA binding/activation domain determined for yeast TFIID, a near absolute conservation of component structural motifs (direct repeats, central basic core/lysine repeat, and sigma homology), providing further support for their functional importance, and a unique N-terminal structure that suggests involvement in species-specific regulatory factor interactions.

Amino Acid Sequence↗
PubMed2004

Genomic structure and expression analysis of the mouse testis-specific ribbon protein (Trib) gene.

During our analyses of genes required for the development and function of the mouse gonads, we identified a novel testis-specific mRNA, transcribed from a gene that we have named testis-specific ribbon protein (Trib). In the mouse, Trib is located on chromosome 15, overlapping with and transcribed in the opposite orientation of the meiosis specific gene Smc1beta. The deduced amino acid sequence of testis ribbon (TRIB) protein is highly conserved between human, mouse, and rat and contains the ribbon motifs found in the largely uncharacterized microtubule ribbon protein ribbon43a (RIB43A). We show by Northern blot analyses and reverse transcription-polymerase chain reaction (RT-PCR) that Trib mRNA is specifically expressed in the adult testis. In situ hybridization indicates that Trib is expressed solely in germ cells during the leptotene-pachytene stages of spermatogenesis. The high level of evolutionary conservation and the cellular and temporal expression suggest that Trib may be required for mouse spermatogenesis and male fertility. Here, we describe the genomic structure and expression profile of mouse Trib and compare its homology with other ribbon proteins.

Amino Acid Sequence↗
PubMed1991

rab3A attachment to the synaptic vesicle membrane mediated by a conserved polyisoprenylated carboxy-terminal sequence.

rab3A is a small neuronal GTP-binding protein specifically localized to synaptic vesicles. Membrane-bound rab3A behaves like an intrinsic membrane protein in vitro, but reversibly dissociates from synaptic vesicles after exocytosis in vivo. Here we demonstrate that rab3A is attached to synaptic vesicle membranes by a carboxy-terminal Cys-X-Cys sequence that is posttranslationally modified. This modification is inhibited by compactin in a mevalonate-dependent manner, suggesting that the Cys-X-Cys sequence represents a novel polyisoprenylation sequence. Isolation of a rab3 homolog from D. melanogaster reveals high evolutionary conservation of rab3A, including its carboxy-terminal Cys-X-Cys sequence. The posttranslational modifications of soluble and membrane-bound rab3A are biochemically different, but both require the carboxy-terminal Cys-X-Cys sequence and are faithfully reproduced in nonneuronal cells. Our results suggest that the carboxy-terminal Cys-X-Cys sequence of rab3A is polyisoprenylated and is used as its regulatable membrane anchor. Furthermore, the hydrophobic modification of rab3A and its correct intracellular targeting to synaptic vesicles are independent, presumably consecutive events.

Amino Acid Sequence↗
PubMed1993

Cloning the RAD51 homologue of Schizosaccharomyces pombe.

The RAD51 gene of Saccharomyces cerevisiae encodes a RecA like protein, which is involved in the recombinational repair of double strand breaks. We have isolated the RAD51 homologue, rhp51+, of the distantly related yeast strain Schizosaccharomyces pombe by heterologous hybridization. DNA sequence analysis of the rhp51+ gene revealed an open reading frame of 365 amino acids. Comparison of the amino acid sequences of RAD51 and rhp51+ showed a high level of conservation: 69% identical amino acids. There are two Mlul sites in the upstream region which may be associated with cell cycle regulation of the rhp51+ gene. The rhp51+ null allele, constructed by disruption of the coding region, is extremely sensitive to X-rays, indicating that the rhp51+ gene, like RAD51, is also involved in the repair of X-ray damage. The structural and functional homology between rhp51+ and RAD51 suggests evolutionary conservation of certain steps in the recombinational repair pathway.

Amino Acid Sequence↗
PubMed1995

Isolation and characterization of a chicken homolog of the c-ret proto-oncogene.

The c-ret proto-oncogene encodes a receptor tyrosine kinase that plays important roles in human disease and in normal mammalian development. Mutations in the human RET gene are associated with multiple endocrine neoplasia syndromes and Hirschsprung's disease in humans, while targeted mutagenesis of murine c-ret resulted in severe developmental abnormalities affecting the excretory and peripheral nervous systems. To examine the evolutionary conservation of the ret protein sequence and its developmental expression pattern, we isolated and sequenced cDNA clones of chicken c-ret and examined its expression in chick embryos and adult tissues. The cytoplasmic domains of chicken and human ret were relatively well conserved (91% similar), but the extracellular domains were more divergent (68% similar), although the conservation of cysteine residues in this region suggests a conserved secondary structure. As in mouse and human, chicken c-ret encodes two protein isoforms. The number and sizes of the transcripts were similar to those in human and mouse cells, and during chick embryogenesis, c-ret mRNA was observed in many of the same sites as in the mouse, including the Wolffian duct and ureteric bud, the enteric, dorsal root, sympathetic and facioacoustic ganglia, and the ventral spinal cord. Evolutionary differences in expression were observed in the trigeminal ganglion, the ventral roots of the spinal cord, the mesenchymal cells of the branchial arches and the adult testes. The results are discussed with regard to the role of the ret receptor in normal development and disease.

Amino Acid Sequence↗
PubMed1993

cDNA cloning and chromosomal mapping of the mouse type VII collagen gene (Col7a1): evidence for rapid evolutionary divergence of the gene.

Type VII collagen is the major component of anchoring fibrils, critical attachment structures at the dermal-epidermal basement membrane zone. Genetic linkage analyses with recently cloned human type VII collagen cDNAs have indicated that the corresponding gene, COL7A1, is the candidate gene in the dystrophic forms of epidermolysis bullosa. To gain insight into the evolutionary conservation of COL7A1, in this study we have isolated mouse type VII collagen cDNAs by screening a mouse epidermal keratinocyte cDNA library with a human COL7A1 cDNA. Two overlapping mouse cDNAs were isolated, and Northern hybridization of mouse epidermal keratinocyte RNA with one of them revealed the presence of a mRNA transcript of approximately 9.5 kb, the approximate size of the human COL7A1 mRNA. Nucleotide sequencing of the mouse cDNAs revealed a 2760-bp open reading frame that encodes the 5' half of the collagenous domain and a segment of the NC-1, the noncollagenous amino-terminal domain of type VII collagen. Comparison of the mouse amino acid sequences with the corresponding human sequences deduced from cDNAs revealed 82.5% identity. The evolutionary divergence of the gene was relatively rapid in comparison to other collagen genes. Despite the high degree of sequence variation, several sequences, including the size and the position of noncollagenous imperfections and interruptions within the Gly-X-Y repeat sequence, were precisely conserved. Finally, the mouse Col7a1 gene was located by interspecific backcross mapping to mouse Chromosome 9, a region that corresponds to human chromosome 3p21, the position of human COL7A1. This assignment confirms and extends the relationship between the mouse and the human chromosomes in this region of the genome.

Amino Acid Sequence↗
PubMed2007

Molecular phylogeny, evolution, and functional divergence of the LSD1-like gene family: inference from the rice genome.

The identification of LSD1-like genes in parasite, green algae, moss, pine, and monocot and dicot species allowed us to trace the phylogenetic history of this gene family. Computational analysis showed that the diversification of members of this family could be dated back to the early stage of plant evolution. The evolution of plant LSD1-like genes was possibly shaped by two duplication events. These proteins, which contain three copies of the LSD1 zinc finger (zf-LSD1) domain within their entire polypeptides and play crucial roles in modulating disease defense and cell death, resulted from the second duplication. A gain of zf-LSD1 domain model was reasonable for explaining the origination of three-zf-LSD1 domain-containing proteins. The zf-LSD1 domain phylogeny showed that the middle (M) and C-terminal (C) domains originated from a common ancestor; the N-terminal (N) domain might be more ancient than the former two. The divergence of the N, M, and C domains was well before the monocot-dicot split. Coevolution analysis revealed that four intramolecular domain pairs, including the N domain and the interregion between the M and the C domains (INTER2), the M and C domain, the N- and C-terminus, and the M domain and C-terminus, possibly coevolved during the evolution of three-zf-LSD1 domain-containing proteins. The three zf-LSD1 domains are evolutionary conserved. Thus, the differences at the N- and C-terminus would be crucial for functional specificity of LSD1 genes. Strong functional constraints should work on the zf-LSD1 domains, whereas reduced functional constraint was found in the INTER2 region. Functional divergence analysis showed that three-zf-LSD1 domain-containing proteins were significantly functionally divergent from those proteins containing only one zf-LSD1 domain, a result demonstrating that shifted evolutionary rates between the two clusters were significantly different from each other.

Amino Acid Sequence↗
PubMed2001

Evolutionarily conserved nuclear migration genes required for early embryonic development in Caenorhabditis elegans.

The nudF and nudC genes of the fungus Aspergillus nidulans encode proteins that are members of two evolutionarily conserved families. In A. nidulans these proteins mediate nuclear migration along the hyphae. The human ortholog of nudF is Lis1, a gene essential for neuronal migration in the developing cerebral cortex. The mammalian ortholog of nudC encodes a protein that interacts with Lis1. We have identified orthologs of nudC and Lis1 from the nematode Caenorhabditis elegans. Heterologous expression of the C. elegans nudC ortholog, nud-1, complements the A. nidulans nudC3 mutant, demonstrating evolutionary conservation of function. A C. elegans nud-1::GFP fusion produces sustained fluorescence in sensory neurons and embryos, and transient fluorescence in the gonad, gut, vulva, ventral cord, and hypodermal seam cells. Fusion of GFP to C. elegans lis-1 revealed expression in all major neuronal processes of the animal as well as the multinucleate spermathecal valves and adult seam cells. Phenotypic analysis of either nud-1 and lis-1 by RNA interference yielded similar phenotypes, including embryonic lethality, sterility, altered vulval morphology, and uncoordinated movement. Digital time-lapse video microscopy was used to determine that RNAi-treated embryos exhibited nuclear positioning defects in early embryonic cell division similar to those reported for dynein/dynactin depletion. These results demonstrate that the LIS-1/NUDC-like proteins of C. elegans represent a link between nuclear positioning, cell division, and neuronal function.

Animals↗
PubMedDate not supplied

Mouse Pum1 and Pum2 genes, members of the Pumilio family of RNA-binding proteins, show differential expression in fetal and adult hematopoietic stem cells and progenitors.

Self-renewal is the common functional property of all types of stem cells and is thought to be regulated by unknown conserved intrinsic and extrinsic molecular mechanisms. Recently, an evolutionarily conserved Pumilio family of RNA-binding proteins that regulate asymmetric cell division was found to be essential for stem cell maintenance and self-renewal in Drosophila and Caenorhabditis elegans. Based on conserved function in invertebrates and lower vertebrates it was recently proposed that an ancestral function of Pumilio proteins is to support proliferation and self-renewal of stem cells. This raises an interesting possibility that Pumilio could be part of evolutionarily conserved intrinsic molecular mechanism that regulates self-renewal of mammalian stem cells. Here we describe cloning and comparative sequence analysis of Pum1 and Pum2 genes, mouse members of the Pumilio family, and for the first time demonstrate expression of Pumilio genes in mammalian hematopoietic stem cells (HSC). Pum1 and Pum2 share 51 and 55% overall similarity with the fly Pum, whereas their RNA-binding domains show a very high degree of evolutionary conservation (86-88% homology). Both genes are expressed in a variety of tissues suggesting that they have widespread function. During blood cell development Pum1 and Pum2 exhibit differential expression in cell populations enriched for HSC and progenitors. Both genes are highly transcribed in populations of adult HSC (Rho-123(low)Sca-1(+)c-kit(+)Lin(-) cells). In a more heterogeneous population of HSC (Lin(-)Sca-1(+)) and in progenitors (Lin(-)Sca-1(-) cells) Pum1 is not transcribed, whereas Pum2 expression is significantly down-regulated. Ongoing in vitro and in vivo functional analysis of mouse Pumilio genes will help to elucidate the biological role of mammalian Pumilio genes and determine whether they play any role in maintenance of mammalian stem cells, such as HSC.

Amino Acid Sequence↗
PubMed2003

The modifier of mdg4 locus in Drosophila: functional complexity is resolved by trans splicing.

The modifier of mdg4 (mod(mdg4)) gene of Drosophila melanogaster has been identified in many different genetic assays. It has been independently identified through mutations isolated for their effects on position effect variegation (PEV), the properties of insulator sequences, correct pathfinding of growing nerve cells, meiotic pairing of chromosomes, or apoptosis. Molecular analysis of the mod(mdg4) locus revealed that it encodes a family of at least 26 protein isoforms. Inspired by the fact that some mod(mdg4) transcripts are encoded by both antiparallel DNA strands, it was shown that mRNA trans splicing is the mechanism used by this locus to produce mature transcripts. All Mod(mdg4) protein isoforms share a common N-terminal region of 402 amino acids, which includes the conserved BTB/POZ domain. However, the isoforms differ in their C-terminal ends. Most of the C-termini contain a conserved Cys2His2 protein motif, which we have named the FLYWCH motif. Genetic and immunological data indicate that mod(mdg4) encodes a family of related chromatin proteins. Recent results indicate a functional correlation between the large number of different isoforms and the pleiotropic mutant phenotypes of most mod(mdg4) mutations. We discuss the putative function of Mod(mdg4) proteins as chromatin modulators involved in higher order chromatin domains. We also provide evidence for the evolutionary conservation of several of the isoforms and the unusual structure of the locus.

Amino Acid Motifs↗
PubMed2001

Use of comparative physical and sequence mapping to annotate mouse chromosome 16 and human chromosome 21.

Distal mouse chromosome 16 (MMU16) shares conserved linkage with human chromosome 21 (HSA21), trisomy for which causes Down syndrome (DS). A 4.5-Mb physical map extending from Cbr1 to Tmprss2 on MMU16 provides a minimal tiling path of P1 artificial chromosomes (PACs) for comparative mapping and genomic sequencing. Thirty-four expressed sequences were positioned on the mouse map, including 19 that were not physically mapped previously. This region of the mouse:human comparative map shows a high degree of evolutionary conservation of gene order and content, which differs only by insertion of one gene (in mouse) and a small inversion involving two adjacent genes. "Low-pass" (2.2x) mouse sequence from a portion of the contig was ordered and oriented along 510 kb of finished HSA21 sequence. In combination with 68 kb of unique PAC end sequence, the comparison provided confirmation of genes predicted by comparative mapping, indicated gene predictions that are likely to be incorrect, and identified three candidate genes in mouse and human that were not observed in the initial HSA21 sequence annotation. This comparative map and sequence derived from it are powerful tools for identifying genes and regulatory regions, information that will in turn provide insights into the genetic mechanisms by which trisomy 21 results in DS.

Animals↗
PubMed2006

Conservation and divergence of the Emicro3' enhancer in the IGH locus of teleosts.

The core region of the Emicro3' transcriptional enhancer that drives the expression of the teleost IGH locus has been characterized functionally in two species, the catfish (Ictalurus punctatus) and the zebrafish (Danio rerio). These studies have suggested important differences: whereas the catfish enhancer acts through an E-box and two octamer motifs, the zebrafish enhancer exerts its major effects through two E-box motifs alone. In this study, the function of the catfish enhancer was reexamined in a broader comparative context within the teleosts. Electrophoretic mobility shift assays of motifs from catfish, zebrafish, and Fugu were conducted to determine their ability to bind catfish E-protein and Oct transcription factors. Transient expression assays were conducted using a region of the catfish core enhancer that includes a newly described hybrid octamer/E-box motif. Sequences homologous to the Emicro3' enhancer region from six teleosts were aligned to determine conserved regions ("phylogenetic footprinting"). These studies allowed the following conclusions to be drawn: (1) The important 3'E-box motif described in the zebrafish corresponds in the homologous region of the catfish enhancer to an Oct motif with a newly described negative regulatory function and (2) Comparison of the Emicro3' enhancer sequences of six teleosts indicates that while a variety of octamer and E-box motifs are found in this region, strict evolutionary conservation of the important functional elements of the teleost Emicro3' enhancer has not occurred.

Animals↗
PubMed2005

Evolution versus constitution: differences in chromosomal inversion.

We compared the chromosomal breakpoints of evolutionary conserved and constitutional inversions. Multicolor banding and human-specific bacterial artificial chromosomes were applied to map the breakpoints of constitutional pericentric inversions on human chromosomes 2 and 9. For the first time, we present a high-resolution analysis of the breakpoint regions, which are characterized by gene destitution, co-localization with fragile sites, multitude repeats as well as pseudogenes and, remarkably, a large sequence homology to the opposite breakpoint. In contrast, evolutionary inversion breakpoints lack such extensive cross-hybridizing regions and are often associated with fragile sites of the genome and low-copy repeats. These molecular characteristics gave evidence for different types of inversion formation and indicate that evolutionary inversions cannot originate from constitutional inversions like those of chromosomes 2 and 9. Finally, the constitutional inversion breakpoints were investigated on three different great ape species and on four test persons each bearing the same cytogenetically determined inversion on chromosomes 2 and 9, respectively. Our data indicate the existence of different molecular breakpoints for the two variant chromosomes.

Animals↗
PubMed2006

Bioinformatic and comparative localization of Rab proteins reveals functional insights into the uncharacterized GTPases Ypt10p and Ypt11p.

A striking characteristic of a Rab protein is its steady-state localization to the cytosolic surface of a particular subcellular membrane. In this study, we have undertaken a combined bioinformatic and experimental approach to examine the evolutionary conservation of Rab protein localization. A comprehensive primary sequence classification shows that 10 out of the 11 Rab proteins identified in the yeast (Saccharomyces cerevisiae) genome can be grouped within a major subclass, each comprising multiple Rab orthologs from diverse species. We compared the locations of individual yeast Rab proteins with their localizations following ectopic expression in mammalian cells. Our results suggest that green fluorescent protein-tagged Rab proteins maintain localizations across large evolutionary distances and that the major known player in the Rab localization pathway, mammalian Rab-GDI, is able to function in yeast. These findings enable us to provide insight into novel gene functions and classify the uncharacterized Rab proteins Ypt10p (YBR264C) as being involved in endocytic function and Ypt11p (YNL304W) as being localized to the endoplasmic reticulum, where we demonstrate it is required for organelle inheritance.

Animals↗
PubMed1989

A protein target site in an early replicated human DNA sequence: a highly conserved binding motif.

We have previously reported that a human nuclear factor, probably corresponding to the USF/MLTF protein [1,2], is able to bind specifically to a DNA sequence present in DNA replicated at the onset of S-phase [3]. Here we demonstrate that the same factor binds also to several other similar sequences, present in eukaryotic and viral genomes. Mutations or methylation in a CpG dinucleotide, central in the palindromic binding site, completely abolish binding. Furthermore, we present evidence for the existence of at least two other nuclear proteins in human cells with the same DNA binding specificity. The data presented suggest a strong evolutionary conservation, among distantly related organisms, of the binding motif, which is probably the target of a number of nuclear factors that share the same DNA binding specificity albeit in the context of different functions.

Base Composition↗
PubMed1997

Relationship between the genomic organization and the overlapping embryonic expression patterns of the zebrafish dlx genes.

To understand the relationship between the expression and the genomic organization of the zebrafish dlx genes, we have determined the genomic structure of the dlx2 and dlx4 loci. This led to the identification of the zebrafish dlx1 and dlx6 genes, which are closely linked to dlx2 and dlx4, respectively. Therefore, the inverted convergent configuration of Dlx genes is conserved among vertebrates. Analysis of the expression patterns of dlx1 and dlx6 showed striking similarities to those of dlx2 and dlx4, respectively, the genes to which they are linked. Furthermore, the expression patterns of dlx3 and dlx7, which likely constitute a third pair of convergently transcribed genes, are indistinguishable. Thus, the overlapping expression patterns of linked Dlx genes during embryonic development suggest that they share cis-acting sequences that control their spatiotemporal expression. The evolutionary conservation of the genomic organization and combinatorial expression of Dlx genes in distantly related vertebrates suggest tight control mechanisms that are essential for their function during development.

Amino Acid Sequence↗
PubMed1992

The mouse beta-globin locus control region: hypersensitive sites 3 and 4.

The human beta-globin LCR plays a key role in the transcriptional regulation of the beta-globin locus and comprises four erythroid specific DNase I hypersensitive sites, designated 5'HS1-4. We have now isolated genomic clones containing 5'HS3 and 5'HS4 of the mouse beta-globin LCR. 5'HS3 and 5'HS4 are located 15 kb and 22 kb upstream of the mouse epsilon y-globin gene, respectively. Sequence analysis of murine 5'HS3 and 5'HS4 reveals a significant degree of sequence conservation with their human homologues, including the presence of recognition sites for functionally relevant transcription factors. 5'HS3 and 5'HS4 regions were found to form hypersensitive sites in nuclei from murine erythroid cells, but not in nuclei from a variety of nonerythroid haematopoietic cell lines. Analysis of different mouse strains revealed the existence of a polymorphism that alters the spacing between 5'HS3 and 5'HS4. Taken together, our results emphasize the extent of evolutionary conservation and complexity of mammalian beta-globin LCRs. Finally, the cloning of mouse 5'HS3 and 5'HS4 will facilitate the molecular analysis of LCR function in the mouse model.

Animals↗
PubMed1999

The ubiquitin system in gametogenesis.

Ubiquitin is a ubiquitous and highly conserved protein of 76 amino acid residues, that can be covalently attached to cellular acceptor proteins. The attachment of ubiquitin to target proteins is achieved through a multi-step enzymatic pathway, which involves activities of ubiquitin-activating E1 enzymes, ubiquitin-conjugating E2 enzymes, and ligating E3 enzymes. Mono- or poly-ubiquitination of proteins can lead to protein degradation or modification of protein activity. Many components of the complex ubiquitin system show remarkable evolutionary conservation, from yeast to mammalian species. The ubiquitin system is essential to all eukaryotic cells. Among others, several signal transduction cascades show involvement of the ubiquitin system, but there are currently little data supporting a specific role of the ubiquitin system in hormonal control of reproduction. Interestingly, during gametogenesis, many specialized and important aspects of the ubiquitin system become apparent. Components of the ubiquitin system appear to be involved in different steps and processes during gametogenesis, including control of meiosis, and reorganization of chromatin structure.

Animals↗