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PubMed2006

Protein complexity, gene duplicability and gene dispensability in the yeast genome.

Using functional genomic and protein structural data we studied the effects of protein complexity (here defined as the number of subunit types in a protein) on gene dispensability and gene duplicability. We found that in terms of gene duplicability the major distinction in protein complexity is between hetero-complexes, each of which includes at least two different types of subunits (polypeptides), and homo-complexes, which include monomers and complexes that consist of only subunits of one polypeptide type. However, gene dispensability decreases only gradually as the number of subunit types in a protein complex increases. These observations suggest that the dosage balance hypothesis can explain well gene duplicability of complex proteins, but cannot completely explain the difference in dispensabilities between hetero-complex subunits. It is likely that knocking out a gene coding for a hetero-complex subunit would disrupt the function of the whole complex, so that the deletion effect on fitness would increase with protein complexity. We also found that multi-domain polypeptide genes are less dispensable but more duplicable than single-domain polypeptide genes. Duplicate genes derived from the whole genome duplication event in yeast are more dispensable (except for ribosomal protein genes) than other duplicate genes. Further, we found that subunits of the same protein complex tend to have similar expression levels and similar effects of gene deletion on fitness. Finally, we estimated that in yeast the contribution of duplicate genes to genetic robustness against null mutation is approximately 9%, smaller than previously estimated. In yeast, protein complexity may serve as a better indicator of gene dispensability than do duplicate genes.

Computational Biology↗
PubMed1997

Paralogous histidine biosynthetic genes: evolutionary analysis of the Saccharomyces cerevisiae HIS6 and HIS7 genes.

The HIS6 gene from Saccharomyces cerevisiae strain YNN282 is able to complement both the S. cerevisiae his6 and the Escherichia coli hisA mutations. The cloning and the nucleotide sequence indicated that this gene encodes a putative phosphoribosyl-5-amino-1-phosphoribosyl-4-imidazolecarboxiamide isomerase (5' Pro-FAR isomerase, EC 5.3.1.16) of 261 amino acids, with a molecular weight of 29,554. The HIS6 gene product shares a significant degree of sequence similarity with the prokaryotic HisA proteins and HisF proteins, and with the C-terminal domain of the S. cerevisiae HIS7 protein (homologous to HisF), indicating that the yeast HIS6 and HIS7 genes are paralogous. Moreover, the HIS6 gene is organized into two homologous modules half the size of the entire gene, typical of all the known prokaryotic hisA and hisF genes. The structure of the yeast HIS6 gene supports the two-step evolutionary model suggested by Fani et al. (J. Mol. Evol. 1994; 38: 489-495) to explain the present-day hisA and hisF genes. According to this idea, the hisF gene originated from the duplication of an ancestral hisA gene which, in turn, was the result of an earlier gene elongation event involving an ancestral module half the size of the extant gene. Results reported in this paper also suggest that these two successive paralogous gene duplications took probably place in the early steps of molecular evolution of the histidine pathway, well before the diversification of the three domains, and that this pathway was one of the metabolic activities of the last common ancestor. The molecular evolution of the yeast HIS6 and HIS7 genes is also discussed.

Aldose-Ketose Isomerases↗
PubMedDate not supplied

House keeping genes and gene expression analysis in transplant recipients: a note of caution.

BACKGROUND: House keeping genes are often used as a means of standardising results obtained in gene expression investigations. This study was performed to investigate whether beta-actin, beta2-microglobulin (two genes frequently quoted as house keeping genes) and/or transferrin receptor would be suitable house keeping genes for use in gene expression analysis of renal transplant recipients. METHODS: Sequential expression of all three genes was measured in the peripheral blood mononuclear cells of 13 living donors and 45 renal transplant recipients, pre-operatively and then daily for up to 2 weeks. Fifteen of the recipients experienced an episode of biopsy proven acute rejection. Gene expression measurement was performed using quantitative real time 'TaqMan' PCR technology. RESULTS: Gene expression of all three genes was unchanged in the living donor cohort. However, in the transplant recipients there were significant increases in expression following transplantation in the non-rejectors, and preceding the diagnosis of acute rejection. In the latter group, levels returned to pre-transplant values after the commencement of anti-rejection therapy. CONCLUSIONS: Beta-actin, beta2-microglobulin and transferrin receptor gene expression, although not influenced by surgery, is influenced by transplantation, acute rejection and anti-rejection therapy making these genes unsuitable as house keeping genes following renal transplantation. These findings may cast doubt on the results of some studies that used these genes for the purposes of standardisation when looking at cDNA measurement. We suggest that any group wishing to use a house keeping gene ensure that its expression is independent of study parameters prior to the start of the study.

Actins↗
PubMed2003

Evolution of mitochondrial gene content: gene loss and transfer to the nucleus.

Mitochondrial gene content is highly variable across extant eukaryotes. The number of mitochondrial protein genes varies from 3 to 67, while tRNA gene content varies from 0 to 27. Moreover, these numbers exclude the many diverse lineages of non-respiring eukaryotes that lack a mitochondrial genome yet still contain a mitochondrion, albeit one often highly derived in ultrastructure and metabolic function, such as the hydrogenosome. Diversity in tRNA gene content primarily reflects differential usage of imported tRNAs of nuclear origin. In the case of protein genes, most of this diversity reflects differential degrees of functional gene transfer to the nucleus, with more minor contributions resulting from gene loss from the cell as a consequence of either substitution via a functional nuclear homolog or the cell's dispensation of the function of the gene product. The tempo and pattern of mitochondrial gene loss is highly episodic, both across the broad sweep of eukaryotes and within such well-studied groups as angiosperms. All animals, some plants, and certain other groups of eukaryotes are mired in profound stases in mitochondrial gene content, whereas other lineages have experienced relatively frequent gene loss. Loss and transfer to the nucleus of ribosomal protein and succinate dehydrogenase genes has been especially frequent, sporadic, and episodic during angiosperm evolution. Potential mechanisms for activation of transferred genes have been inferred, and intermediate stages in the process have been identified by comparative studies. Several hypotheses have been proposed for why mitochondrial genes are transferred to the nucleus, why mitochondria retain genomes, and why functional gene transfer is almost exclusively unidirectional.

Cell Nucleus↗
PubMed1993

DNA sequencing of the seven remaining structural genes of the gene cluster encoding the energy-transducing NADH-quinone oxidoreductase of Paracoccus denitrificans.

In our previous papers, seven structural genes (NQO1-7) of the energy-transducing NADH-quinone (Q) oxidoreductase of Paracoccus denitrificans were characterized [Xu, X., Matsuno-Yagi, A., & Yagi, T. (1991a) Biochemistry 30, 8678-8684; (1991b) Biochemistry 30, 6422-6428; (1992a) Biochemistry 31, 6925-6932; (1992b) Arch. Biochem. Biophys. 296, 40-48]. This paper reports the identification, cloning, and sequencing of seven additional structural genes in the same gene cluster (P. denitrificans enzyme complex). These seven genes, designated NQO8-14, are composed of 1038, 492, 603, 306, 2112, 1542, and 1500 base pairs, respectively. The polypeptides encoded by the NQO8-14 genes are homologous, respectively, to the ND1 product, the 23-kDa polypeptide, and the ND6, ND4L, ND5, ND4, and ND2 products of the bovine NADH-Q oxidoreductase. The order of the 14 structural genes of the Paracoccus energy-transducing NADH-Q oxidoreductase in the gene cluster is NQ07, NQO6, NQO5, NQO2, NQO1, NQO3, NQO8, NQO9, NQO10, NQO11, NQO12, NQO13, and NQO14. Downstream from the NQO14 gene an open reading frame (designated URF240) was detected which encodes a predicted polypeptide homologous to the biotin [acetyl-CoA-carboxylase] ligase of Escherichia coli. In addition, a putative terminal sequence motif was observed downstream of the NQO14 gene, suggesting that the structural gene NQO14 is the 3'-terminal gene of the Paracoccus NADH-Q oxidoreductase gene cluster. Nucleotide sequencing of the entire gene cluster revealed the presence of three unidentified reading frames: one between the NQO3 and NQO8 genes and other two between the NQO9 and NQO10 genes. These are designated URF4, URF5, and URF6 and are composed of 768, 393, and 405 base pairs, respectively. The possible functions of the putative proteins encoded by URF5 and URF6 are discussed.

Amino Acid Sequence↗
PubMedDate not supplied

Amplified gene location in chromosomal DNA affected recombinant protein production and stability of amplified genes.

Previously, we established an easy and quick construction method for obtaining a stable and highly productive gene-amplified recombinant Chinese hamster ovary (CHO) cell line. With a gradual increase in methotrexate (MTX) concentration, gene-amplified cell pools had high and stable specific growth and production rates. Moreover, the phenotype of gene-amplified cells seemed to be affected by the location of the amplified gene in chromosomal DNA. We suspected that various kinds of gene-amplified cells might appear during the long-term selection to construct gene-amplified cell pools. To clarify the behavior of gene-amplified cell pools during a stepwise increase of MTX concentration, we isolated gene-amplified clones derived from gene-amplified cell pools. We compared the characteristics of isolated clones, such as the productivity of recombinant protein, stability of amplified genes, and the location of amplified genes. As a result, telomere-type clones, in which the amplified gene was located near the telomeric region, were found to be more stable and productive than other types of clones. Telomere-type clones had over 100 copies of amplified genes in the chromosomal DNA. In contrast, a large number of other types of clones had less than 10 copies of amplified genes. During long-term cultivation in the absence of MTX, in other types of clones, amplified genes rapidly decreased in the chromosomal DNA.

Animals↗
PubMed1998

Tumourigenicity of MTG8, a leukaemia-related gene, in concert with v-Ha-ras gene in BALB/3T3 cells.

The MTG8 (ETO) gene has been identified as the translocation partner of AML1 (PEBP2alphaB or CBFalpha2) gene in the AML1/MTG8 (ETO) fused gene caused by t(8;21) translocation in human acute myeloid leukaemia, M2 type. Although AML1/MTG8 chimaeric protein is known to inhibit the functioning of AML1 protein, the precise function of MTG8 gene itself is not known yet. We studied the significance of MTG8 gene in the oncogenicity of AML1/MTG8 fused gene, by introducing full-length MTG8 cDNA into both BALB/3T3 cells containing v-Ha-ras gene (Bhas 42 cells) and BALB/3T3 cells without v-Ha-ras gene. Irrespective of the overexpression of MTG8 gene in both groups of cells, Bhas-MTG8 clones which contained v-Ha-ras gene and expressed the MTG8 gene at a level more than twice that of parental Bhas 42 cells induced cell transformation, whereas BALB-MTG8 clones without v-Ha-ras gene did not. Furthermore, injection of the transformed Bhas-MTG8 clones into the subcutaneous tissue of nude mice induced tumours, whereas that of BALB-MTG8 clones did not. These results suggest that MTG8 gene product, in cooperation with viral Ras protein, resulted in tumour formation. We provide the first evidence that MTG8 gene by itself has a carcinogenic property within the AML1/MTG8 (ETO) fused gene.

3T3 Cells↗
PubMed1990

Molecular evidence that the H-2D and H-2L genes arose by duplication. Differences between the evolution of the class I genes in mice and humans.

To resolve issues regarding the evolution of D region class I MHC genes and their relationship to other class I-encoding regions of the mouse, as well as man, we characterized the class I genes from the Dq region of the B10.AKM mouse strain. The Dq region was selected because it was known to express multiple gene products, yet two of the products previously characterized have structural features in common with the Ld molecule. Since DNA hybridization data defined similarities between the Dd and Dq regions, we used low-copy genomic or oligonucleotide probes derived from the Dd region of BALB/c (H-2d) to screen a B10.AKM cosmid library. Cosmid clones containing Dq, D2q, D3q, D4q, Lq, and Q1q genes have been isolated and aligned with the corresponding genes of the BALB/c MHC, thus demonstrating a similar gene organization. The two classical transplantation genes, Dq and Lq were found to be strikingly similar to each other such that exons 1-3 of Dq and Lq, are approximately 97% homologous, and exons 4-8 are identical. Furthermore, the implied amino acid sequences of both Lq and Dq molecules show considerable homology to Ld, particularly in regions presumed to be involved in ligand binding. These comparisons suggest not only that the Dq and Lq genes arose from the duplication of an Ld-like progenitor, but also that there is a selective advantage for the maintenance of an Ld-like structure. In addition, the 5' portion of the D4q gene was sequenced and found to have a 13-bp deletion and a 4-bp insertion within the alpha 2 exon. These result in a frame shift that creates a premature termination codon and potential polyadenylation site, respectively. Thus, D4q does not encode a typical class I molecule. Sequence comparisons suggest that the D4q gene did not arise from a duplication event involving an Ld-like gene such as Dq and Lq. Interestingly, the D4q molecule, if produced, would have amino acid residues in common with K and/or Q molecules that differ from those observed in D/L molecules. These findings, in conjunction with hybridization data, provide evidence that the D2, D3, and D4 genes were derived from Q genes by an unequal crossover event. Additional hybridization data using low-copy D region probes suggest that several different D region gene organizations exist among mice of different haplotypes. These and other recent molecular studies provide multiple examples of expansion and contraction of the class I genes in the D region.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed2001

Evaluation of the role of lipoprotein metabolism genes in systemic cationic liposome-mediated gene transfer in vivo.

Germ line gene disruption and gene insertion are often used to study the function of selected genes in vivo. We used selected knockout and transgenic mouse models to attempt to identify lipoprotein-related genes and gene products that regulate the process of intravenous cationic liposome-DNA complex (CLDC)-based gene delivery. Several observations suggested that proteins involved in lipoprotein metabolism might be important in influencing the delivery and/or expression of CLDC. First, in vitro transfection of either K562 or CHO cells by CLDCs was enhanced by the presence of a functional low-density lipoprotein receptor (LDLR). Second, pretreatment of mice with 4-aminopyrazolopyrimidine (4APP), an agent that alters lipoprotein profiles in mice, significantly decreased expression of luciferase (luc) after intravenous injection of CLDC-luc complexes in mice. Therefore, we tested mouse model systems either deficient for, or overexpressing, selected genes involved in lipoprotein metabolism, for their potential to regulate intravenous, CLDC-based gene delivery. Although homozygous knockout mutation in the apoE gene caused a significant decrease in gene expression in many tissues of apoE-deficient mice, mice with homozygous deletion of both the apoE and LDLR genes showed wild-type levels of gene transfer efficiency. Thus, a secondary event, produced by homozygous deletion of apoE, but compensated for by the concomitant deletion of LDLR, and/or effects resulting from strain-related, genetic background differences, appeared to play a significant role in mediating intravenous, CLDC-based gene delivery. Secondary alterations resulting from germ line knockouts, as well as epigenetic effects produced by strain differences, may limit the ability to assign specific, gene transfer-related functions to the deleted gene.

Animals↗
PubMed2001

ORI-GENE: gene classification based on the evolutionary tree.

MOTIVATION: Genome projects have produced large amounts of data on the sequences of new genes whose functions are as yet unknown. The functions of new genes are usually inferred by comparing their sequences with those of known genes, but evaluation of the sequence homology of individual genes does not make the most of the available sequence information. Therefore, new methods and tools for extracting more biological information from homology searches would be advantageous. RESULTS: We have developed a computational tool, ORI-GENE, to analyze the results of sequence homology searches from the perspective of the evolution of selected sets of new genes. ORI-GENE has a graphical interface and accomplishes two important tasks: first, based on the output of homology searches, it identifies species with similar genes and displays their pattern of distribution on the phylogenetic tree. This function enables one to infer the way in which a given gene may have propagated among species over time. Second, from the distribution patterns, it predicts the point at which a given gene may have been first acquired (i.e. its 'origin'), then classifies the gene on that basis. Because it makes use of available evolutionary information to show the way in which genes cluster among species, ORI-GENE should be an effective tool for the screening and classification of new genes revealed by genome analysis. AVAILABILITY: ORI-GENE is retrievable via the Internet at: http://www.rtc.riken.go.jp/jouhou/ORI-GENE.

Animals↗
PubMed1997

Isolation and characterisation of the NBR2 gene which lies head to head with the human BRCA1 gene.

To study the regulation of BRCA1 gene expression and the potential importance of dysregulation of this gene in breast and ovarian cancer, we have examined the 5' region of the human BRCA1 gene in detail. We have identified a new gene, NBR2, which is partially related to the NBR1 gene (formerly known as 1A1-3B and mapping directly adjacent to the pseudo-BRCA1 gene) and which lies head to head with the BRCA1 gene. The physical distance between the transcription start sites of the NBR2 and BRCA1 genes is 218 bp, suggesting that regulation of the expression of both genes may be co-ordinated through a bi-directional promoter. The NBR2 gene contains five exons spanning a genomic region of approximately 30 kb between the BRCA1 and pseudo-BRCA1 genes. Northern analysis showed that the NBR2 gene is expressed in all the tissues examined. The NBR2 cDNA contains an open reading frame of 112 amino acids and is predicted to encode a protein of approximately 12 kDa. Single-strand conformation polymorphism (SSCP) analysis of the NBR2 gene failed to identify any mutations in either breast or ovarian cancer, suggesting that if the NBR2 gene is involved in the development of these cancers, other mechanisms for tumorigenesis may exist. Hybridisation of NBR2 probes to zoo blots showed that the NBR2 gene is present in human and other primates. No hybridisation to DNA from other species was observed, suggesting that genomic elements controlling BRCA1 expression may differ between species.

Amino Acid Sequence↗
PubMed2006

Gene cluster analysis method identifies horizontally transferred genes with high reliability and indicates that they provide the main mechanism of operon gain in 8 species of gamma-Proteobacteria.

The formation mechanism of operons remains unresolved: operons may form by rearrangements within a genome or by acquisition of genes from other species, that is, horizontal gene transfer (HGT). One hindrance to its elucidation is the unavailability of a method to accurately identify HGT, although it is generally considered to occur. It is critically important first to select horizontally transferred (HT) genes reliably and then to determine the extent to which HGT is involved in operon formation. For this purpose, we considered indels in terms of gene clusters instead of individual genes and chose candidates of HT genes in 8 species of Escherichia, Shigella, and Salmonella based on the minimization of indels. To select a benchmark set of positively HT genes against which we can evaluate the candidate set, we devised another procedure using intergenetic alignments. Comparison with the benchmark set demonstrated the absence of a significant number of false positives in the candidate set, showing the high reliability of the method. Analyses of Escherichia coli K-12 operons revealed that although approximately 20 operons were probably gained from the last common ancestor of the 8 gamma-proteobacteria, deletion of intervening genes accounts for the formation of no operons, whereas horizontal transfer expanded 2 operons and introduced 4 entire operons. Based on these observations and reasoning, we suggest that the main mechanism of operon gain is HGT rather than intragenomic rearrangements. We propose that genes with related essential functions tend to reside in conserved operons, whereas genes in nonconserved operons mostly confer slight advantage to the organisms and frequently undergo horizontal transfer and decay. HT genes constitute at least 5.5% of the genes in the 8 species and approximately 45% of which originate from other gamma-proteobacteria. Genes involved in viral functions and mobile and extrachromosomal element functions are HT more often than expected. This finding indicates frequent mediation of HGT by bacteriophages. On the other hand, not only informational genes (those involved in transcription, translation, and related processes) but also operational genes (those involved in housekeeping) are HT less frequently than expected.

Cluster Analysis↗
PubMed2004

Gene and enhancer trap tagging of vascular-expressed genes in poplar trees.

We report a gene discovery system for poplar trees based on gene and enhancer traps. Gene and enhancer trap vectors carrying the beta-glucuronidase (GUS) reporter gene were inserted into the poplar genome via Agrobacterium tumefaciens transformation, where they reveal the expression pattern of genes at or near the insertion sites. Because GUS expression phenotypes are dominant and are scored in primary transformants, this system does not require rounds of sexual recombination, a typical barrier to developmental genetic studies in trees. Gene and enhancer trap lines defining genes expressed during primary and secondary vascular development were identified and characterized. Collectively, the vascular gene expression patterns revealed that approximately 40% of genes expressed in leaves were expressed exclusively in the veins, indicating that a large set of genes is required for vascular development and function. Also, significant overlap was found between the sets of genes responsible for development and function of secondary vascular tissues of stems and primary vascular tissues in other organs of the plant, likely reflecting the common evolutionary origin of these tissues. Chromosomal DNA flanking insertion sites was amplified by thermal asymmetric interlaced PCR and sequenced and used to identify insertion sites by reference to the nascent Populus trichocarpa genome sequence. Extension of the system was demonstrated through isolation of full-length cDNAs for five genes of interest, including a new class of vascular-expressed gene tagged by enhancer trap line cET-1-pop1-145. Poplar gene and enhancer traps provide a new resource that allows plant biologists to directly reference the poplar genome sequence and identify novel genes of interest in forest biology.

Amino Acid Sequence↗
PubMed2003

Presence of the tet(O) gene in erythromycin- and tetracycline-resistant strains of Streptococcus pyogenes and linkage with either the mef(A) or the erm(A) gene.

Sixty-three recent Italian clinical isolates of Streptococcus pyogenes resistant to both erythromycin (MICs >or=1 microg/ml) and tetracycline (MICs >or= 8 microg/ml) were genotyped for macrolide and tetracycline resistance genes. We found 19 isolates carrying the mef(A) and the tet(O) genes; 25 isolates carrying the erm(A) and tet(O) genes; and 2 isolates carrying the erm(A), tet(M), and tet(O) genes. The resistance of all erm(A)-containing isolates was inducible, but the isolates could be divided into two groups on the basis of erythromycin MICs of either >128 or 1 to 4 microg/ml. The remaining 17 isolates included 15 isolates carrying the erm(B) gene and 2 isolates carrying both the erm(B) and the mef(A) genes, with all 17 carrying the tet(M) gene. Of these, 12 carried Tn916-Tn1545-like conjugative transposons. Conjugal transfer experiments demonstrated that the tet(O) gene moved with and without the erm(A) gene and with the mef(A) gene. These studies, together with the results of pulsed-field gel electrophoresis experiments and hybridization assays with DNA probes specific for the tet(O), erm(A), and mef(A) genes, suggested a linkage of tet(O) with either erm(A) or mef(A) in erythromycin- and tetracycline-resistant S. pyogenes isolates. By amplification and sequencing experiments, we detected the tet(O) gene ca. 5.5 kb upstream from the mef(A) gene. This is the first report demonstrating the presence of the tet(O) gene in S. pyogenes and showing that it may be linked with another gene and can be moved by conjugation from one chromosome to another.

Anti-Bacterial Agents↗
PubMed2004

Identification of a novel gene family that includes the interferon-inducible human genes 6-16 and ISG12.

BACKGROUND: The human 6-16 and ISG12 genes are transcriptionally upregulated in a variety of cell types in response to type I interferon (IFN). The predicted products of these genes are small (12.9 and 11.5 kDa respectively), hydrophobic proteins that share 36% overall amino acid identity. Gene disruption and over-expression studies have so far failed to reveal any biochemical or cellular roles for these proteins. RESULTS: We have used in silico analyses to identify a novel family of genes (the ISG12 gene family) related to both the human 6-16 and ISG12 genes. Each ISG12 family member codes for a small hydrophobic protein containing a conserved ~80 amino-acid motif (the ISG12 motif). So far we have detected 46 family members in 25 organisms, ranging from unicellular eukaryotes to humans. Humans have four ISG12 genes: the 6-16 gene at chromosome 1p35 and three genes (ISG12(a), ISG12(b) and ISG12(c)) clustered at chromosome 14q32. Mice have three family members (ISG12(a), ISG12(b1) and ISG12(b2)) clustered at chromosome 12F1 (syntenic with human chromosome 14q32). There does not appear to be a murine 6-16 gene. On the basis of phylogenetic analyses, genomic organisation and intron-alignments we suggest that this family has arisen through divergent inter- and intra-chromosomal gene duplication events. The transcripts from human and mouse genes are detectable, all but two (human ISG12(b) and ISG12(c)) being upregulated in response to type I IFN in the cell lines tested. CONCLUSIONS: Members of the eukaryotic ISG12 gene family encode a small hydrophobic protein with at least one copy of a newly defined motif of approximately 80 amino-acids (the ISG12 motif). In higher eukaryotes, many of the genes have acquired a responsiveness to type I IFN during evolution suggesting that a role in resisting cellular or environmental stress may be a unifying property of all family members. Analysis of gene-function in higher eukaryotes is complicated by the possibility of functional redundancy between family-members. Genetic studies in organisms (e.g. Dictyostelium discoideum) with just one family member so far identified may be particularly helpful in this respect.

Amino Acid Sequence↗
PubMed2006

ALK1 signalling analysis identifies angiogenesis related genes and reveals disparity between TGF-beta and constitutively active receptor induced gene expression.

BACKGROUND: TGF-beta1 is an important angiogenic factor involved in the different aspects of angiogenesis and vessel maintenance. TGF-beta signalling is mediated by the TbetaRII/ALK5 receptor complex activating the Smad2/Smad3 pathway. In endothelial cells TGF-beta utilizes a second type I receptor, ALK1, activating the Smad1/Smad5 pathway. Consequently, a perturbance of ALK1, ALK5 or TbetaRII activity leads to vascular defects. Mutations in ALK1 cause the vascular disorder hereditary hemorrhagic telangiectasia (HHT). METHODS: The identification of ALK1 and not ALK5 regulated genes in endothelial cells, might help to better understand the development of HHT. Therefore, the human microvascular endothelial cell line HMEC-1 was infected with a recombinant constitutively active ALK1 adenovirus, and gene expression was studied by using gene arrays and quantitative real-time PCR analysis. RESULTS: After 24 hours, 34 genes were identified to be up-regulated by ALK1 signalling. Analysing ALK1 regulated gene expression after 4 hours revealed 13 genes to be up- and 2 to be down-regulated. Several of these genes, including IL-8, ET-1, ID1, HPTPeta and TEAD4 are reported to be involved in angiogenesis. Evaluation of ALK1 regulated gene expression in different human endothelial cell types was not in complete agreement. Further on, disparity between constitutively active ALK1 and TGF-beta1 induced gene expression in HMEC-1 cells and primary HUVECs was observed. CONCLUSION: Gene array analysis identified 49 genes to be regulated by ALK1 signalling and at least 14 genes are reported to be involved in angiogenesis. There was substantial agreement between the gene array and quantitative real-time PCR data. The angiogenesis related genes might be potential HHT modifier genes. In addition, the results suggest endothelial cell type specific ALK1 and TGF-beta signalling.

Activin Receptors, Type II↗
PubMed2023

Diverse evolutionary rates and gene duplication patterns among families of functional olfactory receptor genes in humans.

In humans, odors are detected by ~400 functional olfactory receptor (OR) genes. The superfamily of functional OR genes can be further divided into tens of families. In large part, the OR genes have experienced extensive tandem duplications, which have led to gene gains and losses. However, whether different OR gene families have experienced distinct modes of gene duplication has yet to be reported. We conducted comparative genomic and evolutionary analyses for human functional OR genes. Based on analysis of human-mouse 1-1 orthologs, we found that human functional OR genes show higher-than-average evolutionary rates, and there are significant differences among families of functional OR genes. Via comparison with seven vertebrate outgroups, families of human functional OR genes show different extents of gene synteny conservation. Although the superfamily of human functional OR genes is enriched in tandem and proximal duplications, there are particular families which are enriched in segmental duplications. These findings suggest that human functional OR genes may be governed by different evolutionary mechanisms and that large-scale gene duplications have contributed to the early evolution of human functional OR genes.

Humans↗
PubMed2001

Gene transfer into nonhuman primate hematopoietic stem cells: implications for gene therapy.

Hematopoietic stem cells (HSCs) are desirable targets for gene therapy because of their self-renewal and multilineage differentiation abilities. Retroviral vectors are extensively used for HSC gene therapy. However, the initial human trials of HSC gene marking and therapy showed that the gene transfer efficiency into human HSCs with retroviral vectors was very low in contrast to the much higher efficiency observed in murine experiments. The more quiescent nature of human HSCs and the lower density of retroviral receptors on them hindered the efficient gene transfer with retroviral vectors. Since nonhuman primates have marked similarity to humans in all aspects including the HSC biology, their models are considered to be important to evaluate and improve gene transfer into human HSCs. Using these models, clinically relevant levels (around 10% or even more) of gene-modified cells in peripheral blood have recently been achieved after gene transfer into HSCs and their autologous transplantation. This has been made possible by improving ex vivo transduction conditions such as introduction of Flt-3 ligand and specific fibronectin fragment (CH-296) into ex vivo culture during transduction, and the use of retroviral vectors pseudotyped with the gibbon ape leukemia virus or feline endogenous retrovirus envelope. Other strategies including the use of lentiviral vectors and in vivo selective expansion of gene-modified cells with the drug resistance gene or selective amplifier gene (also designated the molecular growth switch) are now being tested to further increase the fraction of gene-modified cells using nonhuman primate models. In addition to the high gene transfer efficiency, high-level and long-term expression of transgenes in human HSCs and their progeny is also required for effective HSC gene therapy. For this purpose, other backbones of retroviral vectors such as the murine stem cell virus and cis-DNA elements, such as the ss-globin locus control region and the chromatin insulator, also need to be tested in nonhuman primate models. Nonhuman primate studies will continue to provide an important framework for human HSC gene therapy. Well-designed nonhuman primate studies will also offer unique insights into the HSCs, immune system, and transplantation biology characteristic of large animals.

Animals↗