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PubMed2002

The role of lineage-specific gene family expansion in the evolution of eukaryotes.

A computational procedure was developed for systematic detection of lineage-specific expansions (LSEs) of protein families in sequenced genomes and applied to obtain a census of LSEs in five eukaryotic species, the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the green plant Arabidopsis thaliana. A significant fraction of the proteins encoded in each of these genomes, up to 80% in A. thaliana, belong to LSEs. Many paralogous gene families in each of the analyzed species are almost entirely comprised of LSEs, indicating that their diversification occurred after the divergence of the major lineages of the eukaryotic crown group. The LSEs show readily discernible patterns of protein functions. The functional categories most prone to LSE are structural proteins, enzymes involved in an organism's response to pathogens and environmental stress, and various components of signaling pathways responsible for specificity, including ubiquitin ligase E3 subunits and transcription factors. The functions of several previously uncharacterized, vastly expanded protein families were predicted through in-depth protein sequence analysis, for example, small-molecule kinases and methylases that are expanded independently in the fly and in the nematode. The functions of several other major LSEs remain mysterious; these protein families are attractive targets for experimental discovery of novel, lineage-specific functions in eukaryotes. LSEs seem to be one of the principal means of adaptation and one of the most important sources of organizational and regulatory diversity in crown-group eukaryotes.

Animals↗
PubMed2006

Transposition of reversed Ac element ends generates novel chimeric genes in maize.

The maize Activator/Dissociation (Ac/Ds) elements are members of the hAT (hobo, Ac, and Tam3) superfamily of type II (DNA) transposons that transpose through a "cut-and-paste" mechanism. Previously, we reported that a pair of Ac ends in reversed orientation is capable of undergoing alternative transposition reactions that can generate large-scale chromosomal rearrangements, including deletions and inversions. We show here that rearrangements induced by reversed Ac ends transposition can join the coding and regulatory sequences of two linked paralogous genes to generate a series of chimeric genes, some of which are functional. To our knowledge, this is the first report demonstrating that alternative transposition reactions can recombine gene segments, leading to the creation of new genes.

Alleles↗
PubMed2006

Secretory COPII coat component Sec23a is essential for craniofacial chondrocyte maturation.

An increasing number of human disorders have been linked to mutations in genes of the secretory pathway. The chemically induced zebrafish crusher variant results in malformed craniofacial skeleton, kinked pectoral fins and a short body length. By positional cloning, we identified a nonsense mutation converting leucine to a stop codon (L402X) in the sec23a gene, an integral component of the COPII complex, which is critical for anterograde protein trafficking between endoplasmic reticulum and Golgi apparatus. Zebrafish crusher mutants develop normally until the onset of craniofacial chondrogenesis. crusher chondrocytes accumulate proteins in a distended endoplasmic reticulum, resulting in severe reduction of cartilage extracellular matrix (ECM) deposits, including type II collagen. We demonstrate that the paralogous gene sec23b is also an essential component of the ECM secretory pathway in chondrocytes. In contrast, knockdown of the COPI complex does not hinder craniofacial morphogenesis. As SEC23A lesions cause the cranio-lenticulo-sutural dysplasia syndrome, crusher provides the first vertebrate model system that links the biology of endoplasmic reticulum to Golgi trafficking with a clinically relevant dysmorphology.

Animals↗
PubMed2001

The gene yghK linked to the glc operon of Escherichia coli encodes a permease for glycolate that is structurally and functionally similar to L-lactate permease.

In Escherichia coli the glc operon involved in glycolate utilization is located at 67.3 min and formed by genes encoding the enzymes glycolate oxidase (glcDEF) and malate synthase G (glcB). Their expression from a single promoter upstream of glcD is induced by growth on glycolate and regulated by the activator encoded by the divergently transcribed gene glcC. Gene yghK, located 350 bp downstream of glcB, encodes a hydrophobic protein highly similar to the L-lactate permease encoded by lldP. Expression studies have shown that the yghK gene (proposed name glcA) is transcribed from the same promoter as the other glc structural genes and thus belongs to the glc operon. Characterization of a glcA::cat mutant showed that GlcA acts as glycolate permease and that glycolate can also enter the cell through another transport system. Evidence is presented of the involvement of L-lactate permease in glycolate uptake. Growth on this compound was abolished in a double mutant of the paralogous genes glcA and lldP, and restored with plasmids expressing either GlcA or LldP. Characterization of the putative substrates for these two related permeases showed, in both cases, specificity for the 2-hydroxymonocarboxylates glycolate, L-lactate and D-lactate. Although both GlcA and LldP recognize D-lactate, mutant analysis proved that L-lactate permease is mainly responsible for its uptake.

Alcohol Oxidoreductases↗
PubMed1993

A Saccharomyces cerevisiae protein-serine kinase related to mammalian glycogen synthase kinase-3 and the Drosophila melanogaster gene shaggy product.

The glycogen synthase kinase-3 (GSK-3) family of protein-serine kinases is implicated in the development and hormonal regulation of higher eukaryotes. GSK-3-related genes have been cloned and characterized in mammals (alpha and beta forms), Drosophila melanogaster (shaggy/zeste-white3) and Saccharomyces cerevisiae (MCK1). Using the polymerase chain reaction and primers designed to hybridize to conserved catalytic domain sequences of this family, a genomic fragment was amplified from budding yeast DNA. Genomic clones encompassing the entire reading frame were subsequently isolated and sequenced. The protein encoded by this gene, termed ScGSK-3, displays high identity with members of the GSK-3 family, sharing several structural features including a regulatory Tyr residue. A phylogenetic analysis of the catalytic domains of these protein kinases suggests that ScGSK-3 represents the bona fide homologue of GSK-3 and the shaggy product, while the related MCK1 protein kinase is encoded by a paralogous gene which originated by a gene duplication event in the yeast lineage.

Amino Acid Sequence↗
PubMed2003

Duplication and selection in the evolution of primate beta-defensin genes.

BACKGROUND: Innate immunity is the first line of defense against microorganisms in vertebrates and acts by providing an initial barrier to microorganisms and triggering adaptive immune responses. Peptides such as beta-defensins are an important component of this defense, providing a broad spectrum of antimicrobial activity against bacteria, fungi, mycobacteria and several enveloped viruses. Beta-defensins are small cationic peptides that vary in their expression patterns and spectrum of pathogen specificity. Disruptions in beta-defensin function have been implicated in human diseases, including cystic fibrosis, and a fuller understanding of the variety, function and evolution of human beta-defensins might form the basis for novel therapies. Here we use a combination of laboratory and computational techniques to characterize the main human beta-defensin locus on chromosome 8p22-p23. RESULTS: In addition to known genes in the region we report the genomic structures and expression patterns of four novel human beta-defensin genes and a related pseudogene. These genes show an unusual pattern of evolution, with rapid divergence between second exon sequences that encode the mature beta-defensin peptides matched by relative stasis in first exons that encode signal peptides. CONCLUSIONS: We conclude that the 8p22-p23 locus has evolved by successive rounds of duplication followed by substantial divergence involving positive selection, to produce a diverse cluster of paralogous genes established before the human-baboon divergence more than 23 million years ago. Positive selection, disproportionately favoring alterations in the charge of amino-acid residues, is implicated as driving second exon divergence in these genes.

Amino Acid Sequence↗
PubMed2006

Conservation of noncoding microsatellites in plants: implication for gene regulation.

BACKGROUND: Microsatellites are extremely common in plant genomes, and in particular, they are significantly enriched in the 5' noncoding regions. Although some 5' noncoding microsatellites involved in gene regulation have been described, the general properties of microsatellites as regulatory elements are still unknown. To address the question of microsatellites associated with regulatory elements, we have analyzed the conserved noncoding microsatellite sequences (CNMSs) in the 5' noncoding regions by inter- and intragenomic phylogenetic footprinting in the Arabidopsis and Brassica genomes. RESULTS: We identified 247 Arabidopsis-Brassica orthologous and 122 Arabidopsis paralogous CNMSs, representing 491 CT/GA and CTT/GAA repeats, which accounted for 10.6% of these types located in the 500-bp regions upstream of coding sequences in the Arabidopsis genome. Among these identified CNMSs, 18 microsatellites show high conservation in the regulatory regions of both orthologous and paralogous genes, and some of them also appear in the corresponding positions of more distant homologs in Arabidopsis, as well as in other plants. A computational scan of CNMSs for known cis-regulatory elements showed that light responsive elements were clustered in the region of CT/GA repeats, as well as salicylic acid responsive elements in the (CTT)n/(GAA)n sequences. Patterns of gene expression revealed that 70-80% of CNMS (CTT)n/(GAA)n associated genes were regulated by salicylic acid, which was consistent with the prediction of regulatory elements in silico. CONCLUSION: Our analyses showed that some noncoding microsatellites were conserved in plants and appeared to be ancient. These CNMSs served as regulatory elements involved in light and salicylic acid responses. Our findings might have implications in the common features of the over-represented microsatellites for gene regulation in plant-specific pathways.

Arabidopsis↗
PubMed2004

Convergent evolution in primates and an insectivore.

The cardiovascular risk factor LPA has a puzzling distribution among mammals, its presence being limited to a subset of primates and a member of the insectivore lineage, the hedgehog. To explore the evolutionary history of LPA, we performed extensive genomic sequence comparisons of multiple species with and without an LPA gene product, such as human, baboon, hedgehog, lemur, and mouse. This analysis indicated that LPA arose independently in a subset of primates, including baboon and human, and an insectivore, the hedgehog, and was not simply lost by species lacking it. The similar structural domains shared by the hedgehog and primate LPA indicate that they were formed by a unique molecular mechanism involving the convergent evolution of paralogous genes in these distant species.

Animals↗
PubMed2006

PHOG: a database of supergenomes built from proteome complements.

BACKGROUND: Orthologs and paralogs are widely used terms in modern comparative genomics. Existing procedures for resolving orthologous/paralogous relationships are often based on manual revision of clusters of orthologous groups and/or lack any rigorous evolutionary base. DESCRIPTION: We developed a completely automated procedure that creates clusters of orthologous groups at each node of the taxonomy tree (PHOGs--Phylogenetic Orthologous Groups). As a result of this procedure, a tree of orthologous groups was obtained. Each cluster is a "supergene" and it is represented by an "ancestral" sequence obtained from the multiple alignment of orthologous and paralogous genes. The procedure has been applied to the taxonomy tree of organisms from all three domains of life. Protein complements from 50 bacterial, archaeal and eukaryotic species were used to create PHOGs at all tree nodes. 51367 PHOGs were obtained at the root node. CONCLUSION: The PHOG database demonstrates that it is possible to automatically process any number of sequenced genomes and to reconstruct orthologous and paralogous relationships between genomes using a rigorous evolutionary approach. This database can become a very useful tool in various areas of comparative genomics.

Databases, Genetic↗
PubMed2003

Rapid sequence divergence in mammalian beta-defensins by adaptive evolution.

beta-Defensin genes encode broad spectrum antimicrobial cationic peptides. We have analysed the largest murine and human clusters of these genes, which localise to mouse and human chromosome 8. Using hidden Markov models, we identified novel mouse and human beta-defensin genes. We subsequently found full-length expressed transcripts for these novel genes. Expression in the mouse was high in brain and reproductive tissues. Fourteen murine beta-defensins could be grouped into two clear sub-groups by virtue of their position and high signal sequence (exon 1 encoded) identity. In contrast, there was a very low level of sequence conservation in the exon 2 region encoding the mature antimicrobial peptide. Evolutionary analysis revealed strong evidence that following gene duplication, exon 1 and surrounding non-coding DNA show little divergence within subfamilies. The focus for rapid sequence divergence is localised in the DNA encoding the mature peptide and this is driven by accelerated positive selection. In the human we also conclude that the locus has evolved by successive rounds of duplication followed by substantial divergence involving positive selection, to produce a diverse cluster of paralogous genes prior to human-baboon divergence. This mechanism of adaptive evolution is consistent with the role of this gene family as defence against bacterial pathogens. In order to look at function of these rapidly evolving genes, we characterised one of the novel mouse beta-defensin genes. This gene deviates from the canonical six cysteine motif present in the mature functional peptide of all other beta defensins. This defensin related gene (Defr1) is most highly expressed in testis and heart and the genomic organisation is highly similar to Defb3-6. A synthetic Defr1 peptide was shown to exist as a dimer and yet displayed both antimicrobial and chemotactic activity. The antimicrobial activity of Defr1 against S. aureus, E. coli and B. cepacia was found to be reduced in raised concentration of NaCl, but its action against P. aeruginosa was independent of NaCl concentration. These data have major implications on the structure and functions of these important host defence molecules.

Adaptation, Physiological↗
PubMed2005

Primate-specific endogenous cis-antisense transcription in the human 5q31 protocadherin gene cluster.

Protocadherins (PCDH), localized to synaptic junctions, contribute to the formation of neuronal networks during brain development; thus, it is speculated that protocadherins may play a role in evolution of neuronal complexity. While protocadherin genes are highly conserved in vertebrates, EST evidence from the locus suggests apparently species-specific cis-antisense transcripts. Novel cis-antisense transcripts, which partially overlap the PCDHalpha12 variable exon, PCDHbeta3 single-exon gene, and PCDHpsi5 unprocessed pseudogene in the human 5q31 PCDHalpha/beta/gamma gene cluster and which are coexpressed with sense-strand transcripts in fetal and adult brain, were identified computationally and validated by gene-specific strand-specific reverse transcriptase PCR (SSRTPCR) and sequencing. Absence of antisense transcripts arising from equivalent genomic locations in mouse indicates that the antisense transcripts originated in the primates after the primate-rodent divergence. Furthermore, not all expected orthologues of human sense and antisense PCDH transcripts were detected in rhesus macaque brain, implying that protocadherin expression patterns differ between primate species. RT followed by quantitative real-time PCR (QPCR) analysis of the three genes in the brain of all three species, and of the PCDHbeta15 gene paralogous to PCDHpsi5 in human and rhesus, revealed that the presence of antisense transcripts was significantly associated with lower sense expression levels across all orthologues. This inverse relationship, along with the pattern of sense and antisense coexpression in the brain, is consistent with a regulatory role for the primate-specific PCDH cis-antisense transcripts, which may represent recent evolutionary inventions modulating the activity of this conserved gene cluster.

Animals↗
PubMed2003

Characterization of a pseudogene for murine methylenetetrahydrofolate reductase.

Methylenetetrahydrofolate reductase (MTHFR) reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the major carbon donor in the remethylation of homocysteine to methionine. Mild MTHFR deficiency, due to a common variant at nucleotide 677, has been reported to influence risk for several disorders including cardiovascular disease, neural tube defects, pregnancy complications and cancer. In recent work, we characterized the complete cDNA and gene sequences in the human and mouse genes, which had previously been mapped to chromosomes 1 and 4, respectively. During the course of this work, we observed that PCR primers in exons 1 and 2 of Mthfr generated amplicons of the expected size for the normal Mthfr transcript, using both reverse-transcribed RNA and genomic DNA as templates. These findings alluded to the existence of a pseudogene in the murine genome. Here, we report the characterization of this pseudogene. The absence of intron 1, the partial retention of intron 2, the location of this gene on chromosome 5, and the presence of sequences unrelated to Mthfr at the 5' and 3' ends of the 1259 bp fragment are features that are indicative of a partially-processed pseudogene, that we have designated Mthfr-ps. A Mthfr-ps transcript was not detectable by sensitive RT-PCR using assays designed to simultaneously detect the authentic Mthfr transcript. The structure of this paralogous gene and the identification of a repeat sequence at the 3' end of this pseudogene suggest that it arose by retrotransposition of a mis-spliced Mthfr transcript. Investigations of the Mthfr gene should take into account the presence of the non-functional Mthfr-ps to avoid misinterpretation of results.

Animals↗
PubMed1993

Dating the primigenial C4-CYP21 duplication in primates.

C4 and CYP21 are two adjacent, but functionally unrelated genes residing in the middle of the mammalian major histocompatibility complex (Mhc). The C4 gene codes for the fourth component of the complement cascade, whereas the CYP21 gene specifies an enzyme (cytochrome P450c21) of the glucocorticoid and mineralocorticoid pathways. The genes occur frequently in multiple copies on a single chromosome arranged in the order C4 ... CYP21 ... C4 ... CYP21. The unit of duplication (a module) is the C4-CYP21 gene pair. We sequenced the flanking regions of the C4-CYP21 modules and the intermodular regions of the chimpanzee, gorilla, and orangutan, as well as the intermodular region of an Old World monkey, the pigtail macaque. By aligning the sequences, we could identify the duplication breakpoints in these species. The breakpoint turned out to be at exactly the same position as that found previously in humans. The sequences flanking paralogous genes in the same species were found to be more similar to one another than sequences flanking orthologous genes in different species. We interpret these results as indicating that the original (primigenial) duplication occurred before the separation of apes from Old World monkeys more than 23 million years ago. The nature of the sequence at the breakpoint suggests that the duplication occurred by nonhomologous recombination. Since then, the C4-CYP21 haplotypes have been expanding and contracting by homologous crossing over which has homogenized the sequences in each species.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

The Arabidopsis R2R3 MYB proteins FOUR LIPS and MYB88 restrict divisions late in the stomatal cell lineage.

The two guard cells of a stoma are produced by a single symmetric division just before terminal differentiation. Recessive mutations in the FOUR LIPS (FLP) gene abnormally induce at least four guard cells in contact with one another. These pattern defects result from a persistence of precursor cell identity that leads to extra symmetric divisions at the end of the cell lineage. FLP is likely to be required for the correct timing of the transition from cell cycling to terminal differentiation. FLP encodes a two-repeat (R2R3) MYB protein whose expression accumulates just before the symmetric division. A paralogous gene, MYB88, overlaps with FLP function in generating normal stomatal patterning. Plants homozygous for mutations in both genes exhibit more severe defects than flp alone, and transformation of flp plants with a genomic MYB88 construct restores a wild-type phenotype. Both genes compose a distinct and relatively basal clade of atypical R2R3 MYB proteins that possess an unusual pattern of amino acid substitutions in their putative DNA binding domains. Our results suggest that two related transcription factors jointly restrict divisions late in the Arabidopsis thaliana stomatal cell lineage.

Amino Acid Substitution↗
PubMed2005

New human and mouse microRNA genes found by homology search.

Conservation of microRNAs (miRNAs) among species suggests that they bear conserved biological functions. However, sequencing of new miRNAs has not always been accompanied by a search for orthologues in other species. I report herein the results of a systematic search for interspecies orthologues of miRNA precursors, leading to the identification of 35 human and 45 mouse new putative miRNA genes. MicroRNA tracks were written to visualize miRNAs in human and mouse genomes on the UCSC Genome Browser. Based on their localization, miRNA precursors can be excised either from introns or exons of mRNAs. When intronic miRNAs are antisense to the apparent host gene, they appear to originate from ill-characterized antisense transcription units. Exonic miRNAs are, in general, nonprotein-coding, poorly conserved genes in sense orientation. In three cases, the excision of an miRNA from a protein-coding mRNA might lead to the degradation of the rest of the transcript. Moreover, three new examples of miRNAs fully complementary to an mRNA are reported. Among these, miR135a might control the stability and/or translation of an alternative form of the glycerate kinase mRNA by RNA interference. I also discuss the presence of human miRNAs in introns of paralogous genes and in miRNA clusters.

Animals↗
PubMed2002

Evidence for a wide occurrence of proton-translocating pyrophosphatase genes in parasitic and free-living protozoa.

Proton-translocating inorganic pyrophosphatases (H(+)-PPase, EC 3.6.1.1) are integral membrane proteins that have been extensively studied in higher plants, the photosynthetic bacterium Rhodospirillum rubrum and, more recently, in some human pathogenic protozoa. By using a PCR-based approach, fragments of genes coding for H(+)-PPases in a number of protists, both free-living and parasites of animals and plants, that belong to diverse taxonomic groups (trypanosomatids, ciliates, apicomplexans, euglenoids, amoeboid mycetozoa, heterokonts) have been isolated. The experimental procedure involved the use of degenerate oligonucleotides designed from protein domains conserved in H(+)-PPases from plants and bacteria. The PCR-amplified DNA fragments exhibited the characteristic genomic structure and codon usage of the corresponding protozoan group. Paralogous genes were found in some species suggesting the occurrence of protein isoforms. These results indicate that H(+)-PPases are more widely distributed among protozoa than previously thought.

Amino Acid Sequence↗
PubMed2003

Multiple roles of Hoxa11 and Hoxd11 in the formation of the mammalian forelimb zeugopod.

Mutations in the 5' or posterior murine Hox genes (paralogous groups 9-13) markedly affect the formation of the stylopod, zeugopod and autopod of both forelimbs and hindlimbs. Targeted disruption of Hoxa11 and Hoxd11 or Hoxa10, Hoxc10 and Hoxd10 result in gross mispatterning of the radius and ulna or the femur, respectively. Similarly, in mice with disruptions of both Hoxa13 and Hoxd13, development of the forelimb and hindlimb autopod is severely curtailed. Although these examples clearly illustrate the major roles played by the posterior Hox genes, little is known regarding the stage or stages at which Hox transcription factors intersect with the limb development program to ensure proper patterning of the principle elements of the limb. Moreover, the cellular and/or molecular bases for the developmental defects observed in these mutant mice have not been described. In this study, we show that malformation of the forelimb zeugopod in Hoxa11/Hoxd11 double mutants is a consequence of interruption at multiple steps during the formation of the radius and ulna. In particular, reductions in the levels of Fgf8 and Fgf10 expression may be related to the observed delay in forelimb bud outgrowth that, in turn, leads to the formation of smaller mesenchymal condensations. However, the most significant defect appears to be the failure to form normal growth plates at the proximal and distal ends of the zeugopod bones. As a consequence, growth and maturation of these bones is highly disorganized, resulting in the creation of amorphous bony elements, rather than a normal radius and ulna.

Animals↗
PubMed2005

Ancient gene duplications and the root(s) of the tree of life.

Tracing organismal histories on the timescale of the tree of life remains one of the challenging tasks in evolutionary biology. The hotly debated questions include the evolutionary relationship between the three domains of life (e.g., which of the three domains are sister domains, are the domains para-, poly-, or monophyletic) and the location of the root within the universal tree of life. For the latter, many different points of view have been considered but so far no consensus has been reached. The only widely accepted rationale to root the universal tree of life is to use anciently duplicated paralogous genes that are present in all three domains of life. To date only few anciently duplicated gene families useful for phylogenetic reconstruction have been identified. Here we present results from a systematic search for ancient gene duplications using twelve representative, completely sequenced, archaeal and bacterial genomes. Phylogenetic analyses of identified cases show that the majority of datasets support a root between Archaea and Bacteria; however, some datasets support alternative hypotheses, and all of them suffer from a lack of strong phylogenetic signal. The results are discussed with respect to the impact of horizontal gene transfer on the ability to reconstruct organismal evolution. The exchange of genetic information between divergent organisms gives rise to mosaic genomes, where different genes in a genome have different histories. Simulations show that even low rates of horizontal gene transfer dramatically complicate the reconstruction of organismal evolution, and that the different most recent common molecular ancestors likely existed at different times and in different lineages.

Carbamoyl-Phosphate Synthase (Ammonia)↗