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PubMed2004

Pattern of divergence of amino acid sequences encoded by paralogous genes in human and pufferfish.

We used phylogenetic analyses of protein families containing two or more pairs of orthologues in the genomes of human and pufferfish (Takifugu rubripes) to test the hypothesis that these sequences show a strong signal of polyploidization events hypothesized to have occurred early in vertebrate history. In order to test for evidence of two distinct rounds of polyploidization (the 2R hypothesis), we compared the pattern of amino acid sequence divergence of proteins encoded by genes duplicated just prior to the most recent common ancestor of human and pufferfish with that of proteins encoded genes duplicated earlier. These sequence divergences were statistically indistinguishable, contrary to the prediction of the 2R hypothesis. The variance of amino acid sequence divergences between paralogues was significantly greater than expected from that of orthologues in the same families. Estimation of gene duplication times assuming a molecular clock provided earlier estimates than expected, suggesting that it may not be appropriate to time the duplication of paralogues using rate estimates derived from orthologous comparisons. Overall, the results indicate that amino acid sequences do not provide a strong signal supporting the hypothesis that gene duplications early in vertebrate history occurred by polyploidization. On the other hand, the data are easily explained under an alternative model that gene duplications occurred at different times in different vertebrate gene families.

Animals↗
PubMed2001

Paralogous gene analysis reveals a highly enantioselective 1,2-O-isopropylideneglycerol caprylate esterase of Bacillus subtilis.

Carboxylesterase NP of Bacillus subtilis Thai I-8, characterized in 1992 as a very enantioselective (S)-naproxen esterase, was found to show no enantiopreference towards (S)-1,2-O-isopropylideneglycerol (IPG) esters. The ybfK gene was identified by the B. subtilis genome project as an unknown gene with homology to carboxylesterase NP. The purpose of the present study was to characterize the ybfK gene product in order to determine whether this paralogue of carboxylesterase NP had an altered or enhanced stereospecificity. The ybfK gene was cloned and expressed in B. subtilis using a combination of two strong promoters in a multicopy vector. The enzyme was purified from the cytoplasm of B. subtilis by means of anion exchange and hydrophobic interaction chromatography. The purified YbfK is an enzyme of 296 amino acids and shows an apparent molecular mass of 32 kDa (SDS/PAGE). Comparison of the activities of YbfK and carboxylesterase NP towards caprylate esters of IPG revealed that YbfK produces (S)-IPG with 99.9% enantioselectivity. Therefore, we conclude that we have isolated a paralogue of carboxylesterase NP that can be used for the enantioselective production of (S)-IPG.

Bacillus subtilis↗
PubMed1998

Amyrel, a paralogous gene of the amylase gene family in Drosophila melanogaster and the Sophophora subgenus.

We describe a gene from Drosophila melanogaster related to the alpha-amylase gene Amy. This gene, which exists as a single copy, was named Amyrel. It is strikingly divergent from Amy because the amino acid divergence is 40%. The coding sequence is interrupted by a short intron at position 655, which is unusual in amylase genes. Amyrel has also been cloned in Drosophila ananassae, Drosophila pseudoobscura, and Drosophila subobscura and is likely to be present throughout the Sophophora subgenus, but, to our knowledge, it has not been detected outside. Unexpectedly, there is a strong conservation of 5' and 3' flanking regions between Amyrel genes from different species, which is not the case for Amy and which suggests that selection acts on these regions. In contrast to the Amy genes, Amyrel is transcribed in larvae of D. melanogaster but not in adults. However, the protein has not been detected yet. Amyrel evolves about twice as fast as Amy in the several species studied. We suggest that this gene could result from a duplication of Amy followed by accelerated and selected divergence toward a new adaptation.

Amino Acid Sequence↗
PubMed2002

Rat encodes the paralogous gene equivalent of the human histo-blood group ABO gene. Association with antigen expression by overexpression of human ABO transferase.

We cloned a rat ABO homologue and established human A- and B-transferase transgenic rats. A DNA fragment corresponding to exon 7 of the human ABO gene was amplified from Wistar rat genomic DNA and sequenced. Using the amplified fragments as a probe for Southern blotting, multiple hybridized bands appeared on both EcoRI- and BamHI-digested genomes of seven rat strains, which showed variations in the band numbers among the strains. Four cDNAs were cloned from a Wistar rat, three of which showed A-transferase activity and one of which showed B-transferase activity. These activities were dependent on the equivalent residues at 266 and 268 of human ABO transferase. Wild Wistar rats expressed A-antigen in salivary gland, intestine, and urinary bladder tissue, but B-antigen was not stained in any organs studied, whereas a transcript from the ABO homologue with B-transferase activity was ubiquitous. Human A-transferase and B-transferase were transferred into Wistar rats. A-transgenic rats expressed A-antigen in ectopic tissue of the brain plexus, type II lung epithelium, pancreas, and epidermis. B-antigen in the B-transgenic rat was expressed in the same organs as A-transgenic rats. These results may shed light on the function and evolution of the ABO gene in primates.

ABO Blood-Group System↗
PubMed2001

Evidence for recurrent paralogous gene conversion and exceptional allelic divergence in the Attacin genes of Drosophila melanogaster.

Insects produce a limited variety of antibacterial peptides to combat a wide diversity of pathogens. These peptides are often conserved across evolutionarily distant taxa, but little is known about the level and structure of polymorphism within species. We have surveyed naturally occurring genetic variation in the promoter and coding regions of three Attacin antibacterial peptide genes from 12 lines of Drosophila melanogaster. These genes exhibit high levels of silent nucleotide variations (1-3% per nucleotide heterozygosity), but are not excessively polymorphic at the amino acid level. There is extensive variation in the Attacin promoters, some of which may affect transcriptional efficiency, and one line carries a deletion in the Attacin A coding region that renders this gene nonfunctional. Two of the genes, Attacins A and B, are arranged in tandem and show evidence of repeated interlocus gene conversion. Attacin C, more divergent and located 1.3 Mbp upstream of Attacins A and B, does not appear to have been involved in such exchanges. All three genes are characterized by divergent haplotypes, and one Attacin AB allele appears to have recently increased rapidly in frequency in the population.

Alleles↗
PubMed2000

Multiple paralogous genes related to the Streptomyces coelicolor developmental regulatory gene whiB are present in Streptomyces and other actinomycetes.

The whiB sporulation gene of Streptomyces coelicolor was shown [Davis, N. K. & Chater, K. F. (1992). Mol Gen Genet 232, 351-358] to encode a small, cysteine-rich putative transcription factor unlike any that had been described previously. The large database of DNA sequences of mycobacteria (like Streptomyces, members of the Actinomycetales) has revealed a family of genes encoding proteins related to WhiB. Mycobacterium tuberculosis contains at least six such genes (whiB homologues in mycobacteria: whmA-F) and a likely seventh, whmG. Using conserved features of Whm proteins, a PCR-based approach led to the discovery that S. coelicolor A3(2) contains several similar genes. Cloning and sequencing of these whiB-like (wbI) genes revealed likely orthologues of four of the whm genes of M. tuberculosis. In all, S. coelicolor contains at least five wbI genes in addition to whiB itself. All five were shown by RT-PCR to be transcribed. A Southern blotting survey using each wbI gene as a probe showed that nearly all of a series of representatives of ten actinomycete genera (including morphologically simple organisms) contain close homologues of several wbI genes, suggesting that the ancient progenitor of all these organisms already contained a family of such genes, which have not been found in any other organisms.

Actinomycetales↗
PubMed2004

Two sets of paralogous genes encode the enzymes involved in the early stages of clavulanic acid and clavam metabolite biosynthesis in Streptomyces clavuligerus.

Recently, a second copy of a gene encoding proclavaminate amidinohydrolase (pah1), an enzyme involved in the early stages of clavulanic acid and clavam metabolite biosynthesis in Streptomyces clavuligerus, was identified and isolated. Using Southern analysis, we have now isolated second copies of the genes encoding the carboxyethylarginine synthase (ceaS) and beta-lactam synthetase (bls) enzymes. These new paralogues are given the gene designations ceaS1 and bls1 and are located immediately upstream of pah1 on the chromosome. Furthermore, sequence analysis of the region downstream of pah1 revealed a second copy of a gene encoding ornithine acetyltransferase (oat1), thus indicating the presence of a cluster of paralogue genes. ceaS1, bls1, and oat1 display 73, 60, and 63% identities, respectively, at the nucleotide level to the original ceaS2, bls2, and oat2 genes from the clavulanic acid gene cluster. Single mutants defective in ceaS1, bls1, or oat1 were prepared and characterized and were found to be affected to variable degrees in their ability to produce clavulanic acid and clavam metabolites. Double mutants defective in both copies of the genes were also prepared and tested. The ceaS1/ceaS2 and the bls1/bls2 mutant strains were completely blocked in clavulanic acid and clavam metabolite biosynthesis. On the other hand, oat1/oat2 double mutants still produced some clavulanic acid and clavam metabolites. This may be attributed to the presence of the argJ gene in S. clavuligerus, which encodes yet another ornithine acetyltransferase enzyme that may be able to compensate for the lack of OAT1 and -2 in the double mutants.

Amino Acid Sequence↗
PubMed2003

The Ti plasmid of Agrobacterium tumefaciens harbors an attM-paralogous gene, aiiB, also encoding N-Acyl homoserine lactonase activity.

The Agrobacterium tumefaciens C58 genome contains three putative N-acyl homoserine lactone (acyl-HSL) hydrolases, which are closely related to the lactonase AiiA of Bacillus. When expressed in Escherichia coli, two of the putative acyl-HSL hydrolases, AttM and AiiB, conferred the ability to degrade acyl-HSLs on the host. In Erwinia strain 6276, the lactonases reduced the endogenous acyl-HSL level and the bacterial virulence in planta.

4-Butyrolactone↗
PubMed2006

Liberation of zinc-containing L31 (RpmE) from ribosomes by its paralogous gene product, YtiA, in Bacillus subtilis.

We have found that alternative localization of two types of L31 ribosomal protein, RpmE and YtiA, is controlled by the intracellular concentration of zinc in Bacillus subtilis. The detailed mechanisms for the alternation of L31 proteins under zinc-deficient conditions were previously unknown. To obtain further information about this regulatory mechanism, we have studied the stability of RpmE in vivo and the binding affinity of these proteins to ribosomes in vitro, and we have found that liberation of RpmE from ribosomes is triggered by the expression of ytiA, which is induced by the derepression of Zur under zinc-deficient conditions.

Bacillus subtilis↗
PubMed2002

The bric à brac locus consists of two paralogous genes encoding BTB/POZ domain proteins and acts as a homeotic and morphogenetic regulator of imaginal development in Drosophila.

The bric à brac (bab) locus acts as a homeotic and morphogenetic regulator in the development of ovaries, appendages and the abdomen. It consists of two structurally and functionally related genes, bab1 and bab2, each of which encodes a single nuclear protein. Bab1 and Bab2 have two conserved domains in common, a BTB/POZ domain and a Psq domain, a motif that characterizes a subfamily of BTB/POZ domain proteins in Drosophila. The tissue distribution of Bab1 and Bab2 overlaps, with Bab1 being expressed in a subpattern of Bab2. Analysis of a series of mutations indicates that the two bab genes have synergistic, distinct and redundant functions during imaginal development. Interestingly, several reproduction-related traits that are sexually dimorphic or show diversity among Drosophila species are highly sensitive to changes in the bab gene dose, suggesting that alterations in bab activity may contribute to evolutionary modification of sex-related morphology.

Abdomen↗
PubMed2002

Genetic variability and stability of Anaplasma phagocytophila msp2 (p44).

Anaplasma (Ehrlichia) phagocytophila's major immunodominant surface protein antigen, Msp2 (P44, 44-kDa antigen), is encoded by a family of paralogous genes characterized by conserved sequences flanking a hypervariable region. The antigenic profiles of most strains of A. phagocytophila are different, and the differences are principally related to Msp2 expression. To date, multiple unique msp2 gene paralogs have been found in A. phagocytophila isolates, but the overall number in the genome of a single strain is not yet known. Changes in msp2 expression may be related to antigenic variability; thus, we examined the minimal complement of msp2 genes or pseudogenes in two strains of A. phagocytophila and the number of transcriptionally active msp2 gene paralogs during low-passage, steady-state, in vitro propagation. Of 15 BDS strain clones, 1 had a hypervariable region identical to the region in a clone obtained from a BDS strain genomic library previously prepared from organisms after only two horse passages. When 124 Webster strain clones were examined, 18 unique hypervariable regions were identified. Of 64 Webster strain cDNA clones, 56 (87.5%) were derived from a single gene, and transcripts from six additional msp2 genes were also identified. The sequences of several hypervariable regions that were > or = 97% similar to regions present in other strains were identified by performing a BLAST analysis of sequences deposited in the GenBank database. These findings suggest that antigenic variability results from transcription of one or a few of the multiple paralogs and not from genetic instability that results in random accumulated mutations, although the possibility that gene recombination plays a role cannot be eliminated. The predominant Msp2 pattern in vitro is determined by transcription from a single gene.

Anaplasma↗
PubMed1995

Mutations in paralogous Hox genes result in overlapping homeotic transformations of the axial skeleton: evidence for unique and redundant function.

Hoxd-4 (previously known as Hox-4.2 and -5.1) is a mouse homeobox-containing gene homologous to the Drosophila homeotic gene Deformed. During embryogenesis, Hoxd-4 is expressed in the presumptive hindbrain and spinal cord, prevertebrae, and other tissues. In the adult, Hoxd-4 transcripts are expressed predominantly in the testis and kidney, and to a lesser extent in intestine and heart. To understand the role of Hoxd-4 during mouse embryogenesis, we generated Hoxd-4 mutant mice. Mice heterozygous or homozygous for the Hoxd-4 mutation exhibit homeotic transformations of the second cervical vertebrae (C2) to the first cervical vertebrae (C1) and malformations of the neural arches of C1 to C3 and of the basioccipital bone. The phenotype was incompletely penetrant and showed variable expressivity on both an F2 hybrid and 129 inbred genetic background. The mutant phenotype was detected in the cartilaginous skeleton of 14.5-day (E14.5) mutant embryos but no apparent differences were detected in the somites of E9.5 mutant embryos, suggesting that the abnormalities develop after E9.5 perhaps during or after resegmentation of the somites to form the prevertebrae. These results suggest that Hoxd-4 plays a role in conferring position information along the anteroposterior axis in the skeleton. The phenotypic similarities and differences between Hoxd-4 and previously reported Hoxa-4 and Hoxb-4 mutant mice suggest that Hox gene paralogs have both redundant and unique functions.

Animals↗
PubMed2004

Detection of aneuploidies by paralogous sequence quantification.

BACKGROUND: Chromosomal aneuploidies are a common cause of congenital disorders associated with cognitive impairment and multiple dysmorphic features. Pre-natal diagnosis of aneuploidies is most commonly performed by the karyotyping of fetal cells obtained by amniocentesis or chorionic villus sampling, but this method is labour intensive and requires about 14 days to complete. METHODS: We have developed a PCR based method for the detection of targeted chromosome number abnormalities termed paralogous sequence quantification (PSQ), based on the use of paralogous genes. Paralogous sequences have a high degree of sequence identity, but accumulate nucleotide substitutions in a locus specific manner. These sequence differences, which we term paralogous sequence mismatches (PSMs), can be quantified using pyrosequencing technology, to estimate the relative dosage between different chromosomes. We designed 10 assays for the detection of trisomies of chromosomes 13, 18, and 21 and sex chromosome aneuploidies. RESULTS: We evaluated the performance of this method on 175 DNAs, highly enriched for abnormal samples. A correct and unambiguous diagnosis was given for 119 out of 120 aneuploid samples as well as for all the controls. One sample which gave an intermediate value for the chromosome 13 assays could not be diagnosed. CONCLUSIONS: Our data suggests that PSQ is a robust, easy to interpret, and easy to set up method for the diagnosis of common aneuploidies, and can be performed in less than 48 h, representing a competitive alternative for widespread use in diagnostic laboratories.

Aneuploidy↗
PubMed1999

A set of highly conserved RNA-binding proteins, alphaCP-1 and alphaCP-2, implicated in mRNA stabilization, are coexpressed from an intronless gene and its intron-containing paralog.

Gene families normally expand by segmental genomic duplication and subsequent sequence divergence. Although copies of partially or fully processed mRNA transcripts are occasionally retrotransposed into the genome, they are usually nonfunctional ("processed pseudogenes"). The two major cytoplasmic poly(C)-binding proteins in mammalian cells, alphaCP-1 and alphaCP-2, are implicated in a spectrum of post-transcriptional controls. These proteins are highly similar in structure and are encoded by closely related mRNAs. Based on this close relationship, we were surprised to find that one of these proteins, alphaCP-2, was encoded by a multiexon gene, whereas the second gene, alphaCP-1, was identical to and colinear with its mRNA. The alphaCP-1 and alphaCP-2 genes were shown to be single copy and were mapped to separate chromosomes. The linkage groups encompassing each of the two loci were concordant between mice and humans. These data suggested that the alphaCP-1 gene was generated by retrotransposition of a fully processed alphaCP-2 mRNA and that this event occurred well before the mammalian radiation. The stringent structural conservation of alphaCP-1 and its ubiquitous tissue distribution suggested that the retrotransposed alphaCP-1 gene was rapidly recruited to a function critical to the cell and distinct from that of its alphaCP-2 progenitor.

3' Untranslated Regions↗
PubMed2004

Meiotic recombination between paralogous RBCSB genes on sister chromatids of Arabidopsis thaliana.

Paralogous genes organized as a gene cluster can rapidly evolve by recombination between misaligned paralogs during meiosis, leading to duplications, deletions, and novel chimeric genes. To model unequal recombination within a specific gene cluster, we utilized a synthetic RBCSB gene cluster to isolate recombinant chimeric genes resulting from meiotic recombination between paralogous genes on sister chromatids. Several F1 populations hemizygous for the synthRBCSB1 gene cluster gave rise to Luc+ F2 plants at frequencies ranging from 1 to 3 x 10(-6). A nonuniform distribution of recombination resolution sites resulted in the biased formation of recombinant RBCS3B/1B::LUC genes with nonchimeric exons. The positioning of approximately half of the mapped resolution sites was effectively modeled by the fractional length of identical DNA sequences. In contrast, the other mapped resolution sites fit an alternative model in which recombination resolution was stimulated by an abrupt transition from a region of relatively high sequence similarity to a region of low sequence similarity. Thus, unequal recombination between paralogous RBCSB genes on sister chromatids created an allelic series of novel chimeric genes that effectively resulted in the diversification rather than the homogenization of the synthRBCSB1 gene cluster.

Arabidopsis↗
PubMedDate not supplied

Ortholog search of proteins involved in copper delivery to cytochrome C oxidase and functional analysis of paralogs and gene neighbors by genomic context.

Cytochrome c oxidase (COX) is a multi-subunit enzyme of the mitochondrial respiratory chain. Delivery of metal cofactors to COX is essential for assembly, which represents a long-standing puzzle. The proteins Cox17, Sco1/2, and Cox11 are necessary for copper insertion into CuA and CuB redox centers of COX in eukaryotes. A genome-wide search in all prokaryotic genomes combined with genomic context reveals that only Sco and Cox11 have orthologs in prokaryotes. However, while Cox11 function is confined to COX assembly, Sco acts as a multifunctional linker connecting a variety of biological processes. Multifunctionality is achieved by gene duplication and paralogs. Neighbor genes of Sco paralogs often encode cuproenzymes and cytochrome c domains and, in some cases, Sco is fused to cytochrome c. This led us to suggest that cytochrome c might be relevant to Sco function and the two proteins might jointly be involved in COX assembly. Sco is also related, in terms of gene neighborhood and phylogenetic occurrence, to a newly detected protein involved in copper trafficking in bacteria and archaea, but with no sequence similarity to the mitochondrial copper chaperone Cox17. By linking the assembly system to the copper uptake system, Sco allows COX to face alternative copper trafficking pathways.

Animals↗
PubMed2004

A novel Giraffidae-specific interspersed repeat with a microsatellite, originally found in an intron of a ruminant paralogous p97bcnt gene.

The ruminant-specific p97bcnt gene (bcntp97) is a paralogous gene that includes a region derived from a retrotransposable element 1 (RTE-1). The region comprises an exon (RTE-1 exon) encoding 325 amino acids in the middle of the p97bcnt protein. To understand how the bcntp97 paralog evolved, we examined its organization in several ruminants. We found a 700-base pair (bp) insert in the 5' intron of the RTE-1 exon in giraffe bcntp97. This insert is missing in the corresponding regions of bovine and sika deer. Furthermore, the sequence of the insert is interspersed in the genome of giraffe but not bovine and also contains a (GA)n microsatellite. A highly homologous insert harboring significantly different (GA)n microsatellite was detected in the corresponding region of okapi bcntp97. Therefore, the interspersed fragments with (GA)n microsatellite might serve as a marker for tracking how duplicated genes evolve in a family-specific manner.

Animals↗