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PubMed1959

Macronuclear duplication in the ciliated protozoan Euplotes.

The ribbon-like macronucleus of Euplotes eurystomus pinches in half amitotically at each cell division. Several hours before the actual division two lightly staining duplication bands (reorganization bands) appear at the ends of the nucleus and approach each other slowly, finally meeting near the middle. Distal to the bands, that is, in regions through which the bands have already passed, the concentration of DNA (Feulgen) and "histone" (alkaline fast green) is greater than in the central zone. These facts suggest the hypothesis that DNA-histone synthesis takes place in a sequential fashion starting at the tips of the nucleus and proceeding to the middle. That this hypothesis is correct is shown by autoradiographic and photometric observations. Tritium-labelled thymidine is incorporated only in a limited region immediately distal to the bands. The average amount of Feulgen dye bound by the nucleus rises as the duplication bands approach each other, and is double the presynthesis value by the time the bands meet. A similar rise in the alkaline fast green dye is seen in duplicating nuclei, although no completely post-synthesis values were obtained in this study. The quantitative data are consistent with the assumption that the macronucleus contains a number of DNA-histone "units," presumably chromosomes, each of which duplicates once and only once.

Animals↗
PubMed1997

Identification of mutations in the duplicated region of the polycystic kidney disease 1 gene (PKD1) by a novel approach.

Mutation screening of the major autosomal dominant polycystic kidney disease gene (PKD1) has been complicated by the large transcript size (> 14 kb) and by reiteration of the genomic area encoding 75% of the protein on the same chromosome (the HG loci). The sequence similarity between the PKD1 and HG regions has precluded specific analysis of the duplicated region of PKD1, and consequently all previously described mutations map to the unique 3' region of PKD1. We have now developed a novel anchored reverse-transcription-PCR (RT-PCR) approach to specifically amplify duplicated regions of PKD1, employing one primer situated within the single-copy region and one within the reiterated area. This strategy has been incorporated in a mutation screen of 100 patients for more than half of the PKD1 exons (exons 22-46; 37% of the coding region), including 11 (exons 22-32) within the duplicated gene region, by use of the protein-truncation test (PTT). Sixty of these patients also were screened for missense changes, by use of the nonisotopic RNase cleavage assay (NIRCA), in exons 23-36. Eleven mutations have been identified, six within the duplicated region, and these consist of three stop mutations, three frameshifting deletions of a single nucleotide, two splicing defects, and three possible missense changes. Each mutation was detected in just one family (although one has been described elsewhere); no mutation hot spot was identified. The nature and distribution of mutations, plus the lack of a clear phenotype/genotype correlation, suggest that they may inactivate the molecule. RT-PCR/PTT proved to be a rapid and efficient method to detect PKD1 mutations (differentiating pathogenic changes from polymorphisms), and we recommend this procedure as a firstpass mutation screen in this disorder.

Adult↗
PubMed2003

Fission yeast cdc31p is a component of the half-bridge and controls SPB duplication.

The fission yeast spindle pole body (SPB) is a nucleus-associated organelle that duplicates once each cell cycle during interphase. Duplicated SPBs serve as the poles of an intranuclear mitotic spindle after their insertion into the nuclear envelope in mitosis (Ding et al., Mol. Biol. Cell 8, 1461-1479). Here, we report the identification and characterization of Schizosaccharomyces pombe cdc31p, a member of the conserved calcium-binding centrin/CDC31 family. Immunofluorescence and immunoelectron microscopy show that cdc31p is a SPB component localized at the half-bridge structure of the SPB. cdc31 is an essential gene and Deltacdc31 cells and cdc31 conditional mutant cells arrest in mitosis with a monopolar mitotic spindle organized from a single SPB. EM analysis demonstrates that mutant cdc31 cells fail to duplicate the SPB. In addition, cdc31p exhibits genetic interactions with the SPB component sad1p and is required for sad1p localization. Finally, cdc31 mutant can undergo single or multiple rounds of septation before the exit from mitosis, suggesting that cdc31p activity or SPB duplication may be required for the proper coordination between the exit from mitosis and the initiation of septation.

Amino Acid Sequence↗
PubMed2005

Basal body duplication and maintenance require one member of the Tetrahymena thermophila centrin gene family.

Centrins, small calcium binding EF-hand proteins, function in the duplication of a variety of microtubule organizing centers. These include centrioles in humans, basal bodies in green algae, and spindle pole bodies in yeast. The ciliate Tetrahymena thermophila contains at least four centrin genes as determined by sequence homology, and these have distinct localization and expression patterns. CEN1's role at the basal body was examined more closely. The Cen1 protein localizes primarily to two locations: one is the site at the base of the basal body where duplication is initiated. The other is the transition zone between the basal body and axoneme. CEN1 is an essential gene, the deletion of which results in the loss of basal bodies, which is likely due to defects in both basal body duplication and basal body maintenance. Analysis of the three other centrins indicates that two of them function at microtubule-rich structures unique to ciliates, whereas the fourth is not expressed under conditions examined in this study, although when artificially expressed it localizes to basal bodies. This study provides evidence that in addition to its previously known function in the duplication of basal bodies, centrin is also important for the integrity of these organelles.

Amino Acid Sequence↗
PubMed1988

A highly revertible cyc1 mutant of yeast contains a small tandem duplication.

A mutant, cyc1-96, that reverts spontaneously at an extremely high rate, was uncovered after examining approximately 500 cyc1 mutants which lack or have defective iso-1-cytochrome c in the yeast Saccharomyces cerevisiae. Cloning and DNA sequencing of appropriate fragments revealed that the cyc1-96 mutation contained a 19 bp duplication whereas the spontaneously arising revertants contained the normal wild-type sequence. Because the 19 bp segment in the wild-type sequence is flanked by a 5 bp repeat and because the cyc1-96 mutation arose spontaneously, the 19 bp duplication may have arisen by slippage and misalignment during DNA synthesis. The high reversion rate was not diminished in strains containing the rad52 mutation, which generally reduces mitotic recombination, including recombination associated with the elimination of a segment of a long direct repeat. Thus the loss of segments from short and long duplications occur by different mechanisms. We suggest that the high reversion rates of cyc1-96 and other short duplications are due to misalignment errors during replication.

Amino Acid Sequence↗
PubMed1988

Evolution by gene duplication and compensatory advantageous mutations.

Relaxation of selective constraint is thought to play an important role for evolution by gene duplication, in connection with compensatory advantageous mutant substitutions. Models were investigated by incorporating gene duplication by unequal crossing over, selection, mutation and random genetic drift into Monte Carlo simulations. Compensatory advantageous mutations were introduced, and simulations were carried out with and without relaxation, when genes are redundant on chromosomes. Relaxation was introduced by assuming that deleterious mutants have no effect on fitness, so long as one or more genes free of such mutations remain in the array. Compensatory mutations are characterized by the intermediate deleterious step of their substitutions, and therefore relaxation by gene redundancy is important. Through extensive Monte Carlo simulations, it was found that compensatory mutant substitutions require relaxation in addition to gene duplication, when mutant effects are large. However when mutant effects are small, such that the product of selection coefficient and population size is around unity, evolution by compensatory mutation is enhanced by gene duplication even without relaxation.

Biological Evolution↗
PubMed1989

Recombination between small X chromosome duplications and the X chromosome in Caenorhabditis elegans.

Twelve new X chromosome duplications were identified and characterized. Eight are translocated to autosomal sites near four different telomeres, and four are free. Ten include unc-1(+), which in wild type is near the left end of the X chromosome, and two of these, mnDp72(X;IV) and mnDp73(X;f), extend rightward past dpy-3. Both mnDp72 and mnDp73 recombined with the one X chromosome in males in the unc-1-dpy-3 interval at a frequency 15- to 30-fold higher than was observed for X-X recombination in hermaphrodites in the same interval. Recombinant duplications and recombinant X chromosomes were both recovered. Recombination with the X chromosome in the unc-1-dpy-3 interval was also detected for five other unc-1(+) duplications, even though their right breakpoints lie within the interval. In hermaphrodites, mnDp72 and mnDp73 promoted meiotic X nondisjunction and recombined with an X chromosome in the unc-1-dpy-3 interval at frequencies comparable to that found for X-X recombination; mnDp72(X;IV) also promoted trisomy for chromosome IV. A mutation in him-8 IV was identified that severely reduced recombination between the two X chromosomes in hermaphrodites and between mnDp73 and the X chromosome in males. Recombination between the X chromosome and duplications of either the right end of the X or a region near but not including the left end was rare. We suggest that the X chromosome has one or more elements near its left end that promote meiotic chromosome pairing.

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↗
PubMed1994

Further examples of evolution by gene duplication revealed through DNA sequence comparisons.

To test the theory that evolution by gene duplication occurs as a result of positive Darwinian selection that accompanies the acceleration of mutant substitutions, DNA sequences of recent duplication were analyzed by estimating the numbers of synonymous and nonsynonymous substitutions. For the troponin C family, at the period of differentiation of the fast and slow isoforms, amino acid substitutions were shown to have been accelerated relative to synonymous substitutions. Comparison of the first exon of alpha-actin genes revealed that amino acid substitutions were accelerated when the smooth muscle, skeletal and cardiac isoforms differentiated. Analysis of members of the heat shock protein 70 gene family of mammals indicates that heat shock responsive genes including duplicated copies are evolving rapidly, contrary to the cognitive genes which have been evolutionarily conservative. For the alpha 1-antitrypsin reactive center, the acceleration of amino acid substitution has been found for gene paris of recent duplication.

Actins↗
PubMed1995

Molecular evolution of the duplicated Amy locus in the Drosophila melanogaster species subgroup: concerted evolution only in the coding region and an excess of nonsynonymous substitutions in speciation.

From the analysis of restriction maps of the Amy region in eight sibling species belonging to the Drosophila melanogaster species subgroup, we herein show that the patterns of duplication of the Amy gene are almost the same in all species. This indicates that duplication occurred before speciation within this species subgroup. From the nucleotide sequence data, we show a strong within-species similarity between the duplicated loci in the Amy coding region. This is in contrast to a strong similarity in the 5' and 3' flanking regions within each locus (proximal or distal) throughout the species subgroup. This means that concerted evolution occurred only in the Amy coding region and that differentiated evolution between the duplication occurred in the flanking regions. Moreover, when comparing the species, we also found a significant excess of nonsynonymous substitutions. In particular, all the fixed substitutions specific to D. erecta were found to be nonsynonymous. We thus conclude that adaptive protein evolution occurred in the lineage of D. erecta that is a "specialist" species for host plants and probably also occurs in the process of speciation in general.

Amino Acid Sequence↗
PubMed2004

Genomic duplication, fractionation and the origin of regulatory novelty.

Having diverged 50 MYA, rice remained diploid while the maize lineage became tetraploid and then fractionated by losing genes from one or the other duplicate region. We sequenced and annotated 13 maize genes (counting the duplicate gene as one gene) on one or the other of the pair of homeologous maize regions; 12 genes were present in one cluster in rice. Excellent maize-rice synteny was evident, but only after the fractionated maize regions were condensed onto a finished rice map. Excluding the gene we used to define homeologs, we found zero retention. Once retained, fractionation (loss of functioning DNA sequence) could occur within cis-acting gene space. We chose a retained duplicate basic leucine zipper transcription factor gene because it was well marked with big, exact phylogenetic footprints (CNSs). Detailed alignments of lg2 and retained duplicate lrs1 to their rice ortholog found that fractionation of conserved noncoding sequences (CNSs) was rare, as expected. Of 30 CNSs, 27 were conserved. The 3 unexpected, missing CNSs and a large insertion support subfunctionalization as a reflection of fractionation of cis-acting gene space and the recent evolution of lg2's novel maize leaf and shoot developmental functions. In general, the principles of fractionation and consolidation work well in making sense of maize gene and genomic sequence data.

Chromosomes, Artificial, Bacterial↗
PubMed1993

A large inverted duplicated DNA region associated with an amplified oncogene is stably maintained in a YAC.

In the polyoma virus (Py) transformed 3B rat cell line the Py oncogene and adjacent cellular DNA are amplified in arrays of very large inverted duplications. A region of the 3B amplified DNA was cloned as a 550 kb insert in a Yeast Artificial Chromosome (YAC) vector, designated y3B01. Analysis of the y3B01 cloned insert revealed it contained a large inverted duplicated DNA region which was approximately 400 kb in size (two palindromic arms of about 200 kb). At least 420 kb of the 550 kb YAC insert has been identified as being derived from the 3B amplified DNA and the amplicon in 3B cells is at least 220 kb in size. No DNA instability of the y3B01 YAC clone was detected. The y3B01 DNA replicated as efficiently as yeast chromosomes and was structurally stable in yeast cells during more than 30 cell divisions. Comparison of the restriction endonuclease maps of the inverted duplicated region of the y3B01 DNA insert and the amplified 3B genomic DNA did not reveal any gross differences suggesting that no rearrangements had occurred during or after the cloning into the YAC vector. These results suggest that large inverted duplications, which can show instability in prokaryotic cloning systems, can be stably cloned and maintained in YAC vectors in yeast.

Animals↗
PubMed1994

Are duplications of mitochondrial DNA characteristic of Kearns-Sayre syndrome?

The phenotypes of Kearns-Sayre syndrome (KSS) and chronic progressive external ophthalmoplegia (CPEO) are closely associated with deletions of mitochondrial DNA (mtDNA). Recent evidence suggesting that more than one type of rearrangement may be present in KSS led us to reinvestigate 18 patients with KSS or CPEO for the presence of mtDNA rearrangements other than deletion. mtDNA duplication was detectable in 10 of 10 patients with KSS, while deletion monomers were the only recombinant mtDNA easily detectable in eight of eight patients with CPEO. Deletion dimers were found only in cases having duplications. Thus, duplications of mtDNA seem to be a hallmark of KSS, including a patient where Pearson's syndrome was the first manifestation. We suggest that duplication of mtDNA is characteristic of the early-onset disease KSS, and that the balance of mtDNA rearrangements may be central to the pathogenesis of this unique group of disorders.

Adolescent↗
PubMed1996

Recurrent duplication and deletion polymorphisms on the long arm of the Y chromosome in normal males.

Deletion of the 50f2/C (DYS7C) locus in interval 6 of Yq has previously been reported as a polymorphism in three males. We describe a survey of worldwide populations for further instances of this deletion. Of 859 males tested, 55 (approximately 6%) show absence of the 50f2/C locus; duplication of the locus was also detected in eight out of 595 males (approximately 1.4%). Populations having the deletion are confined to Asia, Australasia, and southern and northern Europe; of those of reasonable sample size, Finns had the highest deletion frequency (55%; n = 21). The deletions vary in size and the larger ones remove some of the RBM (RNA Binding Motif) genes, but none of the deletion males lack DAZ (Deleted in AZoospermia), a candidate gene for the azoospermia factor. On a tree of Y haplotypes, 28 deletion and eight duplication chromosomes fall into six and four haplotypic groups respectively, each of which is likely to represent an independent deletion or duplication event. Microsatellite and other haplotyping data suggest the existence of at least two further classes of deletion. Thus duplications and deletions in this region of Yq have occurred many times in human evolution, but remain useful markers for paternal lineages.

Asia↗
PubMed1996

Genomic structure of HOXD13 gene: a nine polyalanine duplication causes synpolydactyly in two unrelated families.

Synpolydactyly (SPD) is a limb malformation that shows a characteristic manifestation in both hands and feet. This condition is inherited as an autosomal dominant trait with reduced penetrance. We have recently mapped this locus centromeric to the HOXD8 intragenic marker and suggested the HOXD13 gene as a potential candidate for this condition. The genomic structure of HOXD13 established in this study consists of two exons that encodes a polypeptide of 335 amino acids. The downstream exon at the 3' end of this gene contains the homeodomain sequences that are highly conserved. Sixty-three bp upstream of this exon lies a stretch of intronic CA-repeats that proved to be polymorphic in two different populations. The upstream exon encodes 75% of the entire protein and contains a stretch of 15 normal alanines at its 5' end. Sequence comparison at this position in the homozygous affected individuals identified a total of 24 alanine residues that resulted from a duplication of nine polyalanines. In two unrelated SPD families, this duplication was directly transmitted from the affected parents to their affected, but not unaffected, offspring; in one family its size has remained constant for at least 150 years spanning over seven generations. The presence of this duplication confirmed the status of four normal gene carriers, one incomplete penetrance and two affected individuals who were recombinants for HOXD8 or HOXD13-CA repeat markers. This duplication was not present in 150 chromosomes of unrelated healthy subjects of two different populations.

Adolescent↗
PubMed2004

Early duplication and functional diversification of the opsin gene family in insects.

Recent analysis of the complete mosquito Anopheles gambiae genome has revealed a far higher number of opsin genes than for either the Drosophila melanogaster genome or any other known insect. In particular, the analysis revealed an extraordinary opsin gene content expansion, whereby half are long wavelength-sensitive (LW) opsin gene duplicates. We analyzed this genomic data in relationship to other known insect opsins to estimate the relative timing of the LW opsin gene duplications and to identify "missing" paralogs in extant species. The inferred branching patterns of the LW opsin gene family phylogeny indicate at least one early gene duplication within insects before the emergence of the orders Orthoptera, Mantodea, Hymenoptera, Lepidoptera, and Diptera. These data predict the existence of one more LW opsin gene than is currently known from most insects. We tested this prediction by using a degenerate PCR strategy to screen the hymenopteran genome for novel LW opsin genes. We isolated two LW opsin gene sequences from each of five bee species, Bombus impatiens, B. terrestris, Diadasia afflicta, D. rinconis, and Osmia rufa, including 1.1 to 1.2 kb from a known (LW Rh1) and 1 kb from a new opsin gene (LW Rh2). Phylogenetic analysis suggests that the novel hymenopteran gene is orthologous to A. gambiae GPRop7, a gene that is apparently missing from D. melanogaster. Relative rate tests show that LW Rh2 is evolving at a slower rate than LW Rh1 and, therefore, may be a useful marker for higher-level hymenopteran systematics. Site-specific rate tests indicate the presence of several amino acid sites between LW Rh1 and LW Rh2 that have undergone shifts in selective constraints after duplication. These sites and others are discussed in relationship to putative structural and functional differences between the two genes.

Amino Acid Sequence↗
PubMed2006

Evidence of interaction network evolution by whole-genome duplications: a case study in MADS-box proteins.

Recent investigations on metazoan transcription factors (TFs) indicate that single-gene duplication events and the gain and loss of protein domains are 2 crucial factors in shaping their protein-protein interaction networks. Plant genomes, on the other hand, have a history of polyploidy and whole-genome duplications (WGDs), and thus, their study helps to understand whether WGDs have also had a significant influence on protein network evolution. Here we investigate the evolution of the interaction network in the well-studied MADS domain MIKC-type proteins, a TF family which plays an important role in both the vegetative and the reproductive phases of plant life. We combine phylogenetic reconstruction, protein domain analysis, and interaction data from different species. We show that, unlike previously analyzed interaction networks, the MIKC-type protein network displays a characteristic topology, with overall high inter-subfamily connectivity, shared interactors between paralogs, and conservation of interaction patterns across species. The evaluation of the number of MIKC-type proteins at key time points throughout the evolution of land plants in the lineage leading to Arabidopsis suggested that most duplicates were retained after each round of WGD. We provide evidence that an initial network, formed by 9-11 homodimerizing proteins interacting with each other, existed in the common ancestor of all seed plants. This basic structure has been conserved after each round of WGD, adding layers of paralogs with similar interaction patterns. We thus present the first model where we can show that a network of eukaryotic TFs has evolved via rounds of WGD. Furthermore, we found that in subfamilies in which the K domain is most diverged, the interactions with other subfamilies have been largely lost. We discuss the possibility that such a high proportion of genes were retained after each WGD because of their capacity to form higher order complexes involving proteins from different subfamilies. The simultaneous duplications allowed for the conservation of the quantitative balance between the constituents and facilitated sub- and neofunctionalization through differential expression of whole units.

Computational Biology↗
PubMed1993

Duplicated KOX zinc finger gene clusters flank the centromere of human chromosome 10: evidence for a pericentric inversion during primate evolution.

Two related zinc finger (ZNF) gene clusters from the pericentromeric region of human chromosome 10, defined by cDNAs of the KOX series, have been cloned in yeast artificial chromosomes (YACs). The two clusters evolved by duplication of an ancestral gene cluster before the divergence of the human and great ape lineages. Included in cluster A are the ZNF gene sequences ZNF11A, ZNF33A, and ZNF37A, while cluster B comprises the related sequences ZNF11B, ZNF33B and ZNF37B. Genes from both clusters are expressed: cDNAs KOX2, KOX31 and KOX21 derive from ZNF11B, ZNF33A and ZNF37A, respectively. Further YACs have been isolated which link ZNF11A and ZNF33A to another gene, ZNF25, defined by cDNA clone KOX19. Therefore ZNF25 also forms part of cluster A, but has no counterpart in cluster B. Surprisingly, the KOX ZNF gene clusters are located on opposite sides of the centromere: cluster A maps to 10p11.2, while cluster B is in 10q11.2. This suggests the occurrence during primate evolution of a previously undescribed pericentric inversion subsequent to the cluster duplication. The evolution of this subset of KOX ZNF genes has therefore involved three types of genetic event: local gene duplication, gene cluster duplication, and chromosome rearrangement.

Amino Acid Sequence↗