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PubMed1998

Duplication-based measures of difference between gene and species trees.

In the framework of a duplication-based method for comparing gene and species trees, the concepts of "duplication" and "loss" are reformulated in set-theoretic terms. A number of related tree dissimilarity measures is suggested, and relations between them are analyzed. For any node in the species tree, the number of gene duplications for which it is a "non-child" loss coincides with the number of times when the node's parent is an intermediate between the mapping images of a gene node and its parent. This implies that the total number of losses is equal to the number of intermediate nodes plus the number of one-side duplications and, thus, provides an alternative proof for a conjecture made by Mirkin, Muchnik, and Smith (1995). Another formula proven involves crossings (incompatible gene-species node pairs): the number of losses equals the number of crossings plus the number of duplications.

Animals↗

PubMed1998

Gallbladder duplication and laparoscopic management.

Gallbladder duplication can present a significant challenge to the laparoscopic surgeon, primarily due to difficulties with diagnosis and recognition. Previous reports of attempted laparoscopic cholecystectomy in patients with gallbladder duplication resulted in incomplete or staged multiple procedures. The case report of a 35-year-old woman with successful laparoscopic management of symptomatic gallbladder duplication is described, emphasizing several important considerations. Preoperatively when evaluating radiologic studies a high index of suspicion is necessary in interpreting atypical findings. To further evaluate these abnormalities, liberal use of preoperative ERCP is helpful, and specific endoscopic techniques may be necessary as well. Intraoperatively, the findings may be confusing, and cholangiography can help clarify ductular anomalies, especially if the gallbladder duplication is contained within a common serosal coat. Missing a second gallbladder can result in persistent symptoms postoperatively necessitating further surgery. Laparoscopic cholecystectomy in the management of gallbladder duplication can be safely done and an awareness is necessary to avoid complications or multiple procedures.

Adult↗

PubMed1998

New alleles of the yeast MPS1 gene reveal multiple requirements in spindle pole body duplication.

In Saccharomyces cerevisiae, the Mps1p protein kinase is critical for both spindle pole body (SPB) duplication and the mitotic spindle assembly checkpoint. The mps1-1 mutation causes failure early in SPB duplication, and because the spindle assembly checkpoint is also compromised, mps1-1 cells proceed with a monopolar mitosis and rapidly lose viability. Here we report the genetic and molecular characterization of mps1-1 and five new temperature-sensitive alleles of MPS1. Each of the six alleles contains a single point mutation in the region of the gene encoding the protein kinase domain. The mutations affect several residues conserved among protein kinases, most notably the invariant glutamate in subdomain III. In vivo and in vitro kinase activity of the six epitope-tagged mutant proteins varies widely. Only two display appreciable in vitro activity, and interestingly, this activity is not thermolabile under the assay conditions used. While five of the six alleles cause SPB duplication to fail early, yielding cells with a single SPB, mps1-737 cells proceed into SPB duplication and assemble a second SPB that is structurally defective. This phenotype, together with the observation of intragenic complementation between this unique allele and two others, suggests that Mps1p is required for multiple events in SPB duplication.

Alleles↗

PubMed1991

An analysis of duplicate testing of prothrombin time and activated partial thromboplastin time assays.

An evaluation of duplicate prothrombin time (PT) and activated partial thromboplastin time (aPTT) assays determined by the MCA 110 coagulation analyzer was undertaken to develop analytical duplicate performance criteria to quantitate the risks associated with single versus duplicate procedures. Included in the study were 1,277 patient samples. On the basis of the currently recommended therapeutic range for prothrombin ratios, a variation of approximately 10% or more between duplicates was considered to be unacceptable. For aPTT assays, the recommended therapeutic range for heparin therapy was usually 1.5 to 2.5 times the baseline value, and variations of up to 25% might be considered acceptable. With these relatively lenient criteria, approximately 2% of PT and 1.3% of aPTT assays had differences between duplicate values that were unacceptable. From this data the authors concluded that the frequency of errors produced by single estimations was too great for satisfactory clinical practice.

Humans↗

PubMed1997

Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases.

A clinical and electrophysiological study was performed in 119 Type 1A Charcot-Marie-Tooth disease (CMT1A) patients with proven 17p11.2 duplication. Onset of the first functional manifestations was in the first decade in 50% of cases and before the age of 20 years in 70% of cases. The predominant clinical signs were muscle weakness and wasting in the lower limbs. None of the patients was normal on clinical examination and all presented at least pes cavus or ankle jerk areflexia. Motor nerve conduction velocity (MNCV) was uniformly reduced in all nerves, and was < or = 33 m/s in the median nerve for all patients. Sensory potentials were abnormal in all cases, even where there was no clinical sensory loss. Needle electromyography recruitment was reduced in distal muscles for all patients. MNCV slowing was fully consistent with the presence of duplication even in clinically asymptomatic individuals or in children, confirming the complete electrophysiological penetrance of 17p11.2 duplication and making median nerve MNCV a reliable tool for screening affected at-risk individuals. Functional disability was mild. Ninety-six percent of patients were autonomous; 25% were asymptomatic and diagnosed by systematic family investigation especially on the basis of median nerve MNCV reduction. Early age at onset and greatly reduced median nerve MNCV were predictive of a more severe disease course; the earlier the onset the more reduced the median nerve MNCV and the higher the functional disability tended to be after an equivalent disease duration. Cross-sectional analysis of neurological deficit, functional deficit and MNCV according to disease duration showed that, regardless of age at onset, CMT1A disease with 17p11.2 duplication is a clinically progressive disorder. Neurological deficit and functional disability increased, whereas median nerve MNCV and compound muscle action potential (CMAP) amplitude did not change with disease course. Intrafamilial phenotype variation between parents and children and between siblings was studied in large families. Functional disability and neurological deficit differed widely and the highest range of median nerve MNCV within a family reached 23 m/s. Clinical and electrophysiological data were compared with those of CMT1B patients with peripheral myelin P0 protein point mutation. CMT1A patients were found to be more severely affected with more prolonged distal motor latency and more reduced CMAP amplitude, whereas MNCV did not significantly differ, indicating that peripheral myelin P0 protein point mutation is not always associated with a severe phenotype. The same genetic defect (17p11.2 duplication) results in variable expression within the phenotype, even in siblings with variations in age at onset, clinical severity and MNCV slowing. This phenotypic variation could be due to additional genetic factors related to peripheral myelin protein 22 expression as well as to other endogenous or environmental factors.

Adolescent↗

PubMed2000

The Bbp1p-Mps2p complex connects the SPB to the nuclear envelope and is essential for SPB duplication.

In budding yeast, microtubules are organized by the spindle pole body (SPB), which is embedded in the nuclear envelope via its central plaque structure. Here, we describe the identification of BBP1 in a suppressor screen with a conditional lethal allele of SPC29. Bbp1p was detected at the central plaque periphery of the SPB and bbp1-1 cells were found to be defective in SPB duplication. bbp1-1 cells extend their satellite into a duplication plaque like wild-type cells; however, this duplication plaque then fails to insert properly into the nuclear envelope and does not assemble a functional inner plaque. This function in SPB duplication is probably fulfilled by a stable complex of Bbp1p and Mps2p, a nuclear envelope protein that is also essential for duplication plaque insertion. In addition, we found that Bbp1p interacts with Spc29p and the half-bridge component Kar1p. These interactions are likely to play a role in connecting the SPB with the nuclear envelope and the central plaque with the half-bridge.

Fungal Proteins↗

PubMed1985

Directed formation of deletions and duplications using Mud(Ap, lac).

A genetic procedure is directed for the isolation of chromosomal deletions and duplications with predetermined endpoints. These rearrangements are generated in transduction crosses using a mixture of P22-transducing phage lysates grown on two strains, each carrying a Mud-lac insertion. The formation of duplications and deletions was demonstrated in the his operon using insertions of Mud 1-8 (a transposition-defective Mud-lac phage). This technique was also used to make larger chromosomal duplications between Mud 1-8 insertions in the thr and leu biosynthetic operons and between Mud insertions in the thr and pyrB operons. Genetic evidence is presented that strongly suggests that inheritance of a single Mud prophage by P22-mediated crosses requires two transduced fragments; each carrying part of the Mud prophage. The two fragments must be involved in three recombinational exchanges; one exchange joins the donor Mud fragments and two exchanges occur between the composite fragment and the recipient chromosome, one on either side of the complete donor Mud element. Since duplications only occur between Mud insertions in the same orientation on the chromosome, the method of duplication formation provides a simple means of determining the orientation of Mud 1-8 on the chromosome and, therefore, the direction of transcription of the gene into which Mud is inserted. This method was also used to construct recombinants between a Mud 1-8 prophage and Casadaban's protein fusion vector Mud2 and, thereby, isolate Mud2-8, a Mud derivative containing the protein fusion ability of Mud2 and the defective transposition functions of Mud1-8.

Bacterial Proteins↗

PubMed1987

Metallothionein gene duplications and metal tolerance in natural populations of Drosophila melanogaster.

A search for duplications of the Drosophila melanogaster metallothionein gene (Mtn) yielded numerous examples of this type of chromosomal rearrangement. These duplications are distributed widely--we found them in samples from four continents, and they are functional--larvae carrying Mtn duplications produce more Mtn RNA and tolerate increased cadmium and copper concentrations. Six different duplication types were characterized by restriction-enzyme analyses using probes from the Mtn region. The restriction maps show that in four cases the sequences, ranging in size between 2.2 and 6.0 kb, are arranged as direct, tandem repeats; in two other cases, this basic pattern is modified by the insertion of a putative transposable element into one of the repeated units. Duplications of the D. melanogaster metallothionein gene such as those that we found in natural populations may represent early stages in the evolution of a gene family.

Animals↗

PubMed1989

Time for spreading of compensatory mutations under gene duplication.

Evolution by compensatory mutations is accelerated by gene duplication because selective constraint is relaxed by gene redundancy. A mutation is called compensatory if it corrects the effect of an earlier deleterious mutation. Without duplication, Kimura has shown that the time for spreading of compensatory mutations is much reduced by tight linkage between the two chromosomal sites of mutations. In this report, the time for spreading with gene duplication was studied by using the diffusion equation method of Kimura, together with computer simulations. It was shown that, when 2Nv- is much less than unity, the time for spreading is greatly shortened by gene duplication as compared with the case of complete linkage between the two sites of mutations, where 2N is the effective population size (haploid) and v- is the rate of compensatory mutations. However, if 2Nv- greater than 1, gene duplication is not effective for accelerating the evolution by such mutations.

Biological Evolution↗

PubMed1993

A duplication including the Y allele of Lcp2 and the TRIM retrotransposon at the Lcp locus on the degenerating neo-Y chromosome of Drosophila miranda: molecular structure and mechanisms by which it may have arisen.

Evolutionary changes during the process of sex chromosome differentiation in Drosophila miranda are associated with massive DNA rearrangements. Comparing the DNA structure of the larval cuticle protein (Lcp) region from the X2 and neo-Y chromosome pair, we observed insertions, deletions and a large duplication at the neo-Y chromosomal locus. The duplication encompasses a complete copy of the neo-Y allele of Lcp2, and the ISY3 and the ISY4 insertion sequences. The latter was identified as a retrotransposon, termed TRIM. ISY3 shows DNA sequence similarity to P element homologs identified in the Drosophila obscura species group. We were interested in mechanistic aspects generating the duplication. We cannot exclude unequivocally that unequal sister-chromatid exchange could give rise to the observed duplication; however, recombination is a rare event in Drosophila males. Location and sequence of the retrotransposon TRIM served as molecular markers allowing us to reconstruct two intrachromosomal transposition events that could lead to the observed duplication.

Alleles↗

PubMed1993

Pattern of nucleotide substitutions in growth hormone-prolactin gene family: a paradigm for evolution by gene duplication.

The growth hormone-prolactin gene family in mammals is an interesting example of evolution by gene duplication. Divergence among members of duplicated gene families and among species was examined by using reported gene sequences of growth hormone, prolactin and their receptors. Sequence divergence among species was found to show a general tendency in which a generation-time effect is pronounced for synonymous substitutions but not so for nonsynonymous substitutions. Divergence among duplicated genes is characterized by the relatively high rate of nonsynonymous substitutions, i.e., the rate is close to that of synonymous ones. In view of the stage- and tissue-specific expression of duplicated genes, some of the amino acid substitutions among duplicated genes is likely to be caused by positive Darwinian selection.

Amino Acid Sequence↗

PubMed1993

Effects of uvsX, uvsY and DNA topoisomerase on the formation of tandem duplications of the rII gene in bacteriophage T4.

We have characterized tandem duplications in the rII regions of phage T4. The rII deletion r1589 blocks only the function of the rIIA cistron, although it extends into the B cistron. Another rII deletion, r1236, blocks the function of the rIIB cistron and overlaps r1589. When a cross is made between r1589 and r1236, true rII+ progeny cannot form. Instead, anomalous phenotypically rII+ phages are detected carrying an rII region from each parent. Analyses of nucleotide sequences of the recombination junctions indicate that recombination takes place between short regions of homology (from 2 to 10 bp). Open reading frames of the recombinants deduced from the nucleotide sequences reveal that they contain a normal rIIA cistron and one of a variety of fused, duplicated rIIB cistrons. The T4 uvsX and uvsY genes, which participate in homologous recombination, are involved in this duplication formation. T4 DNA topoisomerase is encoded by genes 39, 52 and 60. Mutations in 52 and 60 reduced the frequency of such duplications, but mutations in gene 39 and some in gene 52 did not. Hence, the effects of topoisomerase mutations are allele-specific. Models are proposed in which these proteins are involved in tandem duplication.

Adenosine Triphosphatases↗

PubMed1994

Characterization of two Segregation distorter revertants: evidence that the tandem duplication is necessary for Sd activity in Drosophila melanogaster.

Segregation Distorter (SD) is a naturally occurring system of meiotic drive in Drosophila melanogaster. Males heterozygous for an SD second chromosome and a normal homolog (SD+) transmit predominantly SD-bearing sperm. To accomplish this, the Segregation distorter (Sd) locus induces the dysfunction of those spermatids that receive the SD+ chromosome. Recently, P. A. Powers and B. Ganetzky isolated overlapping DNA clones spanning the region of DNA known to contain the Sd gene and identified a 5-kb tandem duplication that is present on all SD chromosomes examined, but is apparently absent from wild-type chromosomes. Here we report a molecular analysis of two spontaneous revertants from an Australian SD chromosome (SD-Arm28). Both of these revertants have lost the 5-kb tandem duplication along with the ability to distort transmission; the critical observation, however, is that they retain the DNA haplotype in the flanking regions (both proximally and distally) that is characteristic of the original SD-Arm28. We propose unequal sister chromatid exchange between the tandem repeats as the only plausible explanation for loss of a repeat while retaining flanking markers. This provides direct evidence that the tandem duplication is indeed necessary for the Sd phenotype. Further, we examined testes-specific levels of both RNA and protein for the nearby Topoisomerase 2 gene. Neither revealed a consistent difference between SD and SD+ strains. We also measured testes-specific levels of RNA using the tandem duplication itself as probe. Our results suggest that there is strong up-regulation of one or several 2.0-2.3-kb transcripts from the duplicated region in the testes of an SD strain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Families of mtDNA re-arrangements can be detected in patients with mtDNA deletions: duplications may be a transient intermediate form.

In three patients with mitochondrial DNA duplications, there are two additional re-arranged molecules derived from mitochondrial DNA. Two forms of closed circular deletions of mitochondrial DNA have been characterised in all three patients, one being a monomer, and the other a dimer. The junction fragments appear to be the same in the deletion and the duplication, suggesting that both re-arrangements arose from the same initial recombination event, followed by homologous recombination. Sequential muscle biopsy and cell culture studies suggest that the duplication is present only transiently in muscle and cloned fibroblast lines. The duplicated molecule could thus be an intermediate in the formation of the deletion. Evidence is presented for the presence of duplicated mtDNA in 6/11 patients known to have deletions of mitochondrial DNA in muscle, suggesting that this could be a general mechanism for major re-arrangements of mitochondrial DNA. There may be parallels between the families of re-arrangements found in plant mitochondrial DNA, and the three distinct re-arranged molecules described here.

Blotting, Southern↗

PubMed1993

Maternally transmitted partial direct tandem duplication of mitochondrial DNA associated with diabetes mellitus.

Mitochondrial DNA from a 38 year old male with diabetes mellitus and features of mitochondrial dysfunction was analysed and shown to include a population with a partial duplication. The partially duplicated mitochondrial DNA molecules were evident in both muscle and blood. The region of mitochondrial DNA duplicated includes the origin of heavy strand replication, but not the light strand origin. This patient has features in common with other cases of partial direct tandem duplications and with a family which was reported to harbour a 10.4 kb mtDNA deletion. Initial restriction enzyme analysis of our case produced results consistent with a partial deletion of mitochondrial DNA. This leads us to propose that the rarity of reports of partial mitochondrial DNA duplications may stem in part from the classification of such mutants as partial deletions.

Adult↗

PubMed1998

Members of the olfactory receptor gene family are contained in large blocks of DNA duplicated polymorphically near the ends of human chromosomes.

We have identified three new members of the olfactory receptor (OR) gene family within a large segment of DNA that is duplicated with high similarity near many human telomeres. This segment is present at 3q, 15q, and 19p in each of 45 unrelated humans sampled from various populations. Additional copies are present polymorphically at 11 other subtelomeric locations. The frequency with which the block is present at some locations varies among populations. While humans carry seven to 11 copies of the OR-containing block, it is located in chimpanzee and gorilla predominantly at a single site, which is not orthologous to any of the locations in the human genome. The observation that sequences flanking the OR-containing segment are duplicated on larger and different sets of chromosomes than the OR block itself demonstrates that the segment is part of a much larger, complex patchwork of subtelomeric duplications. The population analyses and structural results suggest the types of processes that have shaped these regions during evolution. From its sequence, one of the OR genes in this duplicated block appears to be potentially functional. Our findings raise the possibility that functional diversity in the OR family is generated in part through duplications and inter-chromosomal rearrangements of the DNA near human telomeres.

Amino Acid Sequence↗

PubMed1989

Tissue-type plasminogen activator variants with domain duplications and rearrangements.

The interactions between tPA domains that are important for catalysis are poorly understood. We have probed the function of interdomain interactions by generating tPA variants in which domains are duplicated or rearranged. The proteins were expressed in a transient mammalian expression system and tested in vitro for their ability to activate plasminogen, induce fibrinolysis and bind to a forming fibrin clot. Duplication of the heavy chain domains of tPA produced enzymatically active tPA variants, many of which demonstrated similar in vitro amidolytic and fibrinolytic activity and similar fibrin affinity to the parent molecule. Zymographic analysis of the domain duplication tPA variants showed one major active species for each variant. Selection of the residues duplicated and the interdomain spacing were found to be critical considerations in the design of tPA variants with duplicated domains. We also rearranged the domains of tPA such that kringle 1 replaced the second kringle domain and vice versa. An analysis of these variants indicates that the first kringle domain can confer fibrin affinity to a tPA variant and function in place of kringle 2. Therefore, in wild-type tPA, the functions of kringle 1 and kringle 2 must be dependent partially on their orientation within the heavy chain of the protein. The functional autonomy of the heavy and light chains of tPA is demonstrated by the activity of a tPA variant in which the order of the heavy and light chains was reversed.

Base Sequence↗

PubMed1993

Properties conferred on Clostridium thermocellum endoglucanase CelC by grafting the duplicated segment of endoglucanase CelD.

The DNA sequence encoding the duplicated 22 amino acid segment of Clostridium thermocellum endoglucanase CelD was fused to the 3'-terminus of the celC gene encoding C.thermocellum endoglucanase CelC. The presence of the duplicated segment endowed CelC with the capacity to form cytoplasmic inclusion bodies containing active enzyme when the hybrid gene was expressed in Escherichia coli. Inclusion body formation prevented proteolytic cleavage of the duplicated segment. The intact hybrid protein CelC-Cel'D was purified from inclusion bodies and characterized. In contrast to CelC, CelC-Cel'D was able to bind to CipA, a protein acting as a scaffolding component of the C.thermocellum cellulase complex (cellulosome). However, the catalytic properties of CelC-Cel'D were similar to those of CelC. These results suggest that foreign proteins tagged with the duplicated segment could be incorporated into the cellulosome in order to modify the enzymatic properties of the complex. The formation of inclusion bodies by proteins carrying the duplicated segment may also prove a convenient means of purifying cloned gene products that are sensitive to proteolytic degradation.

Amino Acid Sequence↗