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PubMed1987

Induction of genetic tandem duplications in Salmonella by polycyclic aromatic hydrocarbon and amine carcinogens.

6 polycyclic aromatic hydrocarbon or similar amine carcinogens were tested as inducers of genetic tandem duplications in a rough strain of Salmonella typhimurium. When metabolically activated by rat-liver microsomes, all 6 were active in inducing genetic tandem duplications, yielding from over 3 times to almost 14 times as many tandem duplicants per viable bacterium as did concurrent uninduced control cultures. These results extend the number and chemical diversity of carcinogens shown to induce genetic duplications in bacterial tester systems. We suggest that polycyclic hydrocarbon carcinogens may act in carcinogenesis by inducing genetic duplications or other genetic rearrangements. Duplication induction may be a useful genetic endpoint for screening potential carcinogens.

2-Acetylaminofluorene↗
PubMed2004

Polo-like kinase-2 is required for centriole duplication in mammalian cells.

Centriole duplication initiates at the G1-to-S transition in mammalian cells and is completed during the S and G2 phases. The localization of a number of protein kinases to the centrosome has revealed the importance of protein phosphorylation in controlling the centriole duplication cycle. Here we show that the human Polo-like kinase 2 (Plk2) is activated near the G1-to-S transition of the cell cycle. Endogenous and overexpressed HA-Plk2 localize with centrosomes, and this interaction is independent of Plk2 kinase activity. In contrast, the kinase activity of Plk2 is required for centriole duplication. Overexpression of a kinase-deficient mutant under S-phase arrest blocks centriole duplication. Downregulation of endogenous Plk2 with small hairpin RNAs interferes with the ability to reduplicate centrioles. Furthermore, centrioles failed to duplicate during the cell cycle of human fibroblasts and U2OS cells after overexpression of a Plk2 dominant-negative mutant. These results show that Plk2 is a physiological centrosomal protein and that its kinase activity is likely to be required for centriole duplication near the G1-to-S phase transition.

Animals↗
PubMed2005

Centrin deficiency in Paramecium affects the geometry of basal-body duplication.

BACKGROUND: Ciliary or flagellar basal bodies and centrioles share the same architecture and remarkable property of duplicating once per cell cycle. Duplication is known to proceed by budding of the daugther organelle close to and at right angles to the mother structure, but the molecular basis of this geometry remains unknown. Among the handful of proteins implicated in basal-body/centriole duplication, centrins seem required in all eukaryotes tested, but their mode of action is not clear. We have investigated centrin function in Paramecium, whose cortical organization allows detection of any spatial or temporal alteration in the pattern of basal-body duplication. RESULTS: We have characterized two pairs of genes, PtCEN2a and PtCEN2b as well as PtCEN3a and PtCEN3b, orthologs of HsCEN2 and HsCEN3, respectively. GFP tags revealed different localization for the two pairs of gene products, at basal bodies or on basal-body-associated filamentous arrays, respectively. Centrin depletion induced by RNAi caused mislocalization of the neoformed basal bodies: abnormal site of budding (PtCen2ap) or absence of separation between mother and daughter organelles (PtCen3ap). Over successive divisions, new basal bodies continued to be assembled, but internalization of the mispositionned basal bodies led to a progressive decrease in the number of cortical basal bodies. CONCLUSIONS: Our observations show that centrins (1) are required to define the site and polarities of duplication and to sever the mother-daughter links and (2) play no triggering or instrumental role in assembly. Our data underscore the biological importance of the geometry of the duplication process.

Amino Acid Sequence↗
PubMed2005

An exceptional combined malformation: duplication of the urinary and intestinal tracts and the vulva (04-80CR).

The authors reported the surgical treatment of a 2-year-old girl with complete duplication of the kidney, ureter, bladder, urethra, and the vulva, associated with intestinal duplication and complete duplication of the appendix and colon. Congenital intestinal malrotation also concurred. After a series of preoperative examinations, exploratory operation including reduction of intestinal malrotation, fusion of bladder and colon, obliteration of the duplicated urethra, resection of the intestinal and appendiceal duplications, and cosmetic repair of the vulva was performed. Incontinence of urine and stool disappeared, and she had been followed up for 10 months until this report. Repeat voiding cystourethrography performed recently demonstrated a fused bladder and the disappearance of the duplicated urethra.

Abnormalities, Multiple↗
PubMed2006

Duplication and paralog sorting of RPB2 and RPB1 genes in core eudicots.

RPB1 and RPB2, which encode the largest and second largest subunits of RNA polymerase II, respectively, are essential single copy genes in fungi, animals and most plants. Two paralogs of the RPB2 gene have been found in some groups of angioperms [Oxelman, B., Yoshikawa, N., McConaughy, B.L., Luo, J., Denton, A.L., Hall, B.D., 2004. RPB2 gene phylogeny in flowering plants, with particular emphasis on asterids. Mol. Phylogenet. Evol. 32, 462-479]. Here, we report the results of experiments designed to identify the evolutionary origin of the RPB2 duplicate copies. Through careful sampling and phylogenetic analysis, we were able to construct the RPB2 gene tree in angiosperms and infer the phylogenetic positions of the gene duplication and gene loss events that occurred. Our study shows that an RPB2 gene duplication occurred early in core eudicot evolution, at or near the time of the Buxaceae/Trochodendraceae divergence. Subsequently, multiple gene duplication and paralog sorting events happened independently in different core eudicot taxa. Differential expression of the two RPB2 gene paralogs may explain the preservation of both paralogs in the asterids. One gene (RPB2-i) accounts for most of the RPB2 mRNA made in the flower organs while the other gene (RPB2-d) is predominantly used in the vegetative tissues. We also found two paralogs of the RPB1 gene in some core eudicot species. The RPB1 gene duplication occurred before core eudicot divergence, around the time of RPB2 gene duplication. Several independent RPB1 paralog sorting events happened in different core eudicot taxa; their occurrence was independent of the RPB2 paralog sorting events. Our results suggest that a polyploidization event happened at or near the time of the Buxaceae/Trochodendraceae divergence. We propose that this polyploidization and the partial diploidization processes thereafter may have been the driving force of core eudicot radiation.

Exons↗
PubMed1976

The incidence and importance of renal duplication.

The excretory urograms performed on 1716 children and 3480 adults have been examined to find the incidence and complications of renal duplication. Ninety-five patients with duplication were found, unilateral in 79 and bilateral in 16 patients. It was equally common on each side and twice as common in females as in males. Non-duplex kidneys had a mean of 9.4 calyces and duplex kidneys had a mean 3.7 upper and 7-6 calyces in lower moieties. In patients without renal disease and with unilateral duplication the two kidneys were equal in size in 39%, and the duplex was smaller in 10%. Twenty-seven per cent of the duplex kidneys examined showed evidence of disease compared to 3% of the non-duplex kidneys-a significant difference (P less than 0-001). Saddle reflux is the only abnormality unique to duplication and was seen in one patient. Extravesical ectopic ureter and ureterocoeles are known to be associated with renal duplication, but in this series ureterocoeles were found only on the non-duplex side. The duplex kidney in children is more susceptible to reflux than is the non-duplex kidney, and this leads to both ureteric and pelvi-calyceal dilation, and to chronic pyelonephritis in the duplex side in those children who develop urinary tract infections. Chronic pyelonephritis was found in 22% of patients under 15, significantly more often than in adults (P less than 0-001), although the incidence of duplication was unchanged. It is concluded that there is no real increase in the number of children with duplex kidneys having urinary tract infections, and the vast majority of duplex kidneys do not become diseased.

Adolescent↗
PubMed1986

Juxtapancreatic intestinal duplications with pancreatic ductal communication: a cause of pancreatitis and recurrent abdominal pain in childhood.

Pancreatic duplications with ductal communications should be included in the differential diagnosis of any child presenting with recurrent abdominal pain of unknown etiology and should be considered as a possible cause of pancreatitis in childhood. Such duplications most likely arise from nonregressing diverticula of the pancreatic bud during embryologic development. Their clinical presentation is unique from other duplications because of their anatomic association with the pancreatic duct. Pain and weight loss are the major presenting complaints, although many patients have nausea and vomiting. Serum chemistries, in particular the serum amylase, are usually normal and are of little help in the differential diagnosis. Radiographic evaluation has not been particularly helpful in the past. ERCP, ultrasonic examination, and CT scan show great promise, however. Operative intervention should be tailored for the individual patient. The operation performed will depend upon operative findings. Intraoperative pancreatograms or cystograms are very helpful in differentiating these cysts from others at the time of operation. Pathologically, most of the duplications have a thickened muscular coat that usually has some evidence of inflammation. They are usually lined with gastric mucosa. Except in the most severe cases, the pancreas is histologically normal, suggesting that most of the pain experienced by these patients is secondary to inflammation within the duplication. The inflammatory response may completely destroy the mucosal lining and cause fibrosis within the muscular coat of the duplication. In those instances, these lesions cannot be differentiated from pancreatic pseudocyst. This may account for some of the "idiopathic" pseudocysts reported in the literature.

Abdomen↗
PubMed2001

Bladder exstrophy associated with complete urethral duplication: a rare malformation with excellent prognosis.

PURPOSE: We report the association of complete urethral duplication and bladder exstrophy in 5 males, and describe the main characteristics to achieve diagnosis. MATERIALS AND METHODS: From 1983 to 2000, 5 males with single bladder exstrophy and complete urethral duplication were seen at 3 institutions. Although bladder exstrophy was obvious at birth, only 1 patient had the preoperative diagnosis of associated urethral duplication. All patients were evaluated with abdominal ultrasound, voiding cystourethrogram after bladder closure and cystoscopy. RESULTS: All patients were totally incontinent, including 4 after primary bladder exstrophy closure. Although it was initially unnoticed by the urologist, most patients had leakage from the tip of the penis during the Valsalva maneuver. In all cases bladder exstrophy was single and deeply situated in the pelvis with excellent elasticity. All patients had a normal sized penis with less severe dorsal chordee and conical shaped glans. The duplicate epispadiac urethra did not have a verumontanum. Only 1 of the 5 patients had the correct diagnosis made before primary closure of bladder exstrophy, while in the other 4 diagnosis of a duplicate ventral urethra was made at the time of epispadias or fistula repair. There were no other associated malformations. In all cases the dorsal epispadiac urethral plate was excised and bladder emptying occurred through the ventral urethra, which at cystoscopy had a normal verumontanum. Postoperatively, all patients became continent and voided with good flow through the ventral urethra and, as opposed to many cases of exstrophy and epispadias, had normal size and excellent cosmesis of the penis. CONCLUSIONS: Complete urethral duplication is a rare variant of the exstrophy-epispadias complex. Patients with this anomaly present with a larger and more deeply situated bladder plate than classical exstrophy and a larger penis. A high index of suspicion is necessary to make a preoperative diagnosis. Excision of the dorsal urethral plate and maintenance of the ventral urethra are the treatment of choice, resulting in a continence and normal voiding.

Adult↗
PubMed2001

The mouse Mps1p-like kinase regulates centrosome duplication.

The yeast Mps1p protein kinase acts in centrosome duplication and the spindle assembly checkpoint. We demonstrate here that a mouse Mps1p ortholog (esk, which we designate mMps1p) regulates centrosome duplication. Endogenous mMps1p and overexpressed GFP-mMps1p localize to centrosomes and kinetochores in mouse cells. Overexpression of GFP-mMps1p causes reduplication of centrosomes during S phase arrest. In contrast, a kinase-deficient mutant blocks centrosome duplication altogether. Control of centrosome duplication by mMps1p requires a known regulator of the process, Cdk2. Inhibition of Cdk2 prevents centrosome reduplication and destabilizes mMps1p, causing its subsequent loss from centrosomes, suggesting that Cdk2 promotes mMps1p's centrosome duplication function by regulating its stability during S phase. Thus, mMps1p, an in vitro Cdk2 substrate, regulates centrosome duplication jointly with Cdk2.

3T3 Cells↗
PubMed1996

A new case of Beckwith-Wiedemann syndrome with an 11p15 duplication of paternal origin [46,XY,-21,+der(21), t(11;21)(p15.2;q22.3)pat].

We present a new case of 11p15 duplication (trisomy 11p15) in a boy (46,XY,-21,+der(21), t(11;21)(p15.2;q22.3)] suffering from Beckwith-Wiedemann syndrome (BWS), whose phenotypically normal father carries a balanced translocation between chromosomes 11 and 21[46,XY, t(11;21)(p15.2;q22.3)]. The paternal grandmother has the same balanced translocation and is also clinically normal. BWS was suspected when the boy was 6 months old because of gigantism, macroglossia, visceromegaly, ear lobe creases and abdominal distention. Apart from the characteristic BWS phenotype, the boy has other features which are almost exclusively observed in 11p trisomy (high forehead with frontal upsweep of hair, wide central nose bridge, slightly beaked nose, chubby cheeks and severe mental retardation). So far, at least eight cases of 11p15 duplication have been described as patients with BWS. In six of these, the duplication was due to inheritance of a translocated or rearranged paternal chromosome. This was also the case in our patient. In the two other previously published cases, the 11p15 duplications were de novo, but in one of these, DNA analysis has subsequently shown that the duplication was of paternal origin. We discuss our observations in relation to the above-mentioned previous cases of 11p15 duplication and the possible role of genomic imprinting in the etiology of BWS.

Beckwith-Wiedemann Syndrome↗
PubMed1991

Unequal crossing-over within the B duplication of Drosophila melanogaster: a molecular analysis.

The B mutation is associated with a tandem duplication of 16A1-16A7. It is unstable, mutating to wild type and to a more extreme form at a frequency of one in 1000 to 3000. The reversion to wild type is associated with the loss of one copy of the duplication, whereas the mutation to extreme B is associated with a triplication of the region. The instability of B has been attributed to unequal crossing-over between the two copies of the duplication. Recent molecular data show that there is a transposable element, B104, between the two copies of the duplication and support the hypothesis that this element generated the duplication via a recombination event. These data suggest that unequal crossing-over within the duplication may not be the cause of the instability of B. Instead, the instability may be caused by a recombination event involving the B104 element. This issue was addressed using probes for the DNA on either side of the B104 element at the B breakpoint. All of the data indicate that the B104 element is not involved in the instability of B and support the original unequal crossing-over model.

Animals↗
PubMed2006

Mechanism limiting centrosome duplication to once per cell cycle.

The centrosome organizes the microtubule cytoskeleton and consists of a pair of centrioles surrounded by pericentriolar material. Cells begin the cell cycle with a single centrosome, which duplicates once before mitosis. During duplication, new centrioles grow orthogonally to existing ones and remain engaged (tightly opposed) with those centrioles until late mitosis or early G1 phase, when they become disengaged. The relationship between centriole engagement/disengagement and centriole duplication potential is not understood, and the mechanisms that control these processes are not known. Here we show that centriole disengagement requires the protease separase at anaphase, and that this disengagement licences centriole duplication in the next cell cycle. We describe an in vitro system using Xenopus egg extract and purified centrioles in which both centriole disengagement and centriole growth occur. Centriole disengagement at anaphase is independent of mitotic exit and Cdk2/cyclin E activity, but requires the anaphase-promoting complex and separase. In contrast to disengagement, new centriole growth occurs in interphase, is dependent on Cdk2/cyclin E, and requires previously disengaged centrioles. This suggests that re-duplication of centrioles within a cell cycle is prevented by centriole engagement itself. We propose that the 'once-only' control of centrosome duplication is achieved by temporally separating licensing in anaphase from growth of new centrioles during S phase. The involvement of separase in both centriole disengagement and sister chromatid separation would prevent premature centriole disengagement before anaphase onset, which can lead to multipolar spindles and genomic instability.

Animals↗
PubMed1997

Spontaneous duplication of a 661 bp element within a two-component sensor regulator gene causes phenotypic switching in colonies of Pseudomonas tolaasii, cause of brown blotch disease of mushrooms.

Spontaneous sectoring of Pseudomonas tolaasii colonies results in a phenotypic switch from the smooth, pathogenic form (designated 1116S) to the rough non-pathogenic form (designated 1116R). This phenotypic switch can also be induced by mutation of the pheN master regulatory locus, which encodes a 99 kDa protein with homology to the conserved family of sensor regulator proteins. Southern blot analysis of genomic DNA from 1116S and 1116R probed with a 3.4 kb Xhol-BamHI fragment containing the pheN gene has revealed restriction fragment length polymorphisms in the pheN locus of 1116R. In order to characterize the genetic basis of this variation, the pheN locus (designated pheN') was cloned from 1116R and its nucleotide sequence determined. A 661 bp duplication was identified within pheN' introducing a frameshift mutation in the predicted pheN open reading frame (ORF). A resulting predicted ORF of pheN' designated ORF2 encodes a polypeptide of 706 amino acid residues, with a predicted molecular weight of 77 kDa, and which lacks part of the PheN sensor domain. Southern blot analysis of genomic DNA using a probe within the duplicated sequence revealed the presence of two bands in 1116R but only one band in the 1116S form. Polymerase chain reaction (PCR) analysis of 25 independently isolated 1116R sectors using primers flanking the duplication site in pheN confirmed the presence of the duplicated 661 bp sequence within this region in all of the sectors and the absence of the duplicated sequence in spontaneous revertants from 1116R to 1116S. Northern blot analysis of RNA from 1116S and 1116R using a pheN probe showed that ORF2 was transcribed in the 1116R form. The presence of a truncated PheN protein in 1116R was verified by Western blot analysis of total cell protein using a LemA antiserum, which revealed the presence of 99kDa and 77kDa cross-reactive bands in 1116S and 1116R respectively. It is concluded that the spontaneous colony-sectoring event that results in the 1116R phenotypic variant form of P. tolaasii arises owing to a 661 bp DNA duplication within the 5' end of the pheN gene, which results in loss of the periplasmic sensor domain of PheN and elimination of normal PheN function.

Fungi↗
PubMed2001

Renal duplication with associated complications in adults: CT findings in 26 cases.

AIM: To review the computed tomography (CT) findings in 26 adult patients with complicated renal duplication, and to assess whether the complications were anomaly-related or superimposed by acquired disease. MATERIALS AND METHODS: Fifteen women and 11 men, aged 17-83 years took part in the study. All CT studies were reviewed to define the moieties affected. RESULTS: The duplication was unilateral in 18 cases and bilateral in six, one patient had a single left kidney and the remaining one a horseshoe kidney. In 14 patients the pathology was related only to the anomaly. Upper pole abnormalities were seen in 13 patients (seven related to the anomaly) and lower pole abnormalities in five (all related to duplication). Both systems were affected in eight cases, six of them by pathological processes unrelated to duplication. Hydronephrosis of the affected collecting system was the most common imaging finding. CONCLUSION: Computed tomography is often used to evaluate abdominal conditions in adults and may therefore be the first imaging modality to reveal a duplex kidney complicated by a pathological process. Involvement of only one moiety was frequently related to the duplication, with a predilection for the upper moiety, while involvement of both systems was used unrelated to the duplication. Zissin, R. (2001). Clinical Radiology, 56, 58-63.

Adolescent↗
PubMed1986

Histopathological investigation of duplications of the alimentary tract.

Lack of information on the morbid anatomy of duplications of the alimentary tract stimulated an evaluation of patients with such duplications seen at the Sophia Children's Hospital, Rotterdam, from 1970 to 1984. There were 14 patients in all, involving 2 foregut, 6 midgut, and 4 hindgut duplications. Resected material of 12 of these patients has been investigated with particular emphasis on the presence of nervous tissue in these duplications. Routine histological as well as histochemical staining procedures have revealed nervous tissue in practically all duplications investigated. Considering the findings reported in the literature with reference to the earliest manifestation of nerve cells throughout the alimentary tract, the results demonstrate that duplications occur well before the 12th week of gestation.

Autonomic Nervous System↗
PubMed1994

Evolution of gene networks by gene duplications: a mathematical model and its implications on genome organization.

Networks of transcriptional regulators have key roles in metazoan development. Important forces in the evolution of these networks are gene duplications and gene deletions, events that may change the spatiotemporal expression pattern of network genes. A measure for the probability of such changes after gene-duplication events is proposed. This measure is based on a simple mathematical model that describes such networks as dynamical systems and on properties of ensembles of these dynamical systems. It is predicted that this probability depends only on the fraction of genes duplicated in a single event and that it is largest if approximately 40% of the genes in a network are duplicated. This property is robust with respect to variations in model parameters. On these grounds, it is argued that (i) evolution of gene networks should preferentially occur either by duplication of single genes or by duplication of all genes involved in a network, and that (ii) tight linkage ("clustering") or strong dispersal are the two evolutionarily most favorable forms of genomic organization of genes forming such networks.

Animals↗
PubMed1994

ALL-1 partial duplication in acute leukemia.

The ALL-1 gene, located on chromosome band 11q23, is fused to a variety of other genes by reciprocal chromosomal translocations present in 5-10% of human acute leukemias. We have recently reported the detection by Southern blot of ALL-1 gene rearrangements in adult patients with acute myeloid leukemia lacking cytogenetic evidence of 11q23 translocations. These include 2 of 19 patients with normal karyotypes as well as 3 of 4 patients with trisomy 11. To characterize the abnormal ALL-1 genes, we cloned the ALL-1 rearrangements from two patients with trisomy 11. Characterization of the clones, together with Southern blot analysis, indicates that the ALL-1 rearrangement in both patients is the result of a direct tandem duplication of a portion of the ALL-1 gene spanning exons 2-6. The partial ALL-1 duplication is also detected by Southern blot analysis in a patient with a normal karyotype. RNA PCR and DNA sequence analysis show that the partially duplicated ALL-1 gene is transcribed into mRNA capable of encoding a partially duplicated protein. Partial duplication of ALL-1, in which a portion of a putative protooncogene is fused with itself, represents an additional genetic mechanism for leukemogenesis. Our findings suggest that the presence of trisomy in malignancy may sometimes indicate the partial duplication of a cellular protooncogene.

Acute Disease↗
PubMed1999

The oral nitrate and nitrite intake in The Netherlands: evaluation of the results obtained by HPIC analysis of duplicate 24-hour diet samples collected in 1994.

In spring and autumn of 1994 duplicates of 24-h diets were collected from 123 respondents. One of the goals of this study was to determine the amount of nitrite and nitrate in the duplicates of 24-h diets to establish the oral daily intake of these analytes. For this purpose an HPIC/UV method for the determination of nitrate and nitrite in duplicate diets was developed and validated. The sample preparation procedure was derived from the in-house method used for the determination of nitrate and nitrite in human blood plasma. The sample is diluted with water, deproteinized with Carrez reagent, followed by chromatographic clean-up on an SPE C18-column. Both the nitrate and the nitrite results are quantitative. The recovery for nitrite was on average 104% (n = 21, spiking levels: 0.84-95 mg/kg) and for nitrate on average 103% (N = 21, spiking levels: 1.8-404 mg/kg). Samples of duplicates of 24-h diets were analysed according to the method developed. The median intake of nitrite calculated from the samples collected in spring 1994 was 0.6 mg/person day (range < 0.1-6.1 mg/person/day). For the samples collected in autumn 1994 these figures were < 0.2 mg/person/day (range < 0.1-16 mg/person/day). The mean intake of nitrate was 73 mg/person/day (range 7-322 mg/person/day) in spring 1994 and 87 mg/person/day (range 1-310 mg/person/day) in autumn 1994. The overall mean intake of nitrate in 1994 was 80 mg/person/day. The daily intake for nitrate was higher than that found in the duplicate diet study carried out in 1984/1985, when an average daily intake of 52 mg/person was measured. The intake of nitrite was also higher than found in the duplicate diets collected in 1984/1985. The findings of the study are discussed in the context of the ADI for nitrate and nitrite as well as the outcome of other recent European intake studies.

Adolescent↗