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PubMed1993

Duplication detection in Japanese Duchenne muscular dystrophy patients and identification of carriers with partial gene deletions using pulsed-field gel electrophoresis.

DNA samples from 21 unrelated Japanese patients with Duchenne muscular dystrophy (DMD) with nondeletion-type abnormality in the dystrophin gene and three samples from possible deletion carriers were analyzed using pulsed-field gel electrophoresis (PFGE). Among the 21 patients, 7 were found to carry partial duplications of the dystrophin gene spanning 50-400 kb. Of these 7 patients, 4 carried duplications corresponding to the major hot-spot regions for deletions (7.5-8.5 kb from the 5' end of cDNA), whereas two cases contained duplications in a region about 10 kb from the 5' end of cDNA, where causative mutations are reported to be rare. Only 1 case was found to contain a duplication of a region about 1 kb from the 5' end of cDNA, which is the reported duplication prone region. A combination of Southern blot analyses of conventional agarose gel electrophoresis and PFGE was confirmed to be useful, not only for detecting duplications and deletions, per se, but also for identifying carriers in the affected family.

Blotting, Southern↗
PubMed1983

Confirmation of a de novo duplication, dup(10)(q24 leads to q26), by GOT1 gene dosage studies.

A girl with mental retardation and the facies associated with the distal 10q duplication syndrome was found to have a tandem duplication of 10q24 to 10q26. This was confirmed by gene dosage studies of glutamic oxaloacetic transaminase 1. The clinical features of this patient are compared with those of other reported cases of the distal 10q duplication syndrome with duplication-deficiency karyotypes due to familial reciprocal translocations or inversions or with tandem duplication of a more proximal region of 10q. Reports of tandem duplications in man and possible mechanisms of origin are discussed.

Aspartate Aminotransferases↗
PubMed1981

Synaptonemal complex analysis of mouse chromosomal rearrangements. I. Cytogenetic observations on a tandem duplication.

Electron microscopy of surface-spread spermatocytes from mice heterozygous for a tandem duplication shows the heteromorphic synaptonemal complex (SC) to comprise two lateral elements of unequal length, the longer of which is buckled out in a characteristic loop, representing the unsynapsed portion of the duplication. The loop is a regular feature of late zygotene-early pachytene nuclei; it is longest at these early stages, but, through equalization of the two axes as a consequence of synaptic adjustment, it is replaced by a normal appearing SC at late pachytene. Because equalization, as indicated by a decrease in the percent difference between axes, may begin shortly after completion of synapsis, estimates of duplication segment length are restricted to a sample selected for least adjustment. --Although the mean position of the loop is constant at various pachytene substages, individual positions vary widely from cell to cell, consistent with the behavior expected of a duplication, but not of a deletion or an inversion. The length of the segment that is duplicated is estimated to be 22% of the normal chromosome, the midpoint of the segment is mapped at 0.61 of the chromosome distal to the kinetochore, and the ends of the segment are mapped at 0.50 to 0.72. Measurements of G-banded mitotic chromosomes give comparable values: duplication length, 24%; midpoint, 0.60, and segment ends, 0.48 and 0.71. This agreement constitutes further validation of the SC/spreading method for detecting and analyzing chromosomal rearrangements at pachytene and substantiates the fidelity with which the axes and SCs represent the behavior of chromosomes in synapsis.

Animals↗
PubMed1981

Synaptosomal complex analysis of mouse chromosomal rearrangements. II. Synaptic adjustment in a tandem duplication.

Surface spread spermatocytes of mice heterozygous for a tandem duplication show nuclei in late zygotene-early pachytene in which the heteromorphic synaptonemal complex (SC) contains a lateral element that is buckled out into a unpaired loop as a consequence of the added length of the duplication (estimated in another study to be 21.7%, with breakpoints at 0.50 and 0.72 of the length of the chromosome). The ends of the buckle, marking the interstitial termini of synapsis proceeding from opposite directions, vary over a wide range of positions, but within limits: the proximal end of the loop does not exceed the distal end of the duplication segment, while the distal end of the loop does not lie closer to the kinetochore than the proximal end of the segment. Thus synapsis (SC formation) at zygotene is restricted to homologous regions (exclusive homosynapsis). --In the last half of pachytene, no buckles are found, only simple SCs with lateral elements of equal length, as a consequence of synaptic adjustment. Intermediate stages of adjustment are found throughout the first half of pachytene. Shortly after homosynapsis is complete, synaptic adjustment begins: the ends of the duplication loop separate (desynapsis of homosynapsed regions); the long axis shortens with respect to the short axis in both the unpaired loop and in the SC portions; asymmetrical twists take up inequalities; the loop is reduced to from 1 to 3 asymmetrical twists; the axes (lateral elements) equalize as the long axis shortens; and a simple SC is formed, indistinguishable from others in the complement, in which the region of the duplication and those adjacent to it have heterosynapsed, while the distal regions of the SC are presumably still homosynapsed. Synaptic adjustment evidently involves two sequential events: localized instability of the homosynapsed condition, leading to desynapsis, then restoration of the SC by heterosynapsis. Adjustment therefore represents the loss of strict homosynapsis. It is concluded that the asymmetry produced by the duplication loop constitutes an instability that triggers synaptic adjustment.

Animals↗
PubMedDate not supplied

The effect of rec-2 on repeat-induced point-mutation (RIP) and recombination events that excise DNA sequence duplications at the his-3 locus in Neurospora crassa.

In Neurospora crassa, duplicated DNA suffers both extensive repeat-induced point-mutation (RIP) and also excision by recombination events during the dikaryotic phase of the life cycle that precedes karyogamy and meiosis (reviewed by Selker 1990). This paper describes experiments designed to test the effect of rec-2, a gene known to modulate the local level of meiotic recombination at his-3, on RIP and the excision of tandem duplications. Duplications carrying his-3 sequences and a marker, hygr, that confers hygromycin resistance were constructed by targeted transformation. RIP and excisive recombination were assessed from the progeny of crosses heterozygous for a duplication and having different combinations of rec-2 alleles. In the presence of rec-2+, excision of hygr was reduced to about half of that in crosses homozygous for rec-2. In contrast, rec-2+ had little influence on the frequency of duplications that escaped RIP. Thus, in addition to reducing recombination between his-3 alleles during meiosis, rec-2+ also influences recombination events that lead to the excision of duplications carrying his-3. However, RIP may be independent.

Crosses, Genetic↗
PubMed1993

Distribution of polymorphic gene duplication at the Gpdh locus in natural populations of Drosophila melanogaster.

The glycerol-3-phosphate dehydrogenase (GPDH, E.C. 1.1.1.8) gene of Drosophila melanogaster contains a tandem duplication of a 4.5-kb-long DNA fragment. Survey of the Gpdh gene region by the Southern blot analysis revealed the following features of this gene duplication: (1) The duplication was not observed in chromosome lines that carry In(2L)t, a cosmopolitan chromosomal inversion in this species. The duplication and the inversion are in linkage disequilibrium. (2) The duplication is polymorphic in the Japan and US natural populations examined. Its frequency is 0.26 on an average in In(2L)t-free chromosomes. (3) Triplication is absent or has not become frequent in the populations surveyed. Possible evolutionary factors of this duplication polymorphism are discussed.

Alleles↗
PubMed1978

A comprehensive examination of protein sequences for evidence of internal gene duplication.

We have implemented a routine procedure for screening protein sequences for evidence of intragenic duplications. We tested 163 protein sequences representing 116 superfamilies of unrelated proteins. Twenty superfamilies contain proteins with internal gene duplications. The intragenic duplications detected can be divided into two major types. (1) One or more duplications of all or part of a gene produce a protein with two or several detectable regions of sequence homology. Sequences from 18 superfamilies contained this type of duplication. (2) Repeated reduplication of a small DNA segment can produce a protein that is repetitive over most of its length. Three superfamilies contain such repetitive sequences. We also investigated the limits of detection of ancient duplications using sequences derived by random mutation of a model sequence consisting of ten 10-residue repeats. The original repetitive nature of the sequence was usually detected after 250 point mutations even though the ancestral segment could not be accurately reconstructed.

Amino Acid Sequence↗
PubMed1992

Duplications of mitochondrial DNA: implications for pathogenesis.

This paper describes the mapping data obtained on two patients in whom there was clear evidence for a rearrangement of mitochondrial DNA, using restriction enzyme analysis of DNA from whole blood and of polymerase chain reaction products. This suggested that a direct tandem duplication was present, and this was confirmed by sequence analysis of the junction fragment between duplicated segments. In each case the gene for cytochrome oxidase subunit I (MTCOX1) was interrupted, creating reading frames which, if transcribed and translated, would result in truncated versions of this peptide. Heteroplasmy and mosaicism for the abnormal mtDNA population were apparent. Preliminary data also suggest that high-molecular-weight rearrangements of the duplicated region are present in all tissues. The hypothesis that these duplicated genomes caused the phenotype was investigated by examining the distribution of duplicated genomes in various tissues using Southern hybridization and by RNA analysis. This included Northern blotting and cDNA sequencing. In order to investigate the origins of the duplicated mtDNAs, their distribution in different cells within a tissue was documented using the polymerase chain reaction.

Child↗
PubMed1992

Split notochord syndrome in an adult presenting with colonic duplication. Report of a case.

A case of tubular colonic duplication, sigmoid colon diverticulum, and lumbar anterior spina bifida in a 28-year-old man was diagnosed as split notochord syndrome. After subtotal colectomy, including the duplicated colon, the patient recovered. Histologic study of the duplicated colon revealed multifocal, ectopic gastric fundic mucosa in a mosaic pattern. Since bleeding and perforation occur most frequently in conjunction with ectopic gastric mucosa within the duplication, we believe that complete resection of the duplicated bowel is the best procedure. Split notochord syndrome is a rare congenital anomaly. It is usually discovered in the first year of life, and the majority of reported cases have involved the cervical or thoracic region. Our patient is exceptional in having reached the age of 28 years without complaints and in that his case involved lumbar anterior spina bifida and tubular colonic duplication.

Adult↗
PubMed1988

Concerted gene duplications in the two keratin gene families.

Evolutionary trees were derived from the keratin protein sequences using the Phylogeny Analysis Using Parsimony (PAUP) set of programs. Three major unexpected conclusions were derived from the analysis: The smallest keratin protein subunit, K#19 (Moll et al. 1982), is not the most primitive one, but has evolved to fulfill a highly specialized function, presumably to redress the unbalanced synthesis of keratin subunits. Second, the ancestors of keratins expressed in the early embryonic stages, K#8 and K#18, were the first to diverge from the ancestors of all the other keratins. The branches leading to these two keratins are relatively short, indicating a comparatively strong selection against changes in the sequences of these two proteins. Third, the two keratin families show extraordinary parallelism in their patterns of gene duplications. In both families the genes expressed in embryos diverged first, later bursts of gene duplications created the subfamilies expressed in various differentiated cells, and relatively recent gene duplications gave rise to the hair keratin genes and separated the basal cell-specific keratin from those expressed under hyperproliferative conditions. The parallelism of gene duplications in the two keratin gene families implies a mechanism in which duplications in one family influence duplication events in the other family.

Animals↗
PubMed1996

Characterization of mutants involving partial exon duplications in the hprt gene of Chinese hamster V79 cells.

Sequencing of hprt cDNA revealed that three spontaneous mutants in V79 Chinese hamster cells exhibit tandem duplications of exon(s), i.e., either exons 2 and 3 or exon 7. Sequences of different sizes (4.5-8 Kb) were found to be duplicated and inserted in tandem into the hprt gene. These mutants demonstrated spontaneous reversion frequencies which were about 40-fold higher than those observed with other types of spontaneous mutants, but on the same order of magnitude as spontaneous reversions in Sp5, a mutant with a duplication insertion involving exon 2 in this gene. These data suggest that all of the duplications found have the same genetic instability, regardless of the type, size or position of the duplicated fragment. The coding sequence of the hprt cDNA and the restriction pattern of the revertants were virtually identical to the wild-type, indicating restoration of a functional hprt gene by precise deletion of the duplicated fragment.

Animals↗
PubMed2005

Collateral damage: spread of repeat-induced point mutation from a duplicated DNA sequence into an adjoining single-copy gene in Neurospora crassa.

Repeat-induced point mutation (RIP) is an unusual genome defense mechanism that was discovered in Neurospora crassa. RIP occurs during a sexual cross and induces numerous G : C to A : T mutations in duplicated DNA sequences and also methylates many of the remaining cytosine residues. We measured the susceptibility of the erg-3 gene, present in single copy, to the spread of RIP from duplications of adjoining sequences. Genomic segments of defined length (1, 1.5 or 2 kb) and located at defined distances (0, 0.5, 1 or 2 kb) upstream or downstream of the erg-3 open reading frame (ORF) were amplified by polymerase chain reaction (PCR), and the duplications were created by transformation of the amplified DNA. Crosses were made with the duplication strains and the frequency of erg-3 mutant progeny provided a measure of the spread of RIP from the duplicated segments into the erg-3 gene. Our results suggest that ordinarily RIP-spread does not occur. However, occasionally the mechanism that confines RIP to the duplicated segment seems to fail (frequency 0.1-0.8%) and then RIP can spread across as much as 1 kb of unduplicated DNA. Additionally, the bacterial hph gene appeared to be very susceptible to the spread of RIP-associated cytosine methylation.

Base Sequence↗
PubMed2000

Tubular duplication of the esophagus. Contribution of magnetic resonance imaging in anatomical analysis before surgery.

The authors report a tubular duplication of the thoracic esophagus in a 17-year-old male. This anomaly, rare in the adult, can be explained either by a failure of esotracheal compartmentalisation, or a notochordodysraphy or more probably by an error during vacuolisation of the esophagus. The anatomical characteristics of the duplication were clearly seen on MRI. This investigation showed the intramural duplication, with only a thin barrier without muscle, between the esophageal lumen and the duplication channel: two communications were present between the esophageal lumen and the duplication. The esophagus was accessed by right thoracotomy. The close contact between the duplication and the esophagus did not allow them to be separated. A subtotal esophagectomy was necessary, with digestive continuity being restored by coloplasty after a left cervicotomy and a laparotomy. The anatomy seen on the MRI should have predicted that an esophagectomy was necessary and that a thoracotomy could have been avoided by performing the procedure with a closed thorax.

Adolescent↗
PubMed2006

Complex patterns of copy number variation at sites of segmental duplications: an important category of structural variation in the human genome.

The structural diversity of the human genome is much higher than previously assumed although its full extent remains unknown. To investigate the association between segmental duplications that display constitutive copy number differences (CNDs) between humans and the great apes and those which exhibit polymorphic copy number variations (CNVs) between humans, we analysed a BAC array enriched with segmental duplications displaying such CNDs. This study documents for the first time that in addition to human-specific gains common to all humans, these duplication clusters (DCs) also exhibit polymorphic CNVs > 40 kb. Segmental duplication is known to have been a frequent event during human genome evolution. Importantly, among the CNV-associated genes identified here, those involved in transcriptional regulation were found to be significantly overrepresented. Complex patterns of variation were evident at sites of DCs, manifesting as inter-individual differentially sized copy number alterations at the same genomic loci. Thus, CNVs associated with segmental duplications do not simply represent insertion/deletion polymorphisms, but rather constitute a wide variety of rearrangements involving differential amplification and partial gains and losses with high inter-individual variability. Although the number of CNVs was not found to differ between Africans and Caucasians/Asians, the average number of variant patterns per locus was significantly lower in Africans. Thus, complex variation patterns characterizing segmental duplications result from relatively recent genomic rearrangements. The high number of these rearrangements, some of which are potentially recurrent, together with differences in population size and expansion dynamics, may account for the greater diversity of CNV in Caucasians/Asians as compared with Africans.

Animals↗
PubMed1994

Ageing-associated tandem duplications in the D-loop of mitochondrial DNA of human muscle.

Using PCR techniques, we detected a approximately 260 bp (type I) and a approximately 200 bp (type II) tandem duplications in the mtDNA of muscle biopsies from aged individuals. Only one 70-year-old subject was found to harbour the type I and 28 out of 58 subjects had type II duplication. About 90% of the subjects harbouring the duplicated mtDNAs also had the 4,977 bp deletion. Moreover, the incidence and quantity of the type II duplication were found to increase with age. The proportion of the type II duplicated mtDNA in the muscle of a 71-year-old subject was 3.1% while that of a 55-year-old individual was only 0.78%. We suggest that the tandem duplications occur alone or with mtDNA deletions in human tissues in an age-dependent manner, and thereby cause synergistic deleterious effects on mitochondrial respiratory functions in human ageing.

Adult↗
PubMed1995

Kearns-Sayre syndrome associated with mitochondrial DNA deletion or duplication: a molecular genetic and pathological study.

The neuropathological findings in 2 patients with Kearns-Sayre syndrome and mitochondrial DNA (mtDNA) rearrangements, one a predominant deletion and the other a predominant duplication, were remarkably similar, showing diffuse vacuolation of white matter. There were some of the pathological features of Leigh's syndrome in the spinal cord of the patient with a duplication. In the patient with a predominant deletion, rearranged mtDNA was undetectable in blood, spleen, and testis, and present in highest amounts in muscle and the brain, but relatively low in cerebellum, reflecting the ratio seen, albeit in much smaller amounts, in normal aged brains. MtDNA rearrangements in this patient were largely deletions or deletion dimers; duplicated mtDNA was present in only trace amounts in some tissues and there was none in skeletal muscle. The patient with a predominant duplication of mtDNA had higher amounts of rearranged mtDNA in blood (mainly duplicated) than muscle (mainly deleted). Correlation of these data with tissue dysfunction is probably complicated by the replicative behaviour of deleted, duplicated and normal mtDNA.

Adolescent↗
PubMed1982

Evaluation of contrast in duplicated radiographs.

This investigation evaluated changes in the contrast of duplicated radiographs made at different ultraviolet light exposures. Increasing ultraviolet light exposure had different effects on the duplicates of originals of different "background" densities. When correctly exposed, a duplicate radiograph enhanced contrast. When originals had the same contrast but different "background" densities, their duplicates did not have the same contrast. It was not possible to duplicate accurately all the different contrasts measured on an original. It was possible, however, to produce duplicates with all contrasts greater than those of the original.

Copying Processes↗
PubMed1981

A history of the human fetal globin gene duplication.

The nucleotide sequence of 11.4 kilobase pairs (kb) of human DNA that includes the two fetal globin genes, G gamma and A gamma, shows that they are part of a 5 kb tandem duplication. A small segment of DNA occurs three times, on either side of and between the two duplicates. We present two models that account for these observations. One model is simple but requires the assumption of a preexisting repetitive element; the other is more complex but does not require the assumption of preexisting repeats. Over much of the 5 kb duplicated region, the present duplicate copies differ by an average of 14% of their bases, from which we calculate that the duplication was first formed about 34 million years ago. However, 1.5 kb of DNA are vitually identical in the two genes analyzed here, probably as a consequence of an intergenic exchange (gene conversion) that replaced part of the diverging A gamma gene with the corresponding part of the G gamma gene. This conversion took place around 1 million years ago. A sequence of repeated dinucleotides may be one signal involved in exchanges leading to this and similar conversions. Cycles of duplication, triplication, deletion and gene conversion on probably common in many multigene families.

Base Sequence↗