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PubMed1985

Demonstration of remarkable sequence divergence in variants of a complex satellite DNA by molecular cloning.

Repeat units of a complex G + C-rich satellite of the Bermuda land crab have been cloned by insertion into either the PstI or EcoRI site of pBR322 or the EcoRI site of pUC9. While most of the recombinants contained inserts of approx. 2.1 kb, the average size of repeat units seen in cellular satellite digests, several inserts were markedly different in size. Two domains that account for major sequence differences among the satellite variants and that may be 'hotspots' for sequence modification have been subcloned to permit characterization of their secondary and tertiary structures independent of the influence of the other unusual sequences present. One of these domains is striking in its content of simple repeats; one strand is highly biased in pyrimidines which may permit the formation of unusual secondary and/or tertiary conformations. The other subcloned domain is rich in Pu/Py; preliminary data indicate a transition from B----Z DNA in this region.

Animals↗
PubMed2006

Nucleolar localization of a reverse transcriptase related to telomere maintenance in Chironomus (Diptera).

A growing number of cellular processes originally thought not to involve the nucleolus now seem to be associated with this organelle. In recent years, a variety of RNAs and proteins with no apparent function in ribosome genesis have been discovered in this nuclear compartment. This paper reports the presence in the nucleolus of a reverse transcriptase (RT) previously found to be associated with telomeres in Chironomus. Immunofluorescence detection using a specific antibody against conserved domains shared by RTs showed a distinct pattern of staining in the giant nucleoli of polytenized cells. This nucleolar localization was confirmed in a number of larval tissues and embryonic cells of Chironomus thummi and C. pallidivitatus; its distribution showed a definite necklace pattern that did not completely colocalize with fibrillarin or nucleolin and appeared to be different to that of typical nucleolar components. There is evidence that both telomerase RT and RNA template subunits are present in the nucleoli of mammalian and yeast cells. However, chironomids do not have typical telomeres or telomerase. As in other Diptera, telomeres lack the short, simple repeats maintained by telomerase and instead have more complex sequences in the range of hundreds of nucleotides. It has been suggested that the RT associated with these telomeres might be involved in their maintenance, perhaps involving a mechanism similar to that of telomerase retrotranscription and retrotransposition in Drosophila. The present results indicate that the putative Chironomus telomere elongation machinery and telomerase share a nucleolar localization. This reinforces the idea that nucleoli are functionally linked to telomere maintenance irrespective of the differences in their molecular organization and therefore in the strategy adopted for their elongation.

Animals↗
PubMed1994

Centromeric and telomeric repeats are stable in nonagenarians as revealed by the double hybridization fluorescent in situ technique.

We report a simple method for simultaneous identification of centromeric and telomeric repeat sequences of human chromosomes. Employing this technique, we investigated the stability of centromeres and telomeres in individuals over 90 years of age and compared them with younger controls (< 40 years). Our findings suggest that centromeric and telomeric repeats remain apparently stable in nonagenarians. These findings are enigmatic because it has been suggested that centromeres are lost in older individuals. Furthermore, telomeric shortening has been observed in aged lymphocytes and cellular senescence. However, stability of telomeric repeats noted in nonagenarians may be masked by loss followed by compensation by a process called telomeric elongation.

Adult↗
PubMed1996

A complete set of human telomeric probes and their clinical application. National Institutes of Health and Institute of Molecular Medicine collaboration.

Human chromosomes terminate with specialized telomeric structures including the simple tandem repeat (TTAGGG)n and additional complex subtelomeric repeats. Unique sequence DNA for each telomere is located 100-300 kilobases (kb) from the end of most chromosomes. A high concentration of genes and a number of candidate genes for recognizable syndromes are known to be present in telomeric regions. The human telomeric regions represent a major diagnostic challenge in clinical cytogenetics, because most of the terminal bands are G negative, and cryptic deletions and translocations in the telomeric regions are therefore difficult to detect by conventional cytogenetic methods. In fact, several submicroscopic chromosomal abnormalities in patients with undiagnosed mental retardation or multiple congenital anomalies have been identified by other molecular methods such as DNA polymorphism analysis. To improve the sensitivity for deletion detection and to determine whether such cryptic rearrangements represent a significant source of human pathology that has not been previously appreciated, it would be valuable to have specific FISH probes for all human telomeres. We report here the isolation and characterization of a complete set of specific FISH probes representing each human telomere. As most of these clones are at a known distance of within 100-300 kb from the end of the chromosome arm, this provides a 10-fold improvement in deletion detection sensitivity compared with high-resolution cytogenetics (2-3 Mb resolution). While testing these probes, we serendipitously identified a family with multiple members carrying a cryptic 1q;11p rearrangement in the balanced or unbalanced state.

DNA Probes↗
PubMed2006

A proposal for standardization in forensic canine DNA typing: allele nomenclature of six canine-specific STR loci.

In this study a proposal for the allele nomenclature of six polymorphic short tandem repeat (STR) loci (PEZ3, PEZ6, PEZ8, PEZ10, FHC2161, and FHC2328) for canine genotyping (Canis lupus familiaris) is presented. The nomenclature is based on the sequence data of the polymorphic region of the microsatellite markers as recommended by the DNA commission of the International Society of Forensic Haemogenetics (ISFH) in 1994 for human DNA typing. To cover commonly and rarely occurring alleles, a selection of homozygous and heterozygous animals were analyzed and subjected to sequence studies. The alleles consisted of simple tri- and tetra-nucleotide repeat patterns as well as compound and highly complex repeat patterns. Several alleles revealing the same fragment size but different repeat structures were found. The allele designation described here was adopted to the number of repeats, including all variable regions within the amplified fragment. In a second step the most commonly occurring alleles were added to an allelic ladder for each marker allowing a reliable typing of all alleles differing in size. A total number of 142 unrelated dogs from surrounding municipal animal homes, private households, and canines in police duty were analyzed. The data were added to a population database providing allele frequencies for each marker.

Alleles↗
PubMed1985

A series of repetitive DNA sequences are associated with human core and H1 histone genes.

Repetitive DNA sequences, derived from the human beta-globin gene cluster, were mapped within a series of human genomic DNA segments containing core (H2A, H2B, H3 and H4) and H1 histone genes. Cloned recombinant lambda CH4A phage with human histone gene inserts were analyzed by Southern blot analysis using the following 32P-labeled (nick translated) repetitive sequences as probes: Alu I, Kpn I and LTR-like. A cloned DNA designated RS002-5'C6 containing (i) a (TG)16 simple repeat, (ii) an (ATTTT)n repeat and (iii) a 52 base pair alternating purine and pyrimidine sequence was also used as a radiolabelled hybridization probe. Analysis of 12 recombinant phage, containing 6 arrangements of core histone genes, indicated the presence of Alu I, Kpn and RS002-5'C6 repetitive sequences. In contrast, analysis of 4 human genomic DNA segments, containing both core and H1 histone genes, indicated the presence of only Alu I family sequences. LTR-like sequences were not detected in association with any of the core or H1 histone genes examined. These results suggest that human histone and beta-globin genes share certain aspects of sequence organization in flanking regions despite marked differences in their overall structure and pattern of expression.

Bacteriophage lambda↗
PubMed1993

Murine radiation myeloid leukaemogenesis: relationship between interstitial telomere-like sequences and chromosome 2 fragile sites.

While the specific nature of chromosomal fragile sites and their relationship to human leukaemogenesis remain obscure, there is evidence that chromosomal fragility may, in some circumstances, be associated with telomere-like repeat sequences and that chromosome 2 fragility in the mouse is involved in the initiation of myeloid leukaemia by ionising radiation. Here we describe the molecular cloning and characterisation of two murine telomere-like sequences, one having an inverted repeat structure and the other a simple tandem repeat organisation. The inverted telomere repeat clone generates an in situ chromosome 2 hybridisation pattern very similar to the distribution of the radiation-sensitive fragile sites previously found to be associated with leukaemogenic initiation. Furthermore, statistical comparison of the distributions of radiation induced breakpoints and sites of inverted telomere repeat hybridization indicates concordance at all chromosome 2 sites excluding the terminal regions. These data are discussed with respect to mechanisms of radiation-induced, site-specific chromosome 2 rearrangement and their implications for leukaemogenic initiation.

Acute Disease↗
PubMed1987

Three transposed elements in the intron of a human VK immunoglobulin gene.

Two gene segments coding for the variable region of human immunoglobulin light chains of the kappa type (VK genes, ref. 2) were found to have unusual structures. The two genes which are called A6 and A22 are located in duplicated gene clusters. Their restriction maps are very similar. About 4 kb of the A22 gene region were sequenced. It turned out that the intron contains an insert with the characteristics of a transposed element. The inserted DNA of 1.2 kb length contains imperfect direct and inverted repeats at its ends; at the insertion site a duplication of five nucleotides was found. Within the inserted DNA one copy each of an Alu element and of the simple sequence motif (T-G)17 were identified. Also these two repetitive sequences are themselves flanked by short direct repeats. The major inserted DNA has no significant homology to published human nucleic acid sequences. The whole structure is interpreted best by assuming a sequential insertion of the three elements. The coding region of the VK gene itself has several mutations which by themselves would render it a pseudogene; we assume that the insertion event(s) occurred prior to the mutations. According to mapping and hybridization data A6 is very similar to A22.

Amino Acid Sequence↗
PubMed1985

Structural organization of rat ribosomal RNA genes: interspersed sequences and their putative role in the alignment of nucleosomes.

We have observed four regions containing highly repetitive interspersed sequences in the nontranscribed spacer (NTS) of the rat rRNA genes. Two of them (A and B) are located at a distance of 3-5 kb upstream from the transcription start point and two others (C and D) at a distance of 2-5 kb downstream from the 3' end of the 28S rRNA gene. These repetitive sequences are widely dispersed in the genome and are included both in small-copy regions and in the families of extended reiterated sequences. The sequences of three fragments were determined: one from the C2 region, 1100 bp in length and two from A and C1 regions, 110-120 bp long. These regions are characterized by the presence of 'simple' sequences, such as (AC)n, (ACC)n, (GAG)n, (GGGA)n, (TAAG)n, and also of long blocks, (G)n and (A)n. In the C2 region two palindromes, 16 and 14 nt long, were found, one of them including a XhoI site. Mobile element B2 was observed in regions B and C. All four regions, A, B, C and D, contain sets of simple sequences, among which some common elements have been found. Theoretical prediction of the nucleosomal disposition in the C region indicates that the combination of simple sequences existing in the given area secures fixed positions of the nucleosomes, one of the nucleosomes being formed on the B2 element. Moreover, a striking periodicity, with the repeat length close to that of the rat nucleosomal DNA, has been observed. A hypothesis is put forward that the simple sequences can dictate the location of nucleosomes on the adjoining DNA sequences, thereby regulating the gene activity.

Animals↗
PubMed1993

Primitive sex chromosomes in poeciliid fishes harbor simple repetitive DNA sequences.

The demonstration of the chromosomal mode of sex determination via genetic experiments as well as the absence of heteromorphic sex chromosomes affirm poeciliid fishes as a unique group among vertebrates that are endowed with the most primitive form of sex chromosomes. In many different taxa the evolutionary process involved in the differentiation of advanced sex chromosomes is outlined through sex specifically organized repetitive sequences. In this investigation hybridization of synthetic probes specific to genomic simple repeat motifs uncovers a sex-specific hybridization pattern in certain viviparous fishes of the family Poeciliidae. The hybridization pattern together with specific staining of the constitutive heterochromatin by C-banding reveals heterogamety in males (Poecilia reticulata) as well as in females (P. sphenops). In P. velifera, however, C-banding alone fails to unravel the heterogametic status. The female specific W-chromosome can be detected by simple repetitive sequence probes. Therefore, the principal significance of heterochromatization as a means of generating differentiated sex chromosomes is evident.

Animals↗
PubMed2006

A complex polymorphic region in the brain-derived neurotrophic factor (BDNF) gene confers susceptibility to bipolar disorder and affects transcriptional activity.

Previous studies have suggested that genetic variations in the brain-derived neurotrophic factor (BDNF) gene may be associated with several neuropsychiatric diseases including bipolar disorder. The present study examined a microsatellite polymorphism located approximately 1.0 kb upstream of the translation initiation site of the BDNF gene for novel sequence variations, association with bipolar disorder, and effects on transcriptional activity. Detailed sequencing analysis revealed that this polymorphism is not a simple dinucleotide repeat, but it is highly polymorphic with a complex structure containing three types of dinucleotide repeats, insertion/deletion, and nucleotide substitutions that gives rise to a total of 23 novel allelic variants. We obtained evidence supporting the association between this polymorphic region (designated as BDNF-linked complex polymorphic region (BDNF-LCPR)) and bipolar disorder. One of the major alleles ('A1' allele) was significantly more common in patients than in controls (odds ratio 2.8, 95% confidential interval 1.5-5.3, P=0.001). Furthermore, a luciferase reporter gene assay in rat primary cultured neurons suggests that this risk allele (A1) has a lower-transcription activity, compared to the other alleles. Our results suggest that the BDNF-LCPR is a functional variation that confers susceptibility to bipolar disorder and affects transcriptional activity of the BDNF gene.

Adult↗
PubMed1998

Sequence analysis of Mus dunni endogenous virus reveals a hybrid VL30/gibbon ape leukemia virus-like structure and a distinct envelope.

Mus dunni endogenous virus (MDEV) can be activated from M. dunni cells by exposing the cells to hydrocortisone or 5-iodo-2'-deoxyuridine. Interference analysis has revealed that MDEV uses a receptor for cell entry that is different from those used by other murine retroviruses. The entire genome has now been sequenced, revealing a long terminal repeat (LTR)-gag-pol-env-LTR structure typical of simple retroviruses of the murine leukemia virus genus, with no additional open reading frames between env and the 3' LTR. The LTRs and other noncoding regions of MDEV are most closely related to those of VL30 elements, while the majority of the coding sequences are most closely related to those of gibbon ape leukemia virus. MDEV represents the first example of a naturally occurring, replication-competent virus with sequences closely related to VL30 elements. The U3 region of MDEV contains six nearly perfect 80-bp repeats and the beginning of a seventh, and the region expected to contain the packaging sequence contains approximately four imperfect 33-bp repeats. The receptor specificity domains of the envelope are unique among retroviruses and show no apparent similarity to regions of known proteins.

Animals↗
PubMed2025

Molecular epidemiological surveillance for non-tuberculous mycobacterial pulmonary disease: a single-center prospective cohort study.

UNLABELLED: Bacterial species cultured from sputum change during treatment or observation for non-tuberculous mycobacterial pulmonary disease; however, strain-level changes remain unrecognized. Variable number tandem repeat typing is a standard technique for strain identification; nonetheless, its labor-intensive and time-consuming nature limits routine clinical use. Therefore, we aimed to elucidate species-subspecies and strain dynamics in non-tuberculous mycobacteria and develop a simple sequence-based strain-level determination method. We performed a single-center prospective cohort study of 112 patients with non-tuberculous mycobacterial pulmonary disease. Whole-genome sequencing was performed on two sputum samples collected at enrollment and at the end of follow-up, followed by variable number tandem repeat (VNTR) typing. We also developed a simple long-read sequencing-based digital VNTR (dVNTR) typing method and evaluated its efficacy. Our results demonstrate that core genome multi-locus sequencing typing revealed species/subspecies changes in 13 patients (11.6%); VNTR typing detected strain changes in 16 patients (14.3%) without species/subspecies changes. Overall, pathogen shifts occurred in 29 patients (shift [+] group, 25.9%), whereas 83 had no detectable pathogen shift (shift [-] group, 74.1%). Interestingly, macrolide and amikacin susceptibility changed in both groups, but resistance remained higher in shift (-) patients. dVNTR results aligned with those of conventional VNTR typing. In conclusion, since susceptibility factors remain unclear, routine species/subspecies identification and molecular typing, such as VNTR, are optimal for patient care. Core genome multi-locus sequencing typing with a dVNTR identified pathogen shifts, innovating non-tuberculous mycobacterial pulmonary disease management.Clinical TrialsThis study is registered with UMIN as UMIN 000056067. IMPORTANCE: Pulmonary non-tuberculous mycobacterial disease is a chronic infection in which the causative pathogens may change at the species, subspecies, or strain level over time. Accurate tracking of these changes is essential for optimizing treatment; however, conventional clinical practice lacks efficient methods for monitoring such dynamics. Our study revealed pathogen changes in approximately one-quarter of patients over 1.5 years, prompting the development of a novel surveillance system that integrates next-generation sequencing for both species-subspecies identification and strain-level molecular epidemiology. This innovation enables real-time monitoring of pathogen dynamics, allowing clinicians to promptly adjust treatment strategies and improve patient care through more informed decision-making.

Humans↗
PubMedDate not supplied

[Features of the structure and evolution of complex, tandemly organized Bsp-repeats in the fox genome. I. Structure and internal organization of the BamHI-dimer].

A 1468 b.p. DNA BamHI-fragment homologous to the Bsp-repeat was isolated from the fox genome and sequenced. This fragment is an hierarchically arranged dimer. Its 734 b.p.-monomers consist of three subrepeats (SR), each 245 b.p. long, abundant with overlapping imperfect tandem repeats which in turn are rich in short direct related repeats (each 4-7 b.p. in size). The latters are mainly composed of AG, TG dinucleotides and their complements CT, CA. All subrepeats in the BamHI-dimer are flanked by motifs homologous to Jeffreys' sites. At certain points the sites are doubled. The above data allow to assume that the Bsp-repeat complex structure is likely to have developed throughout long multi-step evolution of relatively simple DNA sequences which had emerged de novo. Single substitutions, small inserts and deletions, multiple duplication and recombination events seem to have most contributed to the evolution of the Bsp-repeats. Single substitutions in SRs with respect to the consensus are not equally distributed along their length. A wave-like pattern of this distribution is the evidence for non-random character of mutations accumulation. A correspondence was noted between conservative regions in SR and the presence therein of functional motifs homologous to the binding sites of already known regulatory proteins.

Animals↗
PubMed1988

Molecular evolution of intergenic DNA in higher primates: pattern of DNA changes, molecular clock, and evolution of repetitive sequences.

A 3.1-kb intergenic DNA fragment located between the psi beta-globin and delta-globin genes in the beta-globin gene cluster was cloned from gorilla, orangutan, rhesus monkey, and spider monkey, and the nucleotide sequence of each fragment was determined. The phylogeny of these four sequences, together with two previously published allelic sequences from humans and one from chimpanzee, was constructed, and the accumulation of mutations in the region was analyzed. The sites of base substitutions are not evenly distributed within the region: two Alu repeats have accumulated 0.21 + 0.02 substitutions/site with 0.15 + 0.008 substitutions/site in the remainder of the fragment. The occurrence of substitutions at neighboring sites is more frequent than would be expected if they were independent. The observed excesses disappear when ancestral -CG- dinucleotide sites are excluded. The phylogenetic relationships of the sequences indicate that the human sequence shares a most recent coancestor with the chimpanzee sequence. The data also show that great apes have accumulated fewer mutations in this part of the genome than has the rhesus monkey. The relative rates of accumulation of 12 kinds of nucleotide substitution in the region during primate evolution are asymmetric in the DNA strands. From these rates of accumulation, the origin of a simple stretch of sequence near the 3' end of the 3.1-kb fragment was deduced to be a sequence comprising 50% T and 50% C on one strand. The two oppositely oriented Alu sequences in the 3.1-kb region were inserted at their present positions before the divergence of the New-World monkeys from other lineages. Our analysis shows that the nucleotide sequences of the two Alu repeats in spider monkey are unexpectedly similar both to each other and to the deduced ancestral sequence of Alu repeats. The data suggest that there has been some type of recombinational event between the spider monkey Alu repeats but that it was not a simple gene conversion.

Animals↗
PubMed1987

Rapid identification of hybridization probes for chromosomal walking.

The presence of repeated elements in restriction fragments used as hybridization probes for chromosomal walking poses a major obstacle to the success of this gene-cloning strategy. This report describes a simple and rapid means of identifying restriction fragments devoid of repeated sequences and therefore useful as hybridization probes for chromosomal walking. Restriction fragments derived from a genomic DNA clone are Southern blotted and hybridized to nick-translated total genomic [32P]DNA. Fragments of the genomic clone that contain high abundance sequences (i.e., repeated elements) hybridize strongly to their nick-translated counterparts, which, due to their high copy number, comprise a significant proportion of the total genomic DNA probe. Conversely, fragments containing single-copy or low-abundance sequences do not hybridize, as their nick-translated counterparts are poorly represented in the total genomic DNA probe. These latter fragments, by virtue of their low-abundance sequences, are well suited as probes for chromosomal walking. Ensuring the absence of repeated elements in restriction fragments prior to their purification and utilization as chromosomal walking probes results in marked savings of time, effort and materials.

Bacteriophage lambda↗