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PubMed1991

Mechanisms of tandem duplication in the Duchenne muscular dystrophy gene include both homologous and nonhomologous intrachromosomal recombination.

Three tandem duplications were previously identified in patients with Duchenne muscular dystrophy and were shown in each case to have a subset of dystrophin gene exons duplicated. The origin of these duplications was traced to the single X chromosome of the maternal grandfathers, suggesting that an intrachromosomal event (unequal sister chromatid exchange) was involved in the formation of these duplications. In the present study, a DNA segment containing the duplication junction and the normal DNA that corresponds to both ends of the duplicated region have been cloned. Subsequent mapping studies confirmed the tandem arrangement (head to tail) of these duplications and revealed their sizes to be 130 kb, approximately 300 kb, and 35-80 kb, respectively. Sequence analysis of the duplication junctions showed that one duplication was due to homologous recombination between two repetitive elements (Alu sequences) and the other two were due to recombination between unrelated nonhomologous sequences. In the latter cases, the preferred cleavage sites of the eukaryotic type I and II DNA topoisomerases were found at the junctions of these duplications, suggesting a possible role of these enzymes in the chromatid exchange events. This study provides the first insight into the molecular basis of gene duplications formed through unequal sister chromatid exchange in humans.

Base Sequence↗
PubMed1990

Two forms of messenger RNA encoding rat liver mannan-binding protein are generated by differential utilization of polyadenylation sites of one transcript.

Rat liver mannan-binding protein (R-L-MBP) is a lectin specific for mannose and N-acetylglucosamine. Northern blot hybridization analysis with a R-L-MBP cDNA (0.9 kb), which we isolated previously [Oka, S., Itoh, N., Kawasaki, T., & Yamashina, I. (1987) J. Biochem. 101, 135-144], revealed that R-L-MBP was encoded by two species of mRNA of 1.4 and 3.5 kb long, respectively. Analysis of a newly isolated cDNA clone of 3.3 kb long showed that the sequence of the open reading frame of the 3.5 kb mRNA was completely identical to that of the 1.4 kb mRNA. The 3'-untranslated region of the 3.5 kb mRNA contained two inverted copies of the previously described identifier (ID) sequence, which is a repetitive element of the rat genome [Milner, R.J., Bloom, F.E., Lai, C., Lerner, R.A., & Sutcliffe, J.G. (1984) Proc. Natl. Acad. Sci. U.S.A. 81, 713-717]. Southern blot analysis of rat genomic DNA digested with restriction enzymes suggested that each mRNA species arises from one gene, with the differences in size most easily being accounted for by differential utilization of the polyadenylation sites of one transcript.

Amino Acid Sequence↗
PubMed1996

Characterization of a human fovea cDNA library and regional differential gene expression in the human retina.

The primate fovea is the region of the retina responsible for acute vision. This region constitutes less than 5% of the total area of the retina and has not been intensely studied at the molecular level. As a first step in the molecular characterization of the fovea, we have constructed a primary human fovea cDNA library. Experiments confirm that our cDNA library reflects a nonbiased distribution of foveal expressed sequences. Single-pass sequencing was performed on 209 randomly isolated clones from this library. Analysis of the sequences generated reveals that the distributions of fovea clones with either human mitochondrial gene sequences or repetitive elements are different than those observed in cDNA libraries made from other tissues. A significant number of the fovea expressed sequence tags (ESTs) (88, 42.1%) represent novel human ESTs. This suggests that the library will be useful in identifying new human genes. Northern analysis of specific fovea ESTs defined in this study suggests that there are significant quantitative differences in gene expression that distinguish the fovea from the rest of the retina.

Brain Chemistry↗
PubMed1998

Complete sequence of a 93.4-kb contig from chromosome 3 of Trypanosoma cruzi containing a strand-switch region.

We have initiated large-scale sequencing of the third smallest chromosome of the CL Brener strain of Trypanosoma cruzi and we report here the complete sequence of a contig consisting of three cosmids. This contig covers 93.4 kb and has been found to contain 20-30 novel genes and several repeat elements, including a novel chromosome 3-specific 400-bp repeat sequence. The intergenic sequences were found to be rich in di- and trinucleotide repeats of varying lengths and also contained several known T. cruzi repeat elements. The sequence contains 29 open reading frames (ORFs) longer than 700 bp, the longest being 5157 bp, and a large number of shorter ORFs. Of the long ORFs, seven show homology to known genes in parasites and other organisms, whereas four ORFs were confirmed by sequencing of cDNA clones. Two shorter ORFs were confirmed by a database homology and a cDNA clone, respectively, and one RNA gene was identified. The identified genes include two copies of the gene for alanine-aminotransferase as well as genes for glucose-6-phosphate isomerase, protein kinases and phosphatases, and an ATP synthase subunit. An interesting feature of the sequence was that the genes appear to be organized in two long clusters containing multiple genes on the same strand. The two clusters are transcribed in opposite directions and they are separated by an approximately 20-kb long, relatively GC-rich sequence, that contains two large repetitive elements as well as a pseudogene for cruzipain and a gene for U2snRNA. It is likely that this strand switch region contains one or more regulatory and promoter regions. The reported sequence provides the first insight into the genome organization of T. cruzi and shows the potential of this approach for rapid identification of novel genes. [The sequence data described in this paper have been submitted to the GenBank data library under accession nos. AF052831-AF052833.]

ATP Synthetase Complexes↗
PubMed1989

Similarity and divergence among rodent repetitive DNA sequences.

We have analyzed the sequence of 63 B1 and 71 B2 repetitive elements from published data base sequences. The sequences conform to previously published consensus sequences, but are not identical to them. The B2 sequences show seven regions of high variability between family members, which we show points to the B2 family containing subfamilies; no similar evidence is found for subfamilies of the B1 family. The comparisons show no evidence for the emergence of species-specific variants of B1 or B2 sequences since the separation of murine and hamster lines of descent, nor of their concerted evolution within species in the last 10 million years.

Animals↗
PubMed2026

Aging and Reproductive Cancers: An Integrative View on Cell-Free DNA and Transposable Elements.

Aging is one of the strongest risk factors for cancer, and its impact is particularly evident in malignancies of the reproductive system. Ovarian, endometrial, cervical, vulvar, prostate, and penile cancers are mainly diagnosed in older adults and often show different clinical and biological features compared with the same tumors in younger patients. Aging is associated with hormonal changes, immune decline, epigenetic alterations, and accumulation of DNA damage, all of which contribute to cancer development and progression. At the same time, many older patients have frailty and multiple comorbidities, which can limit the use of screening programs and invasive diagnostic procedures. This often leads to delayed diagnosis and worse outcomes. Cell-free DNA (cfDNA) is a minimally invasive biomarker that can be obtained from blood samples and provides molecular information on both tumor and host tissues. Circulating DNA reflects tumor-specific alterations but is also influenced by aging-related changes in DNA release, fragmentation, and methylation. For this reason, aging must be considered when cfDNA-based biomarkers are applied in clinical practice. In this review, we describe how aging influences the biology of reproductive system cancers and how these processes are mirrored in cfDNA profiles. We focus on the clinical use of cfDNA for cancer detection and monitoring in older and fragile patients. Special attention is given to repetitive elements in cfDNA, which are strongly affected by aging and tumor-related epigenetic changes and can be detected with high sensitivity even when the tumor fraction is low. We propose an integrative mechanistic framework in which age-related epigenetic and genomic changes influence both tumor biology and cfDNA composition, with transposable elements acting as a central link between aging and cancer.

Humans↗
PubMed2000

Differences in the meiotic pairing behavior of gonosomal heterochromatin between female and male Microtus agrestis: implications for the mechanism of heterochromatin amplification on the X and Y.

It is generally thought that pairing and recombination between the X and Y chromosome in eutherian mammals is important for the occurrence of normal meiotic division and the production of functional gametes. Microtus agrestis is one of the examples whose giant and heterochromatin-rich sex chromosomes fail to establish a durable association at any stage of the first meiotic division in males. In contrast, in females, synapsis starts in the euchromatic short arm and pairing progresses unidirectionally and continues until both X chromosomes have paired completely, as can be demonstrated by the use of fluorescence in situ hybridization with a sequence confined to the non-centromeric, gonosomal heterochromatin. However, compared with euchromatin, this association is apparently ephemeral and breaks off precociously in the pachytene and metaphase I stages. We demonstrate that a middle repetitive element is localized interspersed in the noncentromeric heterochromatin of both X and Y, except the telomeric region of the Y. No differences could be detected at the molecular level between male and female DNA, indicating that at least the bulk of these elements are organized in the same manner on the X and Y. Our data imply that the loss of synapsis and recombination between the X and Y might have preceded the process of heterochromatin amplification in the course of Microtinae evolution. Since asynapsed elements are particularly susceptible to DNA strand breaks during prophase I, DNA repair of double-strand breaks involving heterochromatic segments of the X and Y could have resulted in translocations of larger segments from the X to the Y or vice versa during the course of chromosome evolution of the gonosomes, explaining the homology at the molecular level between the heterochromatin of the asynaptic X and Y in M. agrestis.

Animals↗
PubMed2000

Molecular characterization of the mouse p47-phox (Ncf1) gene and comparative analysis of the mouse p47-phox (Ncf1) gene to the human NCF1 gene.

The cytosolic factor p47-phox (NCF1) is a key component of the phagocyte NADPH-oxidase system, critical for microbicidal activity. The human p47-phox gene has been well characterized and resides on chromosome 7q11. Here we describe the molecular characterization of the mouse ortholog (Ncf1), which maps to distal chromosome 5, and compare the structure of the genes, commenting on the degree of homology. The mouse and human genes contain the same number of exons and introns, but the mouse gene is more compact (7.8 kb versus 15.2 kb). A percentage identity plot analysis comparing the human and mouse genes indicates that sequence homology is generally restricted to exons and does not include any large segment of introns or the 5' flanking sequence. The mouse gene also contains notably fewer repetitive elements than its human counterpart (34% versus 50%). The start of transcription of the mouse gene has been localized to within 12 nucleotides of the translation start site, similar to the human ortholog. Our findings provide an important foundation for investigating the evolutionary history of the p47-phox gene, particularly as it relates to understanding the molecular basis of the p47-phox-deficient autosomal recessive form of chronic granulomatous disease.

5' Untranslated Regions↗
PubMed1998

Factors affecting ectopic gene conversion in mice.

Duplicated genes and repetitive sequences are distributed throughout the genomes of complex organisms. The homology between related sequences can promote nonallelic (ectopic) recombination, including gene conversion and reciprocal exchange. Resolution of these events can result in translocations, deletions, or other harmful rearrangements. In yeast, ectopic recombination between sequences on nonhomologous chromosomes occurs at high frequency. Because the mammalian genome is replete with duplicated sequences and repetitive elements, high levels of ectopic exchange would cause aneuploidy and genome instability. To understand the factors regulating ectopic recombination in mice, we evaluated the effects of homology length on gene conversion between unlinked sequences in the male germline. Previously, we found high levels of gene conversion between lacZ transgenes containing 2557 bp of homology. We report here that genetic background can play a major role in ectopic recombination; frequency of gene conversion was reduced by more than an order of magnitude by transferring the transgenes from a CF1 strain background to C57BL/6J. Additionally, conversion rates decreased as the homology length decreased. Sequences sharing 1214 bp of sequence identity underwent ectopic conversion less frequently than a pair sharing 2557 bp of identity, while 624 bp was insufficient to catalyze gene conversion at significant levels. These results suggest that the germline recombination machinery in mammals has evolved in a way that prevents high levels of ectopic recombination between smaller classes of repetitive sequences, such as the Alu family. Additionally, genomic location appeared to influence the availability of sequences for ectopic recombination.

Animals↗
PubMed2000

DNA fingerprinting of thermophilic lactic acid bacteria using repetitive sequence-based polymerase chain reaction.

DNA fingerprints of lactic acid bacteria were generated by polymerase chain reaction using a primer based on the repetitive elements found in the genome of Streptococcus pneumoniae (BOX-PCR). The method made it possible to identify 37 isolates from raw milk. industrial starters and yogurt. Differentiation at species, subspecies and strain level was possible for Lactobacillus delbrueckii subsp. lactis, Lb. delbrueckii subsp bulgaricus and Str. thermophilus. BOX-PCR was also applied to studying the strain composition of a starter culture and the direct detection of strains in commercial fermented milk.

Animals↗
PubMed1998

Tandemly repeated genomic sequence demonstrates inter- and intra-strain genetic variation in Schistosoma japonicum.

Genetic variability within and among four geographical strains of Schistosoma japonicum was examined using a novel repetitive element. The element, termed Sirh1.0, was isolated from genomic DNA of a Philippine strain of S. japonicum using a combination of restriction fragment PCR and band-stab PCR. Sjrh1.0 is a tandemly repeated element, the sequence of which appears to be species-specific, in that it hybridized to DNA from S. japonicum but not to DNA from S. mansoni. Its sequence does not match previously deposited sequences in GenBank. When employed as a probe in Southern hybridization analysis, radiolabelled Sjrh1.0 revealed sex-specific and strain-specific differences in genomic DNA of individual worms. We also found individual genetic variation within geographical isolates of the Asian schistosome.

Animals↗
PubMed1987

Deletional rearrangement in the human T-cell receptor alpha-chain locus.

The antigen-specific receptor on the surface of mature T lymphocytes is a heterodimer consisting of polypeptides termed alpha and beta. In the course of characterizing human T-cell tumors with an immature (CD4-, CD8-) surface phenotype, we detected a 2-kilobase alpha-related transcript. Analysis of cDNA clones corresponding to this transcript established that a genetic element (which we call TEA, for "T early alpha") located between the alpha-chain variable- and joining-region genes had been spliced to the alpha constant region. The TEA transcript is present early in thymocyte ontogeny, and its expression declines during T-cell maturation. More important, the TEA area functions as an active site for rearrangement within the alpha gene locus. Blot hybridization of restriction enzyme-digested DNA with a TEA probe revealed a narrowly limited pattern of rearrangement in polyclonal thymic DNA, surprisingly different from the pattern expected for the mature alpha gene with its complex diversity. These DNA blots also showed that TEA is generally present in the germ-line configuration in cells expressing the gamma delta heterodimeric receptor and is deleted from mature (alpha beta-expressing) T-lymphocyte tumors and lines. Moreover, the TEA transcript lacked a long open reading frame for protein but instead possessed multiple copies of a repetitive element resembling those utilized in the heavy-chain class switch of the immunoglobulin genes. The temporal nature of the rearrangements and expression detected by TEA suggests that this recombination could mediate a transition between immature (gamma delta-expressing) T cells and mature (alpha beta-expressing) T cells.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1991

Xenopus laevis c-myc I and II genes: molecular structure and developmental expression.

The structure of the two Xenopus laevis c-myc I and c-myc II genes has been investigated by isolating and sequencing genomic and cDNAs clones. In oocytes, c-myc I mRNAs represent 80-90% of the overall amount of c-myc transcripts. The c-myc I expression is controlled primarily by two differentially regulated tandem promoters P1 and P2 which are separated by 50 bases. During oogenesis, maternal c-myc I mRNAs, are transcribed from both promoters whereas zygotic transcripts seem to initiate only from the P2 promoter. Sequence comparison between the promoter regions of c-myc I and II genes reveals the insertion in the c-myc I promoter region, between positions -831 and -389 relative to the P1 start site of a repetitive element. Comparison of X.laevis and mammalian c-myc promoter sequences reveals furthermore the conservation of cis-regulatory elements, including a motif known to be a negative regulator of the human c-myc transcription, a purine rich region, a binding site for the E2-F transcription factor and three SP1 binding sites. Finally, we report characterization of a new c-myc I mRNA which differ at the 5' end. Transcripts are possibly initiated at a putative alternative promoter located further upstream in the genome, and undergoes alternative splicing.

Amino Acid Sequence↗
PubMed2001

Mechanisms of evolution in Rickettsia conorii and R. prowazekii.

Rickettsia conorii is an obligate intracellular bacterium that causes Mediterranean spotted fever in humans. We determined the 1,268,755-nucleotide complete genome sequence of R. conorii, containing 1374 open reading frames. This genome exhibits 804 of the 834 genes of the previously determined R. prowazekii genome plus 552 supplementary open reading frames and a 10-fold increase in the number of repetitive elements. Despite these differences, the two genomes exhibit a nearly perfect colinearity that allowed the clear identification of different stages of gene alterations with gene remnants and 37 genes split in 105 fragments, of which 59 are transcribed. A 38-kilobase sequence inversion was dated shortly after the divergence of the genus.

Adaptation, Physiological↗
PubMed1991

The rat vitamin D binding protein (Gc-globulin) gene. Structural analysis, functional and evolutionary correlations.

The complete rat vitamin D binding protein (DBP) gene has been cloned and characterized. Genomic mapping suggests that there is only one copy of this gene in the haploid genome. The gene spans 35 kilobase pairs and contains 13 exons. All exons, exon/intron borders, and 2196 base pairs of 5'-flanking region have been sequenced. The transcription cap site, determined by primer extension analysis, is 62 base pairs upstream from the start of translation and predicts that an unusual TGTAAA motif may serve as a surrogate TATA. The promoter region contains about 50% nucleotide sequence similarity to the corresponding region of the partially characterized human DBP gene and is uniquely interrupted by a repetitive element. Although lacking in overall sequence similarity to the albumin (ALB) and alpha-fetoprotein (AFP) genes, the 5'-flanking region of the DBP gene contains a number of conserved segments which may correspond to critical proximal promoter elements in this gene family. The location of the introns in the coding region of the DBP gene is highly conserved when compared with the ALB and AFP genes. Detailed comparison of exon size and content confirms the previous prediction that the smaller size of the DBP protein results from loss of internal exons 12 and 13 from the DBP progenitor gene during its evolutionary divergence from ALB and AFP.

Amino Acid Sequence↗
PubMed1991

Modulation of B2 containing small RNAs during induced differentiation of murine erythroleukemia cells.

We identified a B2 repetitive element approximately 1.9kb down stream from mouse p53 coding gene. This element was then used as a probe to investigate the expression of B2 containing RNA during the induced differentiation of murine erythroleukemia (MEL) cells. This probe revealed two nuclear and one cytoplasmic RNA species. Nuclear small RNAs had a biphasic variation: a decrease followed by a reaccumulation. The cytoplasmic species was essentially non polysomal, and disappeared after the induced differentiation. The presented results suggest that the regulation of these RNAs is associated to cell proliferation and differentiation respectively.

Animals↗
PubMed2002

Evolutionary dynamics of mammalian mRNA untranslated regions by comparative analysis of orthologous human, artiodactyl and rodent gene pairs.

Most evolutionary studies based on molecular data refer to the portion of genomes encoding for proteins. Today, however, more and more attention is paid to the so-called 'non-coding' regions, which constitute a notable portion of the metazoan nuclear genome. Among them, the untranslated regions of messenger RNAs (mRNA UTRs) are particularly important, as they are involved in the regulation of gene expression, controlling translation efficiency as well as mRNA localization and stability. Up to now, only few studies have focused on the analysis of the compositional and structural features of UTRs, or carried out to investigate quantitatively their evolutionary dynamics. For this reason we have carried out an inter-order study on the evolutionary rate of 5' and 3' UTRs with respect to the corresponding coding region in 93 triplets of orthologous genes (selected through a phylogenetic approach, for a total of 645 625 nt) belonging to Primates (Homo sapiens), Artiodactyla (Bos taurus) and Rodentia (Mus spp.). Our study, that considered only likely orthologous genes, has revealed interesting features on the evolution of these regions concerning nucleotide substitution rate and indels and repetitive element distribution. UTRs from different genes showed a remarkable heterogeneity in the evolutionary dynamics, with some homologous so highly divergent to prevent their alignment, and other rather conserved, at least in some regions, most divergent sequence pairs were excluded from our analysis. The comparison between the nucleotide substitution rates calculated for 5' and 3' UTRs with those calculated on synonymous coding position allowed us to verify and measure the existence of functional constraints acting upon the UTRs of different genes which have shown, in many cases, a positive selection driven evolutionary dynamics.

Animals↗
PubMed1985

Assemblies of linear arrays of particles in the apical plasma membrane of mitochondria-rich cells in the gill epithelium of the Atlantic hagfish (Myxine glutinosa).

In the gill epithelium of the Atlantic hagfish Myxine glutinosa a mitochondria-rich cell type is described which ultrastructurally resembles the chloride cells in other fish species. Freeze-fracture replicas reveal different supramolecular structures in the luminal plasma membrane and in the intracellular amplification (tubular system) of the basolateral plasma membrane of these mitochondria-rich cells. In the luminal plasma membrane ordered assemblies of particles and fibril-like elements are regularly found. On the P face, the assemblies are composed of up to 20 linear arrays of particles which are preferentially located in the microvillar membrane on which they show a helicoidal orientation. The arrays are formed by globular (diameter 8-9 nm) and rod-shaped (length 16-20 nm) particles, which occasionally are so tightly end-to-end attached that they generate fibril-like structures. The distances between adjacent arrays within an assembly measure 10-15 nm. On the E face complementary patterns of linear grooves are present. These assemblies have not previously been demonstrated in the freeze-fractured plasma membrane of branchial chloride cells. In the membrane of the tubular system, emerging from the basolateral plasma membrane of the mitochondria-rich cells, infrequently repeating rows of 7-8 nm particles are present in addition to randomly distributed globular particles (diameter 7-8 nm). Complementary patterns of grooves are present on the E face. These intramembranous structures resemble the repetitive elements which have been previously described in the tubular system of branchial chloride cells in euryhaline teleosts and the subunits of which are considered to be the sites of ion pumps.

Animals↗