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PubMed1998

The 5' region of intron 11 of the dystrophin gene contains target sequences for mobile elements and three overlapping ORFs.

We have characterised the 2371 bp 5' end of intron 11 of the dystrophin gene. Comparative analysis of this intronic region revealed homologies with the following sequences: regions containing mobile elements; target sites for numerous transcription factors, two resolvases, and a histone-like DNA binding protein; three eukaryotic promoters. In addition, we identified three partially overlapping ORFs, and transcription analysis confirmed that one of these is expressed, representing the first gene reported to overlap the human dystrophin gene. We have also characterised a 136 bp sequence rearranged in intron 11 in a patient affected by X-linked dilated cardiomyopathy due to a dystrophinopathy. This is a multiple copy sequence with features of a repetitive element. Its comparative analysis showed a very high homology with human genomic and EST regions, adjacent and clustered with Alu, LINE1, and THE elements. The pattern of homology suggests that it may represent a novel Alu-like, transcriptionally active sequence with a possible retrotransposable capacity. We hypothesise that the 5' region of the dystrophin intron 11, containing common target areas for the insertion of mobile elements, may have a role in the rearrangement of this novel Alu-like sequence.

Cardiomyopathy, Dilated↗
PubMed1989

tRNA derived insertion element in histone gene repeating unit of Drosophila melanogaster.

Analysis of 41 histone homologous clones from an isogenic gene library of Drosophila melanogaster showed that non-histone fragments interrupt the histone repetitive clusters at several sites. Long (L) and short (S) forms of the repeating units are distinguished by the insertion of 240 bp into the spacer between H1 and H3 of the L units; Each form appears to be clustered with its own kind. The complete DNA sequence of the histone 5.0 kb repeating unit was determined. Five histone genes (H1, H2A, H2B, H3, H4) were identified in a repeating unit and several sequence blocks common to the five histone genes were found in the 5'- and 3'-regions. The insertion sequence of 240 bp was found to be similar to the Alu family, an element derived from tRNA.

Amino Acid Sequence↗
PubMed1996

Cloning of the human platelet endothelial cell adhesion molecule-1 promoter and its tissue-specific expression. Structural and functional characterization.

Platelet endothelial cell adhesion molecule-1 (PECAM-1; CD31) is a cell adhesion molecule involved in transendothelial migration and expressed by hemopoietic and endothelial cells. To understand the mechanisms underlying its regulated expression, a genomic clone containing 1555 bp of the 5'-flanking region and the first exon of the human PECAM-1 gene has been isolated. The 5'-flanking region of the PECAM-1 gene lacks a consensus TATA box, but contains consensus motifs for Sp1, EGR1, ets, helix-loop-helix (HLH) box, GATA, AP-2, C/EBP, YY1, CCACC, LyF-1, imperfect octamer, heptamer, high mobility group proteins (HMG) box, and nuclear factor-kappaB, as well as shear stress-, retinoic acid-, glucocorticoid-, and acute phase-responsive elements, and an Alu sequence. Successive 5' to 3' or 3' to 5' deletions revealed tissue-specific promoter activity within the two contiguous 0.22-kb NheI/BglII and 0.44-kb BglII/PstI fragments. The transcriptional activity displayed by the 0.22-kb NheI/BglII fragment was specific for the myeloid lineage, whereas the promoter activity of the 0.44-kb BglII/PstI fragment was apparently restricted to endothelial cells. The transcriptional activity of the 0.22-kb NheI/BglII fragment was confirmed by 5' RACE (rapid amplification of 5' cDNA ends) and S1 nuclease protection experiments that revealed previously unidentified transcription start sites. The 0.22-kb NheI/BglII promoter exhibited PMA inducibility in myeloid cells and contained a PMA-responsive element recognized by Sp1 and EGR-1 transcription factors. Isolation and characterization of the human PECAM-1 promoter represent an initial step in elucidating the controlled expression of the PECAM-1 gene.

Base Sequence↗
PubMedDate not supplied

Activation of major histocompatibility complex class I mRNA containing an Alu-like repeat in polyoma virus-transformed rat cells.

Class I genes of the major histocompatibility complex (MHC) appear to be activated in mouse cells transformed by the DNA tumour virus simian virus 40 (SV40). Conversely, suppression of MHC class I genes has been reported in adenovirus-12-transformed baby kidney rat cells. We have now investigated the expression of genes encoded by the rat MHC locus in rat fibroblast cells transformed by polyoma virus (Py). Using a mouse genomic H-2 clone as a probe in Northern transfer hybridization analysis, we have observed a high level of expression of rat MHC class I messenger RNA in all the transformed rat cell lines analysed. The class I 1.6-kilobase (kb) mRNA activated in Py-transformed rat cells appears to contain an Alu-like type II repeat element, as the same 1.6-kb mRNA is detected using either the H-2 class I sequence or a repetitive Alu-like type II element as a probe. High levels of heterogeneous poly(A)+ transcripts of 0.5-0.8 kb are also observed in Py-transformed rat cells using probes containing an Alu-like type II repetitive element.

Animals↗
PubMed2005

Nickel stimulates L1 retrotransposition by a post-transcriptional mechanism.

Sequence studies of the human genome demonstrate that almost half of the DNA is derived from mobile elements. Most of the current retrotransposition activity arises from L1 and the L1-dependent, non-autonomous elements, such as Alu, contributing to a significant amount of genetic mutation and genomic instability. We present data demonstrating that nickel chloride, but not cobalt chloride, is able to stimulate L1 retrotransposition about 2.5-fold. Our data suggest that the stimulation occurs at a post-transcriptional level, possibly during the integration process. The effect of nickel on the cell is highly complex, limiting the determination of the exact mechanism of this stimulation. The observed stimulation of L1 retrotransposition is not due to a general increase in L1 transcription or an increase in the number of genomic nicks caused by nickel, but more likely caused by a decrease in DNA repair activities that influence the downstream events of retrotransposition. Our observations demonstrate the influence of environmental toxicants on human retroelement activity. We present an additional mechanism for heavy-metal carcinogenesis, where DNA damage through mobile element activation must be considered when dealing with genomic damage/instability in response to environmental agents.

Cell Cycle↗
PubMed1981

Direct repeats flank three small nuclear RNA pseudogenes in the human genome.

We previously demonstrated that pseudogenes complementary to the small nuclear RNAs U1, U2 and U3 are dispersed and abundant in the human genome. Here we report that three pseudogenes (U1.101, U2.13 and U3.5) are flanked by perfect short direct repeats of 16 to 19 base pairs. In all three pseudogenes. the upstream direct repeat abuts a DNA sequence corresponding to the 5' end of the mature snRNA; in U2.13 and U3.5, the downstream direct repeat immediately follows the truncated 3' end of the snRNA sequence, whereas in U1.101, the downstream direct repeat is separated from the 3, end of the full-length snRNA sequence by a short A-rich region. We consider the direct repeats to be an indication that these three pseudogenes were created by insertion of snRNA information into a new chromosomal locus. To explain why the upstream repeat abuts a DNA sequence complementary to the 5' end of the mature snRNA, we propose a model for insertion that uses a reverse transcript of the snRNA as an intermediate. Furthermore, we note similarities between the structure of all three pseudogene loci and the Alu family of middle repetitive DNA sequences. These similarities suggest that some Alu family sequences are mobile genetic elements that can transpose to new chromosomal loci using as an intermediate a cDNA copy of an RNA transcribed from the Alu family element by RNA polymerase III.

Animals↗
PubMed2005

Role of poly(A) tail length in Alu retrotransposition.

Alu are mobile noncoding Short INterspersed Elements (SINEs) present at a million copies in the human genome. Using marked Alu sequences in an ex vivo assay, we previously showed that they are mobilized through diversion of the LINE (Long INterspersed Elements) retrotransposition machinery, with the poly(A) tail of the Alu being required for their mobility. Here we show that other homopolymeric tracts cannot functionally replace the Alu poly(A) tail, and that the Alu transposition rate varies over a two-log range depending on the poly(A) tail length. Variation is according to a sigmoid-shaped curve with a lag observed for tails shorter than 15 nt and a plateau reached for tails longer than 50 nt, consistent with the binding of a limited number of a protein component requiring multiple contacts for a productive interaction with the poly(A) stretch. This analysis indicates that most of the naturally occurring genomic Alu, owing to their pA tail length, should be poor substrates for the LINE machinery, a feature possibly "selected" for the host sake.

Alu Elements↗
PubMed2002

A novel approach for identifying candidate imprinted genes through sequence analysis of imprinted and control genes.

Through the sequence analysis of 27 imprinted human genes and a set of 100 control genes we have developed a novel approach for identifying candidate imprinted genes based on the differences in sequence composition observed. The imprinted genes were found to be associated with significantly reduced numbers of short interspersed transposable element (SINE) Alus and mammalian-wide interspersed repeat (MIR) repeat elements, as previously reported. In addition, a significant association between imprinted genes and increased numbers of low-complexity repeats was also evident. Numbers of the Alu classes AluJ and AluS were found to be significantly depleted in some parts of the flanking regions of imprinted genes. A recent study has proposed that there is active selection against SINE elements in imprinted regions. Alternatively, there may be differences in the rates of insertion of Alu elements. Our study indicates that this difference extends both upstream and downstream of the coding region. This and other consistent differences between the sequence characteristics of imprinted and control genes has enabled us to develop discriminant analysis, which can be used to screen the genome for candidate imprinted genes. We have applied this function to a number of genes whose imprinting status is disputed or uncertain.

Female↗
PubMed2002

Molecular genetic characterization of the EWS/CHN and RBP56/CHN fusion genes in extraskeletal myxoid chondrosarcoma.

Extraskeletal myxoid chondrosarcoma (EMC) is a soft-tissue neoplasm cytogenetically characterized by the translocations t(9;22)(q22;q11-12) or t(9;17)(q22;q11), generating EWS/CHN or RBP56/CHN fusion genes, respectively. In the present study, 18 EMCs were studied both cytogenetically and at the molecular level. Chromosomal aberrations were detected in 16 samples: 13 with involvement of 9q22 and 22q11-12, and three with rearrangements of 9q22 and 17q11. Fifteen cases had an EWS/CHN fusion transcript and three had an RBP56/CHN transcript. The most frequent EWS/CHN transcript (type 1; 10 tumors), involved fusion of EWS exon 12 with CHN exon 3, and the second most common (type 5; two cases) was fusion of EWS exon 13 with CHN exon 3. In all tumors with RBP56/CHN fusion, exon 6 of RBP56 was fused to exon 3 of CHN. By genomic XL PCR and sequence analyses, the breakpoints from 14 cases were mapped in the EWS, RBP56, and CHN genes. In CHN, 12 breakpoints were found in intron 2 and only two in intron 1. In EWS, the breaks occurred in introns 7 (one break), 12 (eight breaks), and 13 (one break), and in RBP56 in intron 6. Repetitive elements such as Alu and LINE sequences seem to have limited, if any, importance in the genesis of EWS/CHN and RBP56/CHN chimeras. Furthermore, there were no chi, chi-like, topoisomerase II, or translin consensus sequences in the introns harboring the translocation breakpoints, nor could the number of topo I sites in EWS, RBP56, and CHN introns explain the uneven distribution of the breakpoints among EWS or CHN introns. Additional genetic events, such as nucleotide insertions, homologies at the junction, deletions, duplications, and inversions, were found to accompany the translocations, indicating that the chromosomal translocations do not require sequence-specific recombinases or extensive homology between the recombined sequences.

Adult↗
PubMed1990

Tumour-induced host stromal-cell transformation: induction of mouse spindle-cell fibrosarcoma not mediated by gene transfer.

Tumour-induced host-cell transformation has been addressed by examining human tumours in situ and following xenograft to nude mice. We have found evidence for the transformation of host stromal fibroblasts both in vivo and following the introduction of the tumours to in vitro culture. The in vitro culture of one such xenograft--derived from a human prostatic adenocarcinoma--resulted in the outgrowth of a transformed aneuploid mouse cell line. This transformed line was tumourigenic both in BALB/c nu/nu (nude) mice and in heterozygous nu/+mice, with the morphology of a spindle-cell sarcoma. The cell line did not express human isozymes or human histocompatibility antigens, nor were human chromosomes present. Moreover, human DNA sequences were not detected by human Alu repeat sequence element probing in the transformed cell line grown either in vitro or in vivo. The line contained retroviral long terminal repeat sequences but there was no evidence of proviral activation. These findings indicate that tumour cells may cause transformation of neighbouring stromal cells; that this transformation may proceed in the absence of DNA transfer or activation of endogenous proviruses; and that the means of this observed transformation may involve humoral factors elaborated by the tumour cells.

Adenocarcinoma↗
PubMed1996

Novel heterogeneity exists in the 5'-untranslated region of the beta-galactoside alpha 2,6-sialytransferase mRNAs in the human B-lymphoblastoid cell line, louckes.

Multiple mRNA isoforms are generated from SIAT1, the gene encoding the beta-galactoside alpha 2,6-sialyltransferase (ST6Gal I, SiaT-1, ST6N, alpha 2,6ST). These isoforms are transcriptionally initiated from a number of physically distinct promoter regions. In human B-lymphocytic cells, two SIAT1 mRNA isoforms have been identified. In order to determine if additional SIAT1 mRNA isotypes exist, RNA from Louckes, a human cell line with the mature B-phenotype, was subjected to 5'-RACE analysis. In addition to the two previously characterized mRNA forms, three additional SIAT1 mRNA forms were identified. The new mRNA isoforms incorporate novel sequence blocks into their 5'-UT regions. The data strongly suggest that these novel sequence blocks originate from previously undocumented 5'-noncoding exons and are incorporated into mRNA by alternative splicing events and/or usage of additional transcriptional promoter regions. BLAST analysis reveals no similarity of these novel regions, Exons U, V, and W, to sequences in GenBank. The only exception is Exon V, which contains a portion of Alu, a repetitive element. The data suggest that two of these novel mRNA isotypes are likely to be minor components. However, one form may contribute significantly to the SIAT1 mRNA pool in Louckes cells.

B-Lymphocytes↗
PubMed1993

Fifty sequenced-tagged sites on human chromosome 11.

Fifty novel sequenced-tagged sites (STSs) were identified from cosmid clones mapped to human chromosome 11. DNA sequences were determined for one or both cloning ends of 69 cosmid markers that had each been localized to 1 of 24 subchromosomal regions by means of hybridization to somatic cell hybrid panels. Proper primer sequences and appropriate conditions for a polymerase chain reaction (PCR) were determined for each marker. Twenty-one of the cosmids were not suitable for generating STSs, mainly because both of their ends contained repetitive elements such as Alu and L1 sequences; however, some were inappropriate because the sizes of their PCR products from human DNA, used as template, were same as those from yeast DNA. Finally, 50 STSs were established from 48 clones: 20 were derived from markers localized on the short arm and 30 from the long arm. These STSs can serve as new reagents for investigating human DNA in somatic cell hybrids and for isolating yeast artificial chromosomes to anchor large DNA contigs and fine-scale physical maps of chromosome 11.

Base Sequence↗
PubMed1994

The human microsomal epoxide hydrolase gene (EPHX1): complete nucleotide sequence and structural characterization.

Human microsomal epoxide hydrolase (mEH) is a xenobiotic-metabolizing enzyme that detoxifies reactive epoxides to more water soluble dihydrodiol compounds. We have isolated and sequenced clones that encode the entire human mEH gene (EPHX1). The primary nuclear transcript, extending from the start of transcription to the site of poly(A) addition, is 20,271 nucleotides in length. The human mEH gene contains 9 exons, separated by 8 introns; canonical intron/exon boundary sites are observed at each junction. The introns vary in size from 335 to 6696 bp and contain numerous repetitive DNA elements, including 18 Alu sequences (each > 100 nucleotides in length) within 4 introns. Alu sequences were classified with respect to subfamily assignment. Two thousand eighteen nucleotides 5' of the transcription start and 2501 nucleotides 3' of the poly(A) addition sites were also sequenced. To evaluate the human mEH promoter, chimeric constructs were prepared linking portions of the 5' mEH flanking sequence (up to -693 bp) to a CAT reporter gene, followed by transient transfection in both COS-1. and HepG2 cells. Results from these expression experiments suggest that the human mEH gene contains a weak core promoter and that inclusion of DNA sequences 5' of the minimal promoter region negatively regulates constitutive transcription.

Animals↗
PubMed2001

Three major lineages of Asian Y chromosomes: implications for the peopling of east and southeast Asia.

DNA variation on the non-recombining portion of the Y chromosome was examined in 610 male samples from 14 global populations in north, east, and southeast Asia, and other regions of the world. Eight haplotypes were observed by analyses of seven biallelic polymorphic markers ( DYS257(108), DYS287, SRY(4064), SRY(10831), RPS4Y(711), M9, and M15) and were unevenly distributed among the populations. Maximum parsimony tree for the eight haplotypes showed that these haplotypes could be classified into four distinct lineages characterized by three key mutations: an insertion of the Y Alu polymorphic (YAP) element at DYS287, a C-to-G transversion at M9, and a C-to-T transition at RPS4Y(711). Of the four lineages, three major lineages (defined by the allele of YAP(+), M9-G, and RPS4Y-T, respectively) accounted for 98.6% of the Asian populations studied, indicating that these three paternal lineages have contributed to the formation of modern Asian populations. Moreover, phylogenetic analysis revealed three monophyletic Asian clusters, which consisted of north Asian, Japanese, and Han Chinese/southeast Asian populations, respectively. Coalescence analysis in the haplotype tree showed that the estimated ages for three key mutations ranged from 53,000 to 95,000 years, suggesting that the three lineages were separated from one another during early stages of human evolutionary history. The distribution patterns of the Y-haplotypes and mutational ages for the key markers suggest that three major groups with different paternal ancestries separately migrated to prehistoric east and southeast Asia.

Asia↗
PubMed1997

Y chromosome polymorphisms in native American and Siberian populations: identification of native American Y chromosome haplotypes.

We have initiated a study of ancient male migrations from Siberia to the Americas using Y chromosome polymorphisms. The first polymorphism examined, a C-->T transition at nucleotide position 181 of the DYS199 locus, was previously reported only in Native American populations. To investigate the origin of this DYS199 polymorphism, we screened Y chromosomes from a number of Siberian, Asian, and Native American populations for this and other markers. This survey detected the T allele in all five Native American populations studied at an average frequency of 61%, and in two of nine native Siberian populations, the Siberian Eskimo (21%) and the Chukchi (17%). This finding suggested that the DYS199 T allele may have originated in Beringia and was then spread throughout the New World by the founding populations of the major subgroups of modern Native Americans. We further characterized Native American Y chromosome variation by analyzing two additional Y chromosome polymorphisms, the DYS287 Y Alu polymorphic (YAP) element insertion and a YAP-associated A-->G transition at DYS271, both commonly found in Africans. We found neither African allele associated with the DYS199 T allele in any of the Native American or native Siberian populations. However, we did find DYS287 YAP+ individuals who harbored the DYS199 C allele in one Native American population, the Mixe, and in one Asian group, the Tibetans. A correlation of these Y chromosome alleles in Native Americans with those of the DYS1 locus, as detected by the p49a/p49f (p49a,f) probes on TaqI-digested genomic DNA, revealed a complete association of DYS1 alleles (p49a,f haplotypes) 13, 18, 66, 67 and 69 with the DYS199 T allele, while DYS1 alleles 8 and 63 were associated with both the DYS199 C and T allele.

Asia↗
PubMed1994

Ketoconazole and 25-hydroxycholesterol produce reciprocal changes in the rate of transcription of the human LDL receptor gene.

Sterol-dependent regulation of low-density lipoprotein (LDL) receptor gene expression was studied in the human hepatoma HepG2 cell line. Incubation of HepG2 cells with 20 microM ketoconazole increased the level of LDL receptor mRNA. After a lag of approx. 1.0 h the level rose 6.5-fold within 8.0 h and remained elevated for up to 24 h. Incubation with 10 micrograms 25-hydroxycholesterol/ml for 24 h produced a 40-50% reduction in the level of LDL receptor mRNA. Ketoconazole- and 25-hydroxycholesterol-induced changes in LDL receptor mRNA accumulation were due to alterations in the relative rate of LDL receptor gene transcription as measured by nuclear run-on transcription. Incubation with 20 microM ketoconazole for 4 h or 10 micrograms 25-hydroxycholesterol/ml for 24 h produced a 3.6-fold increase and a 40% reduction, respectively, in the transcription rate of LDL receptor gene. Removal of the Alu-like sequence elements within the LDL receptor cDNA was required to consistently measure changes in LDL receptor gene transcription. No significant changes were noted in the half-life of LDL receptor mRNA in ketoconazole or 25-hydroxycholesterol-treated cells. These data demonstrate that sterol-dependent changes in the level of LDL receptor mRNA can be completely accounted for by changes in the rate of LDL receptor gene transcription.

Base Sequence↗
PubMed1989

Control of expression of the human glutathione S-transferase pi gene differs from its rat orthologue.

We have examined regulation of the glutathione S-transferase pi gene by transient expression assay, and find that a fragment from 8 to 99 bp upstream of the cap site promotes transcription, but there is no evidence for any enhancer activity in a further 6 kb of flanking sequence. Analysis of this sequence by reference to a primate sequence database and Southern blotting revealed that as much as 5 kb of this flanking DNA were composed of repetitive insertion elements including an Alu and a LINE 1 repeat. The promoter fragment has been sequenced (Cowell et al (1988) Biochem. J. 255, 79-83) and contains a consensus AP1 binding site; in some cases, these have been associated with transcriptional induction by phorbol esters and ras oncogenes. We measured the steady state levels of glutathione S-transferase pi mRNA in human cell lines which were known to express ras oncogenes and compared them to human cell lines which have not been identified with ras activation. There was no correlation between expression of activated ras and expression of glutathione S-transferase pi mRNA. Treatment of HeLa cells, HepG2 cells and a small cell lung carcinoma line, GLC 8, with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate failed to alter the steady state levels of endogenous glutathione S-transferase pi mRNA. The differences between these results and those of similar studies on rat glutathione S-transferase subunit 7, a structural orthologue of glutathione S-transferase pi, are discussed.

Animals↗
PubMed1992

Extrachromosomal human immunodeficiency virus type 1 sequences are methylated in latently infected U937 cells.

Long-term human immunodeficiency virus type 1 (HIV-1) infection of the human monocytic cell line U937 resulted in a progressive loss of infectivity that was correlated with the accumulation of stable, extrachromosomal forms of viral DNA. Viral latency was also characterized by reduced levels of HIV-1 transcription. The structure and activity of extrachromosomal viral DNA (E-DNA) in a fully latent U937 cell line was investigated by molecular cloning and DNA transfection. The resulting 18-kb E-DNA clone was composed of an intact HIV-1 sequence flanked by 7 kb of host sequence to one side and 1 kb of host DNA to the other side. This configuration is the result of retroviral integration into a highly repetitive element of the Alu family. Transfection of the E-DNA clone resulted in the production of infectious virus, indicating that viral latency was not the result of mutations in the HIV-1 genome. Analysis of CCGG sites revealed extensive de novo methylation of viral sequences present within E-DNA. These results suggest that modification of extrachromosomal viral DNA sequences is a mechanism for HIV-1 latency in long-term infected U937 cells.

Base Sequence↗