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PubMed1994

Generation and characterization of an ordered lambda clone array for the 460-kb region surrounding the murine Xist sequence.

The Xist sequence has several characteristics that make it a potential candidate for the X-inactivation center. To investigate the role of Xist and adjacent sequences lying within the X-inactivation center candidate region, a 460-kb region surrounding the murine Xist sequence has been arrayed in lambda contigs with a combination of IRS-PCR-based hybridization and YAC fragmentation. The orientation of the Xist sequence in relation to the telomere and centromere of the X Chromosome (Chr) has been established with this contig and shown to be inverted compared to that in human.

Animals↗
PubMed1994

A new polymorphic and multicopy MHC gene family related to nonmammalian class I.

We have used genomic analysis to characterize a region of the central major histocompatibility complex (MHC) spanning approximately 300 kilobases (kb) between TNF and HLA-B. This region has been suggested to carry genetic factors relevant to the development of autoimmune diseases such as myasthenia gravis (MG) and insulin dependent diabetes mellitus (IDDM). Genomic sequence was analyzed for coding potential, using two neural network programs, GRAIL and GeneParser. A genomic probe, JAB, containing putative coding sequences (PERB11) located 60 kb centromeric of HLA-B, was used for northern analysis of human tissues. Multiple transcripts were detected. Southern analysis of genomic DNA and overlapping YAC clones, covering the region from BAT1 to HLA-F, indicated that there are at least five copies of PERB11, four of which are located within this region of the MHC. The partial cDNA sequence of PERB11 was obtained from poly-A RNA derived from skeletal muscle. The putative amino acid sequence of PERB11 shares approximately 30% identity to MHC class I molecules from various species, including reptiles, chickens, and frogs, as well as to other MHC class I-like molecules, such as the IgG FcR of the mouse and rat and the human Zn-alpha 2-glycoprotein. From direct comparison of amino acid sequences, it is concluded that PERB11 is a distinct molecule more closely related to nonmammalian than known mammalian MHC class I molecules. Genomic sequence analysis of PERB11 from five MHC ancestral haplotypes (AH) indicated that the gene is polymorphic at both DNA and protein level. The results suggest that we have identified a novel polymorphic gene family with multiple copies within the MHC.

Adult↗
PubMed1994

Xist is expressed in female embryonal carcinoma cells with two active X chromosomes.

The Xist gene resides on the X chromosome and is expressed in female but not male somatic cells. In female cells, only the Xist allele on the inactive X chromosome is transcribed. We investigated the expression of Xist in diploid P10 female embryonal carcinoma cells that have two active X chromosomes. Xist RNA was present in these P10 cells. The X chromosomes in P10 cells carry different Xist alleles whose transcripts can be distinguished by restriction digestion of their cDNAs. Both alleles were expressed. Clones of P10 cells that had lost an X chromosome did not express Xist from the remaining allele. Thus Xist is expressed in cultured cells developmentally arrested prior to X chromosome inactivation, indicating that the Xist transcript is not always derived from an inactive X chromosome. Therefore, Xist expression per se cannot be a sufficient signal to inactivate an X chromosome.

Alleles↗
PubMed1995

The XIST locus replicates late on the active X, and earlier on the inactive X based on FISH DNA replication analysis of somatic cell hybrids.

We have recently reported results of DNA replication analysis of three X-linked loci (FRAXA, F8C and XIST) on the X chromosomes in male and female fibroblasts using fluorescence in situ hybridization (FISH) (1). Although our findings that XIST replicates later on the active X than on the inactive X are similar to those of Boggs & Chinault (2) based on a FISH assay in female lymphoblasts, they are the opposite of observations recently reported by Hansen et al. (3) using a different technique. Because our conclusions about the inactive X were deduced from the behavior of the active X in male cells, we reexamined the time when these loci replicate on the human inactive X chromosome isolated from its homolog in somatic cell hybrids. We also studied the same chromosome as an active X in related hybrids. The results provide direct evidence that the expressed XIST locus on the inactive X replicates earlier than its repressed homolog on the active X and earlier than the FRAXA locus which is repressed on this chromosome. The silent XIST locus on the active X replicates late along with F8C which is also not transcribed in these cells. Possible reasons for the different results obtained by Hansen et al. (3) are discussed.

Animals↗
PubMed1996

The human/mouse imprinted genes IGF2, H19, SNRPN and ZNF127 map to two conserved autosomal clusters in a marsupial.

The four genes IGF2, H19, SNRPN and ZNF127 are imprinted in mouse and human. IGF2 and H19 form one conserved cluster on the distal part of mouse chromosome 7 and human chromosome 11p15.5, whereas SNRPN and ZNF127 form another on the middle of mouse chromosome 7 and on human chromosome 15q11-13. We have explored the evolution of these imprinted regions by cloning and mapping IGF2, H19, SNRPN and ZNF127 homeologues in marsupials. Specifically, we wished to determine whether the arrangements were shared in eutherian and marsupial mammals, and to determine whether they lay on autosomes, or on the X, as might be predicted by the hypothesis that imprinting evolved from X inactivation. Using fluorescence in situ hybridization, we localized the marsupial homeologues of IGF2 and H19 to the distal part of tammar wallaby chromosome 2p and the marsupial homeologues of SNRPN and ZNF127 to the middle of chromosome 1q. Thus, these genes were originally organized in two separate autosomal clusters in the therian ancestor 180 million years ago, the conservation of which may suggest a functional relationship. The autosomal location of these clusters does not suggest a recent evolutionary relationship between imprinting and X chromosome inactivation.

Animals↗
PubMed1999

Genomic imprinting and chromatin insulation in Beckwith-Wiedemann syndrome.

Genes are recognized as undergoing genomic imprinting when they are capable of being expressed only from the paternal or only from the maternal chromosome. The process can occur coordinately within large physical domains in mammalian chromosomes. One interesting facet of the study of genomic imprinting is that it offers insight into the regulation of large chromosomal regions. Understanding this regulation involves elucidating the cis-acting regulators of gene expression and defining the elements that maintain chromatin insulation, both required for understanding more practically applicable areas of biological research, such as efficient transgene production. This review is focused on the regulation of the imprinted domain of human chromosome 11p15.5, responsible for Beckwith-Wiedemann syndrome (BWS). Recent findings indicate that the maintenance of imprinting within this domain is critically dependent on the stable maintenance of chromatin insulation.

Beckwith-Wiedemann Syndrome↗
PubMed1999

Comparison between two human endogenous retrovirus (HERV)-rich regions within the major histocompatibility complex.

Sixteen human endogenous retrovirus (HERV) sequences were detected within 656 kb of genomic sequence obtained from the alpha- and beta-block of the class I region of the major histocompatibility complex (MHC). The HERVs were identified and characterized as family members of HERV-16 (11 copies), HERV-L (1 copy), HERV-I (2 copies), HERV-K91 (1 copy), and HARLEQUIN (1 copy) by sequence comparison using CENSOR or Repeat Masker, BLAST searches, and dot plots. The 11 copies of HERV-16 arose as products of duplication of genomic segments containing HLA class I (HLAcI) and PERB11 (MIC) genes inter alia, whereas the other five HERVs arose after duplication probably as a consequence of single insertion events or translocations. HERV-L and HERV-I are located between the duplicated genes PERB11.2 (MICB) and PERB11.1 (MICA), and HLA-B and HLA-C, respectively, whereas HERV-K91 and HARLEQUIN are located telomeric of HLA-C. A highly fragmented copy of HERV-I was also found telomeric of PERB11. 4. Structural analysis of open reading frames (ORFs) revealed the absence of intact coding sequence within the putative gag, pol, and env gene regions of all the HERVs with the exception of HERV-K91, which had two large ORFs within the region of the putative protease and pol genes. In addition, the 5'-LTR of HERV-L contained a 2.5-kb element that was AT-rich and large ORFs with putative amino acid sequences rich in tyrosines and isoleucines. HERV-I, HARLEQUIN, and at least four copies of HERV-16 appear to have been receptors for the insertion of other retrotransposons including Alu elements and fragments of L1 and THE1. Examination of flanking sequences suggests that HERV-I and HERV-L had occurred by insertion into ancient L1 fragments. This study has revealed that the alpha- and beta-block region within the MHC is rich in HERV sequences occurring at a much higher ratio (10 to 1) than normally observed in the human genome. These HERV sequences will therefore enhance further studies on disease associations and differences between human haplotypes and primates and their role in the evolution of class I genes in the MHC.

Amino Acid Sequence↗
PubMed1999

Coevolution of PERB11 (MIC) and HLA class I genes with HERV-16 and retroelements by extended genomic duplication.

The recent availability of genomic sequence information for the class I region of the MHC has provided an opportunity to examine the genomic organization of HLA class I (HLAcI) and PERB11/MIC genes with a view to explaining their evolution from the perspective of extended genomic duplications rather than by simple gene duplications and/or gene conversion events. Analysis of genomic sequence from two regions of the MHC (the alpha- and beta-blocks) revealed that at least 6 PERB11 and 14 HLAcI genes, pseudogenes, and gene fragments are contained within extended duplicated segments. Each segment was searched for the presence of shared (paralogous) retroelements by RepeatMasker in order to use them as markers of evolution, genetic rearrangements, and evidence of segmental duplications. Shared Alu elements and other retroelements allowed the duplicated segments to be classified into five distinct groups (A to E) that could be further distilled down to an ancient preduplication segment containing a HLA and PERB11 gene, an endogenous retrovirus (HERV-16), and distinctive retroelements. The breakpoints within and between the different HLAcI segments were found mainly within the PERB11 and HLA genes, HERV-16, and other retroelements, suggesting that the latter have played a major role in duplication and indel events leading to the present organization of PERB11 and HLAcI genes. On the basis of the features contained within the segments, a coevolutionary model premised on tandem duplication of single and multipartite genomic segments is proposed. The model is used to explain the origins and genomic organization of retroelements, HERV-16, DNA transposons, PERB11, and HLAcI genes as distinct segmental combinations within the alpha- and beta-blocks of the human MHC.

Alu Elements↗
PubMed1998

X chromosome inactivation and the Xist gene.

Recent years have seen rapid progress towards understanding the molecular mechanisms involved in X chromosome inactivation (X inactivation). This progress has largely revolved around the discovery of the X inactive specific transcript (Xist) gene, which is known now to represent the master switch locus regulating X inactivation. In adult cells Xist is transcribed exclusively from the inactive X chromosome. The transcript has no apparent protein-coding potential and is retained in the nucleus in close association with the domain occupied by the inactive X chromosome. It is thus thought to represent a functional RNA molecule which acts as the primary signal responsible for the propagation of X inactivation. Developmental regulation of Xist correlates with the developmental timing of X inactivation. Recent results have demonstrated that Xist is both necessary and sufficient for X inactivation. Goals for the future are to understand the mechanism of Xist regulation which underlies the establishment of appropriate X inactivation patterns and to determine how Xist RNA participates in the process of propagating inactivation in cis.

Animals↗
PubMed2006

Loss of imprinting of the insulin-like growth factor 2 and the H19 gene in testicular seminomas detected by real-time PCR approach.

IGF2 and H19 are imprinted genes in normal human tissue, but many studies have observed a loss of imprinting (LOI) of these genes in tumors as an epigenetic alteration of the DNA, that leads to a biallelic expression predisposing cells to carcinogenesis and tumor growth. The aim of this study was to test the reliability of LightCycler-assisted Real-time PCR in detecting LOI of IGF2 and H19 in 39 patients with testicular germ cell tumors by comparing these results with the analysis generated by the golden standard restriction fragment length polymorphism (RFLP). With LightCycler-assisted Real-time PCR for IGF2 44% and for H19 49% of the patients were found to be heterozygous. This was consistent with the results obtained by RFLP, but surprisingly RFLP failed in more than 7% of the patients. In detecting LOI (for IGF2 in 41% and for H19 in 68% of the informative patients) the approach by RFLP was superior, since the results derived from LightCycler-assisted Real-time PCR showed reliable results in 76 and 10% of the samples concerning IGF2 and H19, respectively. Again, no discrepancy between the results obtained by the two methods occurred. In sum, LightCycler-assisted Real-time PCR is a sufficiently working approach for the rapid and reliable detection of heterozygosity of IGF2 or H19 gene and identification of LOI of IGF2 and thus may be helpful in conducting large epidemiological studies. However, for the identification of LOI of the H19 gene in this cohort it possesses only restrictive use.

Cohort Studies↗
PubMed2004

Comparative genetics of functional trinucleotide tandem repeats in humans and apes.

Several human neurodegenerative disorders are caused by the expansion of polymorphic trinucleotide repeat regions. Many of these loci are functional short tandem repeats (STRs) located in brain-expressed genes, and their study is thus relevant from both a medical and an evolutionary point of view. The aims of our study are to infer the comparative pattern of variation and evolution of this set of loci in order to show species-specific features in this group of STRs and on their potential for expansion (therefore, an insight into evolutionary medicine) and to unravel whether any human-specific feature may be identified in brain-expressed genes involved in human disease. We analyzed the variability of the normal range of seven expanding STR CAG/CTG loci (SCA1, SCA2, SCA3-MJD, SCA6, SCA8, SCA12, and DRPLA) and two nonexpanding polymorphic CAG loci (KCNN3 and NCOA3) in humans, chimpanzees, gorillas, and orangutans. The study showed a general conservation of the repetitive tract and of the polymorphism in the four species and high heterogeneity among loci distributions. Humans present slightly larger alleles than the rest of species but a more relevant difference appears in variability levels: Humans are the species with the largest variance, although only for the expanding loci, suggesting a relationship between variability levels and expansion potential. The sequence analysis shows high levels of sequence conservation among species, a lack of correspondence between interruption patterns and variability levels, and signs of conservative selective pressure for some of the STR loci. Only two loci (SCA1 and SCA8) show a human specific distribution, with larger alleles than the rest of species. This could account, at the same time, for a human-specific trait and a predisposition to disease through expansion.

Analysis of Variance↗
PubMed1997

Allelic and interlocus comparison of the PERB11 multigene family in the MHC.

The major histocompatibility complex (MHC) contains at least a hundred genes over 4 megabases of DNA. Within the MHC there are several new multigene families which have been recently described. PERB11 is a multigene family which occurs over the class I and central region of the MHC. Two members of the family have been shown to be functional and share domains with members of the supergene family including HLA class I, FcRn, and Zn-alpha2-glycoprotein molecules. The two functional members are contained within an area of the MHC which has been associated with increased susceptibility to autoimmune diseases such as insulin-dependent diabetes mellitus and also rapid progression to AIDS following HIV-1 infection. Intralocus and interlocus differences between PERB11.1 and PERB11.2 include: (1) several nucleotide substitutions leading to amino acid changes; (2) presence and absence of potential glycosylation sites; (3) insertions and deletions leading to a frame shift resulting in diversity at the amino acid level and an early termination signal. There are ten different alleles of PERB11.1 including one allele which contains a frame shift in the transmembrane region causing a putative truncated molecule lacking the cytoplasmic tail. The significance of this polymorphism in disease associations is under investigation. The most divergent domain is the transmembrane region when PERB11.1 and PERB11.2 are compared. The results suggest that these two molecules may have different functions.

Alleles↗
PubMed1999

The P5 multicopy gene family in the MHC is related in sequence to human endogenous retroviruses HERV-L and HERV-16.

P5 is believed to be a multicopy gene family with at least eight members restricted to the major histocompatibility complex (MHC). Although the function of P5 genes is not known, one of the family members, P5-1, was found previously to be specifically transcribed in lymphoid cells and tissue. In this study, we used computer programs Censor and RepeatMasker, and dot plot analysis to show that the major P5 family members are related in sequence to human endogenous retroviruses, HERV-L and HERV-16. The P5-HERV sequences have at least 60% sequence identity with HERV-L within the pol region but differ significantly within the gag and LTR regions. The LTRs flanking the P5-HERV sequences share about 70% identity with the repeat element LTR16B. Structural analysis of open reading frames (ORFs) confirmed that the P5-1 cDNA is characterized by many stop codons and short putative coding regions resembling the patterns found in the HERV-L nucleotide sequence rather than those found in an mRNA sequence such as expressed by HLA class I genes. A 159 base pair (bp) ORF at the 5' end of the 2535 bp P5-1 mRNA may code for a peptide of 52 amino acids with a domain identical in sequence to the signal peptide of HLA molecules. Furthermore, the P5-1 mRNA is complementary in sequence to retroviral pol mRNA. Therefore, the P5-1 genomic sequence appears to be an example of an HERV within the MHC that expresses an antisense transcript with a possible role in immunity to retrovirus infection.

Amino Acid Sequence↗
PubMed2001

Infection of synoviocytes with HTLV-I induces telomerase activity.

To investigate the mechanism of synovial hyperplasia by human T-lymphotropic virus type I (HTLV-I) infection, the enzymatic activity of telomerase and expression of telomerase-related factors in HTLV-I infected synoviocytes were examined. Cultured synoviocytes obtained from four patients with osteoarthritis (OA) and four with traumatic joint disease (TJD) were infected by HTLV-I. Telomerase activity was detected by telomeric repeat amplification protocol (TRAP) assay. Expression of telomerase-related mRNAs such as telomerase reverse transcriptase (hTERT), telomerase RNA component (hTERC), and telomeric repeat binding factor 2 (TRF2) were also examined. Telomerase activity was detected in all HTLV-I-infected synoviocytes but not in uninfected synoviocytes. A remarkable induction of hTERT mRNA was observed in four of eight HTLV-I-infected synoviocytes, whereas expressions of hTERC, TRF2, and TEP-1 mRNAs were not changed. Our results clearly demonstrate that HTLV-I upregulates telomerase activity in synoviocytes probably via upregulation of hTERT activity. These findings suggest that telomerase activation in synoviocytes has an important role in upregulated proliferative activity of HAAP synoviocytes.

Carrier Proteins↗
PubMed2002

Inheritance patterns of maternal alleles in imprinted regions of the mouse genome at different stages of development.

Deviations from Mendelian 1:1 transmission ratio have been observed in mice and humans. With few exceptions, the mechanism leading to transmission-ratio distortion (TRD) remains obscure. We proposed that a genomic imprinting mechanism plays a key role in the genesis of grandparental origin-dependent TRD (Naumova et al. 2001). To further test this hypothesis, we analyzed the transmission of grandparental alleles at three imprinted regions of the mouse genome known to contain genes required for embryo development. We found and replicated moderate (58%: 42%) TRD in favor of grandmaternal alleles in the imprinted region of maternal distal Chromosome (Chr) 12 among female offspring. Comparison of transmission ratios at the distorted region of Chr 12 among 3-week-old mice with those in embryos suggests that the distortion in favor of grandmaternal alleles is owing to postimplantation embryo loss. The absence of grandparental origin-dependent TRD for maternal Chr 6 and 7 implies that the relationship between TRD and imprinting is complex. Most likely, multiple conditions are required for TRD to occur.

Alleles↗
PubMed2002

Comparative sequence analysis of the INS-IGF2-H19 gene cluster in pigs.

IGF2 is the major candidate gene for a paternally expressed Quantitative Trait Locus (QTL) in the pig primarily affecting muscle development. Here we report two sequence contigs together comprising almost 90 kb containing the INS-IGF2 and H19 genes. A comparative sequence analysis of the pig, human, and mouse genomic sequences was conducted to identify the exon/intron organization, all promoters, and other evolutionarily conserved elements. RT-PCR analysis showed that IGF2 transcripts originated from four different promoters and included various combinations of seven untranslated exons together with three coding exons, in agreement with previous findings in other mammals. The observed sequence similarity in intronic and intragenic regions among the three species is remarkable and is most likely explained by the complicated regulation of imprinting and expression of these genes. The general trend was, as expected, a higher sequence similarity between human and pig than between these species and the mouse, but a few exceptions to this rule were noted. This genomic region exhibits several striking features, including a very high GC content, many CpG islands, and a low amount of interspersed repeats. The high GC and CpG content were more pronounced in the pig than in the two other species. The results will facilitate the further characterization of this important QTL in the pig.

Animals↗