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PubMed1991

Diverse gene sequences are overexpressed in werner syndrome fibroblasts undergoing premature replicative senescence.

Genes that play a role in the senescent arrest of cellular replication are likely to be overexpressed in human diploid fibroblasts (HDF) derived from subjects with Werner syndrome (WS) because these cells have a severely curtailed replicative life span. To identify some of these genes, a cDNA library was constructed from WS HDF after they had been serum depleted and repleted (5 days in medium containing 1% serum followed by 24 h in medium containing 20% serum). Differential screening of 7,500 colonies revealed 102 clones that hybridized preferentially with [32P]cDNA derived from RNA of WS cells compared with [32P]cDNA derived from normal HDF. Cross-hybridization and partial DNA sequence determination identified 18 independent gene sequences, 9 of them known and 9 unknown. The known genes included alpha 1(I) procollagen, alpha 2(I) procollagen, fibronectin, ferritin heavy chain, insulinlike growth factor-binding protein-3 (IGFBP-3), osteonectin, human tissue plasminogen activator inhibitor type I, thrombospondin, and alpha B-crystallin. The nine unknown clones included two novel gene sequences and seven additional sequences that contained both novel segments and the Alu class of repetitive short interspersed nuclear elements; five of these seven Alu+ clones also contained the long interpersed nuclear element I (KpnI) family of repetitive elements. Northern (RNA) analysis, using the 18 sequences as probes, showed higher levels of these mRNAs in WS HDF than in normal HDF. Five selected mRNAs studied in greater detail [alpha 1(I) procollagen, fibronectin, insulinlike growth factor-binding protein-3, WS3-10, and WS9-14] showed higher mRNA levels in both WS and late-passage normal HDF than in early-passage normal HDF at various intervals following serum depletion/repletion and after subculture and growth from sparse to high-density confluent arrest. These results indicate that senescence of both WS and normal HDF is accompanied by overexpression of similar sets of diverse genes which may play a role in the senescent arrest of cellular replication and in the genesis of WS, normal biological aging, and attendant diseases.

Base Sequence↗
PubMed1998

Isolation of an Alu repetitive DNA binding protein and effect of CpG methylation on binding to its recognition sequence.

The structure, expression, and evolution of Alu repetitive DNA elements have been extensively studied, but the role of these sequences in the function of primate genomes has yet to be elucidated. The contribution of Alu repetitive sequences (ARS) to the structure, maintenance, or expression of the human genome is undoubtedly mediated by one or more DNA binding proteins. As part of a larger study in this laboratory to define the molecular mechanisms that result in de-repression of the glycoprotein hormone alpha-subunit (GPH alpha) gene in a variety of tumor cell types, it was found that the gene was hypermethylated in a variety of cell lines that produce alpha-subunit at high levels and significantly less methylated in cell lines where the gene is unexpressed or expressed at low levels. This is in sharp contrast to the majority of genes examined in this regard, which show an inverse correlation between methylation and expression. The analysis was extended to a group of clones isolated from a single cell line (HeLa) that were differentially methylated over the GPH alpha gene and exhibited a 400-fold range in its expression. These analyses demonstrated that methylation of a small number of CpG dinucleotides correlated with high level expression of the gene. Two of these sites are imbedded in oppositely oriented Alu repeats located in the 5'-flanking DNA and second intron. The upstream site was examined in some detail. DNase I footprint analysis demonstrated that the protein protects a region encompassing the sequence 5'-TTGAACCCGGGAG-3', and electrophoretic gel mobility shift analysis demonstrated specific binding of a protein to an oligonucleotide containing the DNase footprint sequence. Chromatography of nuclear extracts on Sephacryl S-200, heparin--agarose, and oligonucleotide--Sepharose produced an apparently homogeneous preparation of the 50-53 kDa DNA-binding protein as judged by silver staining of sodium dodecylsulfate polyacrylamide gels. The affinity-purified material was enriched 15- to 18,000-fold over crude nuclear extracts. Binding of this protein to an oligonucleotide containing the DNase-protected sequence was severely inhibited when CpG dinucleotide in the Msp I recognition site was methylated on either the sense or antisense strands. Based on its properties, this protein has been termed MeSABp50 for methylation-sensitive Alu binding protein of 50 kDa.

Base Sequence↗
PubMed2000

Cloning, sequencing, and analysis of inv8 chromosome breakpoints associated with recombinant 8 syndrome.

Rec8 syndrome (also known as "recombinant 8 syndrome" and "San Luis Valley syndrome") is a chromosomal disorder found in individuals of Hispanic descent with ancestry from the San Luis Valley of southern Colorado and northern New Mexico. Affected individuals typically have mental retardation, congenital heart defects, seizures, a characteristic facial appearance, and other manifestations. The recombinant chromosome is rec(8)dup(8q)inv(8)(p23.1q22.1), and is derived from a parental pericentric inversion, inv(8)(p23.1q22.1). Here we report on the cloning, sequencing, and characterization of the 8p23.1 and 8q22 breakpoints from the inversion 8 chromosome associated with Rec8 syndrome. Analysis of the breakpoint regions indicates that they are highly repetitive. Of 6 kb surrounding the 8p23.1 breakpoint, 75% consists of repetitive gene family members-including Alu, LINE, and LTR elements-and the inversion took place in a small single-copy region flanked by repetitive elements. Analysis of 3.7 kb surrounding the 8q22 breakpoint region reveals that it is 99% repetitive and contains multiple LTR elements, and that the 8q inversion site is within one of the LTR elements.

Abnormalities, Multiple↗
PubMed1997

Alpha coat protein COPA (HEP-COP): presence of an Alu repeat in cDNA and identity of the amino terminus to xenin.

We previously sequenced the 4333-nucleotide cDNA of the COPA (HEP-COP) gene which encodes the human homologue of the alpha-subunit of the coatomer protein complex, involved in intracellular protein transport. Within the 3' untranslated region at nucleotides 4049-4333 was observed an Alu repeat containing conserved A and B block elements, and showing high homology to the human Alu-Sx subfamily consensus sequence. Upstream of the Alu repeat were noted a TATA box, a CAAT motif and two activating transcription factor (ATF)-like binding sites, which represent putative regulatory elements directing Alu transcription. In addition, the 25 and 35 N-terminal amino acid residues of COPA and its bovine homologue were identical to xenin-25 and proxenin, respectively. Xenin-25 is a gastrointestinal hormone that stimulates exocrine pancreatic secretion. This peptide is related to xenopsin, neurotensin and neuromedin N which are bioactive peptides derived from larger precursors via proteolytic cleavage by cathepsin E at processing sites determined by conserved C-terminal sequences, i.e. proline/valine-X-X-hydrophobic amino acid. Given the conformity of the C-terminal residues of xenin-25 (PWIL) and of its progenitor molecule, proxenin (VIQL), it is proposed that these peptides are generated by a similar mechanism of post-translational modification involving a parent precursor represented by the alpha-subunit of coatomer.

Base Sequence↗
PubMed1996

SINE and LINE within human centromeres.

A number of the Alu and L1 elements present within the centromeric regions of the human chromosomes have been analyzed by polymerase chain reaction amplification. The oligonucleotide primers were homologous to the 3' end consensus sequences of either Alu or L1 in conjunction with an oligonucleotide primer homologous to alphoid sequences specific to different chromosomes. This allowed one to detect an unusual number of Alu and L1 polymorphisms at different loci. It is proposed that this results from molecular rearrangements which occur within the alpha-satellite DNA in which they are embedded (Marçais et al. J. Mol. Evol. 33:42-48, 1991) and not because the centromeric regions are targets for new insertions of such elements. The same analyses were made on cosmids and YACs originating from the centromeric region of chromosome 21 as well as on a collection of somatic hybrids containing chromosome 21 centromere as unique common human genetic material. The results were consistent with the above hypothesis.

Centromere↗
PubMed1998

The construction of cDNA libraries from human single preimplantation embryos and their use in the study of gene expression during development.

PURPOSE: The construction and application of polymerase chain reaction (PCR)-based cDNA libraries from unfertilized human oocytes and single preimplantation-stage embryos are described. The purpose of these studies is to provide a readily available resource for the study of gene expression during human preimplantation development. METHODS: Rapid, reproducible, and efficient procedures for the construction of PCR-based cDNA libraries from fewer than 10 cells were first developed in small populations of fibroblast cells. We then constructed cDNA libraries from eight unfertilized oocytes and single two-cell, -4-cell, -7-cell, and blastocyst-stage embryos. Differential display PCR using the libraries as template allows the analysis of stage-specific expression of embryonic genes. Genomic libraries are also prepared from parental samples (cumulus cells and sperm) corresponding to the individual embryo generating the cDNA library. RESULTS: The complexities (between 10(5) and 10(6) clones) of the human embryo libraries indicate that they may represent the entire active gene population at these early stages of human development. Nucleotide sequence analyses of random clones showed the presence of a variety of transcripts, such as the human transposable element. LINE-1, Alu repeat sequences, housekeeping genes, and tissue-specific genes, (e.g., alpha-globin, FMR-1, and interleukin-10). Also present at the expected frequency are the ubiquitous cytoskeletal elements, beta-actin, keratin-18, and alpha-tubulin. In addition to cDNAs corresponding to known expressed sequence tags (ESTs) in the GenBank and dbEST databases, a high proportion of novel sequences was also detected. Several cDNAs were detected only at specific stages of preimplantation development by the differential display analysis. CONCLUSIONS: PCR-based cDNA libraries from single human preimplantation embryos provide a new and important resource for the identification and study of novel genes or gene families. As such, they will increase our basic understanding of the molecular control of human development. In the clinical context, the libraries identify the time of onset of specific genes, and hence the diseases resulting from mutation of these genes, and provide information about new methods of preimplantation diagnosis. The molecular analysis of early gene transcription in human embryogenesis may be expected to lead to advances in contraception, assisted reproduction, and preimplantation genetic diagnosis.

Blastocyst↗
PubMed1998

Distinctive patterns of histone H4 acetylation are associated with defined sequence elements within both heterochromatic and euchromatic regions of the human genome.

The pattern of histone H4 acetylation in different genomic regions has been investigated by immunoprecipitating oligonucleosomes from a human lymphoblastoid cell line with antibodies to H4 acetylated at lysines 5, 8, 12 or 16. DNA from antibody-bound or unbound chromatin was assayed by slot blotting. Pol I and pol II transcribed genes located in euchromatin were shown to have levels of H4 acetylation at lysines 5, 8 and 12 equivalent to those in input chromatin, but to be slightly enriched in H4 acetylated at lysine 16. In no case did the acetylation level correlate with actual or potential transcriptional activity. All acetylated histone H4 isoforms were depleted in non-coding, simple repeat DNA in heterochromatin, though the extent of depletion varied with the type of heterochromatin and with the isoform. Two single copy genes that map within or adjacent to blocks of paracentric heterochromatin are depleted in H4 acetylated at lysines 5, 8 and 12, but not 16. Consensus sequences of repetitive elements of the Alu family (SINES, enriched in R bands) were associated with H4 that was more highly acetylated at all four lysines than input chromatin, while H4 associated with Kpn I elements (LINES, enriched in G bands) was significantly underacetylated.

Acetylation↗
PubMed1995

Identification of a new subclass of Alu DNA repeats which can function as estrogen receptor-dependent transcriptional enhancers.

We have utilized a genetic selection system in yeast to identify novel estrogen-responsive genes within the human genome and to define the sequences in the BRCA-1 gene responsible for its estrogen responsiveness. This approach led to the identification of a new subclass within the Alu family of DNA repeats which have diverged from known Alu sequences and have acquired the ability to function as estrogen receptor-dependent enhancers. Importantly, these new elements confer receptor-dependent estrogen responsiveness to a heterologous promoter when assayed in mammalian cells. This transcriptional activity can be attenuated by the addition of either of three different classes of estrogen receptor antagonists, indicating that these elements function as classical estrogen receptor-dependent enhancers. Furthermore, this enhancer activity is restricted to a specific subset of DNA repeats because consensus Alu elements of four major subfamilies do not respond to the estrogen receptor. Previously, most Alu sequences have been considered to be functionally inert. However, this work provides strong evidence that a significant subset can confer estrogen responsiveness upon a promoter within which they are located. Clearly, Alu sequences must now be considered as important contributors to the regulation of gene transcription in estrogen receptor-containing cells.

Animals↗
PubMed1999

Phylogenetic affinities of tarsier in the context of primate Alu repeats.

Related genomes tend to be colonized by the same or similar repetitive sequence elements. Analysis of these elements provides useful taxonomic information. We have sequenced Alu repeats from tarsier and compared them with those from strepsirhine prosimians (lemurs, sifaka, and galago) and the human genome. Tarsier elements cluster with Alu subfamilies from the human lineage. The oldest subfamily in tarsier and the most abundant human subfamilies share an RNA secondary structure motif which is absent both in the earliest dimeric Alu Jo and in the strepsirhine elements. These findings are consistent with the view that tarsiers form a sister clade with anthropoides rather than with other prosimians. Alu repeats in tarsier genome are relatively old, which indicates a dramatic slowdown or even an arrest of these elements' amplification about 20 Myr ago.

Alu Elements↗
PubMed1994

Alu transcripts: cytoplasmic localisation and regulation by DNA methylation.

Full length Alu transcripts in HeLa cells are detected by primer extension using reverse transcriptase and are also analyzed as cloned cDNA sequences. The 5' end of these transcripts corresponds to the transcriptional start site for RNA polymerase III indicating that these RNAs are transcribed from their internal polymerase III promoters. The Alu transcripts found in cytoplasmic poly A+ RNAs appear to be organized into RNPs as assayed by sucrose gradient sedimentation. Present at about one hundred to one thousand copies per cell, the Alu transcripts are rare as compared to 7SL RNA. In agreement with previous reports that methylation inhibits Pol III-directed transcription of Alu in vitro, treatment of HeLa cells with 5-azacytidine results in Alu DNA hypomethylation and an increase in the abundance of the Alu transcript. Sequence analysis shows that many different Alu repeats including members of all subfamilies are transcribed by Pol III in vivo. cDNA sequences of the Pol III-directed transcripts exactly match the A box of the Pol III promoter element whereas in other Alu transcripts this element is not faithfully conserved.

Azacitidine↗
PubMed1990

Transcription and replication silencer element is present within conserved region of human Alu repeats interacting with nuclear protein.

Human cells contain a nuclear protein interacting with Alu repeats, and this protein seems to recognize a conserved sequence motif, GGAGGC, present within the RNA polymerase III promoter and within the SV40 T-antigen-dependent ARS-like element. To study the potential functional role of this element, we have inserted the sequence into a chloramphenicolacetyltransferase (CAT) expression vector with a SV40 promoter and enhancer element from the up-stream region of the human c-myc gene, and transfected HeLa cells with the resulting plasmid. Analysis of expression by the CAT assay indicates that the Alu-derived sequence supresses transcription of the CAT gene driven by the c-myc enhancer/SV40 promoter. The Alu-derived sequence also inhibits ARS activity of the c-myc enhancer. The data allow the explanation of the transcriptional inactivity of Alu repeats in HeLa cells, and suggest the existence of a negative control of Alu transcription.

DNA Replication↗
PubMed1998

Stabilization and cytoskeletal-association of LDL receptor mRNA are mediated by distinct domains in its 3' untranslated region.

The mRNA encoding the human low density lipoprotein (LDL) receptor is transiently stabilized after phorbol ester treatment of HepG2 cells and has been shown to associate with components of the cytoskeleton in this cell line (G. M. Wilson, E. A. Roberts, and R. G. Deeley, J. Lipid Res. 1997. 38: 437-446). Using an episomal expression system, fragments of the 3' untranslated region (3'UTR) of LDL receptor mRNA were transcribed in fusion with the coding region of beta-globin mRNA in HepG2 cells. Analyses of the decay kinetics of these beta-globin-LDL receptor fusion mRNA deletion mutants showed that sequences in the proximal 3'UTR of LDL receptor mRNA including several AU-rich elements (AREs) were sufficient to confer short constitutive mRNA half-life in the heterologous system. Stabilization of LDL receptor mRNA in the presence of PMA required sequences in the distal 3'UTR, at or near three Alu-like repetitive elements. Furthermore, the 3'UTR of LDL receptor mRNA conferred cytoskeletal association on the otherwise unassociated beta-globin mRNA, by a mechanism involving at least two distinct RNA elements. Comparisons of decay kinetics and subcellular localization of endogenous LDL receptor mRNA and beta-globin-LDL receptor mRNA fusions in HepG2 cells have demonstrated that several cis-acting elements in the receptor 3'UTR contribute to post-transcriptional regulation of receptor expression, and provide further support for involvement of the cytoskeleton in the regulation of LDL receptor mRNA turnover.

Binding Sites↗
PubMed1986

A highly reiterated family of transcribed oligo(A)-terminated, interspersed DNA elements in the genome of Bombyx mori.

A library of low Cot DNA (Cot is the molar concentration of DNA times the incubation time in seconds) from Bombyx mori was used to isolate five independent clones of highly reiterated sequences from the genome of this organism. Sequence analysis revealed that all five clones belong to a single family of repetitive DNA elements, which we have named Bm1, and whose reiteration frequency is approximately 2.3 X 10(4) copies per haploid genome. Probing of a Bombyx genomic library (in lambda phage) with a Bm1 clone reveals that this repetitive sequence is dispersed throughout the genome. The pattern of interspersion was confirmed by Southern blot mapping of a large (270 X 10(3) base-pairs) domain of the chorion locus of Bombyx, where at least 13 independent regions were found to hybridize to Bm1. Four additional Bm1 elements have been sequenced from a 4.8 X 10(3) base-pair genomic fragment containing an early chorion gene. Two of these four elements are bounded by short (4 to 12 base-pairs) direct repeats. The nine Bm1 elements which have been sequenced are greater than 88% homologous to each other, and tend to fall in at least two size classes (253 base-pairs and 450 base-pairs). Seven of the nine Bm1 elements have a short 6 to 10 base-pair oligo(A) sequence at the 3' end. A sequence of about 29 base-pairs at the 3' end, including the oligo(A), shows 86% homology to the equivalent 3'-terminal domain of human Alu family repetitive elements. A 129 base-pair domain at the 5' end of Bm1 shows 66% homology to a Drosophila valine transfer RNA gene; thus the 5' end of Bm1 may contain the split internal RNA polymerase III promoter that is characteristic of most transcribed tRNA-like retroposons. Dot-blot analysis of Bombyx RNA shows that Bm1 DNA is indeed transcribed, and that the transcripts are well-represented in the total RNA of an ovarian-derived permanent cell line and posterior silk glands early in the fifth instar, but are less abundant in the RNA of pupae or silk glands late in the fifth instar.

Animals↗
PubMed1984

Functional insertion of an Alu type 2 (B2 SINE) repetitive sequence in murine class I genes.

The regulation of expression of the family of MHC (major histocompatibility complex) class I genes is complex. Sequence analysis has revealed that class I genes from the H-2D subregion of the MHC (which includes the D and L genes) differ from the class I gene from the H-2K subregion (the K gene) by the insertion of a type 2 Alu-like repetitive element (the murine B2 sequence) within the 3' noncoding region of the D and L genes. The consequence of this insertion in the D and L genes is the introduction of a novel polyadenylation signal, which is preferentially used over the more distal signal, the analog of that found in the K gene. The insertion of the type 2 Alu-like sequence results in a change in the preferred site for endonucleolytic cleavage which is necessary for generating a correct 3' terminus for polyadenylation. The data demonstrate that the type 2 Alu-like sequence has a function; the data also suggest a possible regulatory role of this sequence in the expression of class I genes.

Animals↗
PubMed2006

Identification of distal KIR promoters and transcripts.

A more complete understanding of the transcriptional control of the human and murine class I MHC receptors will help to shed light on the mechanism of selective, stochastic, gene activation that operates in these gene families. Studies of the murine Ly49 class I MHC receptor genes have revealed an important role for distal transcripts originating upstream of the proximal promoter. To date, there have been no reports of distal promoters within the functionally analogous human KIR family of class I MHC receptors. In the current study, reverse transcriptase-polymerase chain reaction (RT-PCR) and RNase protection assays were used to reveal the presence of distal KIR transcripts initiating upstream of the previously characterized proximal KIR promoter. The intergenic promoter elements detected were associated with repetitive elements of the Alu and L1 families. Unlike the proximal KIR promoter, the distal promoter regions were not NK cell-specific. KIR genes expressed in a variegated manner produced a low level of distal transcripts containing a large 5' untranslated region. In contrast, the highly expressed KIR2DL4 gene possessed a higher level of spliced distal transcripts that were capable of producing KIR2DL4 protein. The identification of distal KIR promoter elements suggests that intergenic transcripts may influence the expression of KIR genes.

Cell Line↗
PubMed2004

Severe hemophilia A due to a 1.3 kb factor VIII gene deletion including exon 24: homologous recombination between 41 bp within an Alu repeat sequence in introns 23 and 24.

Partial or complete factor (F)VIII gene deletions are found in about 5% of families with severe hemophilia A. Relatively few deletions have been well characterized and, of these, recombination occurred between either common repeat elements or non-homologous sequences. In evaluating a family with severe hemophilia A, an exon 24 deletion was suspected when no fragment was obtained on attempted PCR amplifications. A combination of the 5' primer of exon 23 and the 3' primer of exon 25 fragments was used with prolonged extension times to amplify a normal 2.9 kb fragment that included exons 23 through 25; the patient's amplified product was 1.6 kb indicating a 1.3 kb deletion. A mixture of normal and patient DNA showed both sized fragments as did that from an obligate carrier. Carrier detection was applied to two women at risk; one was and one was not a carrier. Sequencing the proband's 1.6 kb fragment revealed that a 1328 bp deletion occurred between homologous sequences of 287 and 285 bp in introns 23 and 24, respectively; these share 85% identity. Blast nucleotide search revealed that these represent Alu elements. Comparison with an alignment of each of the two homologous sequences further localized recombination to a 41-bp segment. However, a simple recombination event would not account for the proband's sequence. The most likely explanation is that the homologous recombination was accompanied by incomplete mismatch repair.

Alu Elements↗
PubMed1994

Evolution of secondary structure in the family of 7SL-like RNAs.

Primate and rodent genomes are populated with hundreds of thousands copies of Alu and B1 elements dispersed by retroposition, i.e., by genomic reintegration of their reverse transcribed RNAs. These, as well as primate BC200 and rodent 4.5S RNAs, are ancestrally related to the terminal portions of 7SL RNA sequence. The secondary structure of 7SL RNA (an integral component of the signal recognition particle) is conserved from prokaryotes to distant eukaryotic species. Yet only in primates and rodents did this molecule give rise to retroposing Alu and B1 RNAs and to apparently functional BC200 and 4.5S RNAs. To understand this transition and the underlying molecular events, we examined, by comparative analysis, the evolution of RNA structure in this family of molecules derived from 7SL RNA. RNA sequences of different simian (mostly human) and prosimian Alu subfamilies as well as rodent B1 repeats were derived from their genomic consensus sequences taken from the literature and our unpublished results (prosimian and New World Monkey). RNA secondary structures were determined by enzymatic studies (new data on 4.5S RNA are presented) and/or energy minimization analyses followed by phylogenetic comparison. Although, with the exception of 4.5S RNA, all 7SL-derived RNA species maintain the cruciform structure of their progenitor, the details of 7SL RNA folding domains are modified to a different extent in various RNA groups. Novel motifs found in retropositionally active RNAs are conserved among Alu and B1 subfamilies in different genomes. In RNAs that do not proliferate by retroposition these motifs are modified further. This indicates structural adaptation of 7SL-like RNA molecules to novel functions, presumably mediated by specific interactions with proteins; these functions were either useful for the host or served the selfish propagation of RNA templates within the host genome.

Animals↗
PubMed2006

CpGcluster: a distance-based algorithm for CpG-island detection.

BACKGROUND: Despite their involvement in the regulation of gene expression and their importance as genomic markers for promoter prediction, no objective standard exists for defining CpG islands (CGIs), since all current approaches rely on a large parameter space formed by the thresholds of length, CpG fraction and G+C content. RESULTS: Given the higher frequency of CpG dinucleotides at CGIs, as compared to bulk DNA, the distance distributions between neighboring CpGs should differ for bulk and island CpGs. A new algorithm (CpGcluster) is presented, based on the physical distance between neighboring CpGs on the chromosome and able to predict directly clusters of CpGs, while not depending on the subjective criteria mentioned above. By assigning a p-value to each of these clusters, the most statistically significant ones can be predicted as CGIs. CpGcluster was benchmarked against five other CGI finders by using a test sequence set assembled from an experimental CGI library. CpGcluster reached the highest overall accuracy values, while showing the lowest rate of false-positive predictions. Since a minimum-length threshold is not required, CpGcluster can find short but fully functional CGIs usually missed by other algorithms. The CGIs predicted by CpGcluster present the lowest degree of overlap with Alu retrotransposons and, simultaneously, the highest overlap with vertebrate Phylogenetic Conserved Elements (PhastCons). CpGcluster's CGIs overlapping with the Transcription Start Site (TSS) show the highest statistical significance, as compared to the islands in other genome locations, thus qualifying CpGcluster as a valuable tool in discriminating functional CGIs from the remaining islands in the bulk genome. CONCLUSION: CpGcluster uses only integer arithmetic, thus being a fast and computationally efficient algorithm able to predict statistically significant clusters of CpG dinucleotides. Another outstanding feature is that all predicted CGIs start and end with a CpG dinucleotide, which should be appropriate for a genomic feature whose functionality is based precisely on CpG dinucleotides. The only search parameter in CpGcluster is the distance between two consecutive CpGs, in contrast to previous algorithms. Therefore, none of the main statistical properties of CpG islands (neither G+C content, CpG fraction nor length threshold) are needed as search parameters, which may lead to the high specificity and low overlap with spurious Alu elements observed for CpGcluster predictions.

Algorithms↗