Recent Human-Specific Spreading of a Subtelomeric Domain

Monfouilloux, Sylvaine; Avet-Loiseau, Hervé; Amarger, Valérie; Balazs, Iván; Pourcel, Christine; Vergnaud, Gilles

doi:10.1006/geno.1998.5358

Cited by 43 publications

(45 citation statements)

References 17 publications

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“…The DNF92 sequence (accession number Y13543) not only represents the most distal segment of the proximal subtelomeric region found mainly at chromosomes 1 (1pter), 5 (5qter), 6 (6qter), 8 (8pter) and 17 (17qter) but also is detected at a lower frequency at eight other chromosome ends (Monfouilloux et al, 1998;Der-Sarkissian et al, 2002). This segment is separated from the telomeric tract by the distal subtelomeric region, which spans around 10 kb (Flint et al, 1997;Monfouilloux et al, 1998). As expected, normal fibroblasts displayed a high level of DNF92 methylation (80%) (Figures 2a and c).…”

Section: Resultsmentioning

confidence: 99%

Subtelomeric DNA hypomethylation is not required for telomeric sister chromatid exchanges in ALT cells

et al. 2009

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Most human tumor cells acquire immortality by activating the expression of telomerase, a ribonucleoprotein that maintains stable telomere lengths at chromosome ends throughout cell divisions. Other tumors use an alternative mechanism of telomere lengthening (ALT), characterized by high frequencies of telomeric sister chromatid exchanges (T-SCEs). Mechanisms of ALT activation are still poorly understood, but recent studies suggest that DNA hypomethylation of chromosome ends might contribute to the process by facilitating T-SCEs. Here, we show that ALT/T-SCE high tumor cells display low DNAmethylation levels at the D4Z4 and DNF92 subtelomeric sequences. Surprisingly, however, the same sequences retained high methylation levels in ALT/T-SCE high SV40-immortalized fibroblasts. Moreover, T-SCE rates were efficiently reduced by ectopic expression of active telomerase in ALT tumor cells, even though subtelomeric sequences remained hypomethylated. We also show that hypomethylation of subtelomeric sequences in ALT tumor cells is correlated with genome-wide hypomethylation of Alu repeats and pericentromeric Sat2 DNA sequences. Overall, this study suggests that, although subtelomeric DNA hypomethylation is often coincident with the ALT process in human tumor cells, it is not required for T-SCE.

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Section: Resultsmentioning

confidence: 99%

Subtelomeric DNA hypomethylation is not required for telomeric sister chromatid exchanges in ALT cells

et al. 2009

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“…Over the past decade a large number of both intra-and interchromosomal segmental duplications have been observed (Wong et al 1990;Tomlinson et al 1994;Eichler et al 1997;Mazzarella and Schlessinger 1997;Regnier et al 1997;Zimonjic et al 1997;Eichler 1998;Trask et al 1998a;Jackson et al 1999;Ji et al 1999). These data suggest numerous interchromosomal exchanges during recent hominoid evolution with apparent biases into and between pericentromeric and subtelomeric regions (Eichler et al 1997Monfouilloux et al 1998;Trask et al 1998a;Jackson et al 1999;Horvath et al 2000a). To date, however, no systematic analysis of the genome has been performed to quantify this bias.…”

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confidence: 86%

Segmental Duplications: Organization and Impact Within the Current Human Genome Project Assembly

Bailey¹

2001

Genome Research

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Segmental duplications play fundamental roles in both genomic disease and gene evolution. To understand their organization within the human genome, we have developed the computational tools and methods necessary to detect identity between long stretches of genomic sequence despite the presence of high copy repeats and large insertion-deletions. Here we present our analysis of the most recent genome assembly (January 2001) in which we focus on the global organization of these segments and the role they play in the whole-genome assembly process. Initially, we considered only large recent duplication events that fell well-below levels of draft sequencing error (alignments 90%-98% similar and Ն1 kb in length). Duplications (90%-98%; Ն1 kb) comprise 3.6% of all human sequence. These duplications show clustering and up to 10-fold enrichment within pericentromeric and subtelomeric regions. In terms of assembly, duplicated sequences were found to be over-represented in unordered and unassigned contigs indicating that duplicated sequences are difficult to assign to their proper position. To assess coverage of these regions within the genome, we selected BACs containing interchromosomal duplications and characterized their duplication pattern by FISH. Only 47% (106/224) of chromosomes positive by FISH had a corresponding chromosomal position by BLAST comparison. We present data that indicate that this is attributable to misassembly, misassignment, and/or decreased sequencing coverage within duplicated regions. Surprisingly, if we consider putative duplications >98% identity, we identify 10.6% (286 Mb) of the current assembly as paralogous. The majority of these alignments, we believe, represent unmerged overlaps within unique regions. Taken together the above data indicate that segmental duplications represent a significant impediment to accurate human genome assembly, requiring the development of specialized techniques to finish these exceptional regions of the genome. The identification and characterization of these highly duplicated regions represents an important step in the complete sequencing of a human reference genome.

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“…Sequence analyses indicate that, although the distal and proximal subdomains seem to have evolved independently, frequent exchanges appear to have been taking place between nonhomologous chromosomes (Flint et al 1997a;Mefford et al 2001;Mefford and Trask 2002). Whereas the mechanisms leading to sequence exchange between distal subdomains remain unclear, the dissemination of proximal subtelomeric sequences among nonhomologous chromosome ends may be explained by mechanisms akin to reciprocal translocation processes, in which regions of limited homology could nevertheless be implicated (Monfouilloux et al 1998;Vergnaud 1999).…”

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confidence: 99%

“…Recently, the characterization of particular subtelomeric duplications observed in humans indicated the existence of additional structural boundaries that define discrete regions within the subtelomeric domains (Monfouilloux et al 1998;Vergnaud 1999). Several cosmid probes issued from these regions were alternatively present or absent on a subset of chromosome extremities, thus demonstrating high variability.…”

mentioning

confidence: 99%

“…Several cosmid probes issued from these regions were alternatively present or absent on a subset of chromosome extremities, thus demonstrating high variability. In particular, the most telomeric cosmid probe, carrying minisatellite DNF92 (Monfouilloux et al 1998), was invariably or very frequently observed at some particular locations (referred to as major sites), whereas its presence was quite inconstant at others (minor sites).…”

mentioning

confidence: 99%

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Segmental Polymorphisms in the Proterminal Regions of a Subset of Human Chromosomes

Der-Sarkissian¹,

Vergnaud²,

Borde³

et al. 2002

Genome Res.

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The subtelomeric domains of chromosomes are probably the most rapidly evolving structures of the human genome. The highly variable distribution of large duplicated subtelomeric segments has indicated that frequent exchanges between nonhomologous chromosomes may have been taking place during recent genome evolution. We have studied the extent and variability of such duplications using in situ hybridization techniques and a set of well-defined subtelomeric cosmid probes that identify discrete regions within the subtelomeric domain. In addition to reciprocal translocation and illegitimate recombination events that could explain the observed mosaic pattern of subtelomeric regions, it is likely that homology-based recombination mechanisms have also contributed to the spread of distal subtelomeric sequences among particular groups of nonhomologous chromosome arms. The frequency and distribution of large-scale subtelomeric polymorphisms may have direct implications for the design of chromosome-specific probes that are aimed at the identification of cryptic subtelomeric deletions. Furthermore, our results indicate that the relevance of some of the telomere closures proposed within the present Human Genome Sequence draft are restricted to specific allelic variants of unknown frequencies

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Recent Human-Specific Spreading of a Subtelomeric Domain

Cited by 43 publications

References 17 publications

Subtelomeric DNA hypomethylation is not required for telomeric sister chromatid exchanges in ALT cells

Subtelomeric DNA hypomethylation is not required for telomeric sister chromatid exchanges in ALT cells

Segmental Duplications: Organization and Impact Within the Current Human Genome Project Assembly

Segmental Polymorphisms in the Proterminal Regions of a Subset of Human Chromosomes

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