Instability of Interstitial Telomeric Sequences in the Human Genome

doi:10.1006/geno.2000.6280

Genomics

Volume 68, Issue 2, 1 September 2000, Pages 111-117

https://doi.org/10.1006/geno.2000.6280 Get rights and content

Abstract

The length variability of four human interstitial telomeric sequences (ITs) is described. Three of the ITs contain short telomeric stretches ranging between 53 and 84 bp and are localized in 21q22, 2q31, and 7q36; the fourth IT derives from the subtelomeric domain of chromosome 6p and contains a tract of a few hundred basepairs of exact and degenerate repeats. Using primers flanking the repeats, we amplified the genomic DNA from unrelated individuals and from family members, and we found that all the loci are polymorphic. At the 21q22 IT locus, two equally frequent alleles were found, while the number of alleles at the 2q31, 7q36, and 6pter IT loci was 8, 6, and 4, respectively. Sequence analysis revealed that in the three loci containing short ITs the alleles differ from one another for multiples of the hexanucleotide; it is likely that the mechanism leading to the polymorphism is DNA polymerase slippage. These loci were also unstable in gastric tumor cells characterized by microsatellite instability. At the 6pter IT locus, the four alleles range in length from about 500 to about 700 bp; this variability is probably due to unequal exchange or gene conversion. Our data indicate that stretches of exact internal telomeric repeats can be highly unstable, like microsatellites with shorter units, and that they can be useful polymorphic markers for linkage analysis, for forensic applications, and for the detection of genetic instability in tumors.

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Cited by (51)

Interstitial telomeric sequences in vertebrate chromosomes: Origin, function, instability and evolution
2017, Mutation Research - Reviews in Mutation Research
Citation Excerpt :
This process could explain the formation of few (short) ITSs, like those located at 21q22, 2q31 and 7q36, and the subtelomeric ITSs found at 6pter in the human genome [18,89]. However, the recent evidence reviewed above favors BIR-like mechanisms (like MMBIR) instead of a DNA polymerase slippage process to explain the insertion and expansion of short ITSs in the vertebrate genome [82,87,89]. Besides BIR-like mechanisms, the abovementioned TTI mechanism, recently described in ALT human cancer cells, could also explain the evolutionary origin of ITSs in vertebrate cells [17] (Fig. 3B).
By definition, telomeric sequences are located at the very ends or terminal regions of chromosomes. However, several vertebrate species show blocks of (TTAGGG)n repeats present in non-terminal regions of chromosomes, the so-called interstitial telomeric sequences (ITSs), interstitial telomeric repeats or interstitial telomeric bands, which include those intrachromosomal telomeric-like repeats located near (pericentromeric ITSs) or within the centromere (centromeric ITSs) and those telomeric repeats located between the centromere and the telomere (i.e., truly interstitial telomeric sequences) of eukaryotic chromosomes. According with their sequence organization, localization and flanking sequences, ITSs can be classified into four types: 1) short ITSs, 2) subtelomeric ITSs, 3) fusion ITSs, and 4) heterochromatic ITSs. The first three types have been described mainly in the human genome, whereas heterochromatic ITSs have been found in several vertebrate species but not in humans.
Several lines of evidence suggest that ITSs play a significant role in genome instability and evolution. This review aims to summarize our current knowledge about the origin, function, instability and evolution of these telomeric-like repeats in vertebrate chromosomes.
Expansion of Interstitial Telomeric Sequences in Yeast
2015, Cell Reports
Citation Excerpt :
They are believed to result from the insertions of telomeric repeats during the repair of double-stranded DNA breaks via non-homologous end-joining (NHEJ) (Azzalin et al., 2001; Nergadze et al., 2004), possibly involving telomerase (Nergadze et al., 2007). Like many other microsatellites, s-ITSs are polymorphic in length (Hastie and Allshire, 1989); for instance, their significant length polymorphism has been observed in gastric tumors (Mondello et al., 2000). Cytogenetic analysis has co-localized ITSs with spontaneous and induced chromosome breakage sites in primates (Ruiz-Herrera et al., 2005) and rodents (Musio et al., 1996).
Telomeric repeats located within chromosomes are called interstitial telomeric sequences (ITSs). They are polymorphic in length and are likely hotspots for initiation of chromosomal rearrangements that have been linked to human disease. Using our S. cerevisiae system to study repeat-mediated genome instability, we have previously shown that yeast telomeric (Ytel) repeats induce various gross chromosomal rearrangements (GCR) when their G-rich strands serve as the lagging strand template for replication (G orientation). Here, we show that interstitial Ytel repeats in the opposite C orientation prefer to expand rather than cause GCR. A tract of eight Ytel repeats expands at a rate of 4 × 10⁻⁴ per replication, ranking them among the most expansion-prone DNA microsatellites. A candidate-based genetic analysis implicates both post-replication repair and homologous recombination pathways in the expansion process. We propose a model for Ytel repeat expansions and discuss its applications for genome instability and alternative telomere lengthening (ALT).
Gender and telomere length: Systematic review and meta-analysis
2014, Experimental Gerontology
Citation Excerpt :
The most distal Hinf1/RSA1 recognition site at chromosome Xp/Yp, for instance, is polymorphic, resulting in an apparent increase in the length of this telomere if measured by Southern blotting in this haplotype (Baird et al., 1995). Interstitial telomere repeats are also highly polymorphic due to polymerase template slippage, which can cause either insertion or deletion of hexameric repeat units (Mondello et al., 2000). Both short (Ruiz-Herrera et al., 2008) and long interstitial telomeric repeats are frequent in the human genome, for instance an interstitial repeat at chromosome 22q11 displays length polymorphism ranging from 1 to 4 kb (Samassekou and Yan, 2011).
It is widely believed that females have longer telomeres than males, although results from studies have been contradictory.
We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression.
Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p = 1.00) or cell type (p = 0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error.
Telomere length is longer in females than males, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required.
Endings in the middle: Current knowledge of interstitial telomeric sequences
2008, Mutation Research - Reviews in Mutation Research
Interstitial telomeric sequences (ITSs) consist of tandem repeats of the canonical telomeric repeat and are common in mammals. They are localized at intrachromosomal sites, including those repeats located close to the centromeres and those found at interstitial sites, i.e., between the centromeres and the telomeres. ITSs might originate from ancestral intrachromosomal rearrangements (inversions and fusions), from differential crossing-over or from the repair of double-strand break during evolution. Three classes of ITSs have been described in the human genome, namely, short ITSs, long subtelomeric ITSs and fusion ITSs. The fourth class of ITSs, pericentromeric ITSs, has been found in other species. The function of ITSs can be inferred from the association of heritable diseases with ITS polymorphic variants, both in copy number and sequence. This is one of the most attractive aspects of ITS studies because it leads to new and useful markers for genetic linkage studies, forensic applications, and detection of genetic instability in tumors. Some ITSs also might be hotspots of chromosome breakage, rearrangement and amplification sites, based on the type of clastogens and the nature of ITSs. This study will contribute new knowledge with respect to ITSs’ biology and mechanism, prevalence of diseases, risk evaluation and prevention of related diseases, thus facilitates the design of early detection markers for diseases caused by genomic instability.
Origin of diplochromosomal polyploidy in near-senescent fibroblast cultures: Heterochromatin, telomeres and chromosomal instability (CIN)
2007, Cell Biology International
The near-senescence associated phenomena of increases in cells with chromosomal damage (CIN) and in endopolyploid mitotic cells were analyzed for possible inter-relationships by cytogenetics. Gross chromosomal abnormalities in all phases of mitosis were analyzed in situ. Hetrochromatization of telomeres, centromeres and interstitial chromatin regions (i.e., chromocenters/SAHF) were shown to be specific occurrences in the near-senescent phase. Stickiness between such chromatin regions caused breakage/fragmentation by anaphase-pulls on clumped chromosomes. Gluey heterochromatin is therefore, seen as a cause of CIN in near-senescence. Detrimental effects on chromosomes from heterochromatin have been observed for decades, and can be explained from chromatin remodeling in epigenetics. A consequence of genomic damage was re-replication to polyploidy of arrest-escaped cells with G2/M-DNA content. This second synthetic period produced diplochromosomal cells that cycled by bi-polar division into genome reduced cells. This sequence from h-chromatization to CIN and further to cycling endopolyploidy is believed to be a basic mechanism for the production of genetic variability in neoplasia.
Cytogenetics of the Hybridogenetic Frog Pelophylax grafi and Its Parental Species Pelophylax perezi
2023, Genome Biology and Evolution

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^☆: Sequence data from this article have been deposited with the EMBL/GenBank Data Libraries under Accession Nos. AF236881–AF236886.

¹: To whom correspondence should be addressed. Telephone: 39-0382-546332. Fax: 39-0382-422286. E-mail: [email protected].

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Regular ArticleInstability of Interstitial Telomeric Sequences in the Human Genome☆

Abstract

Genomics

Genomics

Cell

Curr. Opin. Genet. Dev.

Trends Genet.

Cell

Trends Genet.

Curr. Biol.

Mutat. Res.

Genomics

Genomics

Fluorescence in situ hybridization with a synthetic (T2AG3)n polynucleotide detects several intrachromosomal telomere-like repeats on human chromosomes

Cytogenet. Cell. Genet.

Intrachromosomal telomere-like DNA sequences in Chinese hamster

Mamm. Genome

Structure and function of telomeres

Nature

A National Cancer Institute Workshop on Microsatellite Instability for Cancer Detection and Familial Predisposition: Development of international criteria for the determination of microsatellite instability in colorectal cancer

Cancer Res.

Murine radiation myeloid leukaemogenesis: Relationship between interstitial telomere-like sequences and chromosome 2 fragile sites

Genes Chromosomes Cancer

Regular Article
Instability of Interstitial Telomeric Sequences in the Human Genome☆

Fluorescence in situ hybridization with a synthetic (T2AG3)_n polynucleotide detects several intrachromosomal telomere-like repeats on human chromosomes