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Insertion of telomeric repeats at intrachromosomal break sites during primate evolution.

ABSTRACT: Short blocks of telomeric-like DNA (Interstitial Telomeric Sequences, ITSs) are found far from chromosome ends. We addressed the question as to how such sequences arise by comparing the loci of 10 human ITSs with their genomic orthologs in 12 primate species. The ITSs did not derive from expansion of pre-existing TTAGGG units, as described for other microsatellites, but appeared suddenly during evolution. Nine insertion events were dated along the primate evolutionary tree, the dates ranging between 40 and 6 million years ago. Sequence comparisons suggest that in each case the block of (TTAGGG)n DNA arose as a result of double-strand break repair. In fact, ancestral sequences were either interrupted precisely by the tract of telomeric-like repeats or showed the typical modifications observed at double-strand break repair sites such as short deletions, addition of random sequences, or duplications. Similar conclusions were drawn from the analysis of a chimpanzee-specific ITS. We propose that telomeric sequences were inserted by the capture of a telomeric DNA fragment at the break site or by the telomerase enzyme. Our conclusions indicate that human ITSs are relics of ancient breakage rather than fragile sites themselves, as previously suggested.

SUBMITTER: Nergadze SG

PROVIDER: S-EPMC515315 | biostudies-literature | 2004 Sep

REPOSITORIES: biostudies-literature

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Insertion of telomeric repeats at intrachromosomal break sites during primate evolution.

Nergadze Solomon G SG Rocchi Mariano M Azzalin Claus M CM Mondello Chiara C Giulotto Elena E

Genome research 20040812 9

Short blocks of telomeric-like DNA (Interstitial Telomeric Sequences, ITSs) are found far from chromosome ends. We addressed the question as to how such sequences arise by comparing the loci of 10 human ITSs with their genomic orthologs in 12 primate species. The ITSs did not derive from expansion of pre-existing TTAGGG units, as described for other microsatellites, but appeared suddenly during evolution. Nine insertion events were dated along the primate evolutionary tree, the dates ranging bet ...[more]

PMID: 15310657

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Project description:Non-homologous end joining (NHEJ) is the major mechanism of double-strand break repair (DSBR) in mammalian cells. NHEJ has traditionally been inferred from experimental systems involving induced double strand breaks (DSBs). Whether or not the spectrum of repair events observed in experimental NHEJ reflects the repair of natural breaks by NHEJ during chromosomal evolution is an unresolved issue. In primate phylogeny, nuclear DNA sequences of mitochondrial origin, numts, are inserted into naturally occurring chromosomal breaks via NHEJ. Thus, numt integration sites harbor evidence for the mechanisms that act on the genome over evolutionary timescales. We have identified 35 and 55 lineage-specific numts in the human and chimpanzee genomes, respectively, using the rhesus monkey genome as an outgroup. One hundred and fifty two numt-chromosome fusion points were classified based on their repair patterns. Repair involving microhomology and repair leading to nucleotide additions were detected. These repair patterns are within the experimentally determined spectrum of classical NHEJ, suggesting that information from experimental systems is representative of broader genetic loci and end configurations. However, in incompatible DSBR events, small deletions always occur, whereas in 54% of numt integration events examined, no deletions were detected. Numts show a statistically significant reduction in deletion frequency, even in comparison to DSBR involving filler DNA. Therefore, numts show a unique mechanism of integration via NHEJ. Since the deletion frequency during numt insertion is low, native overhangs of chromosome breaks are preserved, allowing us to determine that 24% of the analyzed breaks are cohesive with overhangs of up to 11 bases. These data represent, to the best of our knowledge, the most comprehensive description of the structure of naturally occurring DSBs. We suggest a model in which the sealing of DSBs by numts, and probably by other filler DNA, prevents nuclear processing of DSBs that could result in deleterious repair.

Project description:BackgroundThe p53 tumor suppressor protein is involved in a complicated regulatory network, mediating expression of ~1000 human genes. Recent studies have shown that many p53 in vivo binding sites (BSs) reside in transposable repeats. The relationship between these BSs and functional p53 response elements (REs) remains unknown, however. We sought to understand whether the p53 REs also reside in transposable elements and particularly in the most-abundant Alu repeats.ResultsWe have analyzed ~160 functional p53 REs identified so far and found that 24 of them occur in repeats. More than half of these repeat-associated REs reside in Alu elements. In addition, using a position weight matrix approach, we found ~400,000 potential p53 BSs in Alu elements genome-wide. Importantly, these putative BSs are located in the same regions of Alu repeats as the functional p53 REs - namely, in the vicinity of Boxes A/A' and B of the internal RNA polymerase III promoter. Earlier nucleosome-mapping experiments showed that the Boxes A/A' and B have a different chromatin environment, which is critical for the binding of p53 to DNA. Here, we compare the Alu-residing p53 sites with the corresponding Alu consensus sequences and conclude that the p53 sites likely evolved through two different mechanisms - the sites overlapping with the Boxes A/A' were generated by CG → TG mutations; the other sites apparently pre-existed in the progenitors of several Alu subfamilies, such as AluJo and AluSq. The binding affinity of p53 to the Alu-residing sites generally correlates with the age of Alu subfamilies, so that the strongest sites are embedded in the 'relatively young' Alu repeats.ConclusionsThe primate-specific Alu repeats play an important role in shaping the p53 regulatory network in the context of chromatin. One of the selective factors responsible for the frequent occurrence of Alu repeats in introns may be related to the p53-mediated regulation of Alu transcription, which, in turn, influences expression of the host genes.

Dataset Information

Insertion of telomeric repeats at intrachromosomal break sites during primate evolution.

Publications

Insertion of telomeric repeats at intrachromosomal break sites during primate evolution.

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