Human subtelomeres are hot spots of interchromosomal recombination and segmental duplication

Abstract

Human subtelomeres are polymorphic patchworks of inter-chromosomal segmental duplications at the ends of chromosomes. We provide evidence here that these patchworks arose recently through repeated translocations between chromosome ends. We assess the relative contribution of the major modes of ectopic DNA repair to the formation of subtelomeric duplications and find that nonhomologous end-joining predominates. Once subtelomeric duplications arise, they are prone to homology-based sequence transfers as evidenced by incongruent phylogenetic relationships of neighboring sections. Inter-chromosomal recombination of subtelomeres is a potent force for recent change. Cytogenetic and sequence analyses reveal that pieces of the subtelomeric patchwork changed location and copy number during primate evolution with unprecedented frequency. Half of known subtelomeric sequence formed recently through human-specific sequence transfers and duplications. Subtelomeric dynamics result in a gene-duplication rate significantly higher than the genome average and could have both advantageous and pathological consequences in human biology. More generally, our analyses suggest an evolutionary cycle between segmental polymorphisms and genome rearrangements.The human genome contains an abundance of large DNA segments that duplicated during the last 40 million years 1,2 . These segmental duplications (SDs) represent ≥5% of the genome 2 and are found frequently near centromeres and telomeres 3 . SDs are emerging as significant factors in chromosomal rearrangements leading to disease 4 and rapid gene innovation 2 , but the mechanisms by which they form are not well understood. Here, we focus on the unusually dense concentrations of inter-chromosomal SDs comprising human subtelomeres, which form the transition zones between chromosome-specific sequence and the arrays of telomeric repeats capping each chromosomal end. Previous cytogenetic studies showed that human subtelomeres are strikingly polymorphic in content -large segments can be present in or absent from normal alleles 5 -and that copy number of subtelomeric segments can vary among higher primates 6-9 . This natural plasticity combined with documented expression of several human subtelomeric genes 10,11 suggests that the evolutionary dynamics of subtelomeric regions could contributeCorrespondence and requests for materials should be addressed to B.J.T. (e-mail: btrask@fhcrc.org Complex inter-related structuresOur "paralogy map" of subtelomeric SDs (Fig. 1, Table S1) uses all finished sequences of genomic clones submitted to GenBank before April 2003. The map comprises ~2.6 Mbp of sequence present in two or more of 33 human subtelomeres (including three allelic pairs). The seven completely sequenced subtelomeres in the set are bounded distally by 0.5-2.4 kbp of various tandemly repeated units 13 called telomere-associated repeats (TAR1) and a short sample of the native telomeric arrays 14 . Numerous degenerate telomere-like repeats and TAR1 elements are also situated at varying...

The significance of telomeric aggregates in the interphase nuclei of tumor cells

“…Interestingly, the subtelomeric gene duplication rate is significantly higher than the genome average. Thus, the authors conclude that this is both advantageous for evolution and may also have pathological consequences [Linardopoulou et al, 2005]. In the context of our discussion, we emphasize that telomeres and subtelomeric sequences are hot spots of evolution and genomic instability.…”

“…It has been reported that human subtelomeric sequences are recombination and duplication hot spots [Linardopoulou et al, 2005]. Subtelomeric sequences are involved in interchromosomal recombinations and segmental duplications.…”

Nanopore-based single molecule sequencing for D4Z4 array responsible for facioscapulohumeral muscular dystrophy

“…One possibility is that GRCh38 does not well represent the sequence of chr4 in this region. The other possible reason is chromosomal translocation between chr4 and chr10, which is known to be frequent [23][24][25] .…”

Diagnosing duplications – can it be done?

“…Because reports conflict on the gene content of LCRs [20,21,[67][68][69][70], depending on methodology, species and the quality of the data, it is not clear to what extent LCRs have a role in the duplication of entire genes. However, there is substantial evidence that LCRs contain fragments of coding sequence and are likely to be the sites of new gene formation by domain shuffling.…”

“…In studies of recent duplications, sequence analysis has also been used to diagnose the genomic mechanisms that drive various duplication processes [20,21]. Evidence of transposition can be found in the characteristic sequence patterns associated with known families of TEs and their integration sites.…”