Distribution of segmental duplications in the context of higher order chromatin organisation of human chromosome 7

Abstract

BackgroundSegmental duplications (SDs) are not evenly distributed along chromosomes. The reasons for this biased susceptibility to SD insertion are poorly understood. Accumulation of SDs is associated with increased genomic instability, which can lead to structural variants and genomic disorders such as the Williams-Beuren syndrome. Despite these adverse effects, SDs have become fixed in the human genome. Focusing on chromosome 7, which is particularly rich in interstitial SDs, we have investigated the distribution of SDs in the context of evolution and the three dimensional organisation of the chromosome in order to gain insights into the mutual relationship of SDs and chromatin topology.ResultsIntrachromosomal SDs preferentially accumulate in those segments of chromosome 7 that are homologous to marmoset chromosome 2. Although this formerly compact segment has been re-distributed to three different sites during primate evolution, we can show by means of public data on long distance chromatin interactions that these three intervals, and consequently the paralogous SDs mapping to them, have retained their spatial proximity in the nucleus. Focusing on SD clusters implicated in the aetiology of the Williams-Beuren syndrome locus we demonstrate by cross-species comparison that these SDs have inserted at the borders of a topological domain and that they flank regions with distinct DNA conformation.ConclusionsOur study suggests a link of nuclear architecture and the propagation of SDs across chromosome 7, either by promoting regional SD insertion or by contributing to the establishment of higher order chromatin organisation themselves. The latter could compensate for the high risk of structural rearrangements and thus may have contributed to their evolutionary fixation in the human genome.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-537) contains supplementary material, which is available to authorized users.

Intrauterine phenotype features of fetuses with 7q11.23 microduplication syndrome

“…It is flanked by 3 main clusters of low-copy repeats (LCR) named proximal (LCR-P), central (LCR-C), and distal (LCR-D), and it encompasses many and highly transcribed genes. Indeed, its gene density and transcriptional rate are significantly higher when compared with other segments of chromosome 7 [ 12 ]. To date, the genes between LCR-P and LCR-C have been marked as causative of these two disorders.…”

5‘RUNX1-3’USP42 chimeric gene in acute myeloid leukemia can occur through an insertion mechanism rather than translocation and may be mediated by genomic segmental duplications

“…The relationship between the two SDs blocks and the breakpoints on chromosome 7 and 21 appears anything but random considering the fact that the t(7;21)(p22;q22) in AML is a very rare but recurrent rearrangement. A link between nuclear architecture, in terms of chromatin organization, and SDs across the chromosome 7 has been recently demonstrated [ 24 ]. What might be the circumstances that favor a chromosome pairing mediated by SDs in AML is something still to be clarified.…”

A Polymer Physics Investigation of the Architecture of the Murine Orthologue of the 7q11.23 Human Locus

“…Structural variants at the 7q11.23 locus can cause a variety of neurological, behavioral and other problems. For example, the 7q11.23 duplication syndrome is associated with speech problems and behavioral issues such as increased anxiety levels or autism (see Berg et al, 2007 ; Merla et al, 2010 ; Ramocki et al, 2010 ; Ebert et al, 2014 ). The Williams-Beuren syndrome (WSB) is a complex developmental disorder associated to the deletion of 1.5–1.8 Mb in the 7q11.23 locus, encompassing a couple of dozens genes (see Nature Research Highlights, 2011 ; Sanders et al, 2011 ; Chailangkarn et al, 2016 ; and ref.s therein).…”