Human chromosome 15q11-q14 regions of rearrangements contain clusters of LCR15 duplicons

Abstract

Six breakpoint regions for rearrangements of human chromosome 15q11-q14 have been described. These rearrangements involve deletions found in approximately 70% of Prader-Willi or Angelman's syndrome patients (PWS, AS), duplications detected in some cases of autism, triplications and inverted duplications. HERC2-containing (HEct domain and RCc1 domain protein 2) segmental duplications or duplicons are present at two of these breakpoints (BP2 and BP3) mainly associated with deletions. We show here that clusters containing several copies of the human chromosome 15 low-copy repeat (LCR15) duplicon are located at each of the six described 15q11-q14 BPs. In addition, our results suggest the existence of breakpoints for large 15q11-q13 deletions in a proximal duplicon-containing clone. The study reveals that HERC2-containing duplicons (estimated on 50 ± 400 kb) and LCR15 duplicons (*15 kb on 15q11-q14) share the golgin-like protein (GLP) genomic sequence. Through the analysis of a human BAC library and public databases we have identified 36 LCR15 related sequences in the human genome, most (27) mapping to chromosome 15q and being transcribed. LCR15 analysis in non-human primates and age-sequence divergences support a recent origin of this family of segmental duplications through human speciation.

Recurrent rearrangements in the proximal 15q11–q14 region: a new breakpoint cluster specific to unbalanced translocations

“…Strikingly, none of the 18 cases studied was found to contain the BAC 489D6 (marker D15S144) that marks the most distal boundary of BP5. 18 Indeed, our FISH studies demonstrated that five inv dup (15) had a breakpoint located within BP3 (Figure 1), three had a breakpoint located within BP4 and 10 had a breakpoint within BP5.…”

“…18 Using the Human Genome Segmental Duplication Database Assembly program, we found a LCR15-duplicon element located adjacent to the BAC 64O8, very close to the proximal boundary of the 460 kb interval (Figure 4). This LCR15-duplicon (sequence AC027139) extends through 270 kb and is present at all other BPs that characterize recurrent rearrangements of chr 15.…”

“…18 -20 BP4 and BP5, which are most frequently involved in triplications and inv dup (15) chromosomes, are characterized by duplicons that contain only LCR15 elements. 18 Nevertheless, no specific BP that characterizes unbalanced translocations of the proximal chromosome 15q onto the telomeric band of a partner chromosome has been described. In this study, we characterized the chr 15 breakpoint from eight unbalanced translocations of this type and demonstrated that four of them are clustered in a reduced 460 kb interval located in the proximal 15q14 band.…”

“…Five BPs (BP1 -BP5) have been characterized in the chromosome 15q11 -q13 region. 18 The genetic instability in this region has been attributed to relatively large genomic duplications (duplicons) that map in the vicinity of the BPs. Such duplicons are believed to mediate misalignment during meiosis, leading to unequal recombination events.…”

Clinical and genetic aspects of Angelman syndrome

“…47 The BP1, BP2, and BP3 regions are characterized by low-copy repeat regions that contain repeats mainly derived from the ancestral HECT domain and RCc1 domain protein 2 genes (HERC2). 100 The BP sites distal to BP3 contain other low-copy repeat regions (e.g., without HERC2 duplications) that share chromosome 15-derived repeated DNA elements. A proportion of mothers who have a child with an AS deletion have been found to have inversions in the 15q11.2-q13 region (the region deleted in the offspring with AS).…”