The evolutionary chromosome translocation 4;19 in Gorilla gorilla is associated with microduplication of the chromosome fragment syntenic to sequences surrounding the human proximal CMT1A-REP

Abstract

Many genomic disorders occur as a result of chromosome rearrangements involving low-copy repeats (LCRs). To better understand the molecular basis of chromosome rearrangements, including translocations, we have investigated the mechanism of evolutionary rearrangements. In contrast to several intrachromosomal rearrangements, only two evolutionary translocations have been identified by cytogenetic analyses of humans and greater apes. Human chromosome 2 arose as a result of a telomeric fusion between acrocentric chromosomes, whereas chromosomes 4 and 19 in Gorilla gorilla are the products of a reciprocal translocation between ancestral chromosomes, syntenic to human chromosomes 5 and 17, respectively. Fluorescence in situ hybridization (FISH) was used to characterize the breakpoints of the latter translocation at the molecular level. We identified three BAC clones that span translocation breakpoints. One breakpoint occurred in the region syntenic to human chromosome 5q13.3, between the HMG-CoA reductase gene (HMGCR) and RAS p21 protein activator 1 gene (RASA1). The second breakpoint was in a region syntenic to human chromosome 17p12 containing the 24 kb region-specific low-copy repeat-proximal CMT1A-REP. Moreover, we found that the t(4;19) is associated with a submicroscopic chromosome duplication involving a 19p chromosome fragment homologous to the human chromosome region surrounding the proximal CMT1A-REP. These observations further indicate that higher order genomic architecture involving low-copy repeats resulting from genomic duplication plays a significant role in karyotypic evolution.

Figure 1

Gorilla metaphase chromosomes after hybridization with human BAC clones. Below is shown gorilla chromosome 4 (GGO 4), syntenic to human chromosomes 5 and 17. The vertical arrow indicates the ∼250 kb genomic duplication, originating from the GGO 19 segment, syntenic to human chromosome, (HSA) 17p12. Smith-Magenis syndrome low-copy repeats, SMS-REPs, and Charcot-Marie-Tooth disease type 1A low copy repeats, CMT1A-REPs, in the human chromosome 17p11.2p12 region are shown (telomere to right of figure) with the relative physical position of three BAC clones used in the FISH analysis that is shown above. (a) CTD-3157E16 (HSA 17p12), located proximal to the translocation breakpoint. (b) RP11–726O12 (HSA 17p12), located distal to the translocation breakpoint. (c) RP11-385D13 (HSA 17p12, proximal CMT1A-REP), spans the translocation breakpoint and includes the genomic duplication in gorilla. (d) CTC-428H11 (HSA 5q13.3) spans the breakpoint. Arrows within the FISH picture indicate an additional hybridization signal, which is also located on the long arm of GGO 19. This apparent duplication is located distal to the evolutionary breakpoint identified in this study. Small panels in the lower right corners demonstrate only the gorilla chromosomes 4 and 19 with positive probe hybridization signals.

Figure 2

Schematic representation of the gorilla chromosome 19 duplicated region. Human BAC, PAC, and cosmid clones are shown below. Note that the proximal CMT1A-REP is not present in the gorilla genome. Its position in human is indicated with an arrow.