This section provides an overview on the current knowledge about the genomic context of evolutionary chromosomal breakpoints in human and great apes. By analogy to the functional importance of genomic alterations related with acquired chromosomal aberrations in cancers, it was anticipated that changes of the genomic environment caused by evolutionary chromosome rearrangements might hold the key for a better understanding of the origins of our own species.
Two head-to-head arrays of degenerate telomere repeats are found directly at the fusion site in 2q13 (61). Their inverted orientation indicates a telomeric fusion. Subsequently, the inactivation of one of the two ancestral centromeres must have occurred. Indeed, close to the fusion point in band 2q21 a degenerated alphoid domain was found by low stringency FISH of a satellite DNA probe (62).
Like in other subtelomeric regions, large blocks surrounding the fusion point are comprised of duplicated sequences (63). Chromosome 2q13 paralogs of96-99% identity were identified on chromosome 9pter, 9p11.2, 9q13, 22qter, and 2q11.2. The emergence of some of these segmental duplications could be dated back prior to hominid divergence, whereas others appeared to be of more recent origin. It can be speculated that these duplicons may have been the cause for the fusion and that human chromosome 2 is the product of paralogous recombination between two different chromosomes using a duplicated segment as recombination substrate (63).
The fusion point is located in a gene-rich region, with at least 24 potentially functional genes and 16 pseudogenes located within less than 1 Mb distance or in paralogous regions elsewhere in the genome (64). At least 18 of these genes are transcriptionally active, for example members of the cobalamin synthetase W domain (CBWD) and forkhead domain FOXD4 gene families, thus providing an example of genomic innovation connected with duplication and evolutionary rearrangement of subtelomeric and pericentromeric regions.
A detailed molecular cytogenetic characterization of evolutionary inversion breakpoints in hominoid chromosome 3 homologs revealed that the ancestral pericentromeric region is associated with both large-scale and micro-rearrangements (51). Small segments homologous to human 3q11.2 and 3q21.2 were repositioned intrachromosomally in the orangutan lineage. The breakpoint in the human 3p12.3 homologous region of the orangutan is associated with extensive transchromosomal duplications observed in multiple subtelomeric regions. A second breakpoint in the same region, but with a distinctly different location, is flanked by sequences present in all subtelomeric regions of the Siamang (gibbon) genome.
Reciprocal Translocation t(4;19) in the Gorilla
The breakpoints of the reciprocal translocation t(4;19) in the gorilla are located in regions syntenic to human 5q14.1 between HMGCR and RASA1 genes, and in 17p12 with an approx 383-kb region-specific low-copy repeat (LCR)17pA (65,66). The 17p12 region is also susceptible to constitutional rearrangements in human. The authors proposed a series of consecutive evoloutionary segmental duplications involving LCR17pA and approx 191-kb LCR17pB copies that resulted in complex genome architecture in the rearrangements. Detailed comparative analysis of the corresponding region identified remnants of DNA-transposable element MER1-Charlie3 and retroviral ERVL elements at the translocation breakpoint in a pre-gorilla individual (66). In addition, genomic rearrangements involving LCR17pA and LCR17pB resulted in the creation of novel genes at the breakpoint junctions (66).
Comparative FISH analysis with BAC clones that were derived from the Williams-Beuren syndrome region in 7q11.23 and which contained LCRs including NCF1 (p47-phox) sequences revealed duplicated segments in the 7q11.23 homologous region of chimpanzee, gorilla, orangutan, and a gibbon (67). As in human, cross-hybridization was observed in the inversion breakpoint regions at 7q22 and 7p22 in African apes, but not in the homologous chromosome regions in orangutan and gibbon.
Zoo-FISH analysis employing BAC probes confined the 7p22.1 breakpoint of the pericentric inversion in the human/African ape ancestor to 6,8 Mb on the human reference sequence map and the 7q22.1 breakpoint to 97,1 Mb (57) in regions with predominantly inter-chromosomal duplications with paralogs on human chromosomes 2-4 and 8-15. These duplicons were already present in the orangutan, but spread to a variety of additional chromosomes in the gorilla. The paracentric inversion breakpoints in the common ancestor of human and chimpanzees were found in 7q11.23 between 76,1 Mb and 76,3 Mb and in 7q22.1 at 101,9 Mb, respectively. Intrachromosomal duplicons mark an at least 110-kb stretch of nearly identical DNA sequence, which is most probably directly flanking both breakpoints. The 7q11.23 breakpoint is further located in close proximity to a 200-kb or larger insertion of chromosome 1 material, which could be dated back to the African ape ancestor (57). Considering that the duplicated sequences flanking the four inversion breakpoints as well as the chromosome 1 transposition were already present in the evolutionary ancestral state prior to the inversions, segmental duplications may have been the cause rather than the result of both rearrangements.
Inversions ofChromosome 12 in Chimpanzee and Gorilla
Both chimpanzee and gorilla show derived pericentric inversions of the chromosome 12 homologs. In a first comparative FISH study, the 12p12 breakpoints in both species were mapped to the same YAC clone, whereas the 12q15 breakpoints were shown to be located in distinctly different regions (53). In addition, a chimpanzee BAC clone was identified, which also spanned the 12p12 breakpoint (68). Recently it could be demonstrated that this clone did not span the 12p12 breakpoint in the gorilla, thus, demonstrating that both the 12q and 12p inversion breakpoints differ in chimpanzee and gorilla (69). Sequence analysis of the breakpoints in the chimpanzee genome revealed two large duplications in both breakpoint regions, which probably emerged in concert with the inversion because they were shown to be chimpanzee-specific (69).
Fission ofthe Ancestral Chromosome 14/15 Synteny in the Great Ape Ancestor
The fission that separated human chromosome 14 and 15 homologs led to the inactivation of the ancestral centromere in 15q25 and to the formation of two new centromeres in the locations where they can be found in human. Detailed comparative molecular cytogenetic analysis of the region 15q24-26 revealed 500 kb of duplicons, which flank both sides of the single ancestral centromere in Old World monkeys (70). Notably, the same duplicons are associated with neocentromeres in 15q24-26 in two clinical cases. This suggests that neocentromere formation in human pathology in a region of an evolutionary inactivated centromere may be triggered by the persistence of recombinogenic pericentromeric duplications.
Chimpanzee and bonobo share a derived pericentric inversion of their chromosome 15 homologs. A comparative FISH and in silico approach was used to narrow down the breakpoint interval of this pericentric inversion to the 15q11-q13 homologous region (71). The breakpoint mapped to a 600-kb segmental duplication cluster. Sequence analysis indicated that this region comprises a duplication of the CHRNA7 gene and several Golgin-linked-to-PML duplications. Notably, this evolutionary breakpoint did not colocalize with one of the three major common disease rearrangement breakpoints in 15q11-q13.
FISH was used to investigate the derived pericentric inversion with breakpoints in 17p13 and 17q21.3 homologous regions, by which chimpanzee chromosome 19 differs from human chromosome 17. Breakpoint-spanning BACs were subsequently used to clone and sequence the junction fragments (72). Both breakpoints were localized in intergenic regions rich in Alu and LTR elements, but were not associated with LCRs, duplicated regions, or deletions. The findings suggest that repetitive sequence mediated nonhomologous recombination has facilitated inversion formation. In close proximity of the breakpoints, NGFR and NXPH3 genes are located in 17q21.3 and GUC2D and ALOX15B in 17p13. Most likely, the genomic structure, the expression level or the replication timing of these genes was not affected by the inversion (72).
Human chromosome 18 differs from its great ape homologues by a pericentric inversion, which can be assigned to the human lineage. Recently, chimpanzee BAC clones that span one of the breakpoint regions where were identified by FISH, because in human split signals were observed on 18p11.3 and 18q11 (73,74). Interspecies sequence comparisons indicated that the ancestral break occurred between the ROCK1 and USP14 gene. In human, the inversion translocated ROCK1 near centromeric heterochromatin and USP14 into proximity of 18p subtelo-meric repeats. USP14 is differentially expressed in human and chimpanzee cortex as well as fibroblast cell lines. Further, a 19-kb segmental duplication with paralogs in pericentromeric regions of chromosomes 1, 9 and the acrocentric chromosomes is also flanking both 18p11.3 and 18q11 regions in inverted orientation. The authors propose a model, according to which the 19-kb 18q segment containing part of the ROCKl gene was first locally duplicated and then transposed to the pericentromeric region of the ancestral 18p. Subsequently, the segmental duplication may have mediated an intrachromosomal crossover, resulting in modern human chromosome 18.
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