Segmental duplication associated with the human-specific inversion of chromosome�18: a further example of the impact of segmental duplications on karyotype and genome evolution in primates

Abstract

The human-specific pericentric inversion of chromosome 18 was analysed using breakpoint-spanning BACs from the chimpanzee and human genome. Sequence and FISH analyses disclosed that the breakpoints map to an inverted segmental duplication of 19-kb, which most likely mediated the inversion by intrachromosomal homologous recombination. The 19-kb duplication encompasses the 3' end of the ROCK1 gene and occurred in the human lineage. Only one copy of this segment is found in the chimpanzee. Due to the inversion, the genomic context of the ROCK1 and USP14 genes is altered. ROCK1 flanks USP14 in the long arm of the chimpanzee chromosome 17, which is homologous to human chromosome 18. This order is interrupted by the inversion in humans. ROCK1 is localized close to the pericentromeric region in 18q11 and USP14 is inverted to distal 18p11.3 in direct neighbourhood to LSAU-satellites, beta-satellites and telomere-associated repeats. Our findings essentially confirm the analysis of Dennehey et al. (2004). Intriguingly, USP14 is differentially expressed in human and chimpanzee cortex as well as fibroblast cell lines determined previously by the analysis of oligonucleotide arrays. Either position effects mediated by the proximity to the telomeric region or nucleotide divergence in regulatory regions might account for the differential expression of USP14. The assignment of the breakpoint region to a segmental duplication underlines the significance of the genomic architecture in the context of genome and karyotype evolution in hominoids.

DNA sequence and analysis of human chromosome 18

“…Here we report the finished sequence and gene annotation of human chromosome 18, which will allow a better understanding of the normal and disease biology of this chromosome. Despite the low density of protein-coding genes on chromosome 18, we find that the proportion of non-proteincoding sequences evolutionarily conserved among mammals is close to the genome-wide average. Extending this analysis to the entire human genome, we find that the density of conserved non-protein-coding sequences is largely uncorrelated with gene density.…”

“…We performed full genomic alignments of repeat masked sequence from mouse 4 (builds 31 and 33), rat 21 and dog (CanFam 1.0; K. Lindblad-Toh, personal communication) with the human genome sequence using the PatternHunter program 30 . We did this for human build 34 with the Broad finished chromosomes (8,15,17,18) inserted, and also for human build 35 (mouse build 31 was used against human build 34, and mouse build 33 against human build 35). From these alignments we identified collinear clusters of conserved microsynteny, which were then used to form larger syntenic segments in a hierarchical fashion.…”

A genome-wide survey of structural variation between human and chimpanzee

“…4C; Supplemental Table 4). Indeed, seven of these 15 large-scale events (human chromosomes 4, 5, 9, 12, 15, 17, and 18) do correspond precisely to chimp-human pericentric inversion breakpoints initially described by Yunis and coworkers (Yunis et al 1980;Yunis and Prakash 1982) and subsequently refined at the molecular level (Table 1; Kehrer-Sawatzki et al 2002, 2005aLocke et al 2003b;Dennehey et al 2004;Goidts et al 2004;Nickerson et al 2005) including analysis of the chimpanzee genome assembly (The Chimpanzee Sequencing and Analysis Consortium 2005). Breakpoints for one additional known inversion on chromosome 1 were not identified in corresponding positions, but our set of 15 large-scale inversions does identify a centromere-spanning inversion on chromosome 1 that may represent the cytogenetic inversions on these chromosomes (Supplemental Table 1).…”

Serial segmental duplications during primate evolution result in complex human genome architecture

“…Interestingly, molecular characterization of some primate evolutionary genomic rearrangements showed the association of chromosome breakpoints with LCRs (Nickerson 2000;Stankiewicz et al 2001;Eder et al 2003;Locke et al 2003;Goidts et al 2004;Tsend-Ayush et al 2004). Also, comparison between human and mouse genomes revealed enrichment of segmental duplications in regions of breaks of synteny, suggesting their involvement in evolutionary rearrangements (Probst et al 1999;Armengol et al 2003;Kent et al 2003;Pennacchio 2003;Pevzner and Tesler 2003).…”