Breakpoint analysis of the pericentric inversion distinguishing human chromosome 4 from the homologous chromosome in the chimpanzee (Pan troglodytes)

The study of breakpoints that occurred during primate evolution promises to yield valuable insights into the mechanisms underlying chromosome rearrangements in both evolution and pathology. Karyotypic differences between humans and chimpanzees include nine pericentric inversions, which may have potentiated the parapatric speciation of hominids and chimpanzees 5–6 million years ago. Detailed analysis of the respective chromosomal breakpoints is a prerequisite for any assessment of the genetic consequences of these inversions. The breakpoints of the inversion that distinguishes human chromosome 4 (HSA4) from its chimpanzee counterpart were identified by fluorescence in situ hybridization (FISH) and comparative sequence analysis. These breakpoints, at HSA4p14 and 4q21.3, do not disrupt the protein coding region of a gene, although they occur in regions with an abundance of LINE and LTR‐elements. At 30 kb proximal to the breakpoint in 4q21.3, we identified an as yet unannotated gene, C4orf12, that lacks an homologous counterpart in rodents and is expressed at a 33‐fold higher level in human fibroblasts as compared to chimpanzee. Seven out of 11 genes that mapped to the breakpoint regions have been previously analyzed using oligonucleotide‐microarrays. One of these genes, WDFY3, exhibits a three‐fold difference in expression between human and chimpanzee. To investigate whether the genomic architecture might have facilitated the inversion, comparative sequence analysis was used to identify an ∼5‐kb inverted repeat in the breakpoint regions. This inverted repeat is inexact and comprises six subrepeats with 78 to 98% complementarity. (TA)‐rich repeats were also noted at the breakpoints. These findings imply that genomic architecture, and specifically high‐copy repetitive elements, may have made a significant contribution to hominoid karyotype evolution, predisposing specific genomic regions to rearrangements. Hum Mutat 25:45–55, 2005. © 2004 Wiley‐Liss, Inc.