Hominoid fission of chromosome 14/15 and the role of segmental duplications

Human chromosomes 14 and 15 were generated by fission of an ancestral chromosome composed of chromosome 14 attached, head-to-tail, to chromosome 15 around 25 million years ago (Ventura et al. 2003). The rearrangement occurred in the hominoid ancestor and involved a cluster of olfactory receptor (OR) genes (Rudd et al. 2009). At the point of fission, the 15q telomere and the neocentromere of chromosome 14 were seeded (Ventura et al. 2003). The 15q subtelomeric region experienced numerous structural rearrangements, including interstitial deletions and transfers of material to and from other subtelomeric regions (Rudd et al. 2009). Low-copy repeats (LCR), also named segmental duplications (SDs) (Bailey et al. 2001; Cheung et al. 2001), mediate chromosomal rearrangements through non-allelic homologous recombination (NAHR) events (Hastings et al. 2009) and are enriched at pericentromeric and subterminal regions of the human genome (Bailey and Eichler 2006). LCR15 (low-copy repeats on human chromosome 15) loci have been widely studied (Pujana et al. 2001; Zody et al. 2006); those of primary focus are on 15q11–q13 because of their involvement in the Prader-Willi and Angelman syndromes (Pujana et al. 2002). In this work, we provide insights into and highlight the role of LCR in the evolution of human chromosomes 14 and 15. We assembled a 1.6-Mb contig of macaque BAC clones encompassing the 14/15 boundary and tracked evolutionary changes initiated by the fission in the human lineage. We detected duplications from the newly seeded subtelomeric region on chromosome 15 and pericentromeric region on chromosome 14 to other existing subtelomeric and pericentromeric regions, respectively. Further, we traced the dynamics of the formation of the chromosome 14 neocentromere and demonstrated the recruitment of new pericentromeric sequences mainly from the pericentromeric regions of ancestral chromosomes orthologous to human 2q14–qter and 10. We found a correlation between clusters of LCR15 and evolutionary “hotspot” regions. (Note: For simplicity, we used the orthologous numbering of great ape and human chromosomes as proposed for great ape genome sequencing projects [Supplemental Fig. S1; McConkey 2004].)