Centromere and Pericentromere Changes

Centromeres are regions of DNA (usually heterochromatin) located near the center of chromosomes that join sister chromatids and serve as attachment points for mitotic spindles during cell replication. Centromeres serve as the division point between the p and q arms of a chromosome, and may be defined as metacentric (equal arm lengths), submetacentric (unequal arm lengths), acrocentric (short p arm), telocentric (at the telomere), subtelomeric (near the telomere) and holocentric (involving the entire chromosome). In humans, 5 chromosomes are acrocentric: 13, 14, 15, 21 and 22. Holocentric chromosomes are not present in primates. Lineage specific copy number changes are often found near centromeres, and centromeres can both be novelly created (neocentromeres) or inactivated, as occurred during the chromosome fusion event that produced human chromosome 2, in which the 2q centromere was inactivated. Chromosomal inversions occur when a segment of a chromosome is reversed end-to-end. Pericentric inversions include the centromere, while paracentric inversions do not. Human lineage specific pericentric inversions occur on chromosomes 1 and 18. Pericentric regions are also enriched for segmental duplications (SDs), which are known to be hotspots of chromosomal rearrangement and one third of human-specific SDs reside within pericentromeric regions. The breakpoints for the HLS inversions on chromosomes 1 and 18 occur in regions with human lineage specific SDs that likely mediated the inversion events. Multiple pericentric regions in humans have also undergone lineage-specific duplication events and have duplicated to novel pericentric regions of other nonhomologous chromosomes. These duplication regions include interspersed repeats and duplicons that have exon-intron structure. Pericentric interspersed repeat 4 (PIR4) is a repeat in this region that has undergone a copy number increase in humans greater than in other primate species (40 copies compared to 20 in chimpanzee and 1 in orangutan) and exists in pericentromeric locations on multiple chromosomes. It has been suggested that PIR4 sequences may act similarly to segmental duplications, creating recombination events that produce duplications, deletions and inversions. Additionally, over 30 percent of DNA sequence in pericentromeric regions originated from duplicons in other regions of the genome, many of which then proceeded to duplicate intrachromosomally. It has been postulated that the preponderance of minisatellite-like sequences in pericentromeres facilitate the targeting of duplicated sequences to these regions.