Pericentromeric Regions

Although the phenomenon of pericentromeric duplication is common to both men and mice, the properties of these duplicated regions differ. Typically, those found in mice are relatively small (<75 kb), whereas in humans they may be several 100 kb in length, and the degree of sequence identity between pairs of duplications are often much lower (<97% in mice compared with >97% in humans) (8,28). Although this latter property may be, in part, because the higher neutral mutation rate in mice (29), it suggests that many of the pericentromeric duplications in humans are evolutionary younger, and, therefore, more recently active, than those in mice.

This is supported by the fact that certain pericentromeric duplications are unique to the human lineage, and are either completely absent or occur at different chromosomal locations in other mammalian species. Indeed, the process of pericentromeric duplication appears to have occurred as punctuated events during primate evolution. Certain duplicated segments, such as those containing the genes ALD and CTR, are common to humans, chimpanzees, and

Fig. 2. Segmental duplications on chromosome 22. (A) An overview of duplicated sequence on the long arm of chromosome 22 (27). A total of 715 duplications >1 kb in length and >90% sequence identity were identified. Each horizontal line represents 1 Mb. Top left-hand corner is the most centromeric sequence contig and at the bottom right is the most telomeric sequence. Gray bars, interchromosomal duplications between nonhomologous chromosomes; black bars, intrachromosomal duplications. Overall, 9.1% of the q arm is involved in large (>1 kb) duplications, with interchromosomal and intrachromosomal duplications constituting 3.9 and 6.4% of the total sequence, respectively. Note the preponderance of interchromosomal duplications near the centromere and telomere. (B) A reduced view of chromosome 22 (each tick mark represents 1 Mb) showing the relationship of intrachromosomal duplications (black joining lines). This region is enriched for a variety of genomic disorders (e.g., DiGeorge/velocardiofacial syndrome, cat-eye syndrome). (Reproduced with permission from ref. 95.)

Fig. 2. Segmental duplications on chromosome 22. (A) An overview of duplicated sequence on the long arm of chromosome 22 (27). A total of 715 duplications >1 kb in length and >90% sequence identity were identified. Each horizontal line represents 1 Mb. Top left-hand corner is the most centromeric sequence contig and at the bottom right is the most telomeric sequence. Gray bars, interchromosomal duplications between nonhomologous chromosomes; black bars, intrachromosomal duplications. Overall, 9.1% of the q arm is involved in large (>1 kb) duplications, with interchromosomal and intrachromosomal duplications constituting 3.9 and 6.4% of the total sequence, respectively. Note the preponderance of interchromosomal duplications near the centromere and telomere. (B) A reduced view of chromosome 22 (each tick mark represents 1 Mb) showing the relationship of intrachromosomal duplications (black joining lines). This region is enriched for a variety of genomic disorders (e.g., DiGeorge/velocardiofacial syndrome, cat-eye syndrome). (Reproduced with permission from ref. 95.)

gorillas, but are absent in orangutans, indicating their emergence predates this speciation event approx 12 million years ago (30-33). In contrast, analysis of duplications on chromosome 10 shows that these emerged at various times during primate evolution, ranging from 13 to 28 million years ago (34). This suggests that, at least within the primate lineage, pericentromeric regions are evolutionarily malleable, able to diverge rapidly, and may underlie some of the phenotypic differences present between the great apes.

Analysis of certain pericentromeric regions, such as those on chromosomes 2 and 10, shows not only that these are composed almost exclusively of duplicated sequence, but also provides evidence that duplications often occur preferentially from one pericentromeric region to another (6,35-39). Some duplicated segments, for example those containing ALD and NF1, occur at multiple different pericentromeric regions, with the most divergent, and therefore presumably progenitor, locus located outside the pericentromeric regions. In addition, complex modules

Fig. 3. A two-step model for the generation of pericentromeric duplication. An acceptor region acquires segments 1-200 kb in size from multiple independent regions of the genome (donor loci) by duplicative transposition. These events occur independently over time, creating large blocks of duplicated sequence with a mosaic structure. Secondary duplication events create copies of the initial module at new genomic locations. Because of the whole-scale nature of these latter events, the order and orientation of each constituent duplication is initially preserved within the transposed block. (Reproduced with permission from ref. 68.)

Fig. 3. A two-step model for the generation of pericentromeric duplication. An acceptor region acquires segments 1-200 kb in size from multiple independent regions of the genome (donor loci) by duplicative transposition. These events occur independently over time, creating large blocks of duplicated sequence with a mosaic structure. Secondary duplication events create copies of the initial module at new genomic locations. Because of the whole-scale nature of these latter events, the order and orientation of each constituent duplication is initially preserved within the transposed block. (Reproduced with permission from ref. 68.)

of juxtaposed duplicated sequence are often found in the same order in multiple different pericentromeric regions. This conservation of both order and orientation of the constituent modules strongly suggests that these duplication blocks were transposed from one peri-centromere to another, rather than originating from multiple independent transposition events.

These observations have led to a two-step model for the generation of pericentromeric duplications (31,36) (Fig. 3).

1. An initial series of seeding events in which one or more progenitor loci transpose material together to a pericentromeric acceptor location. This series of events creates a mosaic block of duplicated segments derived from different regions of the genome.

2. Subsequent inter- or intrachromosomal duplication events then transpose these large blocks of duplicated sequence and additional flanking material to create copies of the initial module at new genomic locations. Because of the whole-scale nature of these latter events, the order and orientation of each constituent duplication is preserved within the transposed block.

This model has since gained support from more recent studies (34,40), providing an explanation for the complex paralogous structure of many pericentromeric regions of the primate genome.

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