CAGGG Repeats and the Pericentromeric Duplication of the Hominoid Genome

Abstract

Gene duplication is one of the primary forces of evolutionary change. We present data from three different pericentromeric regions of human chromosomes, which indicate that such regions of the genome have been sites of recent genomic duplication. This form of duplication has involved the evolutionary movement of segments of genomic material, including both intronic and exonic sequence, from diverse regions of the genome toward the pericentromeric regions. Sequence analyses of the target sites of duplication have identified a novel class of interspersed GC-rich repeats located precisely at the boundaries of duplication. Estimates of the evolutionary age of these duplications indicate that they have occurred between 10 and 25 mya. In contrast, comparative analyses confirm that the GC-rich pericentromeric repeats have existed within the pericentromeric regions of primate chromosomes before the divergence of the cercopithecoid and hominoid lineages (∼30 mya). These data provide molecular evidence for considerable interchromosomal duplication of genic segments during the evolution of the hominoid genome and strongly implicate GC-rich repeat elements as playing a direct role in the pericentromeric localization of these events Genome evolution is dependent on the processes of single-base-pair mutation and gene duplication. Duplication of a gene followed by mutation is responsible for the emergence of new genes with specialized functions in an evolving species. Two distinct molecular mechanisms of gene duplication are generally recognized. Tandem duplication of an ancestral gene, vis-à-vis processes of unequal crossover, produces a clustered family of related genes (Smith 1976). In contrast, whole-genome duplication (polyploidy) followed by chromosomal rearrangement and the re-establishment of the disomic state has been proposed as a mechanism for the interchromosomal duplication of large segments of a genome (Ohno 1970). The latter model, put forward originally by Susumu Ohno, explains observations of conserved genic synteny among nonhomologous chromosomes. Because of the genetic consequences of polyploidy, such events, although important in the early expansion of eukaryotic genomes, are rare and ancient (Ohno 1993;Wolfe and Shields 1997). Within the vertebrate lineage, for example, the last tetraploidization event leading to genome duplication is estimated to have occurred >400 mya (Lundin 1993). If polyploidy were the only model by which entire genes could be duplicated among nonhomologous chromosomes, it would then follow that interchromosomal paralogs of recent origin would be unexpected.Recent analyses of data from the Human Genome Project suggest a third form of genomic duplication, which is mechanistically distinct from polyploidy and tandem duplication models of genome evolution. Several independent reports indicate that genic segments, ranging in length from 5 kb to 30 kb, possess duplicate copies within the pericentromeric regions of human autosomes (Borden et

Comprehensive Genome Sequence Analysis of a Breast Cancer Amplicon

“…FISH mapping indicates that in mouse the NABC3 gene is single copy (data not shown). This finding is consistent with the current view that duplicons do not occur outside of primates (Eichler et al 1999). Thus, duplicon's pangenomic migration most likely occurred after the primate-mouse divergence with 20q13.2 being the ancestral element.…”

Genomic Sequence and Transcriptional Profile of the Boundary Between Pericentromeric Satellites and Genes on Human Chromosome Arm 10p

“…First, they evolve by an unusual two-step process termed pericentromeric directed duplication (Eichler et al 1997), where initial duplication into a centromere proximal location is followed by repeat-mediated duplication between chromosomes (Horvath et al 2000b;Luitjen et al 2000). Consistent with this, the distribution of some duplications correlates with the distribution of specific repeats including ␣ satellite superfamily 2 (Regnier et al 1997), CAGGG repeats (Eichler et al 1999) and satellite 3 (Guy et al 2000). Second, repeated rounds of duplication have created tracts of pericentromeric sequence where exons from different genes have been juxtaposed, which has led to the suggestion that these regions are breeding grounds of biological novelty (Eichler et al 1997;1999) and may have contributed to the increased complexity of the human proteome relative to other sequenced eukaryotes (Eichler 2001).…”

Pericentromeric Duplications in the Laboratory Mouse

“…It is also possible that our specific approach and thresholds for aligning sequences led to some of these differences; however, we believe this is unlikely since interspecies comparison of orthologous mouse and rat sequences showed a substantial amount of insertions and deletions within the duplicated segments. A second possible difference is the absence of common, short repeated sequences flanking the duplicated segments, as were encountered with human pericentromeric duplications and suggested to be involved in the duplication events (Eichler et al 1999). We searched for such sequences both within and flanking the duplicated segments on MMU1, MMU5, and MMU6, but found no common sequence motifs.…”

“…In the human genome, duplicated segments of recent origin are sometimes associated with short, interspersed repetitive sequences that reside at the boundaries of duplication integration sites (Eichler et al 1999). To search for the presence of similar repeats in the mouse genome, the unmasked sequences flanking all the duplicated segments on MMU1, MMU5, and MMU6 (Table 1) were carefully scrutinized.…”