Using a pericentromeric interspersed repeat to recapitulate the phylogeny and expansion of human centromeric segmental duplications

Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, USA.
Molecular Biology and Evolution (Impact Factor: 9.11). 10/2003; 20(9):1463-79. DOI: 10.1093/molbev/msg158
Source: PubMed


Despite considerable advances in sequencing of the human genome over the past few years, the organization and evolution of human pericentromeric regions have been difficult to resolve. This is due, in part, to the presence of large, complex blocks of duplicated genomic sequence at the boundary between centromeric satellite and unique euchromatic DNA. Here, we report the identification and characterization of an approximately 49-kb repeat sequence that exists in more than 40 copies within the human genome. This repeat is specific to highly duplicated pericentromeric regions with multiple copies distributed in an interspersed fashion among a subset of human chromosomes. Using this interspersed repeat (termed PIR4) as a marker of pericentromeric DNA, we recovered and sequence-tagged 3 Mb of pericentromeric DNA from a variety of human chromosomes as well as nonhuman primate genomes. A global evolutionary reconstruction of the dispersal of PIR4 sequence and analysis of flanking sequence supports a model in which pericentromeric duplications initiated before the separation of the great ape species (>12 MYA). Further, analyses of this duplication and associated flanking duplications narrow the major burst of pericentromeric duplication activity to a time just before the divergence of the African great ape and human species (5 to 7 MYA). These recent duplication exchange events substantially restructured the pericentromeric regions of hominoid chromosomes and created an architecture where large blocks of sequence are shared among nonhomologous chromosomes. This report provides the first global view of the series of historical events that have reshaped human pericentromeric regions over recent evolutionary time.

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Available from: John Mcpherson, Apr 16, 2014
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    • "These highly plastic segments of the human genome show qualitative and quantitative differences in the distribution of segmental duplications when compared with the great apes, consistent with their recent origin and human-specific sequence transfers (Horvath et al. 2001; Bailey et al. 2002; Horvath et al. 2003; Linardopoulou et al. 2005; Locke et al. 2005). In addition, regions enriched in segmental duplications are more prone to both interspecies and intraspecies structural variation (Newman et al. 2005; Sharp et al. 2005), since these repeated segments may mediate nonallelic homologous recombination (NAHR) (Hastings et al. 2009). "
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    ABSTRACT: Human and chimpanzee genomes are 98.8% identical within comparable sequence. They however differ structurally in nine pericentric inversions, one fusion that originated human chromosome 2 and content and localization of heterochromatin and lineage-specific segmental duplications. The possible functional consequences of these cytogenetic and structural differences are not fully understood and their possible involvement in speciation remains unclear. We show that subtelomeric regions - that have a species-specific organization, are more divergent in sequence, and are enriched in genes and recombination hotspots - are significantly enriched for species-specific histone modifications that decorate transcription start sites in different tissues in both human and chimpanzee. Human lineage-specific chromosome 2 fusion point and ancestral centromere locus as well as chromosome 1 and 18 pericentric inversion breakpoints showed enrichments of human-specific H3K4me3 peaks in prefrontal cortex. Our results reveal an association between plastic regions and potential novel regulatory elements.
    Full-text · Article · Jun 2014 · Genome Research
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    • "Hence, it is not surprising that 18 out of 20 LTR-retrotransposons identified in the core region of CEN4 were found to be CRRs in our study. The extensive segmental duplication mediated by Alu–Alu-mediated recombination (duplicative transposition) events has been observed in the pericentromeric regions of humans and across the human genome (Horvath et al. 2003; She et al. 2004; Locke et al. 2005). However, the preferential amplification of centromere retrotransposons by rounds of segmental duplication was an unexpected finding . "
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    ABSTRACT: The abundance of repetitive DNA varies greatly across centromeres within an individual or between different organisms. To shed light on the molecular mechanisms of centromere repeat proliferation, we performed structural analysis of LTR-retrotransposons, mostly centromere retrotransposons of rice (CRRs), and phylogenetic analysis of CentO satellite repeats harbored in the core region of the rice chromosome 4 centromere (CEN4). The data obtained demonstrate that the CRRs in the centromeric region we investigated have been enriched more significantly by recent rounds of segmental duplication than by original integration of active elements, suggesting that segmental duplication is an important process for CRR accumulation in the centromeric region. Our results also indicate that segmental duplication of large arrays of satellite repeats is primarily responsible for the amplification of satellite repeats, contributing to rapid reshuffling of CentO satellites. Intercentromere satellite homogenization was revealed by genome-wide comparison of CentO satellite monomers. However, a 10-bp duplication present in nearly half of the CEN4 monomers was found to be completely absent in rice centromere 8 (CEN8), suggesting that CEN4 and CEN8 may represent two different stages in the evolution of rice centromeres. These observations, obtained from the only complex eukaryotic centromeres to have been completely sequenced thus far, depict the evolutionary dynamics of rice centromeres with respect to the nature, timing, and process of centromeric repeat amplification.
    Preview · Article · Mar 2006 · Genome Research
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    • "It should be noted, however, that this study likely underestimates the amount of copy-number variation that exists within regions of segmental duplication. By definition , these sequences occur at multiple genomic locations , with some present in 140 copies (Horvath et al. 2003); thus, unlike for unique portions of the genome , the gain or loss of a single duplication will often be below the resolution of array CGH, which undoubtedly biases our results. Despite the sequence complexity of these clones, they provided valuable information. "
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    ABSTRACT: Segmental duplications (also termed “low-copy repeats”) are blocks of DNA that range from 1 to 400 kb in length, occur at more than one site within the genome, and typically share a high level of (>90%) sequence identity (reviewed by Eichler [2001]). Both in situ hybridization and in silico analyses have shown that ∼5% of the human genome is composed of duplicated sequence (Cheung et al. 2001; Bailey et al. 2002; Cheung et al. 2003; She et al. 2004a), and many studies have noted a significant association between the location of segmental duplications and regions of chromosomal instability or evolutionary rearrangement (Ji et al. 2000; Samonte and Eichler 2002; Armengol et al. 2003; Locke et al. 2003a, 2003b; Bailey et al. 2004). Indeed, segmental duplications have been implicated as the probable mediators of >25 recurrent genomic disorders (reviewed by Stankiewicz and Lupski [2002]). Molecular studies have shown that the presence of large, highly homologous flanking repeats predisposes these regions to recurrent rearrangement by nonallelic homologous recombination, resulting in deletion, duplication, or inversion of the intervening sequence (Chance et al. 1994; Shaw et al. 2002).
    Full-text · Article · Aug 2005 · The American Journal of Human Genetics
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