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: 14.31). 10/2003; 20(9):1463-79. DOI: 10.1093/molbev/msg158
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: John Mcpherson, Apr 16, 2014
  • Source
    • "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 . "
    [Show abstract] [Hide abstract]
    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.
    Genome Research 03/2006; 16(2):251-9. DOI:10.1101/gr.4583106 · 13.85 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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).
    The American Journal of Human Genetics 08/2005; 77(1):78-88. DOI:10.1086/431652 · 10.99 Impact Factor
  • Source
    • "es . The DNA was isolated by using the Millipore ( Millipore ) or Perfectprep BAC 96 kit ( Eppendorf ) and resuspended in water . Approxi - mately 15 ng BAC DNA ( 1 / 25 the total volume ) and 15 ng of cosmid DNA ( 1 / 50 the total volume ) were used in subsequent PCR assays . All PCR and sequencing conditions were previously described elsewhere ( Horvath et al . 2003 ) . BAC end sequencing reactions were conducted as previously described ( She et al . 2004a ) . Cosmid end sequencing reactions were identical to BAC end reactions except that only 1 / 12 the total volume of cosmid DNA was used , and only 70 cycles of sequencing were conducted ."
    [Show abstract] [Hide abstract]
    ABSTRACT: Primate genomic sequence comparisons are becoming increasingly useful for elucidating the evolutionary history and organization of our own genome. Such studies are particularly informative within human pericentromeric regions--areas of particularly rapid change in genomic structure. Here, we present a systematic analysis of the evolutionary history of one approximately 700-kb region of 2p11, including the first autosomal transition from pericentromeric sequence to higher-order alpha-satellite DNA. We show that this region is composed of segmental duplications corresponding to 14 ancestral segments ranging in size from 4 kb to approximately 115 kb. These duplicons show 94%-98.5% sequence identity to their ancestral loci. Comparative FISH and phylogenetic analysis indicate that these duplicons are differentially distributed in human, chimpanzee, and gorilla genomes, whereas baboon has a single putative ancestral locus for all but one of the duplications. Our analysis supports a model where duplicative transposition events occurred during a narrow window of evolution after the separation of the human/ape lineage from the Old World monkeys (10-20 million years ago). Although dramatic secondary dispersal events occurred during the radiation of the human, chimpanzee, and gorilla lineages, duplicative transposition seeding events of new material to this particular pericentromeric region abruptly ceased after this time period. The multiplicity of initial duplicative transpositions prior to the separation of humans and great-apes suggests a punctuated model for the formation of highly duplicated pericentromeric regions within the human genome. The data further indicate that factors other than sequence are important determinants for such bursts of duplicative transposition from the euchromatin to pericentromeric regions.
    Genome Research 08/2005; 15(7):914-27. DOI:10.1101/gr.3916405 · 13.85 Impact Factor
Show more