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Published online before print
April 10, 2006, 10.1101/gr.4949406 Genome Res. 16:576-583, 2006 ©2006 by Cold Spring Harbor Laboratory Press; ISSN 1088-9051/06 $5.00
Letter A preliminary comparative analysis of primate segmental duplications shows elevated substitution rates and a great-ape expansion of intrachromosomal duplications1 Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA; 2 Department of Genetics, Case Western Reserve University, Cleveland, Ohio 44106, USA; 3 Bovine Functional Genomics Laboratory, US Department of Agriculture, Beltsville, Maryland 20705, USA; 4 Department of Genetics and Microbiology, University of Bari, 70126 Bari, Italy; 5 The Institute for Genomic Research, Rockville, Maryland 20850, USA; 6 Genome Technology Branch and NIH Intramural Sequencing Center, National Human Genome Research Institute, Bethesda, Maryland 20892, USA; 7 Howard Hughes Medical Institute, Seattle, Washington 98195, USA
Compared with other sequenced animal genomes, human segmental duplications appear larger, more interspersed, and disproportionately represented as high-sequence identity alignments. Global sequence divergence estimates of human duplications have suggested an expansion relatively recently during hominoid evolution. Based on primate comparative sequence analysis of 37 unique duplication–transition regions, we establish a molecular clock for their divergence that shows a significant increase in their effective substitution rate when compared with unique genomic sequence. Fluorescent in situ hybridization (FISH) analyses from 1053 random nonhuman primate BACs indicate that great-ape species have been enriched for interspersed segmental duplications compared with representative Old World and New World monkeys. These findings support computational analyses that show a 12-fold excess of recent (>98%) intrachromosomal duplications when compared with duplications between nonhomologous chromosomes. These architectural shifts in genomic structure and elevated substitution rates have important implications for the emergence of new genes, gene-expression differences, and structural variation among humans and great apes.
Duplications play a pivotal role in disease process, gene evolution, and genome rearrangement. Structurally, these sequences have been linked to an increasing number of human genomic disorders within humans (Stankiewicz et al. 2004  ) as well as evolutionary breakpoints of conserved synteny between humans and other mammals (Armengol et al. 2003; Bailey et al. 2004a; Murphy et al. 2005). Segmental duplications have contributed significantly to large-scale copy number variation within the human population (Iafrate et al. 2004; Sebat et al. 2004; Sharp et al. 2005) and have contributed more to the genetic difference between chimpanzee and human than single-base mutations (Cheng et al. 2005). Importantly, several hominoid-specific genes have been uncovered within these dynamic regions (Johnson et al. 2001; Courseaux et al. 2003; Paulding et al. 2003), due either to fusions or adaptive evolution.
Previous analyses confirm that In this study, we attempt to provide a preliminary, unbiased assessment of rates of substitution and changes in duplication architecture based on genomic comparisons with nonhuman primates. We begin by summarizing the apparent unique properties of human segmental duplications compared with other sequenced vertebrate genomes. We then establish a molecular clock for single-base divergence based on the analysis of orthologous primate sequence located at the transition regions between unique and duplicated sequence, and directly estimate the frequency of segmental duplication among other species based on FISH analysis of random genomic clones. Our data demonstrate a proclivity toward expansion of interspersed duplications during the emergence of humans and the great apes.
Properties of human segmental duplications Segmental duplications are distributed nonrandomly across the human genome. We identified 378 regions in excess of 100 kb in length where duplications have accumulated—this includes 98 regions within 2 Mb of centromere and telomere positions (She et al. 2004a ; Linardopoulou et al. 2005). The others map within euchromatic regions of the human genome, many of which are sites of instability associated with genomic disorders, cancer, and evolutionary rearrangement. We termed these regions "duplication hubs," defined as regions where each neighboring pairwise alignment maps within a 5 or 50-kb genomic distance and the total aligned basepairs exceeds 100 kb (Table 1), to distinguish them from areas of the human genome where duplications occur sporadically and most often represented as a single pairwise alignment. Among these duplication hubs, the number of underlying pairwise alignments ranges from 2 to 676 (mean = 67, median = 41), suggesting that these regions have been bombarded by multiple rounds of duplication during the course of evolution.
Interestingly, duplicated regions are particularly rich in transcripts. Overall, when the best-placement of spliced transcripts was considered, we found a higher exon density (62%) in duplicated regions when compared with unique regions of the human genome (Table 2), consistent with earlier findings of the draft genome sequence (Bailey et al. 2002 ). This effect is only observed for spliced ESTs, as opposed to transcripts identified by RefGene or "known gene" within the UCSC Genome Browser, suggesting either incomplete annotation or a higher frequency of transcribed pseudogenes. Details concerning the structure, composition and organization of the segmental duplications (>90% sequence identity and >1 kb in length) within the finished human genome may be found at http://humanparalogy.gs. washington.edu and as a complementary track on http://genome.ucsc.edu.
Compared with other sequenced vertebrate genomes, three properties of human segmental duplications emerge (Table 3; Methods). Human segmental duplications are larger, more interspersed, and show a high degree of sequence identity. Based on the analysis of 25,318 pairwise alignments, we determined that 86.5% of all duplicated bases are part of alignments that exceed 10 kb in length. A total of 55% of human segmental duplications are distributed in an interspersed fashion, where the paralogous pairs are separated by more than 1 Mb or map to nonhomologous chromosomes (Table 3). More than 77% (119/154 Mb) of duplicated bases are part of alignments with >95% sequence identity. These properties contrast sharply with other sequenced vertebrate genomes (Table 3). One caveat to this analysis is that the quality of the various genome sequences differ substantially. Two observations suggest that the observed differences are biological and not an artifact of assembly. First, assembly of the human genome based strictly on whole-genome shotgun sequence (Istrail et al. 2004 ) shows a similar distribution of interspersed and tandem duplicates. Second, recent experimental analyses (Bailey et al. 2004b) and finishing efforts of the mouse genome assembly (E.E. Eichler, unpubl.) confirm the disparity in the relative distribution of interspersed and tandem duplications seen between human and mouse. It should also be noted that structural variation has been shown to be significantly enriched within regions of recent segmental duplication (Iafrate et al. 2004; Sharp et al. 2005; Tuzun et al. 2005). It has been estimated that  20% of segmental duplications are polymorphic within the human and chimpanzee populations (Cheng et al. 2005; Sharp et al. 2005). In the case of human, however, this effect on our analysis was limited because we observed a similar pattern from two independent measures derived from different human DNA sources (Celera and public assembly) (She et al. 2004b). In the case of model organisms, species are highly inbred and it is expected that most duplications would have been fixed.
We analyzed the divergence of interchromosomal and intrachromosomal alignments and plotted the fraction of duplicated bases as a function of the total number of aligned bases (Fig. 1). Several trends emerge. First, there is mode at 0.05 substitutions per site for interchromosomal duplications, and this dramatically decreases by count and by base-pair representation at lower divergences (Supplemental Fig. S1). Most of the increase in higher sequence identity duplications is due to an expansion of intrachromosomal duplications. The majority of intrachromosomally duplicated bases show <0.03 substitutions per site. These high-identity duplications significantly outnumber interchromosomal duplications by count and by total base pairs (4:1 and 12:1, respectively) at comparable levels of divergence (Supplemental Fig. S1; Fig. 1A). The expansion increases until 0.005 substitutions per site, at which point the number of intrachromosomal alignments reduce. This intrachromosomal expansion of duplications is nonuniformly distributed among human chromosomes, largely restricted to nine autosomes and the sex chromosomes (Fig. 1B). In some cases, as much as 9.4% or 32.1% of the chromosomes total base pairs (chromosome 9 and Y, respectively) arose as a consequence of either recent intrachromosomal duplication or gene conversion events.
A molecular clock for primate segmental duplications We sought to establish a molecular clock to determine the evolutionary age of segmental duplications within the human genome. We first aligned 16.78 Mb of unique noncoding genomic DNA between human and nonhuman primates. Four different nonhuman primate species (chimpanzee, macaque, marmoset, and lemur) were selected, representing different divergence branch points from the human lineage. We limited our analysis to high-quality (i.e., finished) sequences derived from bacterial artificial chromosome (BAC) clones; such sequences were associated with a known error rate. Using these sequences, we calculated the genetic distance (substitutions per base pair) from the human sequence (Fig. 2A; Supplemental Table S1a). Based on estimated divergence times of each primate (Goodman 1999 ), we calculated substitution rates ranging from 1.034 ± 0.04 x 10–9 for human–chimpanzee comparisons to 2.276 x 10–9 substitutions per bp/Mya for lemur–human comparisons. The reduction in the substitution rate among species more closely related to human has been noted before and may reflect an increase in hominoid generation time (Chen and Li 2001; Liu et al. 2003). These data served as a baseline to approximate the neutral genomic DNA as a function of divergence. A slower molecular clock in the humans may also contribute partially to the increase in the abundance of highly homologous segmental duplications observed for the human/ape genomes (see below).
Estimating the age of duplication events, however, is confounded by the propensity for these sequences to undergo gene conversion (Hurles 2001 ; Skaletsky et al. 2003; Jackson et al. 2005; Pavli ek et al. 2005). Such homogenization events might erase patterns of divergence and lead to an underestimation of the true evolutionary age of the duplication. Alternatively, post-speciation gene conversion events might serve as a reservoir to increase substitution rates among orthologous copies. Indeed, there are several notable examples where the degree of sequence divergence is incompatible with the estimated timing of the duplication based on comparative analyses (Orti et al. 1998; DeSilva et al. 1999; Shaikh et al. 2001). To address this issue, we selected 17 different duplicons (99 copies throughout the genome) and assessed whether their divergence (K = 0.018 to K = 0.043) was consistent with their estimated time of expansion based on comparative FISH and/or hybridization data. Of the duplications that we investigated, 14/17 showed levels of sequence divergence consistent with the emergence, as predicted by comparative primate sequence data (Supplemental Table S2). In one case on chromosome 15q11, the higher degree of sequence identity was consistent with apparent large-scale gene conversion. In another case on chromosome LCR16a, duplications of the same locus had occurred independently within multiple lineages (E.E. Eichler, unpubl.). We conclude that gene conversion, while an important consideration, unlikely accounts for the bulk of high-sequence identity duplications and does not significantly complicate the estimated timing of events based on comparative FISH and sequence data.
To quantify the substitution rate for duplicated sequence more precisely, we specifically compared 37 duplicated regions between human and nonhuman primates (chimpanzee and baboon). We selected BACs containing duplications that were completely anchored within unique regions of the genome, allowing for unambiguous determination of orthologous relationships (Methods). Compared with strictly unique genome sequences, duplicated regions are significantly more diverged (Fig. 2B; Supplemental Table S1b). Between chimpanzee and human, we estimated a 10% increase in the rate of mutation, while an
Several possible explanations might account for the increased substitution rate of duplicated DNA, including CpG bias, gene conversion, and/or relaxed selective constraint (Chen and Li 2001
The human great-ape expansion of segmental duplications
The single most important caveat of this model is that our predictions are based on the human reference sequence and infer history based solely on that evolutionary trajectory. Based simply on the sequence, we cannot, for example, exclude the possibility that other nonhuman primate species have similarly undergone independent intrachromosomal expansions. Based on our model, such expansions are expected to be observed among great-ape species, but be less common among Old World and New World monkey species. To estimate the frequency of segmental duplications more directly, we performed FISH analyses with three nonhuman primates (chimpanzee, macaque, and marmoset). We randomly selected 384 BACs from each species and counted the number of clones displaying a multi-site distribution pattern, thereby indirectly providing an estimate of segmental duplication content (Table 4; Supplemental Table S3). The map position of each locus was determined based on matching the end-sequences of each BAC to positions along the human reference sequence. Previous cytogenetic and in silico estimates of segmental duplication in humans revealed that in situ estimates are a remarkably accurate indicator of recent duplication content (Cheung et al. 2001
These FISH analyses augment two important aspects of our model. First, we observed an increase in the number of segmental duplications among chimpanzees compared with either baboon (P = 0.0679, Fisher exact test) or marmoset (P = 0.0002) (Table 4). In fact, the marmoset estimate for segmental duplications ( 2%) is similar to experimental and computational predictions for other mammals, such as the rat and mouse (Table 3) (Cheung et al. 2003b; Bailey et al. 2004b; Tuzun et al. 2004). Additional mammalian genomes of higher quality sequence, however, will need to be analyzed to definitively assess the significance of this primate expansion. Second, an examination of the mapped locations of the chimpanzee segmental duplications revealed that 30% (10/26) of the duplicated BACs map to corresponding unique regions in the human genome. This suggests that both great apes and humans have been predisposed to expansions of interspersed segmental duplications, and that a significant number of these will have occurred within different regions of the genome. These findings of extensive de novo duplication in each lineage are consistent with the recent analysis of the chimpanzee genome (Cheng et al. 2005). In addition, both analyses suggest a trend for increased segmental duplication in the chimpanzee lineage when compared with human.
Our studies establish a baseline for estimating the age of segmental duplication and predict an elevated primate substitution rate for duplicated DNA compared with unique noncoding sequence. Surprisingly, our analyses also show that unique sequence-flanking segmental duplications experienced comparable increases in substitution rate. Evolutionary variability in the boundaries between unique and duplicated DNA (i.e., duplication shadowing) may account for this property. We tested for this effect based on our knowledge of the duplication map of the chimpanzee genome (Cheng et al. 2005
Our assessment of segmental duplication among three nonhuman primates provides the first experimental evidence that humans and great apes are enriched for interspersed segmental duplications compared with other primate lineages. The evolutionary basis for this predilection is unknown, but may be related to smaller effective population size, adaptation, a slowdown in the molecular clock, and/or relaxed selective constraints (Li and Tanimura 1987
Segmental duplication analysis We used a BLAST-based detection scheme (WGAC) (Bailey et al. 2001 ) to identify all pairwise similarities representing duplicated regions within the NCBI genome assemblies of human (May 2004), mouse (May 2004), rat (June 2003) and chicken (February 2004). As a control for heterogeneity in the quality of genome assembly, we previously analyzed the Celera WGSA assembly (Istrail et al. 2004; She et al. 2004b), which was assembled using only whole-genome shotgun sequence. All duplications are longer than 1 kb with sequence identity >90%, except for rat and mouse (>5 kb and >90%). Duplications in the human genome were also identified by another approach using whole-genome shotgun sequence detection (WSSD) strategy (Bailey et al. 2002). Divergence estimates, the number of substitutions per site between the two sequences, were calculated using Kimura’s two-parameter method, which corrects for multiple events and transversion/transition mutational biases (Kimura 1980). Transcript content of unique and duplicated sequence was compared by computing the number of exons in each portion of the genome. Three sets of data were considered, i.e., human ESTs with intron/exon structure (4.56 million), RefSeq annotated genes (22,933), and known annotated genes (36,164). Both best-placement and tied genes/transcripts were distinguished based on BLAT score criteria (www.genome.ucsc.edu). In cases where a transcript could be mapped to two or more duplicated locations with equal score, one location was selected randomly. Exon density was defined as the number of nonoverlapping exons identified within the region.
Substitution rates
FISH analysis
We thank Devin Locke and Matthew Johnson for technical assistance. This work was supported, in part, by NIH grants GM58815 to E.E.E and by funds provided through the NHGRI Intramural Program of the NIH to E.D.G. E.E.E. is an investigator of the Howard Hughes Medical Institute. In addition, the authors gratefully acknowledge CEGBA (Centro di Eccellenza Geni in campo Biosanitario e Agroalimentare), MIUR (Ministero Italiano della Università e della Ricerca; Cluster C03, Prog. L.488/92), the European Commission (INPRIMAT, QLRI-CT-2002-01325), and the BMBF (Bundesministerium für Bildung und Forschung) for financial support.
8 These two authors contributed equally to this work. 
E-mail eee{at}gs.washington.edu; fax (206) 685-7301. [Supplemental material is available online at www.genome.org.] Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.4949406
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Received November 22, 2005; accepted in revised format February 14, 2006.  CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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ABSTRACT
Results and Discussion
-satellite sequences were identified on either side of the hybridizing signal. Non-alphoid multi-site BACs were used to estimate recent duplication content. The BAC-end sequences were used to establish the in silico best placement of each clone in the human genome sequence (build35). In total, 50 BACs yielded multiple FISH signals (chimpanzee 28, baboon 15, marmoset 7) (Supplemental Table S3). Only those BACs where the underlying sequence was determined to be duplicated in human were considered to be concordant. The discordant BACs were further confirmed by FISH using human chromosomal spreads. 
