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Genome Res. 15:1232-1242, 2005 ©2005 by Cold Spring Harbor Laboratory Press; ISSN 1088-9051/05 $5.00 Letter Independent intrachromosomal recombination events underlie the pericentric inversions of chimpanzee and gorilla chromosomes homologous to human chromosome 161 Department of Human Genetics, University of Ulm, 89081 Ulm, Germany 2 Children's Hospital Oakland Research Institute, Oakland, California 94609, USA 3 Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, CF14 4XN, United Kingdom 4 Biostatistics and Bioinformatics Unit, Cardiff University, Heath Park, Cardiff, CF14 4XN, United Kingdom
Analyses of chromosomal rearrangements that have occurred during the evolution of the hominoids can reveal much about the mutational mechanisms underlying primate chromosome evolution. We characterized the breakpoints of the pericentric inversion of chimpanzee chromosome 18 (PTR XVI), which is homologous to human chromosome 16 (HSA 16). A conserved 23-kb inverted repeat composed of satellites, LINE and Alu elements was identified near the breakpoints and could have mediated the inversion by bringing the chromosomal arms into close proximity with each other, thereby facilitating intrachromosomal recombination. The exact positions of the breakpoints may then have been determined by local DNA sequence homologies between the inversion breakpoints, including a 22-base pair direct repeat. The similarly located pericentric inversion of gorilla (GGO) chromosome XVI, was studied by FISH and PCR analysis. The p- and q-arm breakpoints of the inversions in PTR XVI and GGO XVI were found to occur at slightly different locations, consistent with their independent origin. Further, FISH studies of the homologous chromosomal regions in macaque and orangutan revealed that the region represented by HSA BAC RP11-696P19, which spans the inversion breakpoint on HSA 16q11-12, was derived from the ancestral primate chromosome homologous to HSA 1. After the divergence of orangutan from the other great apes  12 million years ago (Mya), a duplication of the corresponding region occurred followed by its interchromosomal transposition to the ancestral chromosome 16q. Thus, the most parsimonious interpretation is that the gorilla and chimpanzee homologs exhibit similar but nonidentical derived pericentric inversions, whereas HSA 16 represents the ancestral form among hominoids.
A variety of different types of genetic change are thought to be responsible for the process of speciation, including gross chromosomal rearrangements and, at least potentially, gene diversification in terms of structure, copy number, and also expression (Taylor et al. 2001  ; Nahon 2003; Hey 2003; Wu and Ting 2004). Comparative analysis of the chimpanzee (Pan troglodytes, PTR) and human (Homo sapiens, HSA) genomes should potentiate the identification of the key events that have taken place during human chromosomal evolution at the same time as providing new insights into the underlying mutational mechanisms that have fashioned extant primate genomes. The study of these evolutionary changes may also shed some light on hominid evolution that occurred under parapatric conditions in East Africa (Marques-Bonet et al. 2004; Vallender and Lahn 2004; Zhang et al. 2004).
The most conspicuous differences between the human and chimpanzee karyotypes are the fusion that gave rise to human chromosome 2 (Fan et al. 2002 Here, we report the detailed study of the pericentric inversion of PTR XVI, homologous to HSA 16. By means of FISH analysis and homology searches, we identified breakpoint-spanning BAC clones from both the human and chimpanzee genomes and used them to characterize the inversion breakpoints at the molecular level. According to the banding patterns of hominoid karyotypes derived by Yunis and Prakash et al. (1982), the gorilla (GGO) manifests a pericentric inversion of its HSA 16 homolog (GGO XVI) that appears to be quite similar to the inversion of PTR XVI. We therefore investigated whether the breakpoints of the inversions of PTR XVI and GGO XVI could be identical. Our findings indicate, however, that the inversions of PTR XVI and GGO XVI are located at nonidentical positions and must therefore have occurred independently in the two lineages.
Molecular description of the inversion breakpoints In order to characterize the breakpoints of the inversion that distinguishes PTR XVI from HSA 16, FISH was performed with human BAC clones that map to 16p11-p12 and 16q11-q12 respectively. The results of these FISH experiments are presented in Table 1. Human BAC RP11-696P19, the proximal clone from the most centromeric contig (NT_010498 [GenBank] ) on 16q11.2, exhibited a split signal on PTR XVI (Fig. 1A,B). Although BLAST analyses of BAC RP11-696P19 indicated significant homology to scaffold_32947 of the chimpanzee draft genome sequence, a 4.8-Mb segment from this scaffold was found to be homologous to sequences on HSA16q11.2, whereas a 1.3-Mb segment was homologous to proximal HSA 16p (Fig. 2A,B). Moreover, the comparison between the PTR scaffold_32947, which is the most proximal scaffold on PTR XVIq, and the human chromosome 16 sequences clearly indicated the presence of an inversion and confirmed that HSA BAC RP11-696P19 spans the evolutionary breakpoint.
To identify an HSA BAC clone spanning the inversion breakpoint on the p-arm, we analyzed the 1.3-Mb fragment of scaffold_32947 that exhibited homology to HSA 16p. The distal part of this 1.3-Mb fragment was found to be homologous to a 144-kb stretch of human BAC CTD-2144E22 sequence (Fig. 2B). FISH analyses confirmed that this BAC spans the inversion breakpoint, since hybridization signals were detected on both PTR XVIp and XVIq (Fig. 1C,D). The breakpoint is located within the very distal portion of BAC CTD-2144E22; most of the corresponding sequence has been inverted and is located on PTR XVIq (Fig. 1D). BLAST analysis with HSA BAC RP11-696P19 was then used to identify breakpoint-spanning BACs from the chimpanzee genome: RP43-007E19 and RP43-001I03. The map positions of these clones are indicated in Figure 2. FISH analyses using these PTR BACs revealed split signals on HSA 16p and 16q (Fig. 1E-H), confirming that the BACs do indeed span the inversion breakpoints. To validate the mapping of the inversion breakpoints, we performed FISH on chromosomes of the bonobo (Pan paniscus, PPA), the other chimpanzee species. Human BACs RP11-696P19 and CTD-2144E22 were also found to be breakpoint-spanning in the bonobo, whereas BAC RP11-20D16 is inverted on PPA XVIq (data not shown). To narrow down the positions of the inversion to specific human and chimpanzee breakpoint-spanning BACs, various PCR analyses were performed. Primers were designed by reference to the sequences of the human BACs (summarized in Supplemental Table 1). In relation to the human sequence, the 16q breakpoint maps to between positions 114667-114943 of BAC RP11-696P19 whereas the 16p breakpoint occurred between 144-kb and 162-kb of BAC CTD-2144E22. The PTR XVIq breakpoint was then characterized at the nucleotide level by comparing the sequence of the chimpanzee scaffold_32947 with that of the human BACs, RP11-696P19 and CTD-2144E22. The break in homology between HSA 16q and PTR XVIq was found to occur at position 114711 of BAC RP11-696P19 (Fig. 3), and the breakpoint on the p-arm was mapped to a short single-copy segment of 756-bp located between an L1-element and a stretch of HSATII satellites (Figs. 3, 4A). Careful analysis of the chimpanzee sequence of PTR XVIq revealed the addition of two nucleotides (AC) at the inversion junction. Under the assumption that HSA 16 represents the status of the ancestral chromosome, the breakpoint on HSA 16p occurred between two copies of an octanucleotide repeat (TGTGAAAG) whereas the breakpoint on HSA 16q occurred within one copy of a juxtaposed pentanucleotide repeat (AATGA) (Fig. 3). It can also be seen that the core of the juxtaposed pentanucleotide repeat (AAT GAAATGA) on 16q corresponds exactly to the core TGAAA motif of both 16p octanucleotide repeat sequences. When q- and p-arm breakpoint sites were further compared, a 22-base pair (bp) direct repeat was also identified. This local homology between 16p and 16q is indicated in Figure 3 by a wavy line.
Putative mechanism underlying the inversion RepeatMasker analysis indicated the presence of long stretches of HSATII satellites in HSA BACs RP11-696P19 and CTD-2144E22, spanning 70-kb and 20-kb, respectively. Pairwise sequence comparisons of both BACs further indicated the presence of two inverted repeats of 23 kb with 97% sequence similarity between them (Fig. 4A). Given that HSA 16 represents the ancestral form of the chromosome, it appears likely that these inverted repeats, together with their flanking HSATII satellite sequences, facilitated the inversion, although the breakpoints did not occur directly within the repeats (Fig. 4B,C).
Expression of the genes surrounding the breakpoints
Evolutionary history of the breakpoint regions
Human BAC CTD-2144E22 hybridized to the p-arm of the HSA 16 homologs of both macaque and orangutan. However, on PTR XVI, PPA XVI, and GGO XVI, this BAC displayed a split signal on the p- and q-arms (data not shown). Taken on their own, these findings are not inconsistent with the view that gorilla and chimpanzee share the same pericentric inversion.
Breakpoint position of the GGO XVI inversion To determine whether or not the inversion breakpoints of PTR XVI and GGO XVI occurred at identical sites, FISH was performed with PTR BACs that span the inversion breakpoints on PTR XVI. These chimpanzee BACs, RP43-007E19 and RP43-001I03, yielded split signals on GGO XVI (data not shown). This finding implies that it is extremely unlikely that the PTR and GGO inversion breakpoints are identical in terms of their location. As previously mentioned, human BACs CTD-2144E22 and RP11-696P19 are split by the inversion in both PTR XVI and GGO XVI. It may therefore be concluded that although the inversion breakpoints in PTR XVI and GGO XVI are in close proximity to each other, they are nevertheless nonidentical. To investigate these breakpoints at the nucleotide level, we performed breakpoint-spanning PCR with primer pair P2 (listed in Supplemental Table 1). The primers were designed according to the sequence of HSA BAC RP11-696P19 and flank the inversion breakpoint on HSA 16q (Fig. 6). PCR P2 was negative in PTR, but positive in HSA and GGO (data not shown). Thus, the sequence at the q-arm breakpoint must differ in GGO XVI from that in PTR XVI. By screening a gorilla BAC library with PCR probes (listed in Supplemental Table 3), we identified breakpoint-spanning BACs CH255-551C4 (AY822675 [GenBank] ) and CH255-39D12 (AY822676 [GenBank] , AY822677 [GenBank] ) from the gorilla genome. The positions of these GGO BAC clones with respect to the breakpoints were confirmed by PCR analysis (P1-P10) (schematically indicated in Fig. 6) and by sequencing the BAC ends. GGO BAC CH255-39D12 mapped distal to the inversion breakpoint in GGO XVIq and was positive for PCR markers P9, P3, P1, and P8 (Fig. 6). This served to confirm the interspecies heterogeneity of the q-arm breakpoints in PTR XVI and GGO XVI. GGO BAC CH255-551C4 was positive for PCR markers P6, P7, P10 and mapped to GGO XVIp. Since PCR marker P6 is directly flanked by HSATII repetitive sequences, further localization of the gorilla p-arm breakpoint by PCR was not possible. We nevertheless conclude that the inversion breakpoint on GGO XVIp lies close to or within the HSATII satellites, as found for the breakpoint on PTR XVIp. It is likely that the GGO XVI inversion was mediated by intrachromosomal recombination within HSATII, as schematically drawn in Figure 7.
The breakpoints of the pericentric inversion of PTR XVI, homologous to HSA 16, were characterized by FISH and comparative sequence analyses of breakpoint-spanning BAC clones from the human and chimpanzee genomes. The breakpoints occurred within sequences homologous to human HSA BACs RP11-696P19 (16q11.2) and CTD-2144E22 (16p11.1-p11.2) in single-copy sequences close to HSATII satellites, but do not appear to have disrupted any gene coding regions (Figs. 1, 2, 3). HSA BACs RP11-696P19 and CTD-2144E22 also spanned the inversion breakpoints of the chromosome 16 homolog in the bonobo, the other chimpanzee species, which became separated from the common chimpanzee, Pan troglodytes, 0.86-2 Mya (Yoder and Yang 2000 ; Won and Hey 2005). Intriguingly, the inversion of PTR XVI was not observed by Martin et al. (2004) in their comparison of the HSA 16 sequence with homologous sequences available in other vertebrates, including the chimpanzee. One possible reason for this might be that the scaffolds of the draft chimpanzee genome sequence from the breakpoint regions had not been assembled into larger contigs and, in the absence of FISH data, this could have hampered the assignment of the orientation of these scaffolds.
Comparative FISH analysis in other primates revealed the evolutionary history of the q-arm breakpoint region (Fig. 5). This region, represented by HSA BAC RP11-696P19, is derived from an ancestral primate chromosome homologous to HSA 1. After the separation of the orangutan from the common ancestral lineage shared with the African hominoids, a duplication of the region in question occurred followed by the interchromosomal transposition of the duplicated copy to the ancestral chromosome 16q. The most parsimonious explanation for our findings is that among the hominoids, humans retained the ancestral form of chromosome 16, whereas GGO and PTR acquired pericentric inversions of their respective homologs. The inversions of GGO XVI and PTR XVI were not detected during the molecular cytogenetic studies previously performed by Misceo et al. (2003 ) because the probes that they used are located distally to the respective breakpoints. Comparative analysis of the inversion breakpoint regions in GGO XVI and PTR XVI indicated that whereas the p-arm breakpoints were located within or very close to HSATII satellite DNA, the q-arm breakpoints occurred at nonidentical locations (Fig. 6). Owing to the repetitive nature of the HSATII satellites, it was not possible to compare the p-arm breakpoints in GGO XVI and PTR XVI. This notwithstanding, q-arm breakpoint heterogeneity is supportive of the view that the pericentric inversions of GGO XVI and PTR XVI occurred independently in the two lineages. PCR with primer pair P2, designed according to the sequence of HSA BAC RP11-696P19 and flanking the inversion breakpoint on HSA 16q, was negative in PTR, but positive in HSA and GGO (data not shown). Sequence analysis of the PCR products also indicated an identical sequence in HSA and GGO at the site where the inversion/fusion took place in PTR. The sequence amplified by primer pair P2 has not been deleted in PTR, but rather was split by the inversion (Figs. 3, 6). This provides unequivocal confirmation that the inversions of GGO XVI and PTR XVI occurred at different sites.
Although pericentromeric regions are generally enriched for duplicated sequences, considerable variability with respect to the length of paralogous sequences is apparent. The 16p11-12 region belongs to the category of region with extensive zones of duplication ranging from 500-kb to 5.5-Mb in length (She et al. 2004
It has been suggested that the abundance of duplicated sequences in pericentromeric and subtelomeric portions of mammalian chromosomes gives rise to genomic instability via unequal crossing over during meiosis and may thus serve to drive evolution (Eichler 1998 ; Samonte and Eichler 2002). The high concentration of paralogous segments within the pericentromeric region of chromosome 16 and its evident plasticity are reflections of its likely importance in an evolutionary context. Further evidence for the instability of proximal 16p and 16q comes from reports of pathological breakpoints in these regions. Thus, the 16p11 and 16q11-12 regions are known to be involved in recurring rearrangements in acute myeloid leukemia (Panagopoulos et al. 1994; Sharma et al. 1999; Yamamoto et al. 2001), Ewing's tumor (Shing et al. 2002), lymphoma (Ueda et al. 2002), and liposarcoma (Willeke et al. 1998).
About 5% of our genome is composed of segmental duplications or low-copy repeats. In several instances, duplications have been found at, or in close proximity to, evolutionary breakpoints. It has been suggested that duplicated segments could have played a pivotal role during genome evolution in higher primates (Samonte and Eichler 2002
Human chromosome 16 is known to manifest one of the highest levels of segmentally duplicated sequences among the autosomes (Martin et al. 2004
Detailed analyses of pericentromeric regions have revealed that paralogous sequences are often located in close proximity to satellite sequences (Horvath et al. 2000
Breakpoint comparisons by both FISH and PCR analysis strongly imply that the inversions of PTR XVI and GGO XVI are independent events (Fig. 6, Table 1). Indeed, the q-arm breakpoint in GGO XVI appears to be at least 70 kb distant from the breakpoint in PTR XVIq. With respect to the p-arm breakpoints of the two inversions, breakpoint identity can neither be confirmed nor excluded, since the breakpoints were mapped to highly repetitive HSATII DNA.
The gorilla branched off 6.2-8 Mya from the main hominoid lineage; the chimpanzee separated later, some 4.6-6.2 Mya (Chen and Li 2001
Although the GGO XVI and PTR XVI inversions appear to have been independent events, the breakpoints nevertheless occurred in the same chromosomal regions. Although this finding is, as far as we are aware, unprecedented during vertebrate evolution, multiple independent yet cytologically identical inversions have been demonstrated by DNA sequence analysis in the Anopheles gambiae complex (Caccone et al. 1998
Bailey et al. (2004 ) have put forward a nonrandom model of chromosomal evolution that proposes that specific regions in mammalian genomes are predisposed to both recurrent small-scale duplication and large-scale evolutionary rearrangements. The occurrence of two independent inversions in GGO and PTR with breakpoints in the same regions provides clear support for this nonrandom model.
Cell lines and BAC clones The Pan troglodytes lymphoblastoid cell line PTR-EB176 (ECACC No. 89072704), the Pan troglodytes primary fibroblast culture CP132 (PTR, ECACC No. 91012416), the orangutan (Pongo pygmaeus) lymphoblastoid cell line PPY-EB185 (ECACC No. 89072705), and the lymphoblastoid cell line EB(JC) (ECACC No. 89072703) from Gorilla gorilla were purchased from the European Collection of Cell Cultures (www.ecacc.org.uk). The Pan troglodytes lymphoblastoid cell line PTR-L2008 was a generous gift from Dr. W. Schempp (University of Freiburg, Germany). The lymphoblast cell line GM03446 from Macaca fascicularis (crab-eating macaque) was obtained from the Coriell Cell Repository. The bonobo (Pan paniscus) lymphoblastoid cell line used in these studies was established from peripheral blood samples (taken from a female animal from Frankfurt Zoo, Germany), a generous gift from Dr. Ulrich Zechner (University of Mainz, Germany). For expression analysis, two foreskin fibroblast cell lines and two EBV-transformed lymphoblastoid cell lines from human donors were used.
Fluorescence in situ hybridization (FISH)
Sequence alignments and database analysis
BAC library screening
RNA isolation and cDNA preparation Cytoplasmic RNA was isolated from lymphoblastoid and fibroblast cell cultures derived from three chimpanzees and four humans, as well as lymphoblastoid cells from one bonobo, one gorilla, one orangutan, and one macaque, using the RNeasy kit (Qiagen). First strand cDNA was prepared with 2 µg total RNA (as determined by absorbance), random hexamers, and the Super-Script Preamplification System (Invitrogen).
Gene expression analysis For each analysis, two Pan troglodytes lymphoblastoid cell lines were used, together with one Pan troglodytes primary fibroblast culture, and single lymphoblastoid cell lines from Pan paniscus, Gorilla gorilla, Pongo pygmaeus, and Macaca fascicularis. Two foreskin fibroblast cell lines and two EBV-transformed lymphoblastoid cell lines from human donors were also used. Each comparison was performed in triplicate.
We thank Antje Kollak and Helene Spöri for technical assistance. This research was funded by the Deutsche Forschungsgemeinschaft (DFG KE 724/2-1).
5 Corresponding author. E-mail hildegard.kehrer-sawatzki{at}medizin.uni-ulm.de; fax 49 731 5002-3438.  [Supplemental material is available online at www.genome.org. The sequence data from this study have been submitted to GenBank under accession nos. AY822675 [GenBank] , AY822676 [GenBank] , and AY822677 [GenBank] .] Article and publication are at http://www.genome.org/cgi/doi/10.1101/gr.3732505.
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Received January 21, 2005; accepted in revised format April 5, 2005.  CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati |
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ABSTRACT
Results
satellite/non-
receptor class I in primates: Molecular evidence for two pericentric inversions during the evolution of human chromosome 1. Cytogenet. Cell Genet. 82: 71-74.