Human Molecular Genetics Advance Access originally published online on July 8, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 17 2201-2208
DOI: 10.1093/hmg/ddg223
© 2003 Oxford University Press
Enrichment of segmental duplications in regions of breaks of synteny between the human and mouse genomes suggest their involvement in evolutionary rearrangements
1Program in Genes and Disease, Center for Genomic Regulation, Barcelona Biomedical Research Park, Barcelona, Catalonia, Spain, 2Program in Genetics and Genomic Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada and 3Life and Health Science Department, Pompeu Fabra University, Barcelona, Catalonia, Spain
Received May 8, 2003; Accepted July 2, 2003
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ABSTRACT |
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The sequence of the mouse genome allows one to compare the conservation of synteny between the human and mouse genome and exploration of regions that might have been involved in major rearrangements during the evolution of these two species (evolutionary genome rearrangements). Recent segmental duplications (or duplicons) are paralogous DNA sequences with high sequence identity that account for about 3.5–5% of the human genome and have emerged during the past
35 million years of evolution. These regions are susceptible to illegitimate recombination leading to rearrangements that result in genomic disorders or genomic mutations. A catalogue of several hundred segmental duplications potentially leading to genomic rearrangements has been reported. The authors and others have observed that some chromosome regions involved in genomic disorders are shuffled in orientation and order in the mouse genome and that regions flanked by segmental duplications are often polymorphic. We have compared the human and mouse genome sequences and demonstrate here that recent segmental duplications correlate with breaks of synteny between these two species. We also observed that nine primary regions involved in human genomic disorders show changes in the order or the orientation of mouse/human synteny segments, were often flanked by segmental duplications in the human sequence. We found that 53% of all evolutionary rearrangement breakpoints associate with segmental duplications, as compared with 18% expected in a random location of breaks along the chromosome (P<0.0001). Our data suggest that segmental duplications have participated in the recent evolution of the human genome, as driving forces for evolutionary rearrangements, chromosome structure polymorphisms and genomic disorders. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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An initial comparison between the genomes of human and mouse has identified over 300 segments of synteny (1), but the nature of rearrangements leading to breaks of synteny (BOS) has not yet been elucidated. While the different segment sizes agree with a random breakage model of genome evolution (2), a tendency for chromosomal breaks to reoccur at certain genome regions has been suggested (1). The identification of sequences that are involved in evolutionary rearrangements should provide important insights into the understanding of genome plasticity, and should pinpoint regions that might be associated with disorders that undergo mutations at the genomic level.
Paralogous segments of high sequence identity in the range of one to several hundred kilobases (segmental duplications or duplicons) account for about 3.5–5% of the human genome sequence (3–5). On the basis of their high sequence identity (90–100%), it has been estimated that human segmental duplications have emerged during the past 35 million years of evolution (6). These regions are susceptible to illegitimate recombination, leading to large and recurrent rearrangements of genetic material, defined as genomic disorders or genomic mutations (7). More than 30 human genomic disorders have been described so far (8), and a catalogue of several hundred segmental duplications potentially leading to genomic rearrangements has been reported (4,5). The authors and others have observed that some chromosome regions involved in genomic disorders are shuffled in orientation and order in the mouse genome (9–12). Furthermore, some chromosome regions flanked by segmental duplications have been shown to be polymorphic in humans, including about 30% of parents of patients with the Williams–Beuren syndrome (WBS) chromosome 7 deletion (13), 60% of mothers of Angelman syndrome (AS) patients with deletions of the 15q11–q13 region (11), and mothers of patients that undergo chromosome 8p and 4p rearrangements (14,15). Some of these genomic variants have frequencies of up to 25% in the general population (14). These observations highlight the plasticity of the human genome and the role of segmental duplications in the predisposition to human disorders due to genomic rearrangements. We report here a comparative analysis of the human and mouse genome sequences and demonstrate a strong relationship between changes in the orientation or order of synteny segments, defined as BOS, and segmental duplications, and between these two genome architectural features and human genomic disorders. We propose here that segmental duplications have played a strong role in BOS between the two species (evolutionary rearrangements), and that regions implicated in BOS are probably involved in genomic mutations and in the evolution of genomes.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Breaks in human/mouse synteny are present at human genomic disorder regions
As a first step to characterize the relationship between segmental duplications and evolutionary rearrangements between human and mouse, we focused on regions implicated in human genomic disorders. Regions of BOS correspond to the locations where continuity of the alignments between mouse and human is lost, leading to contiguous segments of mouse/human synteny to appear in different order or orientation. We observed that nine regions involved in genomic disorders show changes in the order or the orientation of mouse/human synteny segments, often being flanked by segmental duplications in the human sequence (Fig. 1 and Table 1). These include the 7q11.23 region deleted in WBS patients, which is inverted in the mouse sequence (9,10); the 15q11–13 region deleted in Prader–Willi syndrome (PWS) and AS subjects, which is in an inverted orientation in the mouse sequence (11); and several segments of human chromosome 17 involved in the Smith–Magenis syndrome (SMS) deletion and in the corresponding duplication, which are interrupted in the mouse sequence (12). The 22q11 region, where several rearrangements occur that cause DiGeorge and velocardio-facial syndrome (VCFS) (16), inv dup(22), cat eye syndrome (17) and the recurrent constitutional translocation t(11;22), is composed of four segments with changes in the order, the longest being inverted. Similarly, the 5 Mb region of chromosome 8p23 that is inverted in 25% of subjects of the general population and predisposes to chromosome 8p rearrangements (14) is composed of two syntenic segments, one being partially inverted. In addition, the neurofibromatosis type 1 (NF1) deletion region (18) is composed of a segment that is inverted and shows a change in order in the mouse sequence. In the case of the chromosome 17q11.2 rearrangements that lead to peripheral neuropathies (19), a large (9.5 Mb) inverted segment of synteny was detected, involving one of the ends of the duplicated/deleted region. A similar pattern was also detected in the chromosome 2q13 region, deleted in patients with nephronophthisis (20). Finally, the 15q24–26 region, associated with anxiety disorders and joint laxity (21), shows a complex pattern with six rearranged segments and three inversions.
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Identification of breaks of synteny
We sought to identify all regions of BOS between the mouse and human genomes. In the initial analysis of synteny between the mouse and human genomes previously reported (1), segments showing inversions in the orientation or changes in the order were compiled into blocks of synteny, leading to a total of 342 segments further grouped in 217 blocks containing segments that belong to the same chromosome but that show changes in the orientation or order (1). In this work, we considered all segments of synteny without further grouping (Table 2). Thus, the total number of syntenic segments identified and subsequently analysed was 414. The additional segments of synteny detected in our study correspond to segments over 20 kb that fall within larger blocks of synteny already described (22) and that, in some cases, redefine their boundaries. Despite this difference, there was an excellent correlation between results obtained in the two comparisons (1,22) (http://www.crg.es/alignments/). The number of chromosome BOS detected in our study ranged between two (HSA21) and 36 (HSA2). The median size of synteny segments ranged from 1.5 (HSA17) to 13.8 Mb (HSA20) with human chromosomes 1, 2 and 17 showing the highest number of rearranged segments. We have analysed the genetic maps of the human and mouse syntenic segments and have compared them with the assembled sequences. A concordance with the order built in the assembly was observed within segments, for example the comparison for three segments of human chromosome 17 with the mouse chromosome 11 syntenic region yields a segment (CSF3, RARA, IGFBP4, CCR7, SMARCE1) of 0.7 Mb, an inverted segment (SPOP, DLX4, DLX3, CHAD, NME1) of 1.7 Mb, and a third segment (ACE, MAP3K3, PSMD12) of 1.8 Mb.
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Segmental duplications are present in regions of breaks of synteny
We examined the association between mouse/human evolutionary genome rearrangements and segmental duplications in the entire human genome. Previously, we have identified all large and recent segmental duplications in the human genome (5) (complete data available at http://chr7.ocgc.ca/humandup). The compilation of interchromosomal and intrachromosomal data led to a total of 3968 segmental duplications (Table 2), corresponding to 1463 distinct groups of intrachromosomal segmental duplications with chromosomes 13, 14, 18, 20 and 21 having the lowest number of segmental duplications. Once alignments and data of syntenic segments were obtained, we located the human segmental duplications on each human chromosome coordinate. We generated graphical images of each human chromosome where the evolutionary rearrangements with the mouse genome could be correlated with the positions of segmental duplications in the human genome. The alignment for HSA17 with the mouse genome is shown in Figure 2A. In addition to the BOS that occur at regions of known HSA17 genomic disorders, breaks are present in other regions containing a high density of segmental duplications. In total, 92% of rearrangements in this chromosome occur at regions containing segmental duplications (Table 3). In addition to the well-defined regions of BOS considered here, additional segmental duplications are located within regions with interruptions in the order of synteny (Fig. 2B). In some cases, segmental duplications located in regions without BOS tend to share very high sequence identity, as in regions 7–17, 35–45 and 65–80 Mb on HSA17, suggesting a very recent origin.
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We then searched for segmental duplications in BOS regions and their boundaries. Amongst different sizes we finally defined a stringent window of
25 kb around the sites of breaks. In order to determine if the observed presence of segmental duplications around and within regions of BOS was significantly different from that expected by chance, we simulated a random distribution of regions of BOS for each human chromosome. By comparing our observed and simulated results (Table 3), we found that, for 17 of 23 human chromosomes, the co-occurrence of segmental duplications at regions of BOS is significantly different from what one would expect by chance. This association was highly significant for 13 chromosomes (P<0.0001), while chromosomes 7, 10, 14 and X were less significant. For chromosomes 5, 8, 18, 19 and 22, although a considerable number of BOS were associated with segmental duplications, the difference with a random location of breaks was not significant. Overall, our analysis for the whole genome sequence shows that, while 18% of BOS were expected to contain segmental duplications at their ends, 53% rearrangements were found to be associated with segmental duplications (P<0.0001). Complete data of mouse/human breaks of synteny and human segmental duplication are available at http://www.crg.es/alignments.
Mouse segmental duplications are also present at regions of break of synteny on X chromosomes
We expect both human and mouse segmental duplications to be implicated in BOS between these two genomes. From our analysis of recent segmental duplications in the mouse genome using the February 2003 draft genome assembly, we found that its duplication content comprises less than 2% of the genome sequence (23). To evaluate to what extent evolutionary rearrangements between mouse and human is due to mouse segmental duplications, we analysed both the human and mouse chromosome X, as they are almost completely represented as reciprocal syntenic blocks (Fig. 2C). Mouse segmental duplications were present in 53% of BOS. Taken together, the analysis revealed that most (75%) BOS between the two X chromosomes contain either human or murine segmental duplications at 25 kb from the ends of syntenic segments, and that in 35% of BOS segmental duplications coexist in the genomes of both species.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The comparison of the human and mouse genome sequences presented here suggests a putative role for segmental duplications in karyotype evolution, since they appear to associated with regions of BOS significantly more often than expected by chance. Owing to the recent occurrence of segmental duplications, it is tempting to speculate that a reshaping of the human karyotype might have occurred very recently in evolution. In this sense, more reliable information should derive from the comparative analysis with sequences of closer evolutionary species. A proportion of segmental duplications has participated in specific chromosome rearrangements between the two species; others are likely to have occurred between humans and other primates, and some are likely to be specific in some human populations. While segment sizes of synteny between mouse and human genomes have suggested a random breakage model of genome evolution (2), a tendency for chromosomal breaks to occur at certain genome regions has been suggested (1). Our results strongly support a non-random model of occurrence of BOS.
In this study we have not considered all the potential to detect BOS between mouse and human, since we have focused the analysis on regions with BOS 
150 kb. Thus, it is possible that an even stronger association between BOS and segmental duplications would have been detected if all observed BOS were considered in the analysis, as illustrated here for HSA17 (Fig. 2B). Changes affecting several syntenic segments for a given region could be due to the presence of several copies of the corresponding segmental duplication (within the region) or to more complex (multi-step) evolutionary rearrangements. We have found that a large proportion (38%) of human segmental duplications are separated by less than 200 kb with respect to each other (5). Micro-rearrangements within these sequences probably cannot be detected at the resolution level of synteny analysis. However, since several regions containing human segmental duplications still contain unfinished sequences, we cannot exclude the possibility that some sequence misassignments give changes in orientation of syntenic fragments. Despite the strong association between BOS and segmental duplications detected here, there are some chromosomes where this association was not significant. There are several plausible explanations for the lack of association in these chromosomes. These include the draft status of genome sequences, the time since the rearrangement occurred, the low number of segmental duplications and BOS observed in some of these chromosomes, and a potential higher contribution of mouse segmental duplications to the rearrangements of these chromosomes. Moreover, segmental duplications were not expected to map at the precise position of breaks of syntenic segments because: (i) we are examining evolutionary rearrangements that occurred 75 million years ago, with several further genomic reorganizations since the first event; (ii) the human and mouse genome sequences still contain gaps and errors; (iii) the human genome coverage of the axtTight alignments subset is imperfect (at the nucleotide level only 40% of the human genome can be aligned to the mouse genome); and (iv) the existence of masked repeat regions should make bridging between neighbour syntenic segments difficult. These arguments also provide a reasonable explanation for the relatively large distances observed between adjacent syntenic segments (Table 2).
Both the proportion and length of segmental duplications in the mouse genome are smaller than in the human genome (23). Nevertheless, we should emphasize that, owing to the shotgun method used for the mouse genome sequencing, it is likely that a large number of murine segmental duplications are still in an ‘unmapped’ status and that the total proportion and length are higher than these initial observations. However, the comparative analysis of mouse and human X chromosomes presented here suggests that murine segmental duplications have also played an important role in the evolution of mouse chromosomes.
We have extended to other genomic disorders the previously described observations of changes in the order or orientation of syntenic segments in the WBS (9,10), SMS (12), and PWS/AS regions (11). These findings establish a strong relationship between human genomic disorders and evolutionary rearrangements with the mouse genome, segmental duplications being a common feature of both. Thus, the data presented here could help analysis of the identification of candidate regions for new genomic mutations that occur in human. In this sense, we have observed changes in the order of syntenic fragments in regions involved in other diseases where segmental duplications are likely to be present, like the Sotos syndrome, with recurrent deletions in a subgroup of the patients (24), the Gorlin deletion syndrome on 9q22 (25), the Wolf–Hirschhorn terminal deletion syndrome on 4p16 (26), and the Miller–Dieker terminal deletion syndrome on 17p13 (27), among other disorders. Thus, a systematic screening of syndromes characterized by developmental delay and minor or major malformations whose inheritance has not been clarified perhaps would link some of the evolutionary rearrangements to potential genomic disorders. Finally, it is possible that discordances between genetic maps could be related to genomic structure polymorphisms, some of them reported recently (14). The analysis of such regions could help to identify human genomic variability and should facilitate our understanding of genomic polymorphisms associated with human disease.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Identification of BOS
The alignments between mouse MGSCv3 and human build 30 assemblies were downloaded from the University of California, Santa Cruz, ftp://genome.cse.ucsc.edu/goldenPath/. Information about the filtering of the alignments is publicly available at the UCSC website. Alignments were done using blastz (28), and the .lav output was converted into .axt format using lav2axt and then filtered with AxtBest (Jim Kent, UCSC). False synteny of segments is expected to be very low since chromosomal misassignment and misalignment of the assembled mouse sequence have been estimated to be <0.3% (1).
Alignments were parsed using perl and awk scripts and dot-plot type graphical displays were generated. In order to avoid small artefacts owing to errors in the two draft genome sequences, we filtered the mouse/human alignments. This probably caused the loss of small syntenic segments, which should be analysed in detail when finished sequences of both genomes are available. Alignments can be seen at http://www.crg.es/alignments. In order to detect BOS, the data from UCSC was first parsed, looking for all the local alignments between a single mouse chromosome and a given human chromosome. Then, BOS were sought within every human chromosome. A simple algorithm was designed to achieve this goal; since human sequence was totally contiguous in our data set, the algorithm sought non-contiguous fragments (150 kb) of mouse sequence aligned to contiguous human fragments. A break was considered as positive if at least three preceding and three subsequent contiguous alignments having the same orientation could be detected. UCSC's AxtBest alignments represent the best alignment between every single human genomic region and the mouse genome; and so, for instance, different paralogous copies of a segmental duplication in different human chromosomes might have their best scoring pair in the same single mouse genomic region. Our algorithm for identifying BOSs runs on a single human chromosome each time and is based on a continuity solution. Thus, it rejects breaks where no continuity in the alignments is found at both sides of the break. For this reason, it is unlikely that interchromosomal segmental duplications might lead to an erroneous BOSs identification.
Presence of segmental duplications at BOS regions
Information about human segmental duplications was incorporated into the dot-plots. To test whether or not segmental duplications were associated with ends of syntenic segments, we used several Visual Basic functions to identify segmental duplications being totally or partially contained in the location of rearrangements. Different sizes were tested around the rearrangement regions ranging from 25 kb to 1 Mb. We followed the study using the most restrictive window (25 kb) around the rearrangement regions. The 1–25 kb range was chosen because it is the calculated median size of the unaligned sequence between two contiguous aligned segments.
Simulation study
We generated random numbers ranging from the first to the last base of each chromosome and, using the size of the observed breaks of synteny in a given chromosome, we defined new randomly located breaks. We then performed the same test of finding segmental duplications inside or in the immediate surroundings (
25 kb) of those regions. The simulation consisted of reassigning the positions of the rearrangement regions 1000 times. With the data obtained we performed chi-square tests between the simulated and the observed data and obtained the two-sided P-values.
GenBank accession numbers
Sequences for human genes: CSF3, AF388025; RARA, AH007261; IGFBP4, U20982; CCR, NM_001838; SMARCE1, NM_003079; SPOP, NM_003563, DLX4, NM_13281; DLX3, AF028233; CHAD, NM_001267; NME1, NM_000269; ACE, AF229986; MAP3K3, NM_002401; PSMD12, NM_002816.
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ACKNOWLEDGEMENTS |
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We are grateful to Roderic Guigó and Arcadi Navarro for critical reading of the manuscript, and to O. González and G. Parra for bioinformatics support and discussion. This work was supported in part by the Departament d'Universitats, Recerca i Societat de la Informació (DURSI); the Departament de Sanitat; the Marató de TV3 (014330); the Comisión Interministerial de Ciencia y Tecnología (SAF2002-00799); and the Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo (Red G03/184) (to X.E., L.A. and M.A.P.). X.E. is a Senior Scientist of the Centre de Regulació Genòmica (CRG).
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FOOTNOTES |
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* To whom correspondence should be addressed at: Program in Genes and Disease, Center for Genomic Regulation (CRG), Barcelona Biomedical Research Park, Passeig Marítim 37-49, 08003 Barcelona, Catalonia, Spain. Tel: +34 932240959; Fax: +34 932240089; Email: xavier.estivill{at}crg.es
Present address: Cancer Biology, Dana-Farber Cancer Institute, Boston 02115, USA.
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 J. H. De Maeyer, J. Aerssens, P. Verhasselt, and R. A. Lefebvre Alternative splicing and exon duplication generates 10 unique porcine 5-HT4 receptor splice variants including a functional homofusion variant Physiol Genomics, June 10, 2008; 34(1): 22 - 33. [Abstract] [Full Text] [PDF]
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 M. Caceres, National Institutes of Health Intramural Sequencin, R. T. Sullivan, and J. W. Thomas A recurrent inversion on the eutherian X chromosome PNAS, November 20, 2007; 104(47): 18571 - 18576. [Abstract] [Full Text] [PDF]
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 N. Bosch, M. Caceres, M. F. Cardone, A. Carreras, E. Ballana, M. Rocchi, L. Armengol, and X. Estivill Characterization and evolution of the novel gene family FAM90A in primates originated by multiple duplication and rearrangement events Hum. Mol. Genet., November 1, 2007; 16(21): 2572 - 2582. [Abstract] [Full Text] [PDF]
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M. Rocchi, N. Archidiacono, and R. Stanyon Ancestral genomes reconstruction: An integrated, multi-disciplinary approach is needed Genome Res., December 1, 2006; 16(12): 1441 - 1444. [Full Text] [PDF]
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M. D. Wilson, J. Cheung, D. W. Martindale, S. W. Scherer, and B. F. Koop Comparative analysis of the paired immunoglobulin-like receptor (PILR) locus in six mammalian genomes: duplication, conversion, and the birth of new genes Physiol Genomics, November 21, 2006; 27(3): 201 - 218. [Abstract] [Full Text] [PDF]
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X. She, G. Liu, M. Ventura, S. Zhao, D. Misceo, R. Roberto, M. F. Cardone, M. Rocchi, NISC Comparative Sequencing Program, E. D. Green, et al. A preliminary comparative analysis of primate segmental duplications shows elevated substitution rates and a great-ape expansion of intrachromosomal duplications Genome Res., May 1, 2006; 16(5): 576 - 583. [Abstract] [Full Text] [PDF]
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 R. L. Stallings, P. Nair, J. M. Maris, D. Catchpoole, M. McDermott, A. O'Meara, and F. Breatnach High-Resolution Analysis of Chromosomal Breakpoints and Genomic Instability Identifies PTPRD as a Candidate Tumor Suppressor Gene in Neuroblastoma. Cancer Res., April 1, 2006; 66(7): 3673 - 3680. [Abstract] [Full Text] [PDF]
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A. Antonell, O. de Luis, X. Domingo-Roura, and L. A. Perez-Jurado Evolutionary mechanisms shaping the genomic structure of the Williams-Beuren syndrome chromosomal region at human 7q11.23 Genome Res., September 1, 2005; 15(9): 1179 - 1188. [Abstract] [Full Text] [PDF]
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V. Goidts, J. M. Szamalek, P. J. de Jong, D. N. Cooper, N. Chuzhanova, H. Hameister, and H. Kehrer-Sawatzki Independent intrachromosomal recombination events underlie the pericentric inversions of chimpanzee and gorilla chromosomes homologous to human chromosome 16 Genome Res., September 1, 2005; 15(9): 1232 - 1242. [Abstract] [Full Text] [PDF]
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 W. J. Murphy, D. M. Larkin, A. E.-v. der Wind, G. Bourque, G. Tesler, L. Auvil, J. E. Beever, B. P. Chowdhary, F. Galibert, L. Gatzke, et al. Dynamics of Mammalian Chromosome Evolution Inferred from Multispecies Comparative Maps Science, July 22, 2005; 309(5734): 613 - 617. [Abstract] [Full Text] [PDF]
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N. M. El-Sayed, P. J. Myler, G. Blandin, M. Berriman, J. Crabtree, G. Aggarwal, E. Caler, H. Renauld, E. A. Worthey, C. Hertz-Fowler, et al. Comparative Genomics of Trypanosomatid Parasitic Protozoa Science, July 15, 2005; 309(5733): 404 - 409. [Abstract] [Full Text] [PDF]
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 G. C. Ferreri, D. M. Liscinsky, J. A. Mack, M. D. B. Eldridge, and R. J. O'Neill Retention of Latent Centromeres in the Mammalian Genome J. Hered., May 1, 2005; 96(3): 217 - 224. [Abstract] [Full Text] [PDF]
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Y. Zhou and B. Mishra Quantifying the mechanisms for segmental duplications in mammalian genomes by statistical analysis and modeling PNAS, March 15, 2005; 102(11): 4051 - 4056. [Abstract] [Full Text] [PDF]
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 D. Misceo, M. F. Cardone, L. Carbone, P. D'Addabbo, P. J. de Jong, M. Rocchi, and N. Archidiacono Evolutionary History of Chromosome 20 Mol. Biol. Evol., February 1, 2005; 22(2): 360 - 366. [Abstract] [Full Text] [PDF]
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P. Stankiewicz, C. J. Shaw, M. Withers, K. Inoue, and J. R. Lupski Serial segmental duplications during primate evolution result in complex human genome architecture Genome Res., November 1, 2004; 14(11): 2209 - 2220. [Abstract] [Full Text] [PDF]
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J. Gonzalez, F. Casals, and A. Ruiz Duplicative and Conservative Transpositions of Larval serum protein 1 Genes in the Genus Drosophila Genetics, September 1, 2004; 168(1): 253 - 264. [Abstract] [Full Text] [PDF]
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D. C. Chen, J. Saarela, R. A. Clark, T. Miettinen, A. Chi, E. E. Eichler, L. Peltonen, and A. Palotie Segmental Duplications Flank the Multiple Sclerosis Locus on Chromosome 17q Genome Res., August 1, 2004; 14(8): 1483 - 1492. [Abstract] [Full Text] [PDF]
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J. A. Bailey, D. M. Church, M. Ventura, M. Rocchi, and E. E. Eichler Analysis of Segmental Duplications and Genome Assembly in the Mouse Genome Res., May 1, 2004; 14(5): 789 - 801. [Abstract] [Full Text] [PDF]
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