Large synteny blocks revealed between Caenorhabditis elegans and Caenorhabditis briggsae genomes using OrthoCluster
© Vergara and Chen; licensee BioMed Central Ltd. 2010
Received: 9 July 2009
Accepted: 24 September 2010
Published: 24 September 2010
Accurate identification of synteny blocks is an important step in comparative genomics towards the understanding of genome architecture and expression. Most computer programs developed in the last decade for identifying synteny blocks have limitations. To address these limitations, we recently developed a robust program called OrthoCluster, and an online database OrthoClusterDB. In this work, we have demonstrated the application of OrthoCluster in identifying synteny blocks between the genomes of Caenorhabditis elegans and Caenorhabditis briggsae, two closely related hermaphrodite nematodes.
Initial identification and analysis of synteny blocks using OrthoCluster enabled us to systematically improve the genome annotation of C. elegans and C. briggsae, identifying 52 potential novel genes in C. elegans, 582 in C. briggsae, and 949 novel orthologous relationships between these two species. Using the improved annotation, we have detected 3,058 perfect synteny blocks that contain no mismatches between C. elegans and C. briggsae. Among these synteny blocks, the majority are mapped to homologous chromosomes, as previously reported. The largest perfect synteny block contains 42 genes, which spans 201.2 kb in Chromosome V of C. elegans. On average, perfect synteny blocks span 18.8 kb in length. When some mismatches (interruptions) are allowed, synteny blocks ("imperfect synteny blocks") that are much larger in size are identified. We have shown that the majority (80%) of the C. elegans and C. briggsae genomes are covered by imperfect synteny blocks. The largest imperfect synteny block spans 6.14 Mb in Chromosome X of C. elegans and there are 11 synteny blocks that are larger than 1 Mb in size. On average, imperfect synteny blocks span 63.6 kb in length, larger than previously reported.
We have demonstrated that OrthoCluster can be used to accurately identify synteny blocks and have found that synteny blocks between C. elegans and C. briggsae are almost three-folds larger than previously identified.
The conservation of large scale genomic sequences across two or more genomes --synteny blocks-- is of primary interest because their identification sets up a stage for identifying and characterizing sequence and functional differences among genomes . The term synteny has been used in different contexts in the past. Originally, synteny was used to indicate the colocalization of different genes in corresponding chromosomes of different species (a.k.a. "chromosomal synteny") . Recently, with the availability of thousands of sequenced genomes, synteny has been used to describe the conservation of co-localized genes in the same order within different genomes (a.k.a "conserved segment"). In some occasions, the term "conserved synteny" has been used to refer a genomic region in which the chromosomal location of multiple markers is conserved, but not necessarily their precise order . The term "synteny block"  has been defined previously as a segment in one genome that can be converted, through genome rearrangements, into a conserved segment in another genome. As such, a synteny block does not necessarily represent areas of perfectly continuous similarity between genomes. In this paper, we use the term "perfect synteny block" as "a genomic region of perfectly conserved gene content, order and strandedness", as defined by Coghlan and Wolfe . As an extension to this definition, we use "imperfect synteny block" as "a genomic region containing some level of interruption, and in which order and strandedness is not necessarily conserved" .
In the past decade, different methods have been proposed to identify synteny blocks [7–12]. However, these methods usually lack one or more of the following functionalities required for detailed analysis: (1) Comparing more than two genomes, (2) Allowing interruptions within synteny blocks; (3) Capturing the strandedness of genes; and (4) Addressing one-to-many orthologous relationships. Failure to provide these functionalities makes these programs inapplicable for the identification of genome rearrangement events such as inversions, insertions, reciprocal translocations and segmental duplications. To tackle these problems, we have recently developed a new method called OrthoCluster, a computer program for the systematic detection of synteny blocks between two or among multiple genomes . Briefly, OrthoCluster takes as input genetic markers (such as genes and microsatellites) and their relationships (such as orthologous relationships) and scans through two or more genomes for synteny blocks. OrthoCluster distinguishes genetic markers as either in-map or out-map. A genetic marker in one genome is called in-map if it has orthologous genetic markers in all corresponding genomes. In contrast, a genetic marker in one genome is called out-map if it does not have orthologous genetic markers in corresponding genomes.
To facilitate the application of OrthoCluster, we have recently developed a web server called OrthoClusterDB . Additionally, a book chapter describing its usage and application has been published . In addition to its use in identifying synteny blocks, OrthoCluster can be applied to identify segmental duplications within a genome .
C. elegans is a free living soil-dwelling hermaphrodite nematode and a popular model organism for biomedical studies because of its small size, transparent body, short life cycle, ease of propagation and compact genome. C. elegans was also the first multicellular organism subject to whole genome sequencing , and the genome sequence of this species has been declared to be complete, with no remaining gaps in 2002. After more than a decade of annotation after its first publication, the genome of C. elegans is arguably the best annotated of a multicellular organism to date [17, 18]. The sequencing of its sister species Caenorhabditis briggsae, also a hermaphrodite, sets up an excellent platform for comparative genomic analysis [5, 19]. Recently, by applying OrthoCluster, we have identified segmental duplications in the nematode Caenorhabditis elegans genome, including a large duplication that is polymorphic among C. elegans laboratory N2 strains . In this project, we applied OrthoCluster to identify synteny blocks between C. elegans and its sister species Caenorhabditis briggsae, whose genome was sequenced a few years ago .
Synteny block identification and characterization is critical for understanding genome structure and functional domains of genomes. Synteny between C. elegans and C. briggsae was first explored when the first sequenced reads of C. briggsae became available. Using their program WABA (for "Wobble Aware Bulk Alignment") , Kent and colleagues compared the whole genome sequence of C. elegans and 8 Mb of C. briggsae sequences (in 229 cosmids) and found that 59% of these genomes are homologous at the base level, while 41% of the genome sequences are found in nonalignable regions. Using these alignments, they estimated the synteny relationship between C. elegans and C. briggsae and found that ~40% of the genome is resistant to rearrangements. Later, using a gene-based approach, Coghlan and colleagues examined the slightly larger set of sequences (12.9 Mb of C. briggsae genome) for synteny blocks and genome rearrangement events  and found many perfect synteny blocks. They also identified larger imperfect synteny blocks between these two genomes with an average size of 53 kb. The completion of the C. briggsae genome sequencing project enabled the C. briggsae genome analysis group to compare C. elegans and C. briggsae at the whole genome scale at the supercontig level . To identify regions of colinearity, the program WABA  was used to produce base level alignments, followed by merging of adjacent blocks and bridging of small transpositions and inversions. Eventually, 4,837 alignments were obtained that cover 84.6% of the C. elegans genome, with a median length of 5.6 kb (mean = 37.5 kb) . The average size is smaller than that obtained using gene-based analysis reported previously . Recently, a chromosomal-level assembly of the C. briggsae genome  has been constructed, which can be utilized to facilitate synteny identification and analysis. Here, taking advantage of this new assembly and our newly developed program OrthoCluster, we revisit and reanalyze synteny blocks between these two genomes.
Initial comparison between C. elegans and C. briggsae genomes
Synteny-based gene model correction and ortholog assignment
Gene model improvement in C. elegans and C. briggsae
Initial number of genes
Outmap genes replaced by predictions
Predictions added because of split genes
Predictions added because of merged genes
Genes added because of new genes
Genes deleted because of special cases
Predictions added because of special cases
Final number of genes
Ortholog assignment between C. elegans and C. briggsae
Genes in one-to-one relations
Genes in one-to-many relations
Total orthologous relations
Genome-wide identification and analysis of synteny blocks
One-to-one orthologous relationships between C. elegans (rows) and C. briggsae (columns).
Perfect synteny blocks
Perfect synteny blocks, operons, and their corresponding genomic coverage, size and range in C. elegans.
All perfect synteny blocks
Distribution of perfect synteny blocks between C. elegans chromosomes (rows) and C. briggsae chromosomes (columns).
Perfect synteny blocks of different sizes are not evenly distributed in all chromosomes. Our results indicate that perfect synteny blocks on Chromosome X are significantly larger than those on the autosomal ones. The median length of perfect blocks within autosomal chromosomes is 11.8 kb (mean = 16.7 kb), whereas the median length of these type of blocks within Chromosome X is 23.4 kb (mean = 32.4 kb), more than two-folds larger (p <0.01, Mann-Whitney U test). This observation is consistent with previously reported observations [19, 21], suggesting that Chromosome X is subject to fewer rearrangement events. Alternatively, most rearrangements occurring in Chromosome X are lethal and are therefore not preserved in evolution. Taking the definition of clusters and arms provided by Hillier and colleagues, we find that, within autosomes, the median length of perfect synteny blocks in autosomal centers is 11.6 kb (mean = 16.6 kb), whereas the median length of perfect synteny blocks in autosomal arms is 12.2 kb (mean = 16.9 kb). This difference is not statistically significant (p-value = 0.15, Mann-Whitney Test). Among all six chromosomes, the one with the highest genomic coverage is Chromosome X (65.4%). Chromosome V, which is the largest chromosome in C. elegans, also contains the largest number of blocks (22.6%).
Species-specific gene family expansions/contractions were observed previously and many gene family members have been found to form tandem clusters in C. elegans and C. briggsae[19, 23], which is consistent to our recent observation that the C. elegans genome harbors a large number of intrachromosomal duplications, many of which occur in tandem . In this project, we have demonstrated that members of a same gene family can form tandem clusters within synteny blocks identified using OrthoCluster. We found 534 such cases, in which 424 contain more genes in C. elegans while 110 have more genes in C. briggsae within these tandem gene clusters. One example of this is a syntenic region that has a higher presence of members of the GST (glutathione-S-transferase) family of genes in C. elegans than in C. briggsae (Additional file 4, Figure S2). Further exploration of these regions is required to unveil the mechanisms underlying the expansion/contraction of these genes.
Our gene model improvement has greatly enhanced our ability to identify larger synteny blocks. When we use the WS180 annotation (before gene model improvement) for the detection of perfect synteny blocks, we found more (3,075) but smaller blocks (Figure 1a, b; Additional file 5, Figure S3; Additional file 6) compared to those described above. For example, the largest synteny block contains 42 genes using the improved annotation, but only 28 genes if we use the WS180 annotation. In fact, the 28 genes are a subset of the synteny block composed of 42 genes detected using the improved annotation. Compared to the WS180 annotation, the improved annotations increase the coverage of the chromosomes (Additional file 6).
Contribution of operons to perfect synteny blocks
According to WormBase annotation (release WS180), there are 1,120 operons in C. elegans, ranging in size from two to eight genes (Table 4). Previous comparative studies have concluded that these operons are highly conserved between C. elegans and its sister species C. briggsae, with the vast majority of the operons (96%  and 93.2% ) conserved between these two species. What is the contribution of operons to the perfect synteny blocks identified between these two species? In order to address this question, we have examined the contribution of operons to perfectly conserved synteny blocks (Table 4, Figure 4). Our analysis suggests that operons constitute an insignificant part of the perfect synteny blocks.
First, the portion of the C. elegans genome covered by the 1,120 annotated operons (9.8%) is dramatically smaller than that covered by the 3,058 perfect synteny blocks identified in this study (as shown above, 51.1% genomic coverage). More recent studies have shown that operons are not as conserved as previously reported and that there is a greater turnover of operon composition among Caenorhabditis species [25, 26], suggesting that the contribution of operons to the perfect synteny blocks between C. elegans and C. briggsae is even lower.
Second, if we define an operonic synteny block as a perfect synteny block with at least half of its genes being conserved operons, we find 385 such operonic synteny blocks (Figure 4). These operonic syntenic blocks contain 498 operons (or 44.5% of the total operons). These 385 operonic synteny blocks cover only 7.4% of the C. elegans genome, still much smaller than the 51.1% of the C. elegans genome covered by all perfect synteny blocks.
Third, the limited contribution of operons to the observed synteny is further illustrated by the low coverage of the X Chromosome by operons (2.1%, 57 operons) in C. elegans, which is the chromosome that is most covered by perfect synteny blocks (65.4%, 431 perfect synteny blocks) between C. elegans and C. briggsae (Table 4).
Imperfect synteny blocks
In this work we applied our newly developed tool, OrthoCluster, for the detection of synteny blocks between the genome of C. elegans and the newly reconstructed C. briggsae genome. This anchor-based program has a number of features that makes it useful for identifying synteny blocks. In addition to identifying mismatches within syntenic regions, it takes into consideration one-to-many orthologous relationships at the moment of identifying synteny blocks. It is also sensitive to gene strandedness. More importantly, OrthoCluster works with multiple genomes so that users can explore synteny among the expanding number of sequenced genomes. Now that the genomes of three additional Caenorhabditis species (C. remanei, C. japonica, and C. brenneri) have been sequenced, we are eager to apply OrthoCluster to identify and analyze synteny relationships among these genomes. The appropriate handling of these types of features enables users to detect genome rearrangement events such as insertions, deletions, duplications, inversions, and reciprocal translocations. Furthermore, OrthoCluster can be used for the detection of segmental duplications within a single genome . Since OrthoCluster is an anchor-based program, correct annotation of the genetic markers coordinates used as anchors is an essential condition for the accurate estimation of synteny. Taken together, OrthoCluster is a flexible tool for the detection of synteny blocks among species of different evolutionary distance.
We have demonstrated that syntenic information is useful for the improvement of defective gene models and detection of potential new genes and missing orthologous relationships. In this attempt, we have identified 582 new gene models (Table 1) in C. briggsae and 52 candidate new gene models in C. elegans. These improved annotations enabled us to identify 949 new orthologous relationships. Some of the new gene models that we have identified were independently detected by WormBase curators. For example, gene C10A4.10 was absent in WormBase release WS180, but was later curated and released in WS190. This gene was detected also with our procedure (Additional file 8, Figure S5).
The improved genome annotations and orthologous relationships have helped the synteny block analysis since larger synteny blocks are found in contrast to those obtained with WS180 annotations (Figure 1). Also, some conserved operon structures are restored with the improved annotations (Additional file 9, Figure S6). This methodology will be applied for improving the annotation of the newly sequenced genomes of C. remanei, C. brenneri, and C. japonica.
Hillier and colleagues constructed the first chromosomal level assembly of C. briggsae. Taking advantage of OrthoCluster and this newly constructed C. briggsae assembly, we found that 80.8% of the C. elegans genome (and correspondingly 78.3% of the C. briggsae genome) is covered by synteny blocks that contain at least two genes. The amount of genome coverage by synteny blocks is consistent with a previous report . Including "synteny blocks" composed of a single gene (in-map genes) only slightly increases the coverage of the C. elegans genome to 84.4% (corresponding to 81.9% of the C. briggsae). This coverage is also in excellent agreement with the work of Stein and colleagues (84.6% for C. elegans and 80.8% for C. briggsae) . Thus, the conservation observed between the C. elegans and C. briggsae genomes is accounted for largely by synteny blocks that contain two or more genes. However, the synteny blocks discovered between C. elegans and C. briggsae using OrthoCluster (median size of 15.6 kb, average size of 63.6 kb) are much larger than those identified by the previous whole genome analysis (median size of 5.6 kb, average size of 37.5 kb).
Taken together, we have demonstrated that OrthoCluster can be used to accurately identify synteny blocks. Additionally, we have found that synteny blocks between C. elegans and C. briggsae are almost three-folds larger than previously identified.
OrthoCluster algorithm and development was described previously . Briefly, it uses an anchor-based approach to effectively search for synteny blocks between two or more genomes given parameters for controlling synteny block size, mismatches within synteny blocks as well as preservation of order and strandedness (Additional file 10, Figure S7). Since OrthoCluster takes into consideration both order and strandedness of genes, it is useful for the detection of inversions and other genome rearrangement events. In addition to identifying perfect synteny blocks (that contain no mismatches and preserve gene order and strandedness), it can be applied to identify imperfect synteny blocks with various levels of mismatches. OrthoCluster needs two types of input files (Additional file 11, Figure S8): a genome file and a correspondence file. A genome file contains genetic markers (which could be annotated genes) with information regarding chromosome/supercontig names, start and end positions, as well as the strand in which each genetic marker resides. A correspondence file provides orthologous relationships between two (for pair-wise analysis) or more genomes (for multiple-genomes analysis). Genetic markers that are not included in the correspondence file are called out-map genetic markers (in this paper, "genes" and "genetic markers" are used interchangeably). In contrast, genetic markers that are part of the correspondence file are called in-map genetic markers. A synteny block can be non-nested or nested (Additional file 12, Figure S9) with nested block defined as one that is contained within a larger block. A nested synteny results from a segmental duplication of a portion of a larger synteny block in one genome (Additional file 12, Figure S9d).
Genome annotations of C. elegans and C. briggsae were obtained from WormBase http://www.wormbase.org/, release WS180. Since some genes produces multiple alternative isoforms and all of these isoforms represent one gene (locus), we used the longest isoform to represent a gene.
Correspondence file preparation
To generate the correspondence file required by OrthoCluster, we assigned orthologous relationships between different genomes using InParanoid [22, 29] with default settings. InParanoid has been evaluated to be one of the best performing methods for orthology detection . Ortholog assignment between C. elegans and C. briggsae is further improved based on gene model improvement, sequence similarity, and synteny when applying our gene model improvement procedure. A correspondence file contains both one-to-one and one-to-many relationships.
Synteny based gene model improvement and ortholog assignment
We also assigned new orthologous relationships using synteny information and similarity (blast alignment scores). To achieve this, we compared the out-map genes with the new gene models and calculate their percentage identity (PID). We accept a new pair of orthologs if the PID between them is greater than or equal to 40% and the e-value is less or equal than 1e-10. The revised orthologous relationships were then incorporated into the InParanoid-driven orthologous relationships.
We thank Jeffrey Chu and Mei Tang for assistance with validating revised gene models. This project is supported by a Discovery Grant to NC from the Natural Sciences and Engineering Research Council of Canada (NSERC). IAV is supported by a Weyerhaeuser Molecular Biology and Biochemistry Fellowship. NC is also a Michael Smith Foundation for Health Research (MSFHR) Scholar and a Canadian Institutes of Health Research (CIHR) New Investigator.
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