MicroSyn: A user friendly tool for detection of microsynteny in a gene family
© Cai et al; licensee BioMed Central Ltd. 2011
Received: 6 September 2010
Accepted: 18 March 2011
Published: 18 March 2011
The traditional phylogeny analysis within gene family is mainly based on DNA or amino acid sequence homologies. However, these phylogenetic tree analyses are not suitable for those "non-traditional" gene families like microRNA with very short sequences. For the normal protein-coding gene families, low bootstrap values are frequently encountered in some nodes, suggesting low confidence or likely inappropriateness of placement of those members in those nodes.
We introduce MicroSyn software as a means of detecting microsynteny in adjacent genomic regions surrounding genes in gene families. MicroSyn searches for conserved, flanking colinear homologous gene pairs between two genomic fragments to determine the relationship between two members in a gene family. The colinearity of homologous pairs is controlled by a statistical distance function. As a result, gene duplication history can be inferred from the output independent of gene sequences. MicroSyn was designed for both experienced and non-expert users with a user-friendly graphical-user interface. MicroSyn is available from: http://fcsb.njau.edu.cn/microsyn/.
Case studies of the microRNA167 genes in plants and Xyloglucan ndotransglycosylase/Hydrolase family in Populus trichocarpa were presented to show the utility of the software. The easy using of MicroSyn in these examples suggests that the software is an additional valuable means to address the problem intrinsic in the computational methods and sequence qualities themselves in gene family analysis.
Over the past ~ 200 million years, flowering plant (angiosperm) genomes have undergone multiple whole-genome duplications (WGDs), followed by chromosomal rearrangement, gene shuffling and gene loss after each duplication, as well as subsequent inversions, translocations and tandem duplications . In addition, among short DNA segments mobile elements like retrotransposons have caused additional rearrangements and partial or complete gene duplications. As a result, extant angiosperms vary more than 1000-fold in genome sizes and nearly 50-fold in chromosome numbers . Such multilevel rearrangements, accompanied by simultaneous gene loss and tandem duplications, make it very challenging to understand genome evolutions, to infer paleo-polyploidy and to determine the orthology and paralogy among and within plant species.
Fortunately, with the availability of several fully sequenced plant genomes, studies of genome evolution and organization become possible in part by detecting syntenies and colinearities or clustering and ordering of neighboring matching gene pairs . Typically, synteny and colinearity have been identified by searching for statistically supportive conservation between (pairwise) or among (multiway) species . Recent studies on conserved syntenic regions across various plant species at the whole-genome level have provided valuable insights into the evolution and organization of whole genomes and the homology in several plant species [3, 5, 6]. Microsynteny (small-scale of synteny) has been investigated across several plant species using whole-genome sequences or selected discrete sequences to infer shared ancestry [7, 8].
Inferring the evolutionary history of a gene family and related chromosome segments is one of the main tasks in studying biological evolution. The traditional phylogenetic principles and methods are based on amino acid or nucleotide sequence to assess homology, determine orthology and paralogy, and deduce relationships within gene families and/or reconstruct gene evolutionary events. Several approaches have been developed including parsimony, phonetic and maximum likelihood; each has drawbacks, especially when the sequences of the interested genes are truncated, contain gaps or are low quality . Since traces from past evolution events for a gene family can often be detected from the local genome organization , we may be able to take advantage of microsynteny to better infer gene family evolution.
The identification of synteny, whether macro- or micro-synteny, can be laborious and error-prone, and is usually performed manually with some basic tools such as BLAST . Some software packages have been developed to facilitate such searches. ADhoRe was developed to find synteny, particularly for larger genomic regions . An automatic microsynteny analysis pipeline and a synteny database have been developed for animals . However, these tools and pipeline are case-specific or for specialists with extensive training and experiences. Their limited user interface makes themselves difficult to be used by users without specific training; a graphical user interface (GUI) is not available in current microsynteny analysis tools.
We have developed a tool, called MicroSyn, to semi-automatically detect microsynteny within an individual gene family. In particular, MicroSyn was designed for both experienced and non-expert users. To demonstrate the utility and use of MicroSyn, we presented a case study of the evolution of miR167 gene family in Arabidopsis thaliana (Arabidopsis), Populus trichocarpa (Populus), Vitis vinifera (grape) and Oryza sativa (rice). We demonstrate how MicroSyn can be used to overcome problems with the reconstruction of phylogenetic relationships from short nucleic acid sequences in that the quality of the sequence alignments rapidly declines when the pair-wise sequence identity falls below 50 or 60%. The precursor sequences of homologous microRNAs (miRNAs) are often below this threshold. Additionally, we also conducted a case study to confirm the utility of MicroSyn in verifying the phylogenetic relationships of genes in a traditional protein-coding gene family, using Xyloglucan Endotransglycosylase/Hydrolase (XTH) genes in Populus as a test case.
The distance controls the extent of the colinearity for a series of homologous pairs between two fragments. In this way, the homologous pairs that are located in minimum distance are recorded and then the search continues to the next gene pair. According to this criterion, pair "b" is recorded and taken as the new point for searching the adjacent homologous pair. Finally, all the fitted pairs are stored into one cluster that contains gene pairs a, b, d and e in Figure 2. The cluster represents the conserved region between two genomic fragments that have evolution relationship. The searching process is mainly controlled by two parameters: the maximum distance, max(|xi+1- x i |, |yi+1- y i |), between two adjacent genes in each fragment and the actual value of d i between two adjacent homologous pairs.
Statistical validation of conserved genomic fragment
In other words, the value of p c is determined by both the number of homologous gene pairs in a given detected cluster and the total number of genes in two genomic fragments. So, if p c of a cluster exceeds a threshold value, the cluster is considered to be negative and should be discarded.
This section describes the pipeline of the tool and its application to two examples of gene families in plants.
Step 1: Generate MSY file
Step 2: Homologous gene table
The CDSs in MSY file are first translated into corresponding protein sequences by MicroSyn. For gene protein sequences from two gene fragments, for which microsynteny is to be detected, an all-against-all sequence similarity search is initially performed using BLASTP. Homologous genes are determined if two protein sequences have ≥30% sequence identity over an aligned region of ≥100 amino acids. After parsing the sequence similarity search results, a table consisting of all pairs of homologous genes is obtained. For recently tandem-duplicated genes, only the member at the first position is included as a representative for tandem homologous genes.
Step 3: Detection of microsynteny
The homologous gene pairs between two genomic fragments are searched iteratively according to a distance function that controls the colinearity of homologous pairs (see details in algorithm). The selected gene pairs which satisfy the criterion are placed in a cluster which contains the information on microsynteny of two gene fragments. The result of MicroSyn is presented visually and saved in an output file. The graphic file provides an intuitive view of microsynteny that can be saved as an image file. The other information is placed in text format in a main output window (Figure 3).
Step 4: Estimation of synonymous substitutions
The peptide alignments, resulting from BLASTP, of each pair of conserved flanking genes surrounding the target gene(s) are taken as a guide to extract highly quality aligned coding sequence, excluding gaps. The level of synonymous substitution (Ks) for the selected nucleotide sequences is calculated using the method by Nei and Gojobori . The mean Ks value is calculated for all pairs of protein-coding genes between each of genomic fragments.
In this study, we demonstrate the utility of MicroSyn by applying it to exploration of two gene families in plants.
Sequence resource for case studies
The precursor miR167s sequences of Arabidopsis, Populus, grape and rice were downloaded from the miRNA Registry version 13 http://microrna.sanger.ac.uk/. The coordinates of miR167s on Arabidopsis and rice were also downloaded from the miRNA Registry. For Populus and grape miR167s, the coordinates on newly released genome annotation is not available; we calculated the coordinates of miR167s by aligning each gene against the whole-genome assembly. The GFF and complete CDSs of plant species were obtained from public domains. The Arabidopsis CDSs and GFF were downloaded from TAIR release 9 ftp://ftp.arabidopsis.org/home/tair/Genes/TAIR9_genome_release/. The Populus CDSs and GFF were downloaded from ftp://ftp.jgi-psf.org/pub/JGI_data/phytozome/v5.0/Ptrichocarpa/annotation/. The grape CDSs and GFF were downloaded from http://www.genoscope.cns.fr/externe/Download/Projets/Projet_ML/data/12X/annotation/. The rice CDSs and GFF were downloaded from ftp://ftp.plantbiology.msu.edu/pub/data/Eukaryotic_Projects/o_sativa/annotation_dbs/pseudomolecules/version_6.0/all.dir/.
A total of 39 XTH genes in Populus was identified by using the HMMER3 http://hmmer.janelia.org/ and the PF06955 Hidden Markov Model http://pfam.wustl.edu, with the gathering cutoff option (--cut_ga). Multiple protein sequences then were aligned using CLUSTAL W2  with default parameters. The neighbor jointing (NJ) phylogenetic tree and maximum likelihood (ML) tree were constructed using PHYLIP  with default options. Resampling was performed using bootstrapping with replicates of 100.
Evolution of miR167 gene family in plants
Basic information on the miR167 families in Arabidopsis, Populus, grape and rice
Relationship and evolution of miR167s within Arabidopsis, Populus, grape and rice
Eight miR167 genes were identified in Populus. The tandemly duplicated miR167a and miR167b share substantial colinear region with the tandemly duplicated miR167c and miR167d (Figure 4c). miR167f and miR167g share conserved synteny and microsynteny was detected between miR167e and miR167h. According to the extent of conservation within this gene family, miR167f/miR167g and miR167a/miR167b/miR167c/miR167d arose from a duplication event, and the common ancestor of miR167f/miR167g and miR167a/miR167b/miR167c/miR167d, might be evolved from duplication after the ancestor of miR167e/miR167h appeared (Figure 4d).
In grape, there are five members in the miR167 family. The microsynteny between the miR167c and miR167e is extensive, followed by the miR167b and miR167e and then miR167b and miR167c (Figure 4e). Interestingly, the region around miR167a lacks detectable colinear relationship to all other miR167 genes in grape. The predicted syntenic relationships suggest that miR167c/miR167d and miR167e arose from a recent duplication event, and that the miR167b and the ancestor of miR167c/miR167d and miR167e evolved from an ancient duplication (Figure 4f). The region of miR167a lacks significant colinear relations to all other miR167 genes; therefore, miR167a is placed close to miR167b as an outlier (Figure 4f).
Ten miR167 genes were identified in rice. The miR167a and miR167h are tandem genes located on chromosome 12. Microsynteny was detected between 1) miR167c and miR167d, 2) miR167f and miR167g and 3) miR167e and miR167i (Figure 4g). These gene pairs all have conservative regions with miR167a. For miR167j, no conserved regions were observed. In rice, three pairs (miR167c/miR167d, miR167f/miR167g and miR167e/miR167i) appear to have evolved from a recent duplication event as these gene pairs all have a conservative region with miR167a (Figure 4h).
Relationship and evolution of miR167s in eudicots
It is thought that miRNA families evolved from a process of genome-wide duplication, tandem duplication and segmental duplication accompanied by post-duplication diversification, similar to the evolution process of protein-coding gene families . Here we found that the miR167 homologs appear to have arisen via gene duplication events, which are designated as R1, R2 and R3 in this study (Figure 5). Group D appears to be most ancient and few traces of colinearity can be found between it and other groups, indicating either that it evolved via a small duplication event that did not involve surrounding genes, or that microsynteny is too ancient to be detected, or that it occurred via complete transposition and loss of its progenitor.
Estimation of the mean value of Ks for flanking genes around miR167s in Arabidopsis, Populus, grape and rice
Relationship and evolution of miR167s between monocots and eudicots
We used the miR167s in rice to search conserved regions in the genomes of Arabidopsis, Populus and grape to study the relationship of the miR167s between monocots and eudicots. With the inclusion of rice, it was difficult to classify A, B, C and D groups unambiguously to the groups in Arabidopsis, Populus and grape (Additional file 1: Supplemental Fig. S1-S3). Nevertheless, miR167e and miR167i appear to be the most ancient and are classified into group D; other miR167s in rice can only be roughly grouped as a composite "ABC" group. Although miR167d in Arabidopsis and miR167a in grape are likely ancient, weak microsynteny is detected with miR167e in rice and is thus grouped as group D. It has been well documented that the second whole-genome duplication event in rice occurred about 70 MYA, after the divergence of monocots and eudicots . It has also been reported that colinear orthologs between monocots (rice) and the eudicots comprise only ~15% of rice genes distributed over about half of the genome . In this study, it was also challenging to infer the contribution of this recent duplication to the miR167 duplication events, for that reason the orthologous correlation of miR167s in rice to group A, B or C in eudicots is unclear.
Verification of the phylogenetic tree of a protein-coding gene family
Since miRNA genes are very short in sequences by themselves to be used for constructing the phylogenetic trees, microsyntenies among/between their pre-miRNA genes are highly valuable in referring their evolutionary relationships. In using traditional phylogenetic tree to infer the member relationships, low bootstrap values (less than 60%) in some nodes are frequently observed, which suggests the low confidence in placing those gene members in those nodes. We used the XTH family in Populus as the test case for the reasons that it is not only an ancient gene family involved in cell wall biosynthesis (assumably appeared as early as vascular plants appeared), but also has undergone moderate gene expansion, therefore, enabling us to follow the evolutionary history.
Comparison of MicroSyn with existing tools
The current tools related to synteny analysis include i-ADhoRe , DAGChainer , DiagHunter , FISH , Cinteny , Osfinder , OrthoClusterDB , SyntenyTracker , Satsuma , etc. In these tools, the target of analysis is conservative regions within or across species. If researchers are interested in the synteny relationship between regions that contain members in a gene family, they must extract all flanking regions of the genes of interest as the import data. A browser-based tool PLAZA Synteny plot http://bioinformatics.psb.ugent.be/plaza_v1/synteny/index reports the local gene organization for homologous genes within a family . PLAZA Synteny plot presents some pre-computed information on the local gene organization of all homologs of that family. Users are allowed to choose three sets of window size (5, 10 or 15 genes), number of genes around the locus, to query the homologous relationship within a selected gene family. In comparison, MicroSyn is a stand-alone desktop software running in a GUI environment and is more flexible. User can use the family of interest that is not pre-computed in web-based databases, while other online tools are still limited by network latency and the load caused by simultaneous query of concurrent users. In MicroSyn, the window size or number of flanking genes around a member of a gene family is not fixed but can be set by the user, and other parameters of searching are also allowed to be defined by users. Before starting microsynteny detection, parameter settings are defined via user inputs. These inputs include 1) window size - the maximum number of adjacent genes that are allowed in the search on each gene list, 2) tandem gap size - the maximum number of genes allowed to be existed between two tandem homologous genes defined in the study, 3) homologous pairs-minimum number of homologous gene pairs in a detected microsynteny, and 4) expected threshold value - the maximum probability of a microsynteny estimate generated by chance. These parameters are used to customize the search results. In the two examples, the parameters were set as follows: window size of 100 genes, tandem gap value of 2, expected threshold value cut off of 0.01, and 3 homologous pairs to define a syntenic segment. For the window size, we suggest users to choose a value > 30 genes, because a too small window size will decrease the sensitivity.
Application in two examples
For miR167 we only considered the conserved synteny of miR167s intra- and inter-species without using the gene sequences themselves to successfully infer the duplication events of this gene family in plants. This was particularly successful in eudicots, where the microsynteny of miR167s can not only be used to infer the relationships within one species (relationship and evolution resulted from genome or gene duplication), but also be used to infer the orthologous relationships between and among the species (Arabidopsis, Populus and grape). A less definite inference between monocots and eudicots using microsynteny and colinearity was reasonable and possibly due to the far divergence of monocots and eudicots . However, the user-friendly MicroSyn software has been proven to be a new means to study the evolution of gene family among moderately diverged species. We also applied MicroSyn to validate/adjust the evolutionary relationship in the questionable nodes (with low bootstrap values) in traditional phylogenetic trees, such as ML or NJ trees, of a protein-coding gene family, the XTH gene family. Based on the phylogenetic tree of the XTH family constructed by traditional methods using their amino acid sequence homologies, the microsynteny between each pair of members can be easily obtained by using the MicroSyn software. In several poorly supported branches/nodes, the microsynteny can be useful to further check or modify the phylogenetic tree.
Limitations of MicroSyn
MicroSyn is suitable for the analysis of a small or medium size of gene family. If a large set of sequences need to be analyzed, it is better to decrease the window size. Choosing a smaller window size will cause smaller region to be searched for the colinearity between genomic segments. The larger size of flanking region, the greater chance that a synteny will be found. In essence, when a larger widow size is set, the sensitivity is increased while the probability of Random-access memory (RAM) overflows is also increased. By modulating the window size, users can find the best balance of precision and performance that best suits his or her needs. In this study, the two examples were performed on a 2.8 GHz Intel Pentium 4 CPU and 4G RAM based PC with Windows XP operating system. For the XTH family, the window size of flanking genes is set as 100 and the process of detecting cost 7 minutes.
Microsynteny between two members of a gene family is calculated from their flanking genes. If the flanking regions contain assembly errors, gaps or annotation errors, the microsynteny should be artificial. So users should be cautious about it.
In this study, we took advantages of newly available whole genome resources, and developed a program, MicroSyn, a semi-automated tool, to provide an additional valuable means to address the problem intrinsic in the computational methods and sequence qualities themselves in gene family analysis. MicroSyn is particularly useful for identification of conserved synteny among regions surrounding genes in a gene family. This tool can facilitate research related to defining the genome evolution and gene duplication events within a gene family that have led to the extant gene catalog. We demonstrated the utility of this software in the case study of miR167, a miRNA gene family whose evolutionary relationship cannot be inferred based on the traditional phylogenetic tree analysis due to short conserved sequences of these miRNAs. We also demonstrated that MicroSyn can be used to validate or correct the evolutionary relationships in poorly supported nodes in traditional phylogenetic trees.
We plan to continue improving the facility of operation, based on user-feedbacks. In the future, more sophisticated modules, such as automatic tree reconstruction based on the microsynteny information between members of a gene family using some more sophisticated methods. MicroSyn is now implemented in C# on Windows platform. We also plan to produce Mac or Linux versions, since most genomic scientists use these operating systems.
Availability and requirements
Project name: MicroSyn
Project home page: http://fcsb.njau.edu.cn/microsyn
Operating system(s): Windows
Programming language: C#
Requirements: .net framework on Windows
whole genome duplication
graphical user interface
million years ago
The portion of the research carried out at the University of Tennessee is supported in part by the DOE-Bioenergy Science Center grant to ZMC and by the Tennessee Agricultural Experiment Station. The BioEnergy Science Center is a U.S. Department of Energy Bioenergy Research Center supported by the Office of Biological and Environmental Research in the DOE Office of Science.
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