A fast algorithm for the multiple genome rearrangement problem with weighted reversals and transpositions
 Martin Bader^{1}Email author,
 Mohamed I Abouelhoda^{2, 3} and
 Enno Ohlebusch^{1}
https://doi.org/10.1186/147121059516
© Bader et al; licensee BioMed Central Ltd. 2008
Received: 14 March 2008
Accepted: 04 December 2008
Published: 04 December 2008
Abstract
Background
Due to recent progress in genome sequencing, more and more data for phylogenetic reconstruction based on rearrangement distances between genomes become available. However, this phylogenetic reconstruction is a very challenging task. For the most simple distance measures (the breakpoint distance and the reversal distance), the problem is NPhard even if one considers only three genomes.
Results
In this paper, we present a new heuristic algorithm that directly constructs a phylogenetic tree w.r.t. the weighted reversal and transposition distance. Experimental results on previously published datasets show that constructing phylogenetic trees in this way results in better trees than constructing the trees w.r.t. the reversal distance, and recalculating the weight of the trees with the weighted reversal and transposition distance. An implementation of the algorithm can be obtained from the authors.
Conclusion
The possibility of creating phylogenetic trees directly w.r.t. the weighted reversal and transposition distance results in biologically more realistic scenarios. Our algorithm can solve today's most challenging biological datasets in a reasonable amount of time.
Keywords
Background
During evolution both local and global mutations of DNA molecules occur. Local mutations (point mutations) consist of the substitution, insertion, or deletion of single nucleotides, while global mutations (genome rearrangements) change the DNA molecules on a large scale. In unichromosomal genomes, the most common rearrangements are inversions (also called reversals in bioinformatics), where a section of the genome is excised, reversed in orientation, and reinserted. But also transpositions play a role. In a transposition, a section of the genome is excised and inserted at a new position in the genome; this may or may not also involve an inversion. Since genome rearrangements are rare compared to point mutations, they can give us valuable information about the evolutionary history of organisms. Moreover, because of the progress in largescale sequencing in the last decade, hundreds of complete genomes are available to date. As a consequence, we are now able to tackle the problem of reconstructing the evolutionary history of genomes.
In the context of genome rearrangements, a unichromosomal genome is usually represented by an ordering of certain oriented markers (e.g., genes or synteny blocks [1]). Moreover, in the comparison of several genomes, it is typically assumed that the genomes have the same set {1,...,n} of markers. Thus, in the following a unichromosomal genome will be represented by a signed permutation of the sequence (1,...,n), where the sign indicates the corresponding orientation (strandedness) of the marker.
In the multiple genome rearrangement problem, one searches for a phylogenetic tree describing the most "plausible" rearrangement scenario for multiple genomes. Formally, given k genomes, find a tree T with the k genomes as leaf nodes and assign ancestral genomes to internal nodes of T such that the tree is optimal, i.e., the sum of rearrangement distances over all edges of the tree is minimal. The following rearrangement distances have been studied:

The breakpoint distance between two genomes is the smallest number of places where one genome must be broken so that the pieces can be rearranged to form the other genome. It can straightforwardly be computed in linear time.

The reversal distance between two genomes is the minimum number of reversals required to transform one genome into the other. It can also be computed in linear time [2, 3].

In the weighted reversal and transposition distance, the two types of operations are assigned (different) weights, and the rearrangement distance between two genomes is the minimum of the weights of all rearrangement sequences that transform one genome into the other (of course, the weight of a sequence is the sum of the weights of the operations in the sequence). The problem of computing the weighted reversal and transposition distance in polynomial time is yet unsolved, but we developed a 1.5 approximation algorithm that works well in practice [4, 5], extending the work of Hartman and Sharan for equally weighted reversals and transpositions [6].
Ordering of the mitochondrial genes in Drosophila melanogaster
1  2  3  4  5  6  7  8  9  10 

cox1  L2  cox2  K  D  atp8  atp6  cox3  G  nad3 
11  12  13  14  15  16  17  18  19  20 
A  R  N  S1  E  F  nad5  H  nad4  nad4L 
21  22  23  24  25  26  27  28  29  30 
T  P  nad6  cob  S2  nad1  L1  rrnL  V  rrnS 
31  32  33  34  35  36  37  38  
UNK  I  Q  M  nad2  W  C  Y 
Ordering of the mitochondrial genes in the two organisms.
D. melanogaster  1  2  3  4  5  6  7  8  9  10  11  12  13 

14  15  16  17  18  19  20  21  22  23  24  25  26  
27  28  29  30  31  32  33  34  35  36  37  38  
L. forficatus  1  3  4  5  6  7  8  9  10  11  12  13  14 
15  16  17  18  19  20  21  22  23  24  25  26  2  
27  28  29  30  31  37  32  33  34  35  36  38 
The multiple genome rearrangement problem was shown to be NPhard for both the breakpoint and the reversal distance [7, 8]. This is true even if one considers only three genomes [7, 8]. To put it differently, the breakpoint and the reversal median problem are NPhard. Recall that in the median problem, we are given a distance or dissimilarity measure d, three genomes g_{1}, g_{2}, and g_{3}, and we want to find a genome M (a median) such that the sum ${\sum}_{i=1}^{3}d(M,{g}_{i})$ is minimized.
Related work
Breakpoint distance
Sankoff and Blanchette [9] solved the multiple genome rearrangement problem for the breakpoint distance by solving the following problem for each tree topology: Given a tree topology T with the k genomes as leaf nodes, assign ancestral genomes to internal nodes of T such that the tree is optimal (among all trees with this topology). They proposed to use the breakpoint median problem in an iterative manner to refine rough initial guesses for internal nodes. The breakpoint median problem in turn can be reduced to the traveling salesman problem for which very good heuristics exist. The resulting software BPAnalysis, however, was rather slow. Moret et al. [10] provided a reimplementation of BPAnalysis called GRAPPA that resulted in a speedup by several orders of magnitude.
Reversal distance
Moret et al. [11] and Tang et al. [12] showed that using reversal medians instead of breakpoint medians in the method of Sankoff and Blanchette [9] yield better phylogenetic trees, and they further extended the GRAPPA software in this direction. Moreover, Bourque and Pevzner [13] pointed out that the use of the breakpoint distance for generating the tree is disadvantageous because it may result in a tree that is suboptimal under other rearrangement distances. Their own greedy method iteratively builds a phylogenetic tree, based on a heuristic for finding the reversal median (in case of multichromosomal genomes, translocations are taken into account as well). Their method is implemented in the software tool MGR. Wu and Gu devised algorithms that solve an equivalent Steiner tree problem. Besides a nearest path search algorithm on a simple grid [14] (simplifying the grid search algorithm of Sankoff et al. [15]), they also presented a neighbor perturbing algorithm that starts with a minimum spanning tree as a 2approximation of the optimal Steiner tree and tries to iteratively improve the tree by searching for better Steiner nodes in the neighborhoods of the current nodes [16]. Recently, Bernt et al. [17] presented a software tool called amGRP which further significantly improves upon GRAPPA and MGR.
Weighted reversal and transposition distance
To the best of our knowledge, the approach of Cosner et al. [18] is the only one that (indirectly) takes weighted reversals and transpositions into account. In their method, they first use a heuristic to construct a phylogenetic tree according to the breakpoint distance as follows: Genomes are encoded as binary strings, a maximum parsimony technique for binary strings is employed, and then each internal node in the resulting phylogenetic tree is relabeled using BPAnalysis. Then, the weighted reversal and transposition distances on the edges of the tree are heuristically calculated with the software tool DERANGE II [19].
Our contribution
In this paper, we present a new heuristic algorithm for solving the multiple genome rearrangement problem. Our algorithm is the first one that tries to directly construct an optimal phylogenetic tree under the weighted reversal and transposition distance. We conducted experiments on previously published datasets, and the results are very promising. Because there is no other software tool that can deal with the weighted reversal and transposition distance, we conducted the same experiments with the reversal distance and compared our results with those delivered by other software tools. Although our program was not designed for the reversal distance, the results show that it can compete with stateoftheart programs in this field.
Results
Definitions
In this paper, we consider genomes that consist of a single circular chromosome (like mitochondrial, chloroplast or bacterial genomes). Such genomes are modeled by signed circular permutations. A signed circular permutation π = (π_{1} ... π_{ n }) is a permutation of (1...n), in which the indices are cyclic (i.e., n is followed by 1) and each element is labeled by plus or minus. We will use the term "permutation" as short hand for signed circular permutation. The reflection of a permutation π is the permutation (π_{ n }... π_{1}). It is considered to be (biologically) equivalent to π. The permutation id = (+1 + 2...+n) is called the identity permutation. A segment π_{ i }... π_{ j }(with j ≤ i) of a permutation π is a consecutive sequence of elements in π, with π_{ i }as first element and π_{ j }as last element. We consider three possible rearrangement operations on a permutation π. A transposition t(i, j, k) (with i <j and k <i or k > j) is an operation that cuts the segment π_{ i }... π_{j1}out of π, and reinserts it before the element π_{ k }. A reversal r(i, j) (with i <j) is an operation that reverses the order of the elements of the segment π_{ i }... π_{j1}. Additionally, the sign of every element in the segment is flipped. An inverted transposition tr(i, j, k) (with i <j and k <i or k > j) is the composition t(i, j, k) ◦ r(i, j) of a reversal and a transposition. In other words, the segment π_{ i }... π_{j1}will be cut out of π, inverted, and reinserted before π_{ k }. A sequence of rearrangement operations op_{1}, op_{2} ,..., op_{ k }applied to a permutation π yields the permutation $\tilde{\pi}$ = op_{ k }(op_{k1}(...(op_{1}(π))...)). We also say that the sequence is a sorting sequence of p w.r.t. $\tilde{\pi}$, as it sorts π into $\tilde{\pi}$. A permutation $\widehat{\pi}$lies on a sorting sequence op_{1}, op_{2},...,op_{ k }of π if there is a j ≤ k such that op_{ j }(op_{j1}(...op_{1}(π))...)) = $\widehat{\pi}$. Each operation op is assigned a positive weight w(op). The weight of a sequence is the sum of the weights of its operations. An optimal sorting sequence between π and $\tilde{\pi}$ is a sequence of minimum weight transforming π into $\tilde{\pi}$. The weighted genome rearrangement distance between π and $\tilde{\pi}$ (denoted by d(π, $\tilde{\pi}$)) is the weight of an optimal sorting sequence between them. In this paper, we consider two different genome rearrangement distances, the reversal distance and the weighted reversal and transposition distance. For the reversal distance, we restrict the set of allowed operations to reversals. Each reversal has the weight 1, i.e. the reversal distance d_{ r }(π, $\tilde{\pi}$) is the minimum number of reversals required to transform π into $\tilde{\pi}$. For the weighted reversal and transposition distance, the weight of an operation only depends on its type:w(op) = w_{ r }if op is a reversal, and w(op) = w_{ t }if op is a transposition or an inverted transposition. As reversals usually occur much more frequently than transpositions and inverted transpositions, we assume that w_{ r }≤ w_{ t }. In fact, we assume that w_{ r }= 1 ≤ w_{ t }≤ 2 because this results in a biologically meaningful balance between reversals and transpositions (see also in Section "Testing, Weight Ratios"). The weighted reversal and transposition distance between two permutations π and ${\sum}_{i=1}^{3}d(M,{g}_{i})$ is denoted by d_{ w }(π, $\tilde{\pi}$), and a lower bound for this distance is d_{ w }(π, $\tilde{\pi}$) ≥ (w_{ t }/2)·(n  σ(π, $\tilde{\pi}$)), where n is the size of the permutations and σ(π, $\tilde{\pi}$) is the score between the permutations π and $\tilde{\pi}$ (for details, see [4]). A median M(π^{1}, π^{2}, π^{3}) of three permutations π^{1}, π^{2}, and π^{3} is the permutation that minimizes d(M, π^{1}) + d(M, π^{2}) + d(M,π^{3}). Note that in general a median is not unique. An algorithm that solves the median problem (either exactly or heuristically) is called a median solver. A phylogenetic tree of a set of permutations (genomes) P = {π^{1},...,π^{ n }} is a tree T = (V, E), where V is the set of nodes and E is the set of edges of the tree. Each node is labeled by a permutation v_{ i }, and there is a bijection between the labels of the leaves and the permutations in P (i.e., any element of P is label of exactly one leaf). The weight of an edge (v_{ i }, v_{ j }) is the distance d(v_{ i }, v_{ j }). The weight of a tree w(T) is the sum of the weights of its edges. The phylogenetic reconstruction problem is to find a phylogenetic tree with minimum weight, given the set of permutations P.
Algorithm
The algorithm has two different phases. In the first phase, we use a fast heuristic that creates a tree. This heuristic does not rely on median solvers. In the second phase, this tree will be improved until it converges to a local optimum. We use two different improvement algorithms. One improves the tree topology, while the other improves the labeling of internal nodes by using a median solver. These two algorithms can be run alternatingly until the tree does not improve any further. In practice, the topology of the tree created in the first phase is already very good, so the algorithm for improving the topology has to be run only once. The whole algorithm was designed for the weighted reversal and transposition distance, however, it can also be used for other rearrangement distances as it only requires an algorithm that finds an optimal sorting sequence between two permutations, or at least a good approximation algorithm. Only the second improvement algorithm requires a median solver. We implemented the algorithm for the reversal distance and the weighted reversal and transposition distance. For the reversal distance, there is an efficient exact sorting algorithm [20, 21] and a branchandbound algorithm for the median that works well in practice [22]. For the weighted reversal and transposition distance, there is a 1.5approximation for the sorting problem that works well in practice [4, 5]. As median solver, we extended Caprara's reversal median solver [22] such that it works on the lower bound for the weighted reversal and transposition distance instead of using the maximum cycle decomposition of the original algorithm. As the algorithm for the weighted reversal and transposition distance is often able to find exact solutions, especially for short distances, the median solver also finds an exact median w.r.t. the weighted reversal and transposition distance in many cases.
Creating the tree
We create the tree T iteratively, beginning with a tree whose set of nodes consists only of one arbitrary permutation of the set of input permutations P = {π_{1},...,π^{ k }}, i.e. T_{0} = (V_{0}, E_{0}) = ({π}, ∅) with π ∈ P.
In each step, we create the tree T_{ i }from the tree T_{i1}by choosing a permutation π ∈ P\V_{i1}that is not yet a node in the tree, and add this permutation as leaf node. This includes an update of the edge set, and can include the creation of a new internal node. The algorithm terminates when all input permutations are in the tree, i.e., T = T_{ k }. Choosing the next permutation π ∈ P to be added to the tree T_{i1}, as well as determining its ancestor node, is done by a heuristic that minimizes the weight of the resulting tree T_{ i }. In contrast to previous algorithms, we do not use a median solver for this. Instead, we maintain for each edge (v, v') ∈ E_{i1}a set of permutations, called the cloud of the edge. This cloud can be seen as sets of candidate nodes for internal nodes. For a formal definition of a cloud, we first must define the δvicinity of an edge.
Definition 1 Let (v, v') be an edge in a tree and let δ ∈ ℝ. The δvicinity of (v, v') is defined by Vic_{ δ }(v, v') = {s ∈ V  d(v, s) + d(s, v') ≤ d(v, v') + δ}
In the following, we often simply speak of the vicinity of an edge, assuming that δ is fixed.
Intuitively, this means that the dvicinity of an edge (v, v') are all permutations w that lie "in between" v and v'. Splitting the edge into the two edges (v, w) and (w, v'), and adding the edge (w, π) will increase the weight of the tree by at most d(w, π) + δ. Thus, searching for new internal nodes in the vicinity of edges seems to be a good heuristic. However, even the 0vicinity of an edge (v, v') can be of exponential size w.r.t. d(v, v'). Hence, it is not practicable to search the whole vicinities of the edges, and we have to restrict the search space somehow. In the following, we assume that d is a small, fixed number.
Definition 2 The cloud Cloud(v, v') of an edge (v, v') in a tree is a subset of Vic_{ δ }(v, v').
Of course, this definition is quite general and does not reflect how to generate "good" clouds. We will present a heuristic for generating clouds in the next section.
The resulting tree does not necessarily fulfill the definition of a phylogenetic tree, as a permutation π ∈ P may correspond to an internal node v instead of a leaf node. This can easily be fixed by creating an exact copy v' of v and adding the edge (v, v'), i.e. π corresponds now to the leaf v'.
Creating the clouds
The quality and size of the clouds are crucial for the quality of the resulting tree and the running time of the algorithm. Let us consider the two extremes. If the clouds are empty, the algorithm is reduced to Prim's algorithm that finds a minimum spanning tree of P. If the cloud of an edge (v, v') contains the whole vicinity of the edge, the algorithm will always find a best ancestral genome unless it is not in this vicinity. However, in this case the size of the cloud is exponential w.r.t. d(v, v'). Our goal is to find, for each edge (v, v'), a cloud of polynomial size w.r.t. d(v, v') that provides a good coverage of the vicinity of (v, v'). The main idea of our heuristic is to generate different optimal or near optimal sorting sequences between v and v' and to select a subset of the permutations that lie on these sorting sequences as the cloud of the edge. To avoid duplicates in the cloud, our algorithm proceeds as follows. First, we define the set C_{0} = {v}. Then, we iteratively generate the sets C_{ i }out of the sets C_{i1}by applying to each permutation in C_{i1}each operation that decreases the distance to v'. Then, we reduce the size of C_{ i }by selecting a fixed number of disjoint permutations from C_{ i }. As additional heuristic, we select the permutations from C_{ i }that minimize the distance to the closest permutation in the set of input permutations P that is not yet in the tree. These steps are repeated until we reach the permutation v', i.e. C_{ m }= {v'}. As cloud, we use the union of the sets C_{1} to C_{m1}.
Note that the resulting cloud is a subset of Vic_{0}(v, v'). However, this works only for the reversal distance, as we do not have an exact algorithm for the weighted reversal and transposition distance. In this case, we apply operations that decrease the lower bound instead of decreasing the real distance. Thus, the parameter δ depends on the approximation quality of the algorithm for generating the sorting sequence, and we cannot determine it exactly. However, the approximation quality of the algorithm is very good in practice [5], so we can assume that δ is small.
Improving the topology
Note that searching for the edge (w_{1}, w_{2}) is done by an exhaustive search for w_{1} in all nodes in V_{1} and all permutations in the clouds of all edges in E_{1}, and similarly for w_{2}. The improvement step is repeated until no further improvement is found.
Improving internal nodes
Due to the tree construction algorithm, usually some of the internal nodes are not the median of their neighboring nodes, although they are very close to the median in most cases. The second improvement algorithm further improves the tree by relabeling internal nodes until all internal nodes are the median of their neighbors. For this, we first must ensure that each internal node is of degree 3, since our median solver is designed to find the median of three nodes. Thus, for each internal node v with a degree of k > 3, we create a node v' which is an exact copy of v. We reconnect these two nodes such that v is connected to v' and two of its former neighbors, while v' is connected to v and all other neighbors of v. Thus v has now a degree of 3, and v' has a degree of k  1. We repeat this until all internal nodes have a degree of 3.
Now, for each internal node v, we calculate the median M of its three neighboring nodes. If the sum of the distances of the neighbor nodes to M is less than the sum of the distances of the neighbor nodes to v, we replace v with M. For the reversal distance, we used the exact Caprara median solver, which maximizes the number of cycles in the multiple breakpoint graph and then checks the pairwise distances towards the calculated median (for details, see [22]). For the weighted reversal and transposition distance, we extended Caparara's median solver such that it minimizes the sum of the lower bounds between the calculated median and each of the three input permutations, and then checks the pairwise distances towards the calculated median. Note that there is no efficient exact median solver known for the weighted reversal and transposition distance. However, the median solver finds an exact median w.r.t. the lower bound for the weighted reversal and transposition distance. Thus, we only get inaccuracies by using the approximation algorithm for the weighted reversal and transposition distance, and therefore the approximation ratio of our median solver is as least as good as the approximation ratio of the pairwise distances, which is very good in practice.
The improvement of internal nodes is repeated until the tree does not improve any further, i.e. each node is the median of its neighboring nodes.
Testing
Data sets
We tested our algorithm on the following three biological datasets, which can be considered as benchmarks for phylogenetic reconstruction algorithms based on genome rearrangements.
Campanulaceae
This dataset contains 13 chloroplast DNAs of the flowering plant family Campanulaceae, where each genome contains 105 markers. It was created by Cosner et al. as test case for their new method MPBE [18], and at that time was ranked among the most challenging datasets for genome rearrangement algorithms.
Metazoan
This dataset contains 11 metazoan mitochondrial DNAs with 36 different markers. In the context of genome rearrangement algorithms, it was first used in [23]. In the year 2002, Bourque and Pevzner published a tree with 150 reversals, showing that MGR outperforms GRAPPA, as GRAPPA was only able to find a tree with 175 reversals in more than 48 hours [13]. However, GRAPPA has been improved ever since, and the current version is now able to find a tree with 159 reversals in 68 seconds (see Subsection "Experimental results").
Protostomes
This dataset contains 62 protostome mitochondrial DNAs with 36 different markers. It was first published in [24] and later adjusted in [17] to be used as test scenario for amGRP. The increased amount of data and the larger genome distances make this dataset much more complicated than the metazoan dataset.
Weight ratios
Two circular genomes (represented by n markers) are identical if the number of breakpoints between them is zero and the number of cycles in the breakpoint graph is n, respectively (for details, see [25]). Thus, a sequence of rearrangement operations that transforms one genome into the other must reduce the number of breakpoints to zero and increase the number of cycles to n, respectively. Because a reversal removes at most two breakpoints and generates at most one new cycle, while a transposition removes at most three breakpoints and generates at most two new cycles, transpositions are generally favored if the weight ratio is 1:1 (w_{ r }: w_{ t }). On the other hand, if the weight ratio is 1:2 and one uses Eriksen's (1 + ϵ)approximation algorithm [26], then an optimal sequence of rearrangements will consist almost solely of reversals. In our opinion, a realistic weight ratio for most biological datasets must be somewhere between these two extremes. Exemplarily, we are using the weight ratio 1:1.5.
We performed tests for the weighted reversal and transposition distance with the weight ratios 1:2, 1:1.5, and 1:1. The weight w_{ r }for reversals was fixed to 1, while the weight w_{ t }for transpositions was set to the corresponding values. We tested our program with different tree improvement strategies: No tree improvement (phylon), using only the tree perturbation to improve the topology (phylot), using only the median solver to improve the inner nodes (phylom), and the combination of both strategies (phylotm). Since the result of our algorithm depends on which permutation of the set P was chosen as first node, we performed one run for each permutation in P as start node.
Other tools using the reversal distance
As there is no other algorithm that can handle the weighted reversal and transposition distance, we also performed all tests mentioned above with the reversal distance, and compared our results with the results of the following programs.
GRAPPA
We used the current version 2.0 [27], which contains some serious improvements above older versions, especially it includes a median solver. The best results were achieved with the parameters t4 T4 n4 e m a C (for details see the GRAPPA manual). Using DCMGRAPPA [28] only improved the running times, but usually resulted in worse trees.
MGR
We used the current version 2.01. The best results were achieved with the triplet resolution heuristic disabled. Note that the heuristics h3 and h5 are no longer available, thus we could not reproduce some of the results given in [13] and [17].
amGRP
We used the version of April 2007. The best results were achieved with the "skewest" heuristic. As amGRP relies on randomness, we performed 50 runs for each data set. Note that this results in a similar number of runs and overall running time for amGRP and our program when using the reversal distance on the protostomes data set. In Subsection "Experimental results", we will only report the result of the best of these runs. For more information about the variance of the output of amGRP, the reader is referred to [17].
All tests were performed on a standard PC (Athlon 64 3200+ 2 GHz CPU, 512 kB L2 Cache, 4 GB RAM, 1000 MHz Bus Speed, Debian Kernel 2.6.22, GCC 4.1.2).
Comparing the results
While comparing the trees according to the reversal distance is straightforward, one might also be interested in comparing the trees according to the weighted reversal and transposition distance. The only other approach that tackles this task is the one of Cosner et al. [18], however in a very indirect way. First, a phylogenetic tree is generated according to the breakpoint distance, using a maximum parsimony technique for obtaining the tree topology and the software tool BPAnalysis for obtaining the labeling of internal nodes. Then, the weighted reversal and transposition distances of the edges of the tree are heuristically calculated with the software tool DERANGE II [19]. Since BPAnalysis is no longer stateoftheart and software tools have improved ever since, we investigated whether it is worthwhile to create a tree according to the reversal distance, and then to recalculate the weights of the edges using the weighted reversal and transposition distance. The experiments showed that using DERANGE II or the algorithm devised in [4] led to very similar results, thus we only provide the results of the latter algorithm. To avoid misleading results by using an approximation algorithm, we also recalculated the weights of the edges using the lower bound for the weighted reversal and transposition distance, resulting in a lower bound for the tree weight for a given topology and labeling of internal nodes. To put it differently, recalculating the tree weight with an exact algorithm for the weighted reversal and transposition distance cannot give us a result that is lower than this value. This approach was only feasible for MGR and amGRP because GRAPPA does not report the permutations at internal nodes. One might also ask if using Eriksen's (1 + ϵ)approximation algorithm [26] would lead to better results for the weight rato 1:2. However, comparing the calculated tree weights with the lower bounds showed that the approximation ratio of our algorithm is very good in practice, especially for this weight ratio, so we did not perform further tests with Eriksen's algorithm.
Experimental results
Weighted reversal and transposition distance
Results for the Campanulaceae dataset.
phylon  phylot  phylom  phylotm  amGRP  MGR  

1:2  62 (62)  62 (62)  62 (62)  62 (62)  63 (63)  63 (63) 
0:05  0:05  0:08  0:08  
1:1.5  51.5 (51)  50 (49.5)  50 (49.5)  50 (49.5)  52.5 (52)  56 (55) 
0:06  0:09  0:11  0:13  
1:1  40 (39)  39 (38)  38 (37)  39 (38)  42 (41)  49 (47) 
0:08  0:08  0:14  0:14 
Results for the metazoan dataset.
phylon  phylot  phylom  phylotm  amGRP  MGR  

1:2  153 (153)  151 (151)  146 (145)  146 (146)  142 (141)  151 (151) 
1:38  6:03  2:36  6:13  
1:1.5  125 (125)  123.5 (123.5)  119.5 (119.5)  120.5 (120.5)  125.5 (123.5)  134.5 (129) 
2:45  12:09  62:36  80:59  
1:1  87 (87)  87 (87)  85 (85)  85 (85)  110 (106)  116 (107) 
4:03  4:46  95:51  87:47 
Results for the protostomes dataset.
phylon  phylot  phylom  phylopm  amGRP  MGR  

1:2  501 (497)  498 (494)  490 (487)  488 (485)  496 (490)  522 (520) 
11:59  41:39  13:21  43:19  
1:1.5  400.5 (399)  400 (398.5)  392.5 (392.5)  392 (392)  431.5 (418)  446.5 (441.5) 
17:31  77:17  135:48  190:12  
1:1  23:56  30:56  101:11  88:56  365 (347)  388 (363) 
23:56  30:56  101:11  88:56 
Reversal distance
Results for the reversal distance.
phylotm  amGRP  MGR  GRAPPA  

Campanulaceae  64  65  66  64 
0:03  0:01  0:47  20:29  
Metazoan  144  143  151  159 
0:49  0:35  36:42  1:08  
Protostomes  505  501  528  n.a. 
4:41  6:52  1248:49 
Conclusion
Our algorithm achieves two improvements over previous works on this topic. First, it does not rely on a specific genome rearrangement distance. It can be used for any genome rearrangement distance as long as there is at least a good approximation algorithm for generating a sorting sequence between two genomes. Second, it avoids median solvers as long as possible. The median problem is NPhard for the breakpoint distance and the reversal distance, and most likely also for the other genome rearrangement distances. Although solving the median problem may be feasible for small problems, it is getting more and more complicated for larger genomes. Thus, in our opinion, median solvers should be avoided as long as possible. We have shown that our algorithm can compete with the currently best algorithms w.r.t. the reversal distance. To the best of our knowledge, our algorithm is currently the only one that directly tackles the phylogenetic reconstruction problem for the weighted reversal and transposition distance.
We implemented the algorithm in C++. The program is open source and can be obtained from the authors.
Declarations
Acknowledgements
This work was supported by DFGgrant Oh 53/51. The authors wish to thank Jijun Tang for providing DCMGRAPPA, Guillaume Bourque and Glenn Tesler for providing MGR, and Matthias Bernt for providing amGRP and his helpful comments on finding the best parameters for it.
Authors’ Affiliations
References
 Pevzner P, Tesler G: Genome Rearrangements in Mammalian Evolution: Lessons From Human and Mouse Genomes. Genome Research 2003, 13: 37–45.PubMed CentralView ArticlePubMedGoogle Scholar
 Bader D, Moret B, Yan M: A LinearTime Algorithm for Computing Inversion Distance between Signed Permutations with an Experimental Study. Journal of Computational Biology 2001, 8: 483–491.View ArticlePubMedGoogle Scholar
 Bergeron A, Mixtacki J, Stoye J: Reversal Distance without Hurdles and Fortresses. Proc 15th Annual Symposium on Combinatorial Pattern Matching, of Lecture Notes in Computer Science 2004, 3109: 388–399.View ArticleGoogle Scholar
 Bader M, Ohlebusch E: Sorting by Weighted Reversals, Transpositions, and Inverted Transpositions. Journal of Computational Biology 2007, 14(5):615–636.View ArticlePubMedGoogle Scholar
 Bader M: Sorting by Weighted Transpositions and Reversals. Diploma thesis University of Ulm; 2005. [http://www.uniulm.de/fileadmin/website_uni_ulm/iui.inst.190/Mitarbeiter/bader/bad_2005.pdf]Google Scholar
 Hartman T, Sharan R: A 1.5Approximation Algorithm for Sorting by Transpositions and Transreversals. Journal of Computer and System Sciences 2005, 70(3):300–320.View ArticleGoogle Scholar
 Pe'er I, Shamir R: The median problems for breakpoints are NPcomplete. Electronic Colloquium on Computational Complexity 1998., 5(71):Google Scholar
 Caprara A: Formulations and Hardness of Multiple Sorting by Reversals. In Proc 3rd Annual International Conference on Computational Molecular Biology. ACM; 1999:84–93.Google Scholar
 Sankoff D, Blanchette M: Multiple Genome Rearrangement and Breakpoint Phylogeny. Journal of Computational Biology 1998, 5(3):555–570.View ArticlePubMedGoogle Scholar
 Moret B, Wyman S, Bader D, Warnow T, Yan M: A New Implementation and Detailed Study of Breakpoint Analysis. Pacific Symposium on Biocomputing 2001, 583–594.Google Scholar
 Moret B, Siepel A, Tang J, Liu T: Inversion Medians Outperform Breakpoint Medians in Phylogeny Reconstruction from Geneorder Data. In Proc 2nd Workshop on Algorithms in Bioinformatics, of Lecture Notes in Computer Science. Volume 2452. SpringerVerlag; 2002:521–536.Google Scholar
 Tang J, Moret B, Cui L, dePamphilis C: Phylogenetic Reconstruction from Arbitrary Geneorder Data. In Proc 4th IEEE Conference on Bioinformatics and Bioengineering. IEEE Press; 2004:592–599.View ArticleGoogle Scholar
 Bourque B, Pevzner P: GenomeScale Evolution: Reconstructing Gene Orders in the Ancestral Species. Genome Research 2002, 12: 26–36.PubMed CentralPubMedGoogle Scholar
 Wu S, Gu X: Multiple Genome Rearrangement by Reversals. In Pacific Symposium on Biocomputing. World Scientific; 2002:259–270.Google Scholar
 Sankoff D, Sundaram G, Kececioglu J: Steiner Points in the Space of Genome Rearrangements. International Journal of Foundations of Computer Science 1996, 7: 1–9.View ArticleGoogle Scholar
 Wu S, Gu X: Algorithms for Multiple Genome Rearrangement by Signed Reversals. In Pacific Symposium on Biocomputing. World Scientific; 2003:363–374.Google Scholar
 Bernt M, Merkle D, Middendorf M: Using median sets for inferring phylogenetic trees. Bioinformatics 2007, 23: e129e135.View ArticlePubMedGoogle Scholar
 Cosner M, Jansen R, Moret B, Raubeson L, Wang LS, Warnow T, Wyman S: An Empirical Comparison Between BPAnalysis and MPBE on the Campanulaceae Chloroplast Genome Dataset. In Comparative Genomics: Empirical and Analytical Approaches to Gene Order Dynamics, Map Alignment, and the Evolution of Gene Families. Kluwer Academic Publishers; 2000:99–121.View ArticleGoogle Scholar
 Blanchette M, Kunisawa T, Sankoff D: Parametric genome rearrangement. Gene 1996, 172: GC11–17.View ArticlePubMedGoogle Scholar
 Hannenhalli S, Pevzner P: Transforming cabbage into turnip: polynomial algorithm for sorting signed permutations by reversals. Journal of the ACM 1999, 46: 1–27.View ArticleGoogle Scholar
 Tannier E, Bergeron A, Sagot MF: Advances on sorting by reversals. Discrete Applied Mathematics 2007, 155: 881–888.View ArticleGoogle Scholar
 Caprara A: The Reversal Median Problem. INFORMS Journal on Computing 2003, 15: 93–113.View ArticleGoogle Scholar
 Blanchette M, Kunisawa T, Sankoff D: Gene order breakpoint evidence in animal mitochondrial phylogeny. Journal of Molecular Evolution 1999, 49(2):193–203.View ArticlePubMedGoogle Scholar
 Fritzsch G, Schlegel M, Stadler P: Alignments of mitochondrial genome arrangements: Applications to metazoan phylogeny. Journal of Theoretical Biology 2006, 240(4):511–520.View ArticlePubMedGoogle Scholar
 Bafna V, Pevzner P: Genome Rearrangements and Sorting by Reversals. SIAM Journal on Computing 1996, 25(2):272–289.View ArticleGoogle Scholar
 Eriksen N: (1 + ϵ)approximation of Sorting by Reversals and Transpositions. Theoretical Computer Science 2002, 289: 517–529.View ArticleGoogle Scholar
 Moret B, Tang J: GRAPPA's Homepage. World Wide Web [http://www.cs.unm.edu/~moret/GRAPPA]
 Liu T, Tang J, Moret M: QuartetBased Phylogeny Reconstruction from Gene Orders. In Proc 11th Annual International Conference on Computing and Combinatorics, of Lecture Notes in Computer Science. Volume 3595. SpringerVerlag; 2005:63–73.Google Scholar
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