Analysis Of Genomic Rearrangements Research Articles

EPCAM germline and somatic rearrangements in lynch syndrome: identification of a novel 3′EPCAM deletion

3'EPCAM (Epithelial Cell Adhesion Molecule) genomic rearrangements can be a cause of mismatch repair deficiency in rare Lynch syndrome families. 3'EPCAM deletions include the polyadenylation signal and might result in promoter hypermethylation of the centromeric MSH2 gene in cis. A somatic rearrangement in trans affecting MSH2 is responsible for the final mismatch repair deficiency in the corresponding tumors but the mechanisms are not well documented. In this report two germline 3'EPCAM deletions are described together with the corresponding somatic mutations in the patient's colorectal tumors. Mutation and breakpoint analysis resulted in the identification of one novel (c.556-531_*872del) and one known EPCAM deletion (c.859-689_*14697del). Both deletions resulted from Alu mediated homologous recombination causing aberrant EPCAM-MSH2 fusion transcripts. The colorectal tumors of the deletion carriers were MSI-high. Strong hypermethylation of the MSH2 promoter was measured. Analysis of somatic genomic rearrangements showed a 4 Mb deletion including the EPCAM, MSH2 and MSH6 genes in one tumor and copy neutral loss of heterozygosity in the EPCAM-MSH2 region in the other tumor. This indicates that hemi- and homozygous hypermethylation of the MSH2 promoter and hence complete silencing of MSH2 expression was responsible for the mismatch repair deficiency in both colorectal tumors.

Prospective correlation between clinical and pathologic criteria identification of Lynch syndrome (LS) in endometrial carcinoma (EC) patients and relapse.

1543 Background: Prospective comparison of different methods for recognition of LS associated EC is lacking. Microsatellite instability (MSI) has been observed to be inconsistent as a prognostic factor in EC. The aim of this study was to analyze the impact of MSI and Mismatch Repair (MMR)-deficiency on LS identification and prognosis in a prospective series of EC treated in one single institution. Methods: Consecutive and prospective EC patients were included. Clinical data, family history of cancer and criteria for LS were evaluated. MSI and MMR protein expression were performed. When loss of MMR proteins and/or high MSI (MSI-H) was observed, complete sequencing and large genomic rearrangement analysis of germline MLH1, MSH2, MSH6 or PMS2 was done once MLH1 methylation was excluded. Results: Seventy-seven women diagnosed with EC were enrolled from 2009 to 2012 with a median age of 62 (31-87), 84% histological type I, 16% type II and FIGO stages I 83%, II 2.8%, III-IVA 7% and IVB 7%. Among which, 6.6% fulfilled revised Bethesda criteria (rBC), 5.3% criteria defined by the Society Gynecologic Oncology (>20%-to-25% risk of LS) (SGO) and 5.3% Amsterdam II criteria (AII). Seventy-four underwent surgery with curative-intent. Tumor tissue was unavailable in 5 cases for molecular analysis. MSI-H was observed in16 cases (22%) and 18 (24%) had loss of expression of MLH1 (14), MSH2 (2), MSH6 (1) or PMS2 (1). Nine MLH1 hypermethylation, 10 K-RAS and no BRAF mutations were identified. Four (5.5%) pathogenic MMR germline mutations were recognized: 2 MSH2, one MSH6 and one PMS2. One patient (25%) with MSH6 mutation did not fulfil rBC, SGO nor AII criteria and was identified both by MSI-H and loss of MSH6 expression. Median follow-up was 23.4 (0.2-76.3) months. No correlation between MSI-H, MMR gene mutation and relapse was observed in stage I-IVA EC. Conclusions: Based on these results, rBC, AII and SGO criteria for identification of LS in EC do not identify 25% of germline MMR gene mutations. No correlation with relapse and MSI-H could be identified.

Ancestral genome inference using a genetic algorithm approach.

Recent advancement of technologies has now made it routine to obtain and compare gene orders within genomes. Rearrangements of gene orders by operations such as reversal and transposition are rare events that enable researchers to reconstruct deep evolutionary histories. An important application of genome rearrangement analysis is to infer gene orders of ancestral genomes, which is valuable for identifying patterns of evolution and for modeling the evolutionary processes. Among various available methods, parsimony-based methods (including GRAPPA and MGR) are the most widely used. Since the core algorithms of these methods are solvers for the so called median problem, providing efficient and accurate median solver has attracted lots of attention in this field. The “double-cut-and-join” (DCJ) model uses the single DCJ operation to account for all genome rearrangement events. Because mathematically it is much simpler than handling events directly, parsimony methods using DCJ median solvers has better speed and accuracy. However, the DCJ median problem is NP-hard and although several exact algorithms are available, they all have great difficulties when given genomes are distant. In this paper, we present a new algorithm that combines genetic algorithm (GA) with genomic sorting to produce a new method which can solve the DCJ median problem in limited time and space, especially in large and distant datasets. Our experimental results show that this new GA-based method can find optimal or near optimal results for problems ranging from easy to very difficult. Compared to existing parsimony methods which may severely underestimate the true number of evolutionary events, the sorting-based approach can infer ancestral genomes which are much closer to their true ancestors. The code is available at http://phylo.cse.sc.edu.

Functional performance of aCGH design for clinical cytogenetics

Array-comparative genomic hybridization (aCGH) technology enables rapid, high-resolution analysis of genomic rearrangements. With the use of it, genome copy number changes and rearrangement breakpoints can be detected and analyzed at resolutions down to a few kilobases. An exon array CGH approach proposed recently accurately measures copy-number changes of individual exons in the human genome. The crucial and highly non-trivial starting task is the design of an array, i.e. the choice of appropriate (multi)set of oligos. The success of the whole high-level analysis depends on the quality of the design. Also, the comparison of several alternative designs of array CGH constitutes an important step in development of new diagnostic chip. In this paper, we deal with these two often neglected issues.We propose a new approach to measure the quality of array CGH designs. Our measures reflect the robustness of rearrangements detection to the noise (mostly experimental measurement error). The method is parametrized by the segmentation algorithm used to identify aberrations. We implemented the efficient Monte Carlo method for testing noise robustness within DNAcopy procedure. Developed framework has been applied to evaluation of functional quality of several optimized array designs.

Phylogenetic analysis of genome rearrangements among five mammalian orders

Evolutionary relationships among placental mammalian orders have been controversial. Whole genome sequencing and new computational methods offer opportunities to resolve the relationships among 10 genomes belonging to the mammalian orders Primates, Rodentia, Carnivora, Perissodactyla and Artiodactyla. By application of the double cut and join distance metric, where gene order is the phylogenetic character, we computed genomic distances among the sampled mammalian genomes. With a marsupial outgroup, the gene order tree supported a topology in which Rodentia fell outside the cluster of Primates, Carnivora, Perissodactyla, and Artiodactyla. Results of breakpoint reuse rate and synteny block length analyses were consistent with the prediction of random breakage model, which provided a diagnostic test to support use of gene order as an appropriate phylogenetic character in this study. We discussed the influence of rate differences among lineages and other factors that may contribute to different resolutions of mammalian ordinal relationships by different methods of phylogenetic reconstruction.

Structural changes in chloroplast genome accompanying albinism in anther culture of wheat and triticale

The occurrence frequency of structural changes in plastid genome of albino plants from 27 genotypes of Triticum aestivum L. and × Triticosecale Witt. produced by anther culture method was studied. PCR analysis of genome rearrangements in plastids of albino plants has revealed similarity of plasmon changes in the given cereal crops and shown that a number of genes related to photosynthesis exposed to changes in plastid genomes studied. atpB gene, encoding β-subunit of CF1-complex of ATP synthase, was not detected with a high frequency in chlorophyll-deficient plants of wheat and triticale. It is supposed that deletions of photosynthetic genes, especially atpB gene, which take place in evolutionary unstable regions of chloroplast genome with a high frequency, are the major cause of albino plants formation in anther culture of cereals. Genes psbA, psbC, psbD of the photosystem II are amplified practically in all the studied plants of wheat and triticale that verifies the earlier obtained information about conservation of the region including the given genes within the limits of a large singlecopy region of chloroplast DNA.

268 Analysis of Large Genomic Rearrangements of BRCA1/2 Genes in Korean Breast Cancer Patients

268 Analysis of Large Genomic Rearrangements of BRCA1/2 Genes in Korean Breast Cancer Patients

Detection of a large rearrangement in PALB2 in Spanish breast cancer families with male breast cancer

It has been demonstrated that monoallelic PALB2 (Partner and Localizer of BRCA2) gene mutations predispose to familial breast cancer. Some of the families reported with germline PALB2 mutations presented male breast cancer as a characteristic clinical feature. Therefore, we wanted to investigate the contribution of germline PALB2 mutations in a set of 131 Spanish BRCA1/BRCA2-negative breast/ovarian cancer families with at least one male breast cancer case. The analysis included direct sequencing of all coding exons and intron/exon boundaries as well as a Multiplex Ligation-dependent Probe Amplification-based analysis of genomic rearrangements. For the first time we have identified a genomic rearrangement of PALB2 gene involving a large deletion from exon 7 to 11 in a breast cancer family. We have also identified several PALB2 variants, but no other obvious deleterious PALB2 mutation has been found. Thus, our study does not support an enrichment of PALB2 germline mutations in the subset of breast cancer families with male breast cancer cases. The identification of intronic and exonic variants indicates the necessity of assessing the implications of variants that do not lead to PALB2 truncation in the pathoghenicity of the PALB2 gene.

Whole-Genome Sequencing

THE PAST 60 YEARS HAVE WITNESSED REMARKABLE progress in genetics and genomics from the description of the DNA double helix by Watson and Crick to the release of the first draft sequence of the human genome in 2001 and the successful completion of the human genome project in 2003. From that time, there has been increasing hope and expectation that, as soon as the cost of sequencing the whole genome could become affordable, the promise of personalized medicine would be fulfilled. No field of medicine has benefited more from advances in genomics and the application of genetic testing than oncology. These advances have had a substantial influence on cancer risk assessment, determination of prognosis, and choice of treatment. Clinical applications of novel genetic tools include sequencing and analysis of germline genomic rearrangements at key cancer genes like BRCA1, BRCA2, and TP53; mismatch repair genes such as MLH1, MSH2, MSH6, and PMS2; development and widespread use of clinical karyotyping for hematologic malignancies; analysis of ERBB2 overexpression in breast cancer; KRAS gene mutations in colorectal cancer—and even gene expression analysis in breast cancer as a form of molecular pathology. In many cases, these genetic data have not only prognostic value but also important therapeutic implications for the patient. With the advent of more comprehensive, genomewide analyses of large tumor sets by projects like the Cancer Genome Atlas, the number of clinically relevant molecular tests is expected to continue to increase. Yet even these tests of commonly mutated cancer genes have limits and will always lack sensitivity to atypical mutations or gene expression patterns. The complexities of any individual’s cancer genome, and the treatment implications therein, are unlikely to be defined by single genes. For this reason, the latest advances in genomic technology have excited so many in the field. Over the past few years, high-throughput, short-read DNA sequencers have revolutionized the field of genomics and have accelerated the pace of discovery in cancer research. The new technologies simultaneously read millions of short, 50to 200-nucleotide DNA sequences from a pool of randomized genomic fragments in a single experiment. The process, which would have taken months with older technologies, is finished in a few days. Prior to the completion of the Human Genome Project, these short reads would have been difficult to interpret, as their genomic origin would have been unknown. However, the human reference sequence is now used to computationally map these sequences to the genome and to identify polymorphisms and novel mutations in a patient’s DNA. The ability to sequence an individual’s entire genome as well as the patient’s tumor genome is now a feasible enterprise at a cost and speed that was unthinkable even 5 years ago. In less than 3 years, DNA sequencing costs have decreased by more than 100-fold. The rate of improvement exceeds the advancement in computational power over the same time period, which predicts an oncoming wave of genomic data. Today, sequencing a tumor genome is still expensive and requires an infrastructure that is incompatible with a clinical setting, but the trend suggests that we are a lot closer to cost-effective, clinical genomics than most physicians realize. Two articles in this issue of JAMA are remarkable examples of the power that these genomic data hold for patients with a diagnosis of cancer. In one report, Link and colleagues, from Washington University, St Jude Children’s Research Hospital, and University of Chicago, performed whole-genome sequencing on skin and leukemic cells from a woman with suspected cancer susceptibility syndrome based on the early onset of several primary tumors. The patient had breast cancer at age 37 years, had ovarian cancer at age 39 years with recurrence at age 42 years, and developed treatment-related acute myeloid leukemia (t-AML) 6 months later. Genetic testing for mutations of the BRCA1 and BRCA2 genes was unrevealing, and in keeping with guidelines for assessment of high risk for familial cancer, no additional targeted genetic testing was obtained. However, whole-genome DNA sequencing showed that the patient was heterozygous for a novel deletion of 3 exons of the TP53 gene and that the intact copy of TP53 had been

Gremlin: An Interactive Visualization Model for Analyzing Genomic Rearrangements

In this work we present, apply, and evaluate a novel, interactive visualization model for comparative analysis of structural variants and rearrangements in human and cancer genomes, with emphasis on data integration and uncertainty visualization. To support both global trend analysis and local feature detection, this model enables explorations continuously scaled from the high-level, complete genome perspective, down to the low-level, structural rearrangement view, while preserving global context at all times. We have implemented these techniques in Gremlin, a genomic rearrangement explorer with multi-scale, linked interactions, which we apply to four human cancer genome data sets for evaluation. Using an insight-based evaluation methodology, we compare Gremlin to Circos, the state-of-the-art in genomic rearrangement visualization, through a small user study with computational biologists working in rearrangement analysis. Results from user study evaluations demonstrate that this visualization model enables more total insights, more insights per minute, and more complex insights than the current state-of-the-art for visual analysis and exploration of genome rearrangements.

Mutational spectrum and phenotypes in Danish families with hereditary angioedema because of C1 inhibitor deficiency

Hereditary angioedema (HAE), type I and II, is an autosomal dominant disease with deficiency of functional C1 inhibitor protein causing episodic swellings of skin, mucosa and viscera. HAE is a genetically heterogeneous disease with more than 200 different mutations in the SERPING1 gene. A genotype-phenotype relationship does not seem to exist in HAE, although the polymorphism c.-21T>C of exon 2 has been reported to be associated with a more severe phenotype. We aimed to establish the mutational spectrum of C1 inhibitor deficiency in Denmark and investigate the possible disease-aggravating effect of the c.-21T>C polymorphism. Hereditary angioedema was diagnosed based on clinical features and C1 inhibitor deficiency. A general severity score ranging from 0 to 10 was developed based on age at disease onset, clinical manifestations and treatment experiences. SERPING1 gene investigation was performed by exon sequencing followed by multiplex ligation-dependent probe amplification genomic rearrangement analysis in all known Danish HAE families. Fifty-nine patients with HAE from 26 families were included in this study. The mean disease severity score was 7.12 [1-10], and the mean C1 inhibitor function was 26% [20-46%]. The sensitivity of the mutational screening was 96%, and 13 new mutations were found in this Danish patient cohort. Nine patients (15%) carried the c.-21T>C polymorphism, but they didn't have a more severe phenotype. Thirteen new mutations were identified in the Danish HAE population. No correlation between the c.-21T>C polymorphism, the biochemical values of C1 inhibitor function and the clinical severity score was found.

Large BRCA1 and BRCA2 genomic rearrangements in Malaysian high risk breast-ovarian cancer families

Early studies of genetic predisposition due to the BRCA1 and BRCA2 genes have focused largely on sequence alterations, but it has now emerged that 4-28% of inherited mutations in the BRCA genes may be due to large genomic rearrangements of these genes. However, to date, there have been relatively few studies of large genomic rearrangements in Asian populations. We have conducted a full sequencing and large genomic rearrangement analysis (using Multiplex Ligation-dependent Probe Amplification, MLPA) of 324 breast cancer patients who were selected from a multi-ethnic hospital-based cohort on the basis of age of onset of breast cancer and/or family history. Three unrelated individuals were found to have large genomic rearrangements: 2 in BRCA1 and 1 in BRCA2, which accounts for 2/24 (8%) of the total mutations detected in BRCA1 and 1/23 (4%) of the mutations in BRCA2 detected in this cohort. Notably, the family history of the individuals with these mutations is largely unremarkable suggesting that family history alone is a poor predictor of mutation status in Asian families. In conclusion, this study in a multi-ethnic (Malay, Chinese, Indian) cohort suggests that large genomic rearrangements are present at a low frequency but should nonetheless be included in the routine testing for BRCA1 and BRCA2.

SoRT2: a tool for sorting genomes and reconstructing phylogenetic trees by reversals, generalized transpositions and translocations.

SoRT2 is a web server that allows the user to perform genome rearrangement analysis involving reversals, generalized transpositions and translocations (including fusions and fissions), and infer phylogenetic trees of genomes being considered based on their pairwise genome rearrangement distances. It takes as input two or more linear/circular multi-chromosomal gene (or synteny block) orders in FASTA-like format. When the input is two genomes, SoRT2 will quickly calculate their rearrangement distance, as well as a corresponding optimal scenario by highlighting the genes involved in each rearrangement operation. In the case of multiple genomes, SoRT2 will also construct phylogenetic trees of these genomes based on a matrix of their pairwise rearrangement distances using distance-based approaches, such as neighbor-joining (NJ), unweighted pair group method with arithmetic mean (UPGMA) and Fitch–Margoliash (FM) methods. In addition, if the function of computing jackknife support values is selected, SoRT2 will further perform the jackknife analysis to evaluate statistical reliability of the constructed NJ, UPGMA and FM trees. SoRT2 is available online at http://bioalgorithm.life.nctu.edu.tw/SORT2/.

BioSpotlight

BioSpotlight

High-throughput analysis of chromosome translocations and other genome rearrangements in epithelial cancers

Genes that are broken or fused by structural changes to the genome are an important class of mutation in the leukemias and sarcomas but have been largely overlooked in the common epithelial cancers. Large-scale sequencing is changing our perceptions of the cancer genome, and it is now being applied to structural changes, using the 'paired end' strategy. This reveals more clearly than before the extent to which many cancer genomes are rearranged and how much these rearrangements contribute to the mutational burden of epithelial tumors. In particular, there are probably many fusion genes, analogous to those found in leukemias, to be found in common cancers, such as breast carcinoma, and some of these will prove to be important in cancer diagnosis and treatment.

Decoding the Genomic Architecture of Mammalian and Plant Genomes: Synteny Blocks and Large-scale Duplications

Motivation: The existing synteny block reconstruction algorithms use anchors (e.g., orthologous genes) shared over all genomes to construct the synteny blocks for multiple genomes. This approach, while efficient for a few genomes, cannot be scaled to address the need to construct synteny blocks in many mammalian genomes that are currently being sequenced. The problem is that the number of anchors shared among all genomes quickly decreases with the increase in the number of genomes. Another problem is that many genomes (plant genomes in particular) had extensive duplications, which makes decoding of genomic architecture and rearrangement analysis in plants difficult. The existing synteny block generation algorithms in plants do not address the issue of generating non-overlapping synteny blocks suitable for analyzing rearrangements and evolution history of duplications. Results: In this paper we present a new synteny block generation algorithm based on the A- Bruijn graph framework that overcomes these difficulties. We applied our algorithm to derive non- overlapping synteny blocks in Arabidopsis thaliana. We also generalized this approach to synteny block generation for multiple genomes. The algorithm was applied to human-mouse-rat-dog-chicken genomes and it is able to recover synteny blocks missed by algorithms requiring 5-way anchors.

Divergent patterns of breakpoint reuse in Muroid rodents

Multiple Genome Rearrangement (MGR) analysis was used to define the trajectory and pattern of chromosome rearrangement within muroid rodents. MGR was applied using 107 chromosome homologies between Mus, Rattus, Peromyscus, the muroid sister taxon Cricetulus griseus, and Sciurus carolinensis as a non-Muroidea outgroup, with specific attention paid to breakpoint reuse and centromere evolution. This analysis revealed a high level of chromosome breakpoint conservation between Rattus and Peromyscus and indicated that the chromosomes of Mus are highly derived. This analysis identified several conserved evolutionary breakpoints that have been reused multiple times during karyotypic evolution in rodents. Our data demonstrate a high level of reuse of breakpoints among muroid rodents, further supporting the "Fragile Breakage Model" of chromosome evolution. We provide the first analysis of rodent centromeres with respect to evolutionary breakpoints. By analyzing closely related rodent species we were able to clarify muroid rodent karyotypic evolution. We were also able to derive several high-resolution ancestral karyotypes and identify rearrangements specific to various stages of Muroidea evolution. These data were useful in further characterizing lineage-specific modes of chromosome evolution.

Recovering genome rearrangements in the mammalian phylogeny

The analysis of genome rearrangements provides a global view on the evolution of a set of related species. We present a new algorithm called EMRAE (efficient method to recover ancestral events) to reliably predict a wide-range of rearrangement events in the ancestry of a group of species. Using simulated data sets, we show that EMRAE achieves comparable sensitivity but significantly higher specificity when predicting evolutionary events relative to other tools to study genome rearrangements. We apply our approach to the synteny blocks of six mammalian genomes (human, chimpanzee, rhesus macaque, mouse, rat, and dog) and predict 1109 rearrangement events, including 831 inversions, 15 translocations, 237 transpositions, and 26 fusions/fissions. Studying the sequence features at the breakpoints of the primate rearrangement events, we demonstrate that they are not only enriched in segmental duplications (SDs), but that the enrichment of matching pairs of SDs is even stronger within the pairs of breakpoints associated with recovered events. We also show that pairs of L1 repeats are frequently associated with ancestral inversions across all studied lineages. Together, this substantiates the model that regions of high sequence identity have been associated with rearrangement events throughout the mammalian phylogeny.

Complete mitochondrial DNA sequence of oyster Crassostrea hongkongensis-a case of "Tandem duplication-random loss" for genome rearrangement in Crassostrea?

BackgroundMitochondrial DNA sequences are extensively used as genetic markers not only for studies of population or ecological genetics, but also for phylogenetic and evolutionary analyses. Complete mt-sequences can reveal information about gene order and its variation, as well as gene and genome evolution when sequences from multiple phyla are compared. Mitochondrial gene order is highly variable among mollusks, with bivalves exhibiting the most variability. Of the 41 complete mt genomes sequenced so far, 12 are from bivalves. We determined, in the current study, the complete mitochondrial DNA sequence of Crassostrea hongkongensis. We present here an analysis of features of its gene content and genome organization in comparison with two other Crassostrea species to assess the variation within bivalves and among main groups of mollusks.ResultsThe complete mitochondrial genome of C. hongkongensis was determined using long PCR and a primer walking sequencing strategy with genus-specific primers. The genome is 16,475 bp in length and contains 12 protein-coding genes (the atp8 gene is missing, as in most bivalves), 22 transfer tRNA genes (including a suppressor tRNA gene), and 2 ribosomal RNA genes, all of which appear to be transcribed from the same strand. A striking finding of this study is that a DNA segment containing four tRNA genes (trnk1, trnC, trnQ1 and trnN) and two duplicated or split rRNA gene (rrnL5' and rrnS) are absent from the genome, when compared with that of two other extant Crassostrea species, which is very likely a consequence of loss of a single genomic region present in ancestor of C. hongkongensis. It indicates this region seem to be a "hot spot" of genomic rearrangements over the Crassostrea mt-genomes. The arrangement of protein-coding genes in C. hongkongensis is identical to that of Crassostrea gigas and Crassostrea virginica, but higher amino acid sequence identities are shared between C. hongkongensis and C. gigas than between other pairs. There exists significant codon bias, favoring codons ending in A or T and against those ending with C. Pair analysis of genome rearrangements showed that the rearrangement distance is great between C. gigas-C. hongkongensis and C. virginica, indicating a high degree of rearrangements within Crassostrea. The determination of complete mt-genome of C. hongkongensis has yielded useful insight into features of gene order, variation, and evolution of Crassostrea and bivalve mt-genomes.ConclusionThe mt-genome of C. hongkongensis shares some similarity with, and interesting differences to, other Crassostrea species and bivalves. The absence of trnC and trnN genes and duplicated or split rRNA genes from the C. hongkongensis genome is a completely novel feature not previously reported in Crassostrea species. The phenomenon is likely due to the loss of a segment that is present in other Crassostrea species and was present in ancestor of C. hongkongensis, thus a case of "tandem duplication-random loss (TDRL)". The mt-genome and new feature presented here reveal and underline the high level variation of gene order and gene content in Crassostrea and bivalves, inspiring more research to gain understanding to mechanisms underlying gene and genome evolution in bivalves and mollusks.

Phylogenetic reconstruction from transpositions.

BackgroundBecause of the advent of high-throughput sequencing and the consequent reduction in the cost of sequencing, many organisms have been completely sequenced and most of their genes identified. It thus has become possible to represent whole genomes as ordered lists of gene identifiers and to study the rearrangement of these entities through computational means. As a result, genome rearrangement data has attracted increasing attentions from both biologists and computer scientists as a new type of data for phylogenetic analysis. The main events of genome rearrangements include inversions, transpositions and transversions. To date, GRAPPA and MGR are the most accurate methods for rearrangement phylogeny, both assuming inversion as the only event. However, due to the complexity of computing transposition distance, it is very difficult to analyze datasets when transpositions are dominant.ResultsWe extend GRAPPA to handle transpositions. The new method is named GRAPPA-TP, with two major extensions: a heuristic method to estimate transposition distance, and a new transposition median solver for three genomes. Although GRAPPA-TP uses a greedy approach to compute the transposition distance, it is very accurate when genomes are relatively close. The new GRAPPA-TP is available from .ConclusionOur extensive testing using simulated datasets shows that GRAPPA-TP is very accurate in terms of ancestor genome inference and phylogenetic reconstruction. Simulation results also suggest that model match is critical in genome rearrangement analysis: it is not accurate to simulate transpositions with other events including inversions.