gene rearrangement


Summary: The ordered rearrangement of gene regions by DNA recombination such as that which occurs normally during development.

Top Publications

  1. Bos M, Gardizi M, Schildhaus H, Heukamp L, Geist T, Kaminsky B, et al. Complete metabolic response in a patient with repeatedly relapsed non-small cell lung cancer harboring ROS1 gene rearrangement after treatment with crizotinib. Lung Cancer. 2013;81:142-3 pubmed publisher
    ..1). Our case exemplifies the need for rapid implementation of newly discovered rare genetic lung cancer subtypes in routine molecular diagnostics. ..
  2. Li J, Yin W, Takeuchi K, Guan H, Huang Y, Chan J. Inflammatory myofibroblastic tumor with RANBP2 and ALK gene rearrangement: a report of two cases and literature review. Diagn Pathol. 2013;8:147 pubmed publisher
    ..The relation between the clinicopathologic features and poor prognosis of IMT-RA is discussed. The virtual slide(s) for this article can be found here: ..
  3. Zhang C, Leibowitz M, Pellman D. Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements. Genes Dev. 2013;27:2513-30 pubmed publisher
    ..Finally, we summarize current models for underlying mechanisms and discuss strategies for testing these models...
  4. Li H, Shao R, Song F, Zhou X, Yang Q, Li Z, et al. Mitochondrial genomes of two Barklice, Psococerastis albimaculata and Longivalvus hyalospilus (Psocoptera: Psocomorpha): contrasting rates in mitochondrial gene rearrangement between major lineages of Psocodea. PLoS ONE. 2013;8:e61685 pubmed publisher
    ..We conclude that mt gene rearrangement has been substantially faster in the lineage leading to the booklice and the parasitic lice than in the ..
  5. Caria P, Dettori T, Frau D, Borghero A, Cappai A, Riola A, et al. Assessing RET/PTC in thyroid nodule fine-needle aspirates: the FISH point of view. Endocr Relat Cancer. 2013;20:527-36 pubmed publisher
    ..Because fluorescence in situ hybridization (FISH) is the most sensitive method for detecting gene rearrangement in a single cell, we compared results from FISH and conventional RT-PCR obtained in FNA of a large cohort of ..
  6. V Laffert M, Warth A, Penzel R, Schirmacher P, Jonigk D, Kreipe H, et al. Anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer (NSCLC): results of a multi-centre ALK-testing. Lung Cancer. 2013;81:200-6 pubmed publisher
    ..As long as standardized ALK-IHC protocols are missing, ALK protein expression cannot by regarded as the method of choice for identification of patients eligible for treatment with ALK inhibitors. ..
  7. Seto T, Kiura K, Nishio M, Nakagawa K, Maemondo M, Inoue A, et al. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study. Lancet Oncol. 2013;14:590-8 pubmed publisher
    ..The study is still ongoing, since 40 of the 46 patients in the phase 2 portion remain on treatment. CH5424802 is well tolerated and highly active in patients with advanced ALK-rearranged NSCLC. Chugai Pharmaceutical Co, Ltd. ..
  8. Poulsen J, Byrkjedal I, Willassen E, Rees D, Takeshima H, Satoh T, et al. Mitogenomic sequences and evidence from unique gene rearrangements corroborate evolutionary relationships of myctophiformes (Neoteleostei). BMC Evol Biol. 2013;13:111 pubmed publisher
    ..The extent of gene order rearrangements found within the mitochondrial genomes of myctophids is unique for phylogenetic purposes. ..
  9. Wu Y, Su F, Kalyana Sundaram S, Khazanov N, Ateeq B, Cao X, et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 2013;3:636-47 pubmed publisher

Scientific Experts

More Information


  1. Robinson D, Kalyana Sundaram S, Wu Y, Shankar S, Cao X, Ateeq B, et al. Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer. Nat Med. 2011;17:1646-51 pubmed publisher
    ..These findings show that recurrent gene rearrangements have key roles in subsets of carcinomas and suggest that transcriptome sequencing could identify individuals with rare, targetable gene fusions. ..
  2. Kloosterman W, Tavakoli Yaraki M, van Roosmalen M, van Binsbergen E, Renkens I, Duran K, et al. Constitutional chromothripsis rearrangements involve clustered double-stranded DNA breaks and nonhomologous repair mechanisms. Cell Rep. 2012;1:648-55 pubmed publisher
    ..Our work provides detailed insight into the characteristics of chromothripsis and supports a role for clustered DSBs driving some constitutional chromothripsis rearrangements. ..
  3. Caria P, Dettori T, Frau D, Di Oto E, Morandi L, Parmeggiani A, et al. Simultaneous occurrence of PAX8-PPARg and RET-PTC3 rearrangements in a follicular variant of papillary thyroid carcinoma. Am J Surg Pathol. 2012;36:1415-20 pubmed publisher
  4. Camidge D, Theodoro M, Maxson D, Skokan M, O Brien T, Lu X, et al. Correlations between the percentage of tumor cells showing an anaplastic lymphoma kinase (ALK) gene rearrangement, ALK signal copy number, and response to crizotinib therapy in ALK fluorescence in situ hybridization-positive nonsmall cell lung cancer. Cancer. 2012;118:4486-94 pubmed publisher
    ..The inverse relationship between fused and isolated red copy number suggests ALK+ may be a distinct "near-diploid" subtype of NSCLC that develops before significant chromosomal aneusomy occurs. ..
  5. Qiao J, Patel K, Lopez Terrada D, Fang H. Atrophic dermatofibrosarcoma protuberans: report of a case demonstrated by detecting COL1A1-PDGFB rearrangement. Diagn Pathol. 2012;7:166 pubmed publisher
    ..This appears to be the first report of a fusion between COL1A1 exon 31 to exon 2 of PDGFB in atrophic dermatofibrosarcoma protuberans...
  6. Kloosterman W, Hoogstraat M, Paling O, Tavakoli Yaraki M, Renkens I, Vermaat J, et al. Chromothripsis is a common mechanism driving genomic rearrangements in primary and metastatic colorectal cancer. Genome Biol. 2011;12:R103 pubmed publisher
  7. Carvalho C, Ramocki M, Pehlivan D, Franco L, Gonzaga Jauregui C, Fang P, et al. Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome. Nat Genet. 2011;43:1074-81 pubmed publisher
    ..We propose a mechanism that involves both homology-driven events, via inverted repeats, and microhomologous or nonhomologous events. ..
  8. Davila J, Arrieta Montiel M, Wamboldt Y, Cao J, Hagmann J, Shedge V, et al. Double-strand break repair processes drive evolution of the mitochondrial genome in Arabidopsis. BMC Biol. 2011;9:64 pubmed publisher
    ..On a phenotypic level, these patterns of rearrangement likely contribute to the reproductive versatility of higher plants. ..
  9. Daigle S, Olhava E, Therkelsen C, Majer C, Sneeringer C, Song J, et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell. 2011;20:53-65 pubmed publisher
    ..Finally, in vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model. These results provide compelling support for DOT1L inhibition as a basis for targeted therapeutics against MLL. ..
  10. Inaki K, Hillmer A, Ukil L, Yao F, Woo X, Vardy L, et al. Transcriptional consequences of genomic structural aberrations in breast cancer. Genome Res. 2011;21:676-87 pubmed publisher
    ..This gene fusion is caused by tandem duplication on 17q23 and appears to be an indicator of local genomic instability altering the expression of oncogenic components such as MIR21 and RPS6KB1. ..
  11. Talkowski M, Ernst C, Heilbut A, Chiang C, Hanscom C, Lindgren A, et al. Next-generation sequencing strategies enable routine detection of balanced chromosome rearrangements for clinical diagnostics and genetic research. Am J Hum Genet. 2011;88:469-81 pubmed publisher
    ..These findings have implications ranging from genome annotation to de novo assemblies and could enable sequencing screens for structural variations at a cost comparable to that of microarrays in standard clinical practice. ..
  12. Amores A, Catchen J, Ferrara A, Fontenot Q, Postlethwait J. Genome evolution and meiotic maps by massively parallel DNA sequencing: spotted gar, an outgroup for the teleost genome duplication. Genetics. 2011;188:799-808 pubmed publisher
  13. Kilpert F, Held C, Podsiadlowski L. Multiple rearrangements in mitochondrial genomes of Isopoda and phylogenetic implications. Mol Phylogenet Evol. 2012;64:106-17 pubmed publisher
    ..In addition to increased taxon sampling secondary structure, modification in tRNAs and GC-skew inversion may be potentially fruitful subjects for future mt genome studies in a phylogenetic context...
  14. Matthews T, Rabsch W, Maloy S. Chromosomal rearrangements in Salmonella enterica serovar Typhi strains isolated from asymptomatic human carriers. MBio. 2011;2:e00060-11 pubmed publisher
    ..Our results support the hypothesis that the restricted lifestyle of host-specific Salmonella is responsible for the frequent chromosomal rearrangements in these serovars. ..
  15. Shen X, Li X, Sha Z, Yan B, Xu Q. Complete mitochondrial genome of the Japanese snapping shrimp Alpheus japonicus (Crustacea: Decapoda: Caridea): gene rearrangement and phylogeny within Caridea. Sci China Life Sci. 2012;55:591-8 pubmed publisher
  16. Brockman S, McFadden C. The mitochondrial genome of Paraminabea aldersladei (Cnidaria: Anthozoa: Octocorallia) supports intramolecular recombination as the primary mechanism of gene rearrangement in octocoral mitochondrial genomes. Genome Biol Evol. 2012;4:994-1006 pubmed publisher
    ..We speculate that the rate and mechanism of gene rearrangement in octocorals may be influenced by the presence in their mt genomes of mtMutS, a putatively active DNA ..
  17. Warsame A, Aasheim H, Nustad K, Trøen G, Tierens A, Wang V, et al. Splenic marginal zone lymphoma with VH1-02 gene rearrangement expresses poly- and self-reactive antibodies with similar reactivity. Blood. 2011;118:3331-9 pubmed publisher
    ..We produced recombinant antibodies from 5 SMZL cases with VH1-02 gene rearrangement to study the binding reactivity of these antibodies...
  18. Flucke U, Palmedo G, Blankenhorn N, Slootweg P, Kutzner H, Mentzel T. EWSR1 gene rearrangement occurs in a subset of cutaneous myoepithelial tumors: a study of 18 cases. Mod Pathol. 2011;24:1444-50 pubmed publisher
    ..Our study provides a genetic relationship of myoepithelial tumors of the skin with their counterparts in soft tissue, bone and visceral localization by sharing EWSR1 rearrangement...
  19. Magrangeas F, Avet Loiseau H, Munshi N, Minvielle S. Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients. Blood. 2011;118:675-8 pubmed publisher
    ..3% of samples. Moreover, this catastrophic event confers a poor outcome. Because chromothripsis appears to occur in a single crisis, our results suggest that high-risk MM patients use this novel way of cancer evolution. ..
  20. Li J, Zhang W, Tang Y, Li G, Dong D. In situ follicular lymphoma with progressive transformation of the germinal centers confirmed by laser capture microdissection, IGH gene rearrangement analysis, and fluorescence in situ hybridization for t(14;18). Hum Pathol. 2012;43:138-43 pubmed publisher
    ..These findings suggest a case of multicentric in situ follicular lymphoma and provide new insights into the pathogenesis of this disease...
  21. Lin I, Chao J, Yao M. An essential role for the DNA breakage-repair protein Ku80 in programmed DNA rearrangements in Tetrahymena thermophila. Mol Biol Cell. 2012;23:2213-25 pubmed publisher
    ..Together the results suggest multiple roles for Tku80p and indicate that a Ku-dependent DNA-repair pathway is involved in programmed DNA rearrangements in Tetrahymena...
  22. Chalker D, Yao M. DNA elimination in ciliates: transposon domestication and genome surveillance. Annu Rev Genet. 2011;45:227-46 pubmed publisher
    ..This DNA elimination pathway in ciliates shares extensive similarity with piRNA-mediated silencing of metazoans and highlights the remarkable ability of homologous RNAs to shape developing genomes. ..
  23. Jin R, Craddock K, Irish J, Perez Ordonez B, Weinreb I. Recurrent hyalinizing clear cell carcinoma of the base of tongue with high-grade transformation and EWSR1 gene rearrangement by FISH. Head Neck Pathol. 2012;6:389-94 pubmed publisher
    ..It also confirmed that the initial tumor was a HCCC with high-grade transformation...
  24. Togashi Y, Soda M, Sakata S, Sugawara E, Hatano S, Asaka R, et al. KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only. PLoS ONE. 2012;7:e31323 pubmed publisher
    ..This finding will broaden the potential value of archival FFPE tissues and provide further biological and clinical insights into ALK-positive lung cancer. ..
  25. Kijima T, Takeuchi K, Tetsumoto S, Shimada K, Takahashi R, Hirata H, et al. Favorable response to crizotinib in three patients with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion-type oncogene-positive non-small cell lung cancer. Cancer Sci. 2011;102:1602-4 pubmed publisher
    ..In the present study, we report on three cases harboring EML4-ALK rearrangement who were enrolled in the trial (A8081001, NCT00585195). All three patients showed favorable responses to the ALK-specific tyrosine kinase inhibitor. ..
  26. Falzarano S, Zhou M, Carver P, Tsuzuki T, Simmerman K, He H, et al. ERG gene rearrangement status in prostate cancer detected by immunohistochemistry. Virchows Arch. 2011;459:441-7 pubmed publisher
    ..Given the high yield and the easier task of performing immunohistochemistry vs. FISH, ERG assessment by immunohistochemistry may be useful for characterizing ERG status in prostate cancer. ..
  27. McLeer Florin A, Moro Sibilot D, Mélis A, Salameire D, Lefebvre C, Ceccaldi F, et al. Dual IHC and FISH testing for ALK gene rearrangement in lung adenocarcinomas in a routine practice: a French study. J Thorac Oncol. 2012;7:348-54 pubmed publisher
    ..5% of the adenocarcinomas screened. Our results favor ALK IHC prescreening on a daily routine on surgical specimens and on small biopsies before FISH testing. ..
  28. Motl J, Chalker D. Zygotic expression of the double-stranded RNA binding motif protein Drb2p is required for DNA elimination in the ciliate Tetrahymena thermophila. Eukaryot Cell. 2011;10:1648-59 pubmed publisher
    ..These results implicate zygotically expressed Drb2p in the maturation of these nuclear structures, which are necessary for reorganization of the somatic genome. ..
  29. Zhang J, Wu X, Xie M, Li A. The complete mitochondrial genome of Pseudochauhanea macrorchis (Monogenea: Chauhaneidae) revealed a highly repetitive region and a gene rearrangement hot spot in Polyopisthocotylea. Mol Biol Rep. 2012;39:8115-25 pubmed publisher
    ..with that known for Microcotyle sebastis and Polylabris halichoeres, but also contained two noted features-a gene rearrangement hot spot and the highly repetitive region (HRR) in major non-coding region (NCR)...
  30. Holland A, Cleveland D. Chromoanagenesis and cancer: mechanisms and consequences of localized, complex chromosomal rearrangements. Nat Med. 2012;18:1630-8 pubmed publisher
    ..Complex rearrangements are present in a broad spectrum of tumors and in individuals with congenital or developmental defects, highlighting the impact of chromoanagenesis on human disease...
  31. Totoki Y, Tatsuno K, Yamamoto S, Arai Y, Hosoda F, Ishikawa S, et al. High-resolution characterization of a hepatocellular carcinoma genome. Nat Genet. 2011;43:464-9 pubmed publisher
  32. Bass A, Lawrence M, Brace L, Ramos A, Drier Y, Cibulskis K, et al. Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nat Genet. 2011;43:964-968 pubmed publisher
    ..This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events. ..
  33. Shaw A, Yeap B, Solomon B, Riely G, Gainor J, Engelman J, et al. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol. 2011;12:1004-12 pubmed publisher
    ALK gene rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC)...
  34. Perner S, Rupp N, Braun M, Rubin M, Moch H, Dietel M, et al. Loss of SLC45A3 protein (prostein) expression in prostate cancer is associated with SLC45A3-ERG gene rearrangement and an unfavorable clinical course. Int J Cancer. 2013;132:807-12 pubmed publisher
    ..Resultant protein expression data was correlated to the respective gene rearrangement status and clinico-pathological parameters including PSA follow up times...
  35. Nishino M, Klepeis V, Yeap B, Bergethon K, Morales Oyarvide V, Dias Santagata D, et al. Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas. Mod Pathol. 2012;25:1462-72 pubmed publisher
    ..However, morphologic screening alone will not detect a minority of ALK+ lung adenocarcinomas, and the routine use of ancillary studies may be warranted to identify all patients who may benefit from crizotinib treatment. ..
  36. Liu P, Carvalho C, Hastings P, Lupski J. Mechanisms for recurrent and complex human genomic rearrangements. Curr Opin Genet Dev. 2012;22:211-20 pubmed publisher
    ..Both nonhomologous end-joining and aberrant replication have significant roles in chromothripsis. As we study CNV, the processes underlying human genome evolution are revealed. ..
  37. Mraz M, Dolezalova D, Plevova K, Stano Kozubik K, Mayerova V, Cerná K, et al. MicroRNA-650 expression is influenced by immunoglobulin gene rearrangement and affects the biology of chronic lymphocytic leukemia. Blood. 2012;119:2110-3 pubmed publisher
    ..This study underscores the importance of miR-650 in CLL biology and normal B-cell physiology. ..
  38. Jiao X, Rosenlund M, Hooper S, Tellgren Roth C, He L, Fu Y, et al. Structural alterations from multiple displacement amplification of a human genome revealed by mate-pair sequencing. PLoS ONE. 2011;6:e22250 pubmed publisher
    ..While multiple strand displacement amplification may find uses in translocation analyses, it is likely that alternative amplification strategies need to be developed to meet the demands of cancer genomics. ..
  39. Hillmer A, Yao F, Inaki K, Lee W, Ariyaratne P, Teo A, et al. Comprehensive long-span paired-end-tag mapping reveals characteristic patterns of structural variations in epithelial cancer genomes. Genome Res. 2011;21:665-75 pubmed publisher
  40. Yoshida A, Kohno T, Tsuta K, Wakai S, Arai Y, Shimada Y, et al. ROS1-rearranged lung cancer: a clinicopathologic and molecular study of 15 surgical cases. Am J Surg Pathol. 2013;37:554-62 pubmed publisher
    ..Fluorescence in situ hybridization signal patterns were unrelated to 5' fusion partner genes. All ROS1 fusion-positive tumors lacked alteration of EGFR, KRAS, HER2, ALK, and RET genes. ..
  41. Cazes A, Louis Brennetot C, Mazot P, Dingli F, Lombard B, Boeva V, et al. Characterization of rearrangements involving the ALK gene reveals a novel truncated form associated with tumor aggressiveness in neuroblastoma. Cancer Res. 2013;73:195-204 pubmed publisher
    ..These results indicate that genomic rearrangements constitute an alternative mechanism to ALK point mutations resulting in receptor activation. ..
  42. Ilie M, Long E, Butori C, Hofman V, Coelle C, Mauro V, et al. ALK-gene rearrangement: a comparative analysis on circulating tumour cells and tumour tissue from patients with lung adenocarcinoma. Ann Oncol. 2012;23:2907-13 pubmed publisher
    ..A total of five patients showed ALK-gene rearrangement and strong ALK protein expression in CTCs and in the corresponding tumour samples...
  43. Yi E, Chung J, Kulig K, Kerr K. Detection of anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer and related issues in ALK inhibitor therapy: a literature review. Mol Diagn Ther. 2012;16:143-50 pubmed publisher
    Anaplastic lymphoma kinase (ALK) encodes a receptor tyrosine kinase, and ALK gene rearrangement (ALK+) is implicated in the oncogenesis of non-small cell lung carcinomas (NSCLCs), especially adenocarcinomas...
  44. Rausch T, Jones D, Zapatka M, Stütz A, Zichner T, Weischenfeldt J, et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell. 2012;148:59-71 pubmed publisher
    ..These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer. ..
  45. Yoshida A, Tsuta K, Nakamura H, Kohno T, Takahashi F, Asamura H, et al. Comprehensive histologic analysis of ALK-rearranged lung carcinomas. Am J Surg Pathol. 2011;35:1226-34 pubmed publisher
    ..ALK-positive cancers commonly showed coexpression of thyroid transcription factor-1 and p63, and its significance is currently unclear. ..
  46. Arnaiz O, Mathy N, Baudry C, Malinsky S, Aury J, Denby Wilkes C, et al. The Paramecium germline genome provides a niche for intragenic parasitic DNA: evolutionary dynamics of internal eliminated sequences. PLoS Genet. 2012;8:e1002984 pubmed publisher
  47. Del Vecchio C, Giacomini C, Vogel H, Jensen K, Florio T, Merlo A, et al. EGFRvIII gene rearrangement is an early event in glioblastoma tumorigenesis and expression defines a hierarchy modulated by epigenetic mechanisms. Oncogene. 2013;32:2670-81 pubmed publisher
    ..Furthermore, EGFRvIII expression is restricted by epigenetic mechanisms, suggesting that drugs that modulate the epigenome might be used successfully in glioblastoma tumors. ..
  48. Kim H, Yoo S, Choe J, Paik J, Xu X, Nitta H, et al. Detection of ALK gene rearrangement in non-small cell lung cancer: a comparison of fluorescence in situ hybridization and chromogenic in situ hybridization with correlation of ALK protein expression. J Thorac Oncol. 2011;6:1359-66 pubmed publisher
    ..This study evaluates the concordance between ALK gene rearrangement in non-small cell lung cancer assessed by ALK FISH and a newly developed ALK chromogenic in situ ..
  49. Liang X, Branchford B, Greffe B, McGavran L, Carstens B, Meltesen L, et al. Dual ALK and MYC rearrangements leading to an aggressive variant of anaplastic large cell lymphoma. J Pediatr Hematol Oncol. 2013;35:e209-13 pubmed publisher
    ..This case underscores the importance of recognition of close correlation between dual ALK and MYC rearrangements and the characteristic clinical features in this unusual ALCL variant. ..
  50. Kerr R, Robinson C, Essop F, Krause A. Genetic testing for Duchenne/Becker muscular dystrophy in Johannesburg, South Africa. S Afr Med J. 2013;103:999-1004 pubmed publisher
    ..MLPA could also diagnose mutation status in at-risk female relatives, which is not possible with mPCR. ..
  51. Zhang R, Zhang C, Zhao Q, Li D. Spectrin: structure, function and disease. Sci China Life Sci. 2013;56:1076-85 pubmed publisher
    ..This review focuses on recent advances in determining the structure and function of spectrin as well as its role in disease. ..
  52. Shi W, Dicker A. CNS Metastases in Patients With Non-Small-Cell Lung Cancer and ALK Gene Rearrangement. J Clin Oncol. 2016;34:107-9 pubmed publisher
  53. Tsetsarkin K, Liu G, Volkova E, Pletnev A. Synergistic Internal Ribosome Entry Site/MicroRNA-Based Approach for Flavivirus Attenuation and Live Vaccine Development. MBio. 2017;8: pubmed publisher
    ..This developed approach provides a robust platform for reliable attenuation of many flaviviruses and may enable development of live flavivirus vaccines. ..