Distinct epigenomic and transcriptomic modifications associated with Wolbachia-mediated asexuality

Autoři: Xin Wu aff001;  Amelia R. I. Lindsey aff002;  Paramita Chatterjee aff001;  John H. Werren aff004;  Richard Stouthamer aff002;  Soojin V. Yi aff001
Působiště autorů: School of Biological Sciences, Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, United States of America aff001;  Department of Entomology, University of California Riverside, Riverside, California, United States of America aff002;  Current Address: Department of Biology, Indiana University, Bloomington, Indiana, United States of America aff003;  Department of Biology, University of Rochester, Rochester, New York, United States of America aff004
Vyšlo v časopise: Distinct epigenomic and transcriptomic modifications associated with Wolbachia-mediated asexuality. PLoS Pathog 16(3): e1008397. doi:10.1371/journal.ppat.1008397
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008397


Wolbachia are maternally transmitted intracellular bacteria that induce a range of pathogenic and fitness-altering effects on insect and nematode hosts. In parasitoid wasps of the genus Trichogramma, Wolbachia infection induces asexual production of females, thus increasing transmission of Wolbachia. It has been hypothesized that Wolbachia infection accompanies a modification of the host epigenome. However, to date, data on genome-wide epigenomic changes associated with Wolbachia are limited, and are often confounded by background genetic differences. Here, we took sexually reproducing Trichogramma free of Wolbachia and introgressed their genome into a Wolbachia-infected cytoplasm, converting them to Wolbachia-mediated asexuality. Wolbachia was then cured from replicates of these introgressed lines, allowing us to examine the genome-wide effects of wasps newly converted to asexual reproduction while controlling for genetic background. We thus identified gene expression and DNA methylation changes associated with Wolbachia-infection. We found no overlaps between differentially expressed genes and differentially methylated genes, indicating that Wolbachia-infection associated DNA methylation change does not directly modulate levels of gene expression. Furthermore, genes affected by these mechanisms exhibit distinct evolutionary histories. Genes differentially methylated due to the infection tended to be evolutionarily conserved. In contrast, differentially expressed genes were significantly more likely to be unique to the Trichogramma lineage, suggesting host-specific transcriptomic responses to infection. Nevertheless, we identified several novel aspects of Wolbachia-associated DNA methylation changes. Differentially methylated genes included those involved in oocyte development and chromosome segregation. Interestingly, Wolbachia-infection was associated with higher levels of DNA methylation. Additionally, Wolbachia infection reduced overall variability in gene expression, even after accounting for the effect of DNA methylation. We also identified specific cases where alternative exon usage was associated with DNA methylation changes due to Wolbachia infection. These results begin to reveal distinct genes and molecular pathways subject to Wolbachia induced epigenetic modification and/or host responses to Wolbachia-infection.

Klíčová slova:

DNA methylation – Drosophila melanogaster – Gene expression – Genome analysis – Introgression – Invertebrate genomics – Transcriptome analysis – Wolbachia


1. Zug R, Hammerstein P. Still a host of hosts for Wolbachia: Analysis of recent data suggests that 40% of terrestrial arthropod species are infected. PLoS One. 2012;7(6). doi: 10.1371/journal.pone.0038544 22685581

2. Hilgenboecker K, Hammerstein P, Schlattmann P, Telschow A, Werren JH. How many species are infected with Wolbachia?—A statistical analysis of current data. Fems Microbiology Letters. 2008;281(2):215–20. doi: 10.1111/j.1574-6968.2008.01110.x 18312577

3. Werren JH, Baldo L, Clark ME. Wolbachia: master manipulators of invertebrate biology. Nat Rev Micro. 2008;6(10):741–51. doi: 10.1038/nrmicro1969 18794912

4. Stouthamer R, Luck RF, Hamilton WD. Antibiotics cause parthenogenetic Trichogramma (Hymenoptera, Trichogrammatidae) to revert to sex. Proceedings of the National Academy of Sciences. 1990;87(7):2424–7 11607070

5. Stouthamer R, Breeuwer JAJ, Luck RF, Werren JH. Molecular-identification of microorganisms associated with parthenogenesis. Nature. 1993;361(6407):66–8. doi: 10.1038/361066a0 7538198

6. Stouthamer R, Werren JH. Microbes associated with parthenogenesis in wasps of the genus Trichogramma. Journal of Invertebrate Pathology. 1993;61(1):6–9. http://dx.doi.org/10.1006/jipa.1993.1002.

7. Stouthamer R, Russell JE, Vavre F, Nunney L. Intragenomic conflict in populations infected by Parthenogenesis Inducing Wolbachia ends with irreversible loss of sexual reproduction. BMC Evolutionary Biology. 2010;10:12. doi: 10.1186/1471-2148-10-229 20667099

8. Bennett GM, Moran NA. Heritable symbiosis: The advantages and perils of an evolutionary rabbit hole. Proceedings of the National Academy of Sciences. 2015;112(33):10169–76. doi: 10.1073/pnas.1421388112 25713367.

9. Sullivan W. Wolbachia, bottled water, and the dark side of symbiosis. Molecular Biology of the Cell. 2017;28(18):2343–6. doi: 10.1091/mbc.E17-02-0132 28855327

10. Beckmann JF, Ronau JA, Hochstrasser M. A Wolbachia deubiquitylating enzyme induces cytoplasmic incompatibility. Nat Microbiol. 2017;2:17007. Epub 2017/03/02. doi: 10.1038/nmicrobiol.2017.7 28248294.

11. LePage DP, Metcalf JA, Bordenstein SR, On J, Perlmutter JI, Shropshire JD, et al. Prophage WO genes recapitulate and enhance Wolbachia-induced cytoplasmic incompatibility. Nature. 2017;543(7644):243–7. Epub 2017/02/28. doi: 10.1038/nature21391 28241146.

12. Lindsey ARI, Rice DW, Bordenstein SR, Brooks AW, Bordenstein SR, Newton ILG. Evolutionary Genetics of Cytoplasmic Incompatibility Genes cifA and cifB in Prophage WO of Wolbachia. Genome Biol Evol. 2018;10(2):434–51. Epub 2018/01/20. doi: 10.1093/gbe/evy012 29351633.

13. Perlmutter JI, Bordenstein SR, Unckless RL, LePage DP, Metcalf JA, Hill T, et al. The phage gene wmk is a candidate for male killing by a bacterial endosymbiont. PLoS Pathog. 2019;15(9):e1007936. Epub 2019/09/11. doi: 10.1371/journal.ppat.1007936 31504075 applications of wmk in arthropods.

14. Gavotte L, Henri H, Stouthamer R, Charif D, Charlat S, Bouletreau M, et al. A Survey of the bacteriophage WO in the endosymbiotic bacteria Wolbachia. Mol Biol Evol. 2007;24(2):427–35. Epub 2006/11/11. doi: 10.1093/molbev/msl171 17095536.

15. Lindsey ARI, Werren JH, Richards S, Stouthamer R. Comparative genomics of a parthenogenesis-inducing Wolbachia symbiont. G3: Genes|Genomes|Genetics. 2016;6(7):2113–23. Epub 2016/05/20. doi: 10.1534/g3.116.028449 27194801.

16. Stouthamer R, Kazmer DJ. Cytogenetics of microbe-associated parthenogenesis and its consequences for gene flow in Trichogramma wasps. Heredity. 1994;73:317–27. doi: 10.1038/hdy.1994.139

17. Bernstein BE, Meissner A, Lander ES. The mammalian epigenome. Cell. 2007;128(4):669–81. doi: 10.1016/j.cell.2007.01.033 17320505.

18. Harris HL, Braig HR. Sperm chromatin remodelling and Wolbachia-induced cytoplasmic incompatibility in Drosophila. Biochem Cell Biol. 2003;81(3):229–40. doi: 10.1139/o03-053 12897857.

19. Negri I, Franchini A, Gonella E, Daffonchio D, Mazzoglio PJ, Mandrioli M, et al. Unravelling the Wolbachia evolutionary role: the reprogramming of the host genomic imprinting. Proc Biol Sci. 2009;276(1666):2485–91. doi: 10.1098/rspb.2009.0324 19364731.

20. Ye YH, Woolfit M, Huttley GA, Rances E, Caragata EP, Popovici J, et al. Infection with a Virulent Strain of Wolbachia Disrupts Genome Wide-Patterns of Cytosine Methylation in the Mosquito Aedes aegypti. PLoS One. 2013;8(6):e66482. doi: 10.1371/journal.pone.0066482 23840485.

21. Zhang G, Hussain M, O’Neill SL, Asgari S. Wolbachia uses a host microRNA to regulate transcripts of a methyltransferase, contributing to dengue virus inhibition in Aedes aegypti. Proc Natl Acad Sci U S A. 2013;110(25):10276–81. doi: 10.1073/pnas.1303603110 23733960.

22. Bhattacharya T, Newton ILG, Hardy RW. Wolbachia elevates host methyltransferase expression to block an RNA virus early during infection. PLoS Pathog. 2017;13(6):e1006427. doi: 10.1371/journal.ppat.1006427 28617844.

23. Kumar S, Kim Y. An endoparasitoid wasp influences host DNA methylation. Sci Rep. 2017;7:43287. Epub 2017/02/24. doi: 10.1038/srep43287 28230192.

24. Bewick AJ, Vogel KJ, Moore AJ, Schmitz RJ. Evolution of DNA Methylation across Insects. Mol Biol Evol. 2017;34(3):654–65. Epub 2016/12/28. doi: 10.1093/molbev/msw264 28025279.

25. Keller TE, Lasky JR, Yi SV. The multivariate association between genomewide DNA methylation and climate across the range of Arabidopsis thaliana. Mol Ecol. 2016;25(8):1823–37. doi: 10.1111/mec.13573 26850505.

26. Yi SV. Insights into Epigenome Evolution from Animal and Plant Methylomes. Genome Biol Evol. 2017;9(11):3189–201. doi: 10.1093/gbe/evx203 29036466.

27. Lindsey ARI, Kelkar YD, Wu X, Sun D, Martinson EO, Yan Z, et al. Comparative genomics of the miniature wasp and pest control agent Trichogramma pretiosum. BMC Biology. 2018;16(1):54. doi: 10.1186/s12915-018-0520-9 29776407

28. Lindsey ARI, Stouthamer R. Penetrance of symbiont-mediated parthenogenesis is driven by reproductive rate in a parasitoid wasp. PeerJ. 2017;5:e3505. doi: 10.7717/peerj.3505 28663939.

29. Gao S, Zou D, Mao L, Liu H, Song P, Chen Y, et al. BS-SNPer: SNP calling in bisulfite-seq data. Bioinformatics. 2015;31(24):4006–8. doi: 10.1093/bioinformatics/btv507 26319221.

30. Huh I, Yang X, Park T, Yi SV. Bis-class: a new classification tool of methylation status using bayes classifier and local methylation information. BMC Genomics. 2014;15:608. Epub 2014/07/20. doi: 10.1186/1471-2164-15-608 25037738.

31. Lasko P. The drosophila melanogaster genome: translation factors and RNA binding proteins. J Cell Biol. 2000;150(2):F51–6. doi: 10.1083/jcb.150.2.f51 10908586.

32. Coutelis JB, Ephrussi A. Rab6 mediates membrane organization and determinant localization during Drosophila oogenesis. Development. 2007;134(7):1419–30. doi: 10.1242/dev.02821 17329360.

33. Palacios IM, Gatfield D, St Johnston D, Izaurralde E. An eIF4AIII-containing complex required for mRNA localization and nonsense-mediated mRNA decay. Nature. 2004;427(6976):753–7. doi: 10.1038/nature02351 14973490.

34. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997;388(6640):394–7. doi: 10.1038/41131 9237759.

35. Sun H, Towb P, Chiem DN, Foster BA, Wasserman SA. Regulated assembly of the Toll signaling complex drives Drosophila dorsoventral patterning. EMBO J. 2004;23(1):100–10. doi: 10.1038/sj.emboj.7600033 14685264.

36. Richard DS, Gilbert M, Crum B, Hollinshead DM, Schelble S, Scheswohl D. Yolk protein endocytosis by oocytes in Drosophila melanogaster: immunofluorescent localization of clathrin, adaptin and the yolk protein receptor. J Insect Physiol. 2001;47(7):715–23. doi: 10.1016/s0022-1910(00)00165-7 11356418.

37. LePage DP, Jernigan KK, Bordenstein SR. The relative importance of DNA methylation and Dnmt2-mediated epigenetic regulation on Wolbachia densities and cytoplasmic incompatibility. PeerJ. 2014;2:e678. doi: 10.7717/peerj.678 25538866.

38. Serbus LR, Sullivan W. A cellular basis for Wolbachia recruitment to the host germline. PLoS Pathog. 2007;3(12):e190. doi: 10.1371/journal.ppat.0030190 18085821.

39. Newton IL, Savytskyy O, Sheehan KB. Wolbachia utilize host actin for efficient maternal transmission in Drosophila melanogaster. PLoS Pathog. 2015;11(4):e1004798. doi: 10.1371/journal.ppat.1004798 25906062.

40. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome biology. 2014;15(12):550. doi: 10.1186/s13059-014-0550-8 25516281

41. Anders S, Reyes A, Huber W. Detecting differential usage of exons from RNA-seq data. Genome Res. 2012;22(10):2008–17. doi: 10.1101/gr.133744.111 22722343.

42. Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9:559. doi: 10.1186/1471-2105-9-559 19114008.

43. Lyko F, Foret S, Kucharski R, Wolf S, Falckenhayn C, Maleszka R. The honey bee epigenomes: differential methylation of brain DNA in queens and workers. PLoS Biol. 2010;8(11):e1000506. Epub 2010/11/13. doi: 10.1371/journal.pbio.1000506 21072239.

44. Wang X, Wheeler D, Avery A, Rago A, Choi JH, Colbourne JK, et al. Function and evolution of DNA methylation in Nasonia vitripennis. PLoS Genet. 2013;9(10):e1003872. doi: 10.1371/journal.pgen.1003872 24130511.

45. Zeng J, Yi SV. DNA methylation and genome evolution in honeybee: gene length, expression, functional enrichment covary with the evolutionary signature of DNA methylation. Genome Biol Evol. 2010;2:770–80. doi: 10.1093/gbe/evq060 20924039.

46. Sarda S, Zeng J, Hunt BG, Yi SV. The evolution of invertebrate gene body methylation. Mol Biol Evol. 2012;29(8):1907–16. doi: 10.1093/molbev/mss062 22328716.

47. Keller TE, Han P, Yi SV. Evolutionary Transition of Promoter and Gene Body DNA Methylation across Invertebrate-Vertebrate Boundary. Mol Biol Evol. 2015;submitted.

48. Bird AP. Gene number, noise reduction and biological complexity. Trends Genet. 1995;11(3):94–100. doi: 10.1016/S0168-9525(00)89009-5 7732579.

49. Huh I, Zeng J, Park T, Yi SV. DNA methylation and transcriptional noise. Epigenetics Chromatin. 2013;6(1):9. doi: 10.1186/1756-8935-6-9 23618007.

50. Ding XL, Yang X, Liang G, Wang K. Isoform switching and exon skipping induced by the DNA methylation inhibitor 5-Aza-2'-deoxycytidine. Sci Rep. 2016;6:24545. doi: 10.1038/srep24545 27090213.

51. Arsenault SV, Hunt BG, Rehan SM. The effect of maternal care on gene expression and DNA methylation in a subsocial bee. Nat Commun. 2018;9(1):3468. doi: 10.1038/s41467-018-05903-0 30150650.

52. Li S, Zhang J, Huang S, He X. Genome-wide analysis reveals that exon methylation facilitates its selective usage in the human transcriptome. Brief Bioinform. 2018;19(5):754–64. doi: 10.1093/bib/bbx019 28334074.

53. Park J, Peng Z, Zeng J, Elango N, Park T, Wheeler D, et al. Comparative analyses of DNA methylation and sequence evolution using Nasonia genomes. Mol Biol Evol. 2011;28:3345–54. doi: 10.1093/molbev/msr168 21693438

54. Flores K, Wolschin F, Corneveaux JJ, Allen AN, Huentelman MJ, Amdam GV. Genome-wide association between DNA methylation and alternative splicing in an invertebrate. BMC Genomics. 2012;13:480. doi: 10.1186/1471-2164-13-480 22978521.

55. Foret S, Kucharski R, Pellegrini M, Feng S, Jacobsen SE, Robinson GE, et al. DNA methylation dynamics, metabolic fluxes, gene splicing, and alternative phenotypes in honey bees. Proc Natl Acad Sci U S A. 2012;109(13):4968–73. doi: 10.1073/pnas.1202392109 22416128.

56. Lev Maor G, Yearim A, Ast G. The alternative role of DNA methylation in splicing regulation. Trends Genet. 2015;31(5):274–80. doi: 10.1016/j.tig.2015.03.002 25837375.

57. Moran NA. Symbiosis. Curr Biol. 2006;16(20):R866–71. doi: 10.1016/j.cub.2006.09.019 17055966.

58. Werren JH, Zhang W, Guo LR. Evolution and phylogeny of Wolbachia: reproductive parasites of arthropods. Proc Biol Sci. 1995;261(1360):55–63. doi: 10.1098/rspb.1995.0117 7644549.

59. Raychoudhury R, Baldo L, Oliveira DC, Werren JH. Modes of acquisition of Wolbachia: horizontal transfer, hybrid introgression, and codivergence in the Nasonia species complex. Evolution. 2009;63(1):165–83. doi: 10.1111/j.1558-5646.2008.00533.x 18826448.

60. O’Neill SL, Giordano R, Colbert AM, Karr TL, Robertson HM. 16S rRNA phylogenetic analysis of the bacterial endosymbionts associated with cytoplasmic incompatibility in insects. Proc Natl Acad Sci U S A. 1992;89(7):2699–702. Epub 1992/04/01. doi: 10.1073/pnas.89.7.2699 1557375.

61. Turelli M, Cooper BS, Richardson KM, Ginsberg PS, Peckenpaugh B, Antelope CX, et al. Rapid Global Spread of wRi-like Wolbachia across Multiple Drosophila. Curr Biol. 2018;28(6):963–71.e8. Epub 2018/03/13. doi: 10.1016/j.cub.2018.02.015 29526588.

62. Galbraith DA, Yang X, Nino EL, Yi S, Grozinger C. Parallel epigenomic and transcriptomic responses to viral infection in honey bees (Apis mellifera). PLoS Pathog. 2015;11(3):e1004713. Epub 2015/03/27. doi: 10.1371/journal.ppat.1004713 25811620.

63. Liu Y, Aryee MJ, Padyukov L, Fallin MD, Hesselberg E, Runarsson A, et al. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat Biotechnol. 2013;31(2):142–7. doi: 10.1038/nbt.2487 23334450.

64. Dayeh T, Volkov P, Salo S, Hall E, Nilsson E, Olsson AH, et al. Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion. PLoS Genet. 2014;10(3):e1004160. doi: 10.1371/journal.pgen.1004160 24603685.

65. Mendizabal I, Berto S, Usui N, Toriumi K, Chatterjee P, Douglas C, et al. Cell type-specific epigenetic links to schizophrenia risk in the brain. Genome Biol. 2019;20(1):135. doi: 10.1186/s13059-019-1747-7 31288836.

66. Li-Byarlay H, Li Y, Stroud H, Feng S, Newman TC, Kaneda M, et al. RNA interference knockdown of DNA methyl-transferase 3 affects gene alternative splicing in the honey bee. Proc Natl Acad Sci U S A. 2013;110(31):12750–5. doi: 10.1073/pnas.1310735110 23852726.

67. Lindsey ARI, Bhattacharya T, Newton ILG, Hardy RW. Conflict in the Intracellular Lives of Endosymbionts and Viruses: A Mechanistic Look at Wolbachia-Mediated Pathogen-blocking. Viruses. 2018;10(4). doi: 10.3390/v10040141 29561780.

68. Rice DW, Sheehan KB, Newton ILG. Large-Scale Identification of Wolbachia pipientis Effectors. Genome Biol Evol. 2017;9(7):1925–37. Epub 2017/09/01. doi: 10.1093/gbe/evx139 28854601.

69. Werren JH, Windsor DM. Wolbachia infection frequencies in insects: evidence of a global equilibrium? Proc Biol Sci. 2000;267(1450):1277–85. doi: 10.1098/rspb.2000.1139 10972121.

70. Russell JE, Stouthamer R. The genetics and evolution of obligate reproductive parasitism in Trichogramma pretiosum infected with parthenogenesis-inducing Wolbachia. Heredity. 2011;106(1):58–67. doi: 10.1038/hdy.2010.48 20442735

71. Lindsey ARI, Stouthamer R. The effects of outbreeding on a parasitoid wasp fixed for infection with a parthenogenesis-inducing Wolbachia symbiont. Heredity. 2017. doi: 10.1038/hdy.2017.53 28902190

72. Stouthamer R, Hu JG, van Kan F, Platner GR, Pinto JD. The utility of internally transcribed spacer 2 DNA sequences of the nuclear ribosomal gene for distinguishing sibling species of Trichogramma. Biocontrol. 1999;43(4):421–40. doi: 10.1023/a:1009937108715

73. Werren JH, Windsor D, Guo LR. Distribution of Wolbachia among neotropical arthropods. Proceedings of the Royal Society B: Biological Sciences. 1995;262(1364):197–204. doi: 10.1098/rspb.1995.0196

74. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria: URL http://www.R-project.org/; 2014.

75. Greenberg S, Nordlund DA, Wu Z. Influence of Rearing Host on Adult Size and Ovipositional Behavior of Mass Produced FemaleTrichogramma minutumRiley andTrichogramma pretiosumRiley (Hymenoptera: Trichogrammatidae). Biological Control. 1998;11(1):43–8.

76. Panaro NJ, Yuen PK, Sakazume T, Fortina P, Kricka LJ, Wilding P. Evaluation of DNA fragment sizing and quantification by the Agilent 2100 Bioanalyzer. Clin Chem. 2000;46(11):1851–3. 11067828

77. Mardis E, McCombie WR. Library Quantification: Fluorometric Quantitation of Double-Stranded or Single-Stranded DNA Samples Using the Qubit System. Cold Spring Harb Protoc. 2017;2017(6):pdb prot094730. doi: 10.1101/pdb.prot094730 27803271.

78. Urich MA, Nery JR, Lister R, Schmitz RJ, Ecker JR. MethylC-seq library preparation for base-resolution whole-genome bisulfite sequencing. Nat Protoc. 2015;10(3):475–83. doi: 10.1038/nprot.2014.114 25692984.

79. Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A, et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinformatics. 2013;43:1101–33. doi: 10.1002/0471250953.bi1110s43 25431634.

80. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30(15):2114–20. doi: 10.1093/bioinformatics/btu170 24695404

81. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg S. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biology. 2013;14(4):R36. doi: 10.1186/gb-2013-14-4-r36 23618408

82. Anders S, Pyl PT, Huber W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31(2):166–9. doi: 10.1093/bioinformatics/btu638 25260700

83. Benjamini Y, Hochberg Y. Controlling the False Discovery Rate—a Practical and Powerful Approach to Multiple Testing. J Roy Stat Soc B Met. 1995;57(1):289–300.

84. Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnetjournal. 2011;17(1):10–2. http://dx.doi.org/10.14806/ej.17.1.200.

85. Krueger F, Andrews SR. Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications. Bioinformatics. 2011;27(11):1571–2. Epub 2011/04/16. doi: 10.1093/bioinformatics/btr167 21493656.

86. Conesa A, Gotz S, Garcia-Gomez JM, Terol J, Talon M, Robles M. Blast2GO: a universal tool for annotation, visualization and analysis in functional genomics research. Bioinformatics. 2005;21(18):3674–6. doi: 10.1093/bioinformatics/bti610 16081474.

87. Maere S, Heymans K, Kuiper M. BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics. 2005;21(16):3448–9. Epub 2005/06/24. doi: 10.1093/bioinformatics/bti551 15972284.

88. Huh I, Wu X, Park T, Yi SV. Detecting differential DNA methylation from sequencing of bisulfite converted DNA of diverse species. Brief Bioinform. 2017. doi: 10.1093/bib/bbx077 28981571.

89. Dolzhenko E, Smith AD. Using beta-binomial regression for high-precision differential methylation analysis in multifactor whole-genome bisulfite sequencing experiments. BMC Bioinformatics. 2014;15:215. doi: 10.1186/1471-2105-15-215 24962134.

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