The roles of replication-transcription conflict in mutagenesis and evolution of genome organization

Autoři: Jeremy W. Schroeder aff001;  T. Sabari Sankar aff002;  Jue D. Wang aff001;  Lyle A. Simmons aff003
Působiště autorů: Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America aff001;  School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, Thiruvananthapuram, Kerala, India aff002;  Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America aff003
Vyšlo v časopise: The roles of replication-transcription conflict in mutagenesis and evolution of genome organization. PLoS Genet 16(8): e32767. doi:10.1371/journal.pgen.1008987
Kategorie: Review
doi: 10.1371/journal.pgen.1008987


Replication-transcription conflicts promote mutagenesis and give rise to evolutionary signatures, with fundamental importance to genome stability ranging from bacteria to metastatic cancer cells. This review focuses on the interplay between replication-transcription conflicts and the evolution of gene directionality. In most bacteria, the majority of genes are encoded on the leading strand of replication such that their transcription is co-directional with the direction of DNA replication fork movement. This gene strand bias arises primarily due to negative selection against deleterious consequences of head-on replication-transcription conflict. However, many genes remain head-on. Can head-on orientation provide some benefit? We combine insights from both mechanistic and evolutionary studies, review published work, and analyze gene expression data to evaluate an emerging model that head-on genes are temporal targets for adaptive mutagenesis during stress. We highlight the alternative explanation that genes in the head-on orientation may simply be the result of genomic inversions and relaxed selection acting on nonessential genes. We seek to clarify how the mechanisms of replication-transcription conflict, in concert with other mutagenic mechanisms, balanced by natural selection, have shaped bacterial genome evolution.

Klíčová slova:

Bacillus subtilis – Bacterial genomics – Cellular stress responses – DNA replication – Evolutionary genetics – Genomics – Mutagenesis – Substitution mutation


1. Luria SE, Delbruck M. Mutations of Bacteria from Virus Sensitivity to Virus Resistance. Genetics. 1943;28: 491–511. 17247100

2. Schroeder JW, Yeesin P, Simmons LA, Wang JD. Sources of spontaneous mutagenesis in bacteria. Crit Rev Biochem Mol Biol. 2017;2017/11/08: 1–20.

3. Hamperl S, Cimprich KA. Conflict Resolution in the Genome: How Transcription and Replication Make It Work. Cell. 2016;167: 1455–1467. doi: 10.1016/j.cell.2016.09.053 27912056

4. Brewer BJ. When polymerases collide: replication and the transcriptional organization of the E. coli chromosome. Cell. 1988;53: 679–686. doi: 10.1016/0092-8674(88)90086-4 3286014

5. Rocha EP. The replication-related organization of bacterial genomes. Microbiology. 2004;150: 1609–1627. doi: 10.1099/mic.0.26974-0 15184548

6. Rocha EPC. The organization of the bacterial genome. Annu Rev Genet. 2008;42: 211–233. doi: 10.1146/annurev.genet.42.110807.091653 18605898

7. Sankar TS, Wastuwidyaningtyas BD, Dong Y, Lewis SA, Wang JD. The nature of mutations induced by replication-transcription collisions. Nature. 2016;535: 178–181. doi: 10.1038/nature18316 27362223

8. Imielinski M, Guo G, Meyerson M. Insertions and Deletions Target Lineage-Defining Genes in Human Cancers. Cell. 2017;168: 460–472.e14. doi: 10.1016/j.cell.2016.12.025 28089356

9. Letouzé E, Shinde J, Renault V, Couchy G, Blanc J-F, Tubacher E, et al. Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. Nat Commun. 2017;8: 1315. doi: 10.1038/s41467-017-01358-x 29101368

10. Srivatsan A, Tehranchi A, MacAlpine DM, Wang JD. Co-orientation of replication and transcription preserves genome integrity. PLoS Genet. 2010;6: e1000810. doi: 10.1371/journal.pgen.1000810 20090829

11. French S. Consequences of replication fork movement through transcription units in vivo. Science. 1992;258: 1362–1365. doi: 10.1126/science.1455232 1455232

12. Kim N, Abdulovic AL, Gealy R, Lippert MJ, Jinks-Robertson S. Transcription-associated mutagenesis in yeast is directly proportional to the level of gene expression and influenced by the direction of DNA replication. DNA Repair. 2007;6: 1285–1296. doi: 10.1016/j.dnarep.2007.02.023 17398168

13. Vilette D, Ehrlich SD, Michel B. Transcription-induced deletions in plasmid vectors: M13 DNA replication as a source of instability. Mol Gen Genet. 1996;252: 398–403. doi: 10.1007/BF02173004 8879240

14. Mirkin EV, Castro Roa D, Nudler E, Mirkin SM. Transcription regulatory elements are punctuation marks for DNA replication. Proc Natl Acad Sci U S A. 2006;103: 7276–7281. doi: 10.1073/pnas.0601127103 16670199

15. Lang KS, Merrikh H. The Clash of Macromolecular Titans: Replication-Transcription Conflicts in Bacteria. Annu Rev Microbiol. 2018;72: 71–88. doi: 10.1146/annurev-micro-090817-062514 29856930

16. Lang KS, Hall AN, Merrikh CN, Ragheb M, Tabakh H, Pollock AJ, et al. Replication-Transcription Conflicts Generate R-Loops that Orchestrate Bacterial Stress Survival and Pathogenesis. Cell. 2017;170: 787–799 e18. doi: 10.1016/j.cell.2017.07.044 28802046

17. Merrikh CN, Merrikh H. Gene inversion potentiates bacterial evolvability and virulence. Nat Commun. 2018;9: 4662. doi: 10.1038/s41467-018-07110-3 30405125

18. Million-Weaver S, Samadpour AN, Moreno-Habel DA, Nugent P, Brittnacher MJ, Weiss E, et al. An underlying mechanism for the increased mutagenesis of lagging-strand genes in Bacillus subtilis. Proc Natl Acad Sci U S A. 2015;112: E1096–105. doi: 10.1073/pnas.1416651112 25713353

19. Paul S, Million-Weaver S, Chattopadhyay S, Sokurenko E, Merrikh H. Accelerated gene evolution through replication-transcription conflicts. Nature. 2013;495: 512–515. doi: 10.1038/nature11989 23538833

20. Chen X, Zhang J. Why are genes encoded on the lagging strand of the bacterial genome? Genome Biol Evol. 2013;5: 2436–2439. doi: 10.1093/gbe/evt193 24273314

21. Liu H, Zhang J. No support for the adaptive hypothesis of lagging-strand encoding in bacterial genomes. bioRxiv. 2020. p. 2020.01.14.906818. doi: 10.1101/2020.01.14.906818

22. Schroeder JW, Hirst WG, Szewczyk GA, Simmons LA. The Effect of Local Sequence Context on Mutational Bias of Genes Encoded on the Leading and Lagging Strands. Curr Biol. 2016;26: 692–697. doi: 10.1016/j.cub.2016.01.016 26923786

23. Lynch M, Ackerman MS, Gout JF, Long H, Sung W, Thomas WK, et al. Genetic drift, selection and the evolution of the mutation rate. Nat Rev Genet. 2016;17: 704–714. doi: 10.1038/nrg.2016.104 27739533

24. Nei M, Kumar S. Molecular Evolution and Phylogenetics. Oxford University Press; 2000.

25. Christin P-A, Weinreich DM, Besnard G. Causes and evolutionary significance of genetic convergence. Trends Genet. 2010;26: 400–405. doi: 10.1016/j.tig.2010.06.005 20685006

26. Liu B, Alberts BM. Head-on collision between a DNA replication apparatus and RNA polymerase transcription complex. Science. 1995;267: 1131–1137. doi: 10.1126/science.7855590 7855590

27. Nomura M, Morgan EA. Genetics of bacterial ribosomes. Annu Rev Genet. 1977;11: 297–347. doi: 10.1146/ 339818

28. Boubakri H, De Septenville AL, Viguera E, Michel B. The helicases DinG, Rep and UvrD cooperate to promote replication across transcription units in vivo. EMBO J. 2010;29: 145–157. doi: 10.1038/emboj.2009.308 19851282

29. De Septenville AL, Duigou S, Boubakri H, Michel B. Replication fork reversal after replication-transcription collision. PLoS Genet. 2012;8: e1002622. doi: 10.1371/journal.pgen.1002622 22496668

30. Segall A, Mahan MJ, Roth JR. Rearrangement of the bacterial chromosome: forbidden inversions. Science. 1988;241: 1314–1318. doi: 10.1126/science.3045970 3045970

31. Mackiewicz P, Mackiewicz D, Gierlik A, Kowalczuk M, Nowicka A, Dudkiewicz M, et al. The differential killing of genes by inversions in prokaryotic genomes. J Mol Evol. 2001;53: 615–621. doi: 10.1007/s002390010248 11677621

32. Eisen JA, Heidelberg JF, White O, Salzberg SL. Evidence for symmetric chromosomal inversions around the replication origin in bacteria. Genome Biol. 2000;1: RESEARCH0011. doi: 10.1186/gb-2000-1-6-research0011 11178265

33. Darling AE, Miklós I, Ragan MA. Dynamics of genome rearrangement in bacterial populations. PLoS Genet. 2008;4: e1000128. doi: 10.1371/journal.pgen.1000128 18650965

34. Slupska MM, Chiang JH, Luther WM, Stewart JL, Amii L, Conrad A, et al. Genes involved in the determination of the rate of inversions at short inverted repeats. Genes Cells. 2000;5: 425–437. doi: 10.1046/j.1365-2443.2000.00341.x 10886369

35. Schofield MA, Agbunag R, Miller JH. DNA inversions between short inverted repeats in Escherichia coli. Genetics. 1992;132: 295–302. 1427029

36. Gordon AJ, Halliday JA. Inversions with deletions and duplications. Genetics. 1995;140: 411–414. 7635304

37. Lee H, Popodi E, Tang H, Foster PL. Rate and molecular spectrum of spontaneous mutations in the bacterium Escherichia coli as determined by whole-genome sequencing. Proc Natl Acad Sci U S A. 2012;109: E2774–83. doi: 10.1073/pnas.1210309109 22991466

38. Yoshiyama K, Higuchi K, Matsumura H, Maki H. Directionality of DNA replication fork movement strongly affects the generation of spontaneous mutations in Escherichia coli. J Mol Biol. 2001;307: 1195–1206. doi: 10.1006/jmbi.2001.4557 11292335

39. Price MN, Alm EJ, Arkin AP. Interruptions in gene expression drive highly expressed operons to the leading strand of DNA replication. Nucleic Acids Res. 2005;33: 3224–3234. doi: 10.1093/nar/gki638 15942025

40. Fijalkowska IJ, Jonczyk P, Tkaczyk MM, Bialoskorska M, Schaaper RM. Unequal fidelity of leading strand and lagging strand DNA replication on the Escherichia coli chromosome. Proc Natl Acad Sci U S A. 1998;95: 10020–10025. doi: 10.1073/pnas.95.17.10020 9707593

41. Maslowska KH, Makiela-Dzbenska K, Mo J-Y, Fijalkowska IJ, Schaaper RM. High-accuracy lagging-strand DNA replication mediated by DNA polymerase dissociation. Proc Natl Acad Sci U S A. 2018;115: 4212–4217. doi: 10.1073/pnas.1720353115 29610333

42. Lujan SA, Williams JS, Pursell ZF, Abdulovic-Cui AA, Clark AB, Nick McElhinny SA, et al. Mismatch repair balances leading and lagging strand DNA replication fidelity. PLoS Genet. 2012;8: e1003016. doi: 10.1371/journal.pgen.1003016 23071460

43. Pavlov YI, Mian IM, Kunkel TA. Evidence for preferential mismatch repair of lagging strand DNA replication errors in yeast. Curr Biol. 2003;13: 744–748. doi: 10.1016/s0960-9822(03)00284-7 12725731

44. Dillon MM, Sung W, Lynch M, Cooper VS. Periodic Variation of Mutation Rates in Bacterial Genomes Associated with Replication Timing. MBio. 2018;9. doi: 10.1128/mBio.01371-18 30131359

45. Sung W, Ackerman MS, Gout JF, Miller SF, Williams E, Foster PL, et al. Asymmetric Context-Dependent Mutation Patterns Revealed through Mutation-Accumulation Experiments. Mol Biol Evol. 2015;32: 1672–1683. doi: 10.1093/molbev/msv055 25750180

46. Foster PL, Lee H, Popodi E, Townes JP, Tang H. Determinants of spontaneous mutation in the bacterium Escherichia coli as revealed by whole-genome sequencing. Proc Natl Acad Sci U S A. 2015;112: E5990–9. doi: 10.1073/pnas.1512136112 26460006

47. Lind PA, Andersson DI. Whole-genome mutational biases in bacteria. Proc Natl Acad Sci U S A. 2008;105: 17878–17883. doi: 10.1073/pnas.0804445105 19001264

48. Lee H, Doak TG, Popodi E, Foster PL, Tang H. Insertion sequence-caused large-scale rearrangements in the genome of Escherichia coli. Nucleic Acids Res. 2016;44: 7109–7119. doi: 10.1093/nar/gkw647 27431326

49. Bhagwat AS, Hao W, Townes JP, Lee H, Tang H, Foster PL. Strand-biased cytosine deamination at the replication fork causes cytosine to thymine mutations in Escherichia coli. Proc Natl Acad Sci U S A. 2016;113: 2176–2181. doi: 10.1073/pnas.1522325113 26839411

50. McGinn J, Marraffini LA. Molecular mechanisms of CRISPR-Cas spacer acquisition. Nat Rev Microbiol. 2019;17: 7–12. doi: 10.1038/s41579-018-0071-7 30171202

51. Barrangou R, Fremaux C, Deveau H, Richards M, Boyaval P, Moineau S, et al. CRISPR provides acquired resistance against viruses in prokaryotes. Science. 2007;315: 1709–1712. doi: 10.1126/science.1138140 17379808

52. Merrikh H. Spatial and Temporal Control of Evolution through Replication-Transcription Conflicts. Trends Microbiol. 2017. doi: 10.1016/j.tim.2017.01.008 28216294

53. Nicolas P, Mäder U, Dervyn E, Rochat T, Leduc A, Pigeonneau N, et al. Condition-dependent transcriptome reveals high-level regulatory architecture in Bacillus subtilis. Science. 2012;335: 1103–1106. doi: 10.1126/science.1206848 22383849

54. Piironen J, Vehtari A. Sparsity information and regularization in the horseshoe and other shrinkage priors. Electron J Stat. 2017;11: 5018–5051.

55. Michna RH, Zhu B, Mäder U, Stülke J. SubtiWiki 2.0—an integrated database for the model organism Bacillus subtilis. Nucleic Acids Res. 2016;44: D654–D662. doi: 10.1093/nar/gkv1006 26433225

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