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. 2000 Nov;6(11):1483–1491. doi: 10.1017/s1355838200990708

Coupled nucleotide covariations reveal dynamic RNA interaction patterns.

A P Gultyaev 1, T Franch 1, K Gerdes 1
PMCID: PMC1370018  PMID: 11105748

Abstract

Evolutionarily conserved structures in related RNA molecules contain coordinated variations (covariations) of paired nucleotides. Analysis of covariations is a very powerful approach to deduce phylogenetically conserved (i.e., functional) conformations, including tertiary interactions. Here we discuss conserved RNA folding pathways that are revealed by covariation patterns. In such pathways, structural requirements for alternative pairings cause some nucleotides to covary with two different partners. Such "coupled" covariations between three or more nucleotides were found in various types of RNAs. The analysis of coupled covariations can unravel important features of RNA folding dynamics and improve phylogeny reconstruction in some cases. Importantly, it is necessary to distinguish between multiple covariations determined by mutually exclusive structures and those determined by tertiary contacts.

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Selected References

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  1. Ambrós S., Hernández C., Desvignes J. C., Flores R. Genomic structure of three phenotypically different isolates of peach latent mosaic viroid: implications of the existence of constraints limiting the heterogeneity of viroid quasispecies. J Virol. 1998 Sep;72(9):7397–7406. doi: 10.1128/jvi.72.9.7397-7406.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Biebricher C. K., Luce R. In vitro recombination and terminal elongation of RNA by Q beta replicase. EMBO J. 1992 Dec;11(13):5129–5135. doi: 10.1002/j.1460-2075.1992.tb05620.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brion P., Westhof E. Hierarchy and dynamics of RNA folding. Annu Rev Biophys Biomol Struct. 1997;26:113–137. doi: 10.1146/annurev.biophys.26.1.113. [DOI] [PubMed] [Google Scholar]
  4. Cao Y., Woodson S. A. Destabilizing effect of an rRNA stem-loop on an attenuator hairpin in the 5' exon of the Tetrahymena pre-rRNA. RNA. 1998 Aug;4(8):901–914. doi: 10.1017/s1355838298980621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Conn G. L., Gutell R. R., Draper D. E. A functional ribosomal RNA tertiary structure involves a base triple interaction. Biochemistry. 1998 Aug 25;37(34):11980–11988. doi: 10.1021/bi980825+. [DOI] [PubMed] [Google Scholar]
  6. Costa M., Déme E., Jacquier A., Michel F. Multiple tertiary interactions involving domain II of group II self-splicing introns. J Mol Biol. 1997 Apr 4;267(3):520–536. doi: 10.1006/jmbi.1996.0882. [DOI] [PubMed] [Google Scholar]
  7. Costa M., Michel F. Frequent use of the same tertiary motif by self-folding RNAs. EMBO J. 1995 Mar 15;14(6):1276–1285. doi: 10.1002/j.1460-2075.1995.tb07111.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Davies R. W., Waring R. B., Ray J. A., Brown T. A., Scazzocchio C. Making ends meet: a model for RNA splicing in fungal mitochondria. Nature. 1982 Dec 23;300(5894):719–724. doi: 10.1038/300719a0. [DOI] [PubMed] [Google Scholar]
  9. Di Serio F., Daròs J. A., Ragozzino A., Flores R. A 451-nucleotide circular RNA from cherry with hammerhead ribozymes in its strands of both polarities. J Virol. 1997 Sep;71(9):6603–6610. doi: 10.1128/jvi.71.9.6603-6610.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fast N. M., Roger A. J., Richardson C. A., Doolittle W. F. U2 and U6 snRNA genes in the microsporidian Nosema locustae: evidence for a functional spliceosome. Nucleic Acids Res. 1998 Jul 1;26(13):3202–3207. doi: 10.1093/nar/26.13.3202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Franch T., Gerdes K. Programmed cell death in bacteria: translational repression by mRNA end-pairing. Mol Microbiol. 1996 Sep;21(5):1049–1060. doi: 10.1046/j.1365-2958.1996.771431.x. [DOI] [PubMed] [Google Scholar]
  12. Franch T., Gultyaev A. P., Gerdes K. Programmed cell death by hok/sok of plasmid R1: processing at the hok mRNA 3'-end triggers structural rearrangements that allow translation and antisense RNA binding. J Mol Biol. 1997 Oct 17;273(1):38–51. doi: 10.1006/jmbi.1997.1294. [DOI] [PubMed] [Google Scholar]
  13. Gautheret D., Gutell R. R. Inferring the conformation of RNA base pairs and triples from patterns of sequence variation. Nucleic Acids Res. 1997 Apr 15;25(8):1559–1564. doi: 10.1093/nar/25.8.1559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gerdes K., Gultyaev A. P., Franch T., Pedersen K., Mikkelsen N. D. Antisense RNA-regulated programmed cell death. Annu Rev Genet. 1997;31:1–31. doi: 10.1146/annurev.genet.31.1.1. [DOI] [PubMed] [Google Scholar]
  15. Gerdes K., Poulsen L. K., Thisted T., Nielsen A. K., Martinussen J., Andreasen P. H. The hok killer gene family in gram-negative bacteria. New Biol. 1990 Nov;2(11):946–956. [PubMed] [Google Scholar]
  16. Gultyaev A. P., Franch T., Gerdes K. Programmed cell death by hok/sok of plasmid R1: coupled nucleotide covariations reveal a phylogenetically conserved folding pathway in the hok family of mRNAs. J Mol Biol. 1997 Oct 17;273(1):26–37. doi: 10.1006/jmbi.1997.1295. [DOI] [PubMed] [Google Scholar]
  17. Gultyaev A. P., van Batenburg F. H., Pleij C. W. Dynamic competition between alternative structures in viroid RNAs simulated by an RNA folding algorithm. J Mol Biol. 1998 Feb 13;276(1):43–55. doi: 10.1006/jmbi.1997.1384. [DOI] [PubMed] [Google Scholar]
  18. Gultyaev A. P., van Batenburg F. H., Pleij C. W. The computer simulation of RNA folding pathways using a genetic algorithm. J Mol Biol. 1995 Jun 30;250(1):37–51. doi: 10.1006/jmbi.1995.0356. [DOI] [PubMed] [Google Scholar]
  19. Gultyaev A. P., van Batenburg F. H., Pleij C. W. The influence of a metastable structure in plasmid primer RNA on antisense RNA binding kinetics. Nucleic Acids Res. 1995 Sep 25;23(18):3718–3725. doi: 10.1093/nar/23.18.3718. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Gutell R. R., Power A., Hertz G. Z., Putz E. J., Stormo G. D. Identifying constraints on the higher-order structure of RNA: continued development and application of comparative sequence analysis methods. Nucleic Acids Res. 1992 Nov 11;20(21):5785–5795. doi: 10.1093/nar/20.21.5785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Higgs P. G. Compensatory neutral mutations and the evolution of RNA. Genetica. 1998;102-103(1-6):91–101. [PubMed] [Google Scholar]
  22. Hughes J. M. Functional base-pairing interaction between highly conserved elements of U3 small nucleolar RNA and the small ribosomal subunit RNA. J Mol Biol. 1996 Jun 21;259(4):645–654. doi: 10.1006/jmbi.1996.0346. [DOI] [PubMed] [Google Scholar]
  23. James B. D., Olsen G. J., Liu J. S., Pace N. R. The secondary structure of ribonuclease P RNA, the catalytic element of a ribonucleoprotein enzyme. Cell. 1988 Jan 15;52(1):19–26. doi: 10.1016/0092-8674(88)90527-2. [DOI] [PubMed] [Google Scholar]
  24. Lodmell J. S., Dahlberg A. E. A conformational switch in Escherichia coli 16S ribosomal RNA during decoding of messenger RNA. Science. 1997 Aug 29;277(5330):1262–1267. doi: 10.1126/science.277.5330.1262. [DOI] [PubMed] [Google Scholar]
  25. Loss P., Schmitz M., Steger G., Riesner D. Formation of a thermodynamically metastable structure containing hairpin II is critical for infectivity of potato spindle tuber viroid RNA. EMBO J. 1991 Mar;10(3):719–727. doi: 10.1002/j.1460-2075.1991.tb08002.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ma C. K., Kolesnikow T., Rayner J. C., Simons E. L., Yim H., Simons R. W. Control of translation by mRNA secondary structure: the importance of the kinetics of structure formation. Mol Microbiol. 1994 Dec;14(5):1033–1047. doi: 10.1111/j.1365-2958.1994.tb01337.x. [DOI] [PubMed] [Google Scholar]
  27. Matysiak M., Wrzesinski J., Ciesiołka J. Sequential folding of the genomic ribozyme of the hepatitis delta virus: structural analysis of RNA transcription intermediates. J Mol Biol. 1999 Aug 13;291(2):283–294. doi: 10.1006/jmbi.1999.2955. [DOI] [PubMed] [Google Scholar]
  28. Michel F., Ellington A. D., Couture S., Szostak J. W. Phylogenetic and genetic evidence for base-triples in the catalytic domain of group I introns. Nature. 1990 Oct 11;347(6293):578–580. doi: 10.1038/347578a0. [DOI] [PubMed] [Google Scholar]
  29. Michel F., Hanna M., Green R., Bartel D. P., Szostak J. W. The guanosine binding site of the Tetrahymena ribozyme. Nature. 1989 Nov 23;342(6248):391–395. doi: 10.1038/342391a0. [DOI] [PubMed] [Google Scholar]
  30. Michel F., Westhof E. Modelling of the three-dimensional architecture of group I catalytic introns based on comparative sequence analysis. J Mol Biol. 1990 Dec 5;216(3):585–610. doi: 10.1016/0022-2836(90)90386-Z. [DOI] [PubMed] [Google Scholar]
  31. Méreau A., Fournier R., Grégoire A., Mougin A., Fabrizio P., Lührmann R., Branlant C. An in vivo and in vitro structure-function analysis of the Saccharomyces cerevisiae U3A snoRNP: protein-RNA contacts and base-pair interaction with the pre-ribosomal RNA. J Mol Biol. 1997 Oct 31;273(3):552–571. doi: 10.1006/jmbi.1997.1320. [DOI] [PubMed] [Google Scholar]
  32. Nagel J. H., Gultyaev A. P., Gerdes K., Pleij C. W. Metastable structures and refolding kinetics in hok mRNA of plasmid R1. RNA. 1999 Nov;5(11):1408–1418. doi: 10.1017/s1355838299990805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Neefs J. M., De Wachter R. A proposal for the secondary structure of a variable area of eukaryotic small ribosomal subunit RNA involving the existence of a pseudoknot. Nucleic Acids Res. 1990 Oct 11;18(19):5695–5704. doi: 10.1093/nar/18.19.5695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Nielsen A. K., Gerdes K. Mechanism of post-segregational killing by hok-homologue pnd of plasmid R483: two translational control elements in the pnd mRNA. J Mol Biol. 1995 Jun 2;249(2):270–282. doi: 10.1006/jmbi.1995.0296. [DOI] [PubMed] [Google Scholar]
  35. Novick R. P., Iordanescu S., Projan S. J., Kornblum J., Edelman I. pT181 plasmid replication is regulated by a countertranscript-driven transcriptional attenuator. Cell. 1989 Oct 20;59(2):395–404. doi: 10.1016/0092-8674(89)90300-0. [DOI] [PubMed] [Google Scholar]
  36. Olsthoorn R. C., Mertens S., Brederode F. T., Bol J. F. A conformational switch at the 3' end of a plant virus RNA regulates viral replication. EMBO J. 1999 Sep 1;18(17):4856–4864. doi: 10.1093/emboj/18.17.4856. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Pan J., Thirumalai D., Woodson S. A. Folding of RNA involves parallel pathways. J Mol Biol. 1997 Oct 17;273(1):7–13. doi: 10.1006/jmbi.1997.1311. [DOI] [PubMed] [Google Scholar]
  38. Pedersen K., Gerdes K. Multiple hok genes on the chromosome of Escherichia coli. Mol Microbiol. 1999 Jun;32(5):1090–1102. doi: 10.1046/j.1365-2958.1999.01431.x. [DOI] [PubMed] [Google Scholar]
  39. Poot R. A., Tsareva N. V., Boni I. V., van Duin J. RNA folding kinetics regulates translation of phage MS2 maturation gene. Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10110–10115. doi: 10.1073/pnas.94.19.10110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Pouwels P. H., van Luijk N., Leer R. J., Posno M. Control of replication of the Lactobacillus pentosus plasmid p353-2: evidence for a mechanism involving transcriptional attenuation of the gene coding for the replication protein. Mol Gen Genet. 1994 Mar;242(5):614–622. doi: 10.1007/BF00285285. [DOI] [PubMed] [Google Scholar]
  41. Qu F., Heinrich C., Loss P., Steger G., Tien P., Riesner D. Multiple pathways of reversion in viroids for conservation of structural elements. EMBO J. 1993 May;12(5):2129–2139. doi: 10.1002/j.1460-2075.1993.tb05861.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Repsilber D., Wiese S., Rachen M., Schröder A. W., Riesner D., Steger G. Formation of metastable RNA structures by sequential folding during transcription: time-resolved structural analysis of potato spindle tuber viroid (-)-stranded RNA by temperature-gradient gel electrophoresis. RNA. 1999 Apr;5(4):574–584. doi: 10.1017/s1355838299982018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Rousset F., Pélandakis M., Solignac M. Evolution of compensatory substitutions through G.U intermediate state in Drosophila rRNA. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10032–10036. doi: 10.1073/pnas.88.22.10032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Russell R., Herschlag D. New pathways in folding of the Tetrahymena group I RNA enzyme. J Mol Biol. 1999 Sep 3;291(5):1155–1167. doi: 10.1006/jmbi.1999.3026. [DOI] [PubMed] [Google Scholar]
  45. Semrad K., Schroeder R. A ribosomal function is necessary for efficient splicing of the T4 phage thymidylate synthase intron in vivo. Genes Dev. 1998 May 1;12(9):1327–1337. doi: 10.1101/gad.12.9.1327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Sharma K., Tollervey D. Base pairing between U3 small nucleolar RNA and the 5' end of 18S rRNA is required for pre-rRNA processing. Mol Cell Biol. 1999 Sep;19(9):6012–6019. doi: 10.1128/mcb.19.9.6012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Staley J. P., Guthrie C. Mechanical devices of the spliceosome: motors, clocks, springs, and things. Cell. 1998 Feb 6;92(3):315–326. doi: 10.1016/s0092-8674(00)80925-3. [DOI] [PubMed] [Google Scholar]
  48. Stephan W. The rate of compensatory evolution. Genetics. 1996 Sep;144(1):419–426. doi: 10.1093/genetics/144.1.419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Thisted T., Nielsen A. K., Gerdes K. Mechanism of post-segregational killing: translation of Hok, SrnB and Pnd mRNAs of plasmids R1, F and R483 is activated by 3'-end processing. EMBO J. 1994 Apr 15;13(8):1950–1959. doi: 10.1002/j.1460-2075.1994.tb06464.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Thisted T., Sørensen N. S., Gerdes K. Mechanism of post-segregational killing: secondary structure analysis of the entire Hok mRNA from plasmid R1 suggests a fold-back structure that prevents translation and antisense RNA binding. J Mol Biol. 1995 Apr 14;247(5):859–873. doi: 10.1006/jmbi.1995.0186. [DOI] [PubMed] [Google Scholar]
  51. Tillier E. R., Collins R. A. High apparent rate of simultaneous compensatory base-pair substitutions in ribosomal RNA. Genetics. 1998 Apr;148(4):1993–2002. doi: 10.1093/genetics/148.4.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Treiber D. K., Rook M. S., Zarrinkar P. P., Williamson J. R. Kinetic intermediates trapped by native interactions in RNA folding. Science. 1998 Mar 20;279(5358):1943–1946. doi: 10.1126/science.279.5358.1943. [DOI] [PubMed] [Google Scholar]
  53. Wassenegger M., Heimes S., Sänger H. L. An infectious viroid RNA replicon evolved from an in vitro-generated non-infectious viroid deletion mutant via a complementary deletion in vivo. EMBO J. 1994 Dec 15;13(24):6172–6177. doi: 10.1002/j.1460-2075.1994.tb06964.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Williams K. P., Bartel D. P. Phylogenetic analysis of tmRNA secondary structure. RNA. 1996 Dec;2(12):1306–1310. [PMC free article] [PubMed] [Google Scholar]
  55. Woodson S. A., Cech T. R. Alternative secondary structures in the 5' exon affect both forward and reverse self-splicing of the Tetrahymena intervening sequence RNA. Biochemistry. 1991 Feb 26;30(8):2042–2050. doi: 10.1021/bi00222a006. [DOI] [PubMed] [Google Scholar]
  56. Woodson S. A., Emerick V. L. An alternative helix in the 26S rRNA promotes excision and integration of the Tetrahymena intervening sequence. Mol Cell Biol. 1993 Feb;13(2):1137–1145. doi: 10.1128/mcb.13.2.1137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Woodson S. A. Ironing out the kinks: splicing and translation in bacteria. Genes Dev. 1998 May 1;12(9):1243–1247. doi: 10.1101/gad.12.9.1243. [DOI] [PubMed] [Google Scholar]
  58. Zarrinkar P. P., Wang J., Williamson J. R. Slow folding kinetics of RNase P RNA. RNA. 1996 Jun;2(6):564–573. [PMC free article] [PubMed] [Google Scholar]
  59. Zarrinkar P. P., Williamson J. R. The kinetic folding pathway of the Tetrahymena ribozyme reveals possible similarities between RNA and protein folding. Nat Struct Biol. 1996 May;3(5):432–438. doi: 10.1038/nsb0596-432. [DOI] [PubMed] [Google Scholar]
  60. de Smit M. H., van Duin J. Secondary structure of the ribosome binding site determines translational efficiency: a quantitative analysis. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7668–7672. doi: 10.1073/pnas.87.19.7668. [DOI] [PMC free article] [PubMed] [Google Scholar]

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