Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Paramutation and related phenomena in diverse species

Nature Reviews Genetics volume 18, pages 5–23 (2017)Cite this article

Subjects

Key Points

  • Paramutation describes the occurrence of meiotically heritable epigenetic changes in gene regulation and trans-inactivation behaviours. These behaviours are recognized by non-Mendelian inheritance patterns that are found independently of chromosome transmission ratio distortions and, at least in plants, in the absence of parent-of-origin effects.

  • Genetic analyses implicate small RNAs (sRNAs) and RNA interference mechanisms in affecting paramutations operating in both plants and model metazoans.

  • Species-specific elaborations of core RNA interference components provide unique strategies for establishing and maintaining self-reinforcing loops of transcriptional and post-transcriptional control based on sRNA biogenesis from either nascent or messenger RNA scaffolds. Specialized Pol II-related RNA polymerase complexes (exemplified in Zea mays), histone readers and RNA-processing factors (found in Drosophila melanogaster), nuclear Argonaute proteins (as elaborated in Caenorhabditis elegans), and RNA-dependent RNA polymerases (found in both Z. mays and C. elegans) are implicated in paramutation-type behaviours.

  • Paramutations are associated with repeated sequences in Z. mays, D. melanogaster and possibly in mammals, and are recognized when changes occur at regulatory regions of specific genes affecting discernible traits.

  • Gametic transmission of sRNAs themselves seems to be responsible for paramutation-type inheritance patterns in metazoans. In plants, the transmission of locus-specific episomes of sRNA biogenesis seems to be dependent on heritable features of DNA and/or chromatin structure.

  • Paramutations exhibit dynamic behaviours based on allele histories, lead to non-Mendelian inheritance patterns that affect allele frequencies and can facilitate the inheritance of acquired characteristics. Although the biological roles of paramutation remain ill-defined, their deviations from the principle tenets of the modern synthesis represent little understood strategies for evolutionary change.

Abstract

Paramutation describes a process that results in heritable epigenetic changes of gene regulation and trans-homologue interactions. Recent discoveries in model organisms have highlighted roles for the respective nuclear systems that regulate transposons via small RNA molecules both for paramutation and for defining transgenerational inheritance. Differences between plants and animals may influence specific transmission behaviours but the involvement of small RNA-based mechanisms identifies a unifying eukaryotic theme. These mechanisms that specify heritable epigenetic information represent genetic systems adjunct to DNA sequences that contribute to phenotypic diversity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: General paramutation behaviours.
Figure 2: A working model for paramutation in maize.
Figure 3: Paramutation behaviour in flies.
Figure 4: Paramutation behaviour in worms.

Similar content being viewed by others

References

  1. Brink, R. A. Paramutation at the R locus in maize. Cold Spring Harb. Symp. Quant. Biol. 23, 379–391 (1958).

    Article  CAS  PubMed  Google Scholar 

  2. Brink, R. A. A genetic change associated with the R locus in maize which is directed and potentially reversible. Genetics 41, 872–889 (1956). First genetic description of paramutation behaviours.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Brink, R. A. & Weyers, W. H. Invariable genetic change in maize plants heterozygous for marbled aleurone. Proc. Natl Acad. Sci. USA 43, 1053–1060 (1957).

    Article  CAS  PubMed  Google Scholar 

  4. Hagemann, R. Somatische Konversion bei Lycopersicon esculentum Mill. Z. Vererbungsl. 89, 587–613 (in German) (1958).

    CAS  PubMed  Google Scholar 

  5. Brink, R. A. Paramutation. Annu. Rev. Genet. 7, 129–152 (1973).

    Article  CAS  PubMed  Google Scholar 

  6. Hollick, J. B. & Chandler, V. L. Epigenetic allelic states of a transcriptional regulatory locus exhibit overdominant gene action. Genetics 150, 891–897 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Groszmann, M. et al. Changes in 24-nt siRNA levels in Arabidopsis hybrids suggest an epigenetic contribution to hybrid vigor. Proc. Natl Acad. Sci. USA 108, 2617–2622 (2011).

    Article  PubMed  Google Scholar 

  8. Regulski, M. et al. The maize methylome influences mRNA splice sites and reveals widespread paramutation-like switches guided by small RNA. Genome Res. 23, 1651–1662 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Eichten, S. R. et al. Epigenetic and genetic influences on DNA methylation variation in maize populations. Plant Cell 25, 2783–2797 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Greaves, I. K., Groszmann, M., Wang, A., Peacock, W. J. & Dennis, E. S. Inheritance of trans chromosomal methylation patterns from Arabidopsis F1 hybrids. Proc. Natl Acad. Sci. USA 111, 2017–2022 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Kermicle, J. L. & Alleman, M. Gametic imprinting in maize in relation to the angiosperm life cycle. Development (Suppl.) 9–14 (1990).

  12. Mikula, B. C. Environmental programming of heritable epigenetic changes in paramutant r-gene expression using temperature and light at a specific stage of early development in maize seedlings. Genetics 140, 1379–1387 (1995). Paramutation at r1 is affected by environmental conditions during early development.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Alleman, M. et al. An RNA-dependent RNA polymerase is required for paramutation in maize. Nature 442, 295–298 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Hale, C. J., Stonaker, J. L., Gross, S. M. & Hollick, J. B. A novel Snf2 protein maintains transgenerational regulatory states established by paramutation in maize. PLoS Biol. 5, 2156–2165 (2007).

    Article  CAS  Google Scholar 

  15. Erhard, K. J. et al. RNA polymerase IV functions in paramutation in Zea mays. Science 323, 1201–1205 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Stonaker, J. L., Lim, J. P., Erhard, K. F. Jr & Hollick, J. B. Diversity of Pol IV functions is defined by mutations at the maize rmr7 locus. PLoS Genet. 5, e1000706 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sidorenko, L. et al. A dominant mutation in mediator of paramutation2, one of three second-largest subunits of a plant-specific RNA polymerase, disrupts multiple siRNA silencing processes. PLoS Genet. 5, e1000725 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Arteaga-Vazquez, M. et al. RNA-mediated trans-communication can establish paramutation at the b1 locus in maize. Proc. Natl Acad. Sci. USA 107, 12986–12991 (2010).

    Article  PubMed  Google Scholar 

  19. Barbour, J. R. et al. required to maintain repression2 is a novel protein that facilitates locus-specific paramutation in maize. Plant Cell 24, 1761–1775 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rassoulzadegan, M. et al. RNA-mediated non-Mendelian inheritance of an epigenetic change in the mouse. Nature 441, 469–474 (2006). First illustration that microinjected RNAs can confer heritable silencing effects to endogenous gene targets.

    Article  CAS  PubMed  Google Scholar 

  21. Yuan, S. et al. Breeding scheme and maternal small RNAs affect the efficiency of transgenerational inheritance of a paramutation in mice. Sci. Rep. 5, 9266 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wagner, K. D. et al. RNA induction and inheritance of epigenetic cardiac hypertrophy in the mouse. Dev. Cell 14, 962–969 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Grandjean, V. et al. The miR-124-Sox9 paramutation: RNA-mediated epigenetic control of embryonic and adult growth. Development 136, 3647–3655 (2013).

    Article  CAS  Google Scholar 

  24. deVanssay, A. et al. Paramutation in Drosophila linked to emergence of a piRNA-producing locus. Nature 490, 112–117 (2012). First study to implicate inherited maternal sRNAs and locus-specific propagation in mediating heritable trans -silencing in animals.

    Article  CAS  Google Scholar 

  25. Hermant, C. et al. Paramutation in Drosophila requires both nuclear and cytoplasmic actors of the piRNA pathway and induces cis-spreading of piRNA production. Genetics 201, 1381–1396 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shirayama, M. et al. piRNAs initiate an epigenetic memory of non-self RNA in the C. elegans germline. Cell 150, 65–77 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Luteijn, M. J. et al. Extremely stable Piwi-induced gene silencing in Caenorhabditis elegans. EMBO J. 31, 3422–3430 (2012). References 26 and 27 demonstrate the transference of silencing behaviours between homologues. Reference 27 also provides the first genetic proof of a cytoplasmic-based paramutation-type inheritance pattern in worms.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Seth, M. et al. The C. elegans CSR-1 Argonaute pathway counteracts epigenetic silencing to promote germline gene expression. Dev. Cell 27, 656–663 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wedeles, C. J., Wu, M. Z. & Claycomb, J. M. Protection of germline gene expression by the C. elegans Argonaute CSR-1. Dev. Cell 27, 664–671 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Sapetschnig, A., Sarkies, P., Lehrbach, N. J. & Miska, E. A. Tertiary siRNAs mediate paramutation in C. elegans. PLoS Genet. 11, e1005078 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Borges, F. & Martienssen, R. A. The expanding world of small RNAs in plants. Nat. Rev. Mol. Cell Biol. 16, 727–741 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Holoch, D. & Moazed, D. RNA-mediated epigenetic regulation of gene expression. Nat. Rev. Genet. 16, 71–84 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wiedenheft, B., Sternberg, S. H. & Doudna, J. A. RNA-guided genetic silencing systems in bacteria and archaea. Nature 482, 331–338 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Peters, L. & Meister, G. Argonaute proteins: mediators of RNA silencing. Mol. Cell 26, 611–623 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Heard, E. & Martienssen, R. A. Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157, 95–109 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Matzke, M. A., Kanno, T. & Matzke, A. J. RNA-directed DNA methylation: the evolution of a complex epigenetic pathway in flowering plants. Annu. Rev. Plant Biol. 66, 243–267 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Iwasaki, Y. W., Siomi, M. C. & Siomi, H. PIWI-interacting RNA: its biogenesis and functions. Annu. Rev. Biochem. 84, 405–433 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Pilu, R. Paramutation phenomena in plants. Semin. Cell Dev. Biol. 44, 2–10 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Hövel, I., Pearson, N. A. & Stam, M. Cis-acting determinants of paramutation. Semin. Cell Dev. Biol. 44, 22–32 (2015).

    Article  CAS  PubMed  Google Scholar 

  40. Dooner, H. K., Robbins, T. P. & Jorgensen, R. A. Genetic and developmental control of anthocyanin biosynthesis. Annu. Rev. Genet. 25, 173–199 (1991).

    Article  CAS  PubMed  Google Scholar 

  41. Pilu, R. et al. A paramutation phenomenon is involved in the genetics of maize low phytic acid1-241 (lpa1-241) trait. Heredity 102, 236–245 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Brink, R. A. Basis of a genetic change which invariably occurs in certain maize heterozygotes. Science 127, 1182–1183 (1958).

    Article  CAS  PubMed  Google Scholar 

  43. Brink, R. A., Brown, D. F., Kermicle, J. & Weyers, W. H. Locus dependence of the paramutant R phenotype in maize. Genetics 45, 1297–1312 (1960).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Brown, D. F. & Brink, R. A. Paramutagenic action of paramutant Rr and Rg alleles in maize. Genetics 45, 1313–1316 (1960).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Brink, R. A., Kermicle, J. L. & Brown, D. F. Tests for a gene-dependent cytoplasmic particle associated with R paramutation in maize. Proc. Natl Acad. Sci. USA 51, 1067–1074 (1964).

    Article  CAS  PubMed  Google Scholar 

  46. Styles, E. D. & Brink, R. A. The metastable nature of paramutable R alleles in maize. IV. Parallel enhancement of R action in heterozygotes with r and in hemizygotes. Genetics 61, 801–811 (1969).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Kermicle, J. L. Dependence of the R-mottled aleurone phenotype in maize on mode of sexual transmission. Genetics 66, 69–85 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Coe, E. H. Jr A regular and continuing conversion-type phenomenon at the b locus in maize. Proc. Natl Acad. Sci. USA 45, 828–832 (1959).

    Article  CAS  PubMed  Google Scholar 

  49. Hollick, J. B., Patterson, G., Coe, E. H. Jr., Cone, K. C. & Chandler, V. L. Allelic interactions heritably alter the activity of a metastable maize pl allele. Genetics 141, 709–719 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Das, O. P. & Messing, J. Variegated phenotype and developmental methylation changes of a maize allele originating from epimutation. Genetics 136, 1121–1141 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Walbot, V. Imprinting of R-r, paramutation of B-I and Pl, and epigenetic silencing of MuDR/Mu transposons in Zea mays L. are coordinately affected by inbred background. Genet. Res. 77, 219–226 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Goettel, W. & Messing, J. Paramutagenicity of a p1 epiallele in maize. Theor. Appl. Genet. 126, 159–177 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Sidorenko, L. & Peterson, T. Transgene-induced silencing identifies sequences involved in the establishment of paramutation of the maize p1 gene. Plant Cell 13, 319–335 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hollick, J. B., Kermicle, J. L. & Parkinson, S. E. Rmr6 maintains meiotic inheritance of paramutant states in Zea mays. Genetics 171, 725–740 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Henikoff, S. & Comai, L. Trans-sensing effects: the ups and downs of being together. Cell 93, 329–332 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Bender, J. & Fink, G. R. Epigenetic control of an endogenous gene family is revealed by a novel blue fluorescent mutant of Arabidopsis. Cell 83, 725–734 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Todd, J. J. & Vodkin, L. O. Duplications that suppress and deletions that restore expression from a chalcone synthase multigene family. Plant Cell 8, 687–699 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gross, S. M. & Hollick, J. B. Multiple trans-sensing interactions affect meiotically heritable epigenetic states at the maize pl1 locus. Genetics 176, 829–839 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Fulci, V. & Macino, G. Quelling: post-transcriptional gene silencing guided by small RNAs in Neurospora crassa. Curr. Opin. Microbiol. 10, 199–203 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Belele, C. L. et al. Specific tandem repeats are sufficient for paramutation-induced transgenerational silencing. PLoS Genet. 9, e1003773 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Coe, E. H. Jr. The properties, origin, and mechanism of conversion-type inheritance at the B locus in maize. Genetics 53, 1035–1063 (1966). A comprehensive review of paramutation behaviours occurring at the b1 locus with detailed consideration of possible conceptual models.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Erhard, K. F. et al. Maize RNA polymerase IV defines transgenerational epigenetic variation. Plant Cell 25, 808–819 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sidorenko, L. & Chandler, V. RNA-dependent RNA polymerase is required for enhancer-mediated transcriptional silencing associated with paramutation at the maize p1 gene. Genetics 180, 1983–1993 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. McWhirter, K. S. & Brink, R. A. Continuous variation in level of paramutation at the R locus in maize. Genetics 47, 1053–1074 (1962).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Sastry, G. R., Cooper, H. B. Jr & Brink, R. A. Paramutation and somatic mosaicism in maize. Genetics 52, 407–424 (1965).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Axtell, J. D. & Brink, R. A. Chemically induced paramutation at the R locus in maize. Proc. Natl Acad. Sci. USA 58, 181–187 (1967).

    Article  CAS  PubMed  Google Scholar 

  67. Shih, K. L. & Brink, R. A. Effects of X-irradiation and gamma irradiation on paramutation in R heterozygotes in maize. Genetics 65, 473–482 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Panavas, T., Weir, J. & Walker, E. L. The structure and paramutagenicity of the R-marbled haplotype of Zea mays. Genetics 153, 979–991 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Stam, M., Belele, C., Dorweiler, J. E. & Chandler, V. L. Differential chromatin structure within a tandem array 100 kb upstream of the maize b1 locus is associated with paramutation. Genes Dev. 16, 1906–1918 (2002). First illustration of a long-distance enhancer in plants and that its repetitive nature is responsible for paramutagenic action.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Brink, R. A. Paramutation and chromosome organization. Q. Rev. Biol. 35, 120–137 (1960). An excellent synopsis of paramutation as it occurs at the r1 locus and insightful perspective on paramutation as a reflection of endogenous nuclear systems of epigenetic control.

    Article  CAS  PubMed  Google Scholar 

  71. Kermicle, J. L., Eggleston, W. B. & Alleman, M. Organization of paramutagenicity in R-stippled maize. Genetics 141, 361–372 (1995). First combination of molecular and genetic analyses illustrating that paramutagenic behaviour is dependent on repeated features.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Walker, E. L. & Panavas, T. Structural features and methylation patterns associated with paramutation at the r1 locus of Zea mays. Genetics 159, 1201–1215 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Gouil, Q., Novák, O. & Baulcombe, D. C. SLTAB2 is the paramutated SULFUREA locus in tomato. J. Exp. Bot. 67, 2655–2664 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Stam, M. et al. The regulatory regions required for B′ paramutation and expression are located far upstream of the maize b1 transcribed sequences. Genetics 162, 917–930 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Louwers, M. et al. Tissue-and expression level-specific chromatin looping at maize b1 epialleles. Plant Cell 21, 832–842 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Patterson, G. I., Thorpe, C. J. & Chandler, V. L. Paramutation, an allelic interaction, is associated with a stable and heritable reduction of transcription of the maize b regulatory gene. Genetics 135, 881–894 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Eggleston, W. B., Alleman, M. & Kermicle, J. L. Molecular organization and germinal instability of R-stippled maize. Genetics 141, 347–360 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Dorer, D. R. & Henikoff, S. Expansions of transgene repeats cause heterochromatin formation and gene silencing in Drosophila. Cell 77, 993–1002 (1994).

    Article  CAS  PubMed  Google Scholar 

  79. Martienssen, R. A. Maintenance of heterochromatin by RNA interference of tandem repeats. Nat. Genet. 35, 213–214 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Dorweiler, J. E. et al. mediator of paramutation1 is required for the establishment and maintenance of paramutation at multiple maize loci. Plant Cell 12, 2101–2118 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Hollick, J. B. & Chandler, V. L. Genetic factors required to maintain repression of a paramutagenic maize pl1 allele. Genetics 157, 369–378 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Kermicle, J. L. in Epigenetic Mechanisms of Gene Regulation (eds Russo, V. E. A, Martienssen, R. A. & Riggs, A. D.) 267–287 (Cold Spring Harb. Lab. Press, 1996).

    Google Scholar 

  83. Walker, E. L. Paramutation of the r1 locus of maize is associated with increased cytosine methylation. Genetics 148, 1973–1981 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Walker, E. L. et al. Transposon-mediated chromosomal rearrangements and gene duplication in the formation of the maize R-r complex. EMBO J. 14, 2350–2363 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Li, S. et al. Detection of Pol IV/RDR2-dependent transcripts at the genomic scale in Arabidopsis reveals features and regulation of siRNA biogenesis. Genome Res. 25, 235–245 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhai, J. et al. A one precursor one siRNA model for Pol IV-dependent siRNA biogenesis. Cell 163, 445–455 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Blevins, T. et al. Identification of Pol IV and RDR2-dependent precursors of 24 nt siRNAs guiding de novo DNA methylation in Arabidopsis. Elife 4, e09591 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Kasschau, K. D. et al. Genome-wide profiling and analysis of Arabidopsis siRNAs. PLoS Biol. 5, e57 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Wierzbicki, A. T. et al. Noncoding transcription by RNA polymerase Pol IVb/Pol V mediates transcriptional silencing of overlapping and adjacent genes. Cell 135, 635–648 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wierzbicki, A. T. et al. RNA polymerase V transcription guides ARGONAUTE4 to chromatin. Nat. Genet. 41, 630–634 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Giacopelli, B. J. & Hollick, J. B. Trans-homolog interactions facilitating paramutation in maize. Plant Physiol. 168, 1226–1236 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Gent, J. I. et al. Accessible DNA and relative depletion of H3K9me2 at maize loci undergoing RNA-directed DNA methylation. Plant Cell 26, 4903–4917 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Li, Q. et al. Genetic perturbation of the maize methylome. Plant Cell 26, 4602–4616 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Li, Q. et al. RNA-directed DNA methylation enforces boundaries between heterochromatin and euchromatin in the maize genome. Proc. Natl Acad. Sci. USA 112, 14728–14733 (2015).

    Article  CAS  PubMed  Google Scholar 

  95. Haag, J. R. et al. Functional diversification of maize RNA polymerase IV and V subtypes via alternative catalytic subunits. Cell Rep. 9, 378–390 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Sloan, A. E., Sidorenko, L. & McGinnis, K. M. Diverse gene-silencing mechanisms with distinct requirements for RNA polymerase subunits in Zea mays. Genetics 198, 1031–1042 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Sekhon, R. S., Wang, P.-H., Sidorenko, L., Chandler, V. L. & Chopra, S. Maize Unstable factor for orange1 is required for maintaining silencing associated with paramutation at the pericarp color1 and booster1 loci. PLoS Genet. 8, e1002980 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Nobuta, K. et al. Distinct size distribution of endogenous siRNAs in maize: evidence from the deep sequencing in the mop1-1 mutant. Proc. Natl Acad. Sci. USA 105, 14958–14963 (2008).

    Article  PubMed  Google Scholar 

  99. Hale, C. J., Erhard, K. F., Lisch, D. & Hollick, J. B. Production and processing of siRNA precursor transcripts from the highly repetitive maize genome. PLoS Genet. 5, e1000598 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Schnable, P. S. et al. The B73 maize genome: complexity, diversity, and dynamics. Science 326, 1112–1115 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. McClintock, B. Chromosome organization and genic expression. Cold Spring Harb. Symp. Quant. Biol. 16, 13–47 (1951).

    Article  CAS  PubMed  Google Scholar 

  102. Erhard, K. F. Jr., Talbot, J. E., Deans, N. C., McClish, A. E. & Hollick, J. B. Nascent transcription affected by RNA polymerase IV in Zea mays. Genetics 199, 1107–1025 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Du, J. et al. Mechanism of DNA methylation-directed histone methylation by KRYPTONITE. Mol. Cell 55, 495–504 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Law, J. A. et al. Polymerase IV occupancy at RNA-directed DNA methylation sites requires SHH1. Nature 498, 385–389 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Haring, M. et al. The role of DNA methylation, nucleosome occupancy and histone modifications in paramutation. Plant J. 63, 366–378 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. Bennett, S. T. et al. Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. Nat. Genet. 17, 350–352 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Messerschmidt, D. M., Knowles, B. B. & Solter, D. DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos. Genes Dev. 28, 812–828 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Keverne, E. B. Genomic imprinting, action, and interaction of maternal and fetal genomes. Proc. Natl Acad. Sci. USA 112, 6834–6840 (2015).

    Article  CAS  PubMed  Google Scholar 

  109. Herman, H. et al. Trans allele methylation and paramutation-like effects in mice. Nat. Genet. 34, 199–202 (2003). Pedigree analyses demonstrate the first paramutation-like example in metazoans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Park, Y. J. et al. Sequences sufficient for programming imprinted germline DNA methylation defined. PLoS ONE 7, e33024 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Watanabe, T. et al. Role for piRNAs and noncoding RNA in de novo DNA methylation of the imprinted mouse Rasgrf1 locus. Science 332, 848–852 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Kiani, J. et al. RNA-mediated epigenetic heredity requires the cytosine methyltransferase Dmnt2. PLoS Genet. 9, e1003498 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Coolon, J. D., Stevenson, K. R., McManus, C. J., Graveley, B. R. & Wittkopp, P. J. Genomic imprinting absent in Drosophila melanogaster adult females. Cell Rep. 2, 69–75 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. McEachern, L. A., Bartlett, N. J. & Lloyd, V. K. Endogenously imprinted genes in Drosophila melanogaster. Mol. Genet. Genom. 289, 653–673 (2014).

    Article  CAS  Google Scholar 

  115. Brennecke, J. et al. An epigenetic role for maternally inherited piRNAs in transposon silencing. Science 322, 1387–1392 (2008). Bioinformatic analyses of ovary sRNAs provide a molecular model accounting for hybrid dysgenesis based on maternal deposition of piRNAs priming innate immunity against transposons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Laver, J. D., Marsolais, A. J., Smibert, C. A. & Lipshitz, H. D. Regulation and function of maternal gene products during the maternal-to-zygotic transition in Drosophila. Curr. Top. Dev. Biol. 113, 43–84 (2015).

    Article  CAS  PubMed  Google Scholar 

  117. Le Thomas, A. et al. Transgenerationally inherited piRNAs trigger piRNA biogenesis by changing the chromatin of piRNA clusters and inducing precursor processing. Genes Dev. 28, 1667–1680 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Mohn, F., Sienski, G., Handler, D. & Brennecke, J. The Rhino–Deadlock–Cutoff complex licenses noncanonical transcription of dual-strand piRNA clusters in Drosophila. Cell 157, 1364–1379 (2014).

    Article  CAS  PubMed  Google Scholar 

  119. Zhang, Z. et al. The HP1 homolog Rhino anchors a nuclear complex that suppresses piRNA precursor splicing. Cell 157, 1353–1363 (2014). References 117, 118 and 119 led to the current model that involves the conversion of bi-directionally transcribed regions into piRNA-generating features via aberrant RNA processing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Mohn, F., Handler, D. & Brennecke, J. Noncoding, R. N. A. piRNA-guided slicing specifies transcripts for Zucchini-dependent, phased piRNA biogenesis. Science 348, 812–817 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Han, B. W., Wang, W., Li, C., Weng, Z. & Zamore, P. D. Noncoding, R. N. A. piRNA-guided transposon cleavage initiates Zucchini-dependent, phased piRNA production. Science. 348, 817–821 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Le Thomas, A. et al. Piwi induces piRNA-guided transcriptional silencing and establishment of a repressive chromatin state. Genes Dev. 27, 390–399 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Brennecke, J. et al. Discrete small RNA-generating loci as master regulators of transposon activity. Cell 128, 1089–1103 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Youngman, E. M. & Claycomb, J. M. From early lessons to new frontiers: the worm as a treasure trove of small RNA biology. Front. Genet. 5, 416 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Ashe, A. et al. piRNAs can trigger a multigenerational epigenetic memory in the germline of C. elegans. Cell 150, 88–99 (2012). Together with references 26 and 27 this paper shows that RNA-induced epigenetic silencing is mediated by the HRDE-1 nuclear Argonaute and chromatin-modifying components.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Buckley, B. A. et al. A nuclear Argonaute promotes multigenerational epigenetic inheritance and germline immortality. Nature 489, 447–451 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Bagijn, M. P. et al. Function, targets, and evolution of Caenorhabditis elegans piRNAs. Science 337, 574–578 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Gu, S. G. et al. Amplification of siRNA in Caenorhabditis elegans generates a transgenerational sequence-targeted histone H3 lysine 9 methylation footprint. Nat. Genet. 44, 157–164 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Conine, C. C. et al. Argonautes promote male fertility and provide a paternal memory of germline gene expression in C. elegans. Cell 155, 1532–1544 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Rechavi, O. et al. Starvation-induced transgenerational inheritance of small RNAs in C. elegans. Cell 158, 277–287 (2014). Bioinformatic analyses of sRNA populations indicate changes to heritable 22-G RNAs associated with starvation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Lee, H. C. et al. C. elegans piRNAs mediate the genome-wide surveillance of germline transcripts. Cell 150, 78–87 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Duncan, I. W. Transvection effects in Drosophila. Annu. Rev. Genet. 36, 521–556 (2002).

    Article  CAS  PubMed  Google Scholar 

  133. Grimaud, C. et al. RNAi components are required for nuclear clustering of Polycomb group response elements. Cell 124, 957–971 (2006).

    Article  CAS  PubMed  Google Scholar 

  134. Hollick, J. B., Patterson, G. P., Asmundsson, I. M. & Chandler, V. L. Paramutation alters regulatory control of the maize pl locus. Genetics 154, 1827–1838 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Aoki, K., Moriguchi, H., Yoshioka, T., Okawa, K. & Tabara, H. In vitro analyses of the production and activity of secondary small interfering RNAs in C. elegans. EMBO J. 26, 5007–5019 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Cullis, C. A. Mechanisms and control of rapid genomic changes in flax. Ann. Bot. 95, 201–206 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Sarkies, P. & Miska, E. A. Small RNAs break out: the molecular cell biology of mobile small RNAs. Nat. Rev. Mol. Cell. Biol. 15, 525–535 (2014).

    Article  CAS  PubMed  Google Scholar 

  138. Slotkin, R. K. et al. Epigenetic reprogramming and small RNA silencing of transposable elements in pollen. Cell 136, 461–472 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Calarco, J. P. et al. Reprogramming of DNA methylation in pollen guides epigenetic inheritance via small RNA. Cell 151, 194–205 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Martinez, G., Panda, K., Köhler, C. & Slotkin, K. R. Silencing in sperm cells is directed by RNA movement from the surrounding nurse cell. Nat. Plants 2, 16030 (2016).

    Article  CAS  PubMed  Google Scholar 

  141. Ibarra, C. A. et al. Active DNA demethylation in plant companion cells reinforces transposon methylation in gametes. Science 337, 1360–1364 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Coe, E. H. Jr. Some observations bearing on plasmid versus gene hypotheses for a conversion-type phenomenon. Genetics 46, 719–725 (1961).

    PubMed  PubMed Central  Google Scholar 

  143. Zhao, X., Xu, X., Xie, H., Chen, S. & Jin, W. Fertilization and uniparental chromosome elimination during crosses with maize haploid inducers. Plant Physiol. 163, 721–731 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Hollick, J. B. Paramutation: a trans-homolog interaction affecting heritable gene regulation. Curr. Opin. Plant Biol. 15, 536–543 (2012).

    Article  CAS  PubMed  Google Scholar 

  145. Beckett, J. B. in Chromosome Engineering in Plants: Genetics, Breeding, Evolution (eds Gupta, P. K. & Tsuchiya, T.), 493–529 (Elsevier, 1991).

    Book  Google Scholar 

  146. de Albuquerque, B. F., Placentino, M. & Ketting, R. F. Maternal piRNAs are essential for germline development following de novo establishment of endo-siRNAs in Caenorhabditis elegans. Dev. Cell 34, 448–456 (2015).

    Article  CAS  PubMed  Google Scholar 

  147. Phillips, C. M., Brown, K. C., Montgomery, B. E., Ruvkun, G. & Montgomery, T. A. piRNAs and piRNA-dependent siRNAs protect conserved and essential C. elegans genes from misrouting into the RNAi pathway. Dev. Cell 34, 457–465 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Geoghegan, J. L. & Spencer, H. G. The evolutionary potential of paramutation: a population-epigenetic model. Theor. Popul. Biol. 88, 9–19 (2013).

    Article  PubMed  Google Scholar 

  149. Waddington, C. H. Canalization of development and genetic assimilation of acquired characters. Nature 183, 1654–1655 (1959).

    Article  CAS  PubMed  Google Scholar 

  150. Day, T. & Bonduriansky, R. A unified approach to the evolutionary consequences of genetic and nongenetic inheritance. Am. Nat. 178, E18–E36 (2011).

    Article  PubMed  Google Scholar 

  151. Lisch, D. How important are transposons for plant evolution? Nat. Rev. Genet. 14, 49–61 (2013).

    Article  CAS  PubMed  Google Scholar 

  152. Hurst, G. D. & Werren, J. H. The role of selfish genetic elements in eukaryotic evolution. Nat. Rev. Genet. 2, 597–606 (2001).

    Article  CAS  PubMed  Google Scholar 

  153. Guhan, N. & Muniyappa, K. Structural and functional characteristics of homing endonucleases. Crit. Rev. Biochem. Mol. Biol. 38, 199–248 (2008).

    Article  Google Scholar 

  154. Hagemann, R. The foundation of extranuclear inheritance: plastid and mitochondrial genetics. Mol. Genet. Genom. 283, 199–209 (2010).

    Article  CAS  Google Scholar 

  155. Zordan, R. E., Miller, M. G., Galgoczy, D. J., Tuch, B. B. & Johnson, A. D. Interlocking transcriptional feedback loops control white-opaque switching in Candida albicans. PLoS Biol. 5, e256 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Pardo-Manuel de Villena, F. & Sapienza, C. Nonrandom segregation during meiosis: the unfairness of females. Mammal. Genome 12, 331–339 (2001).

    Article  CAS  Google Scholar 

  157. Larracuente, A. M. & Presgraves, D. C. The selfish Segregation Distorter gene complex of Drosophila melanogaster. Genetics 192, 33–53 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Beeman, R. W., Friesen, K. S. & Denell, R. E. Maternal-effect selfish genes in flour beetles. Science 256, 89–92 (1992).

    Article  CAS  PubMed  Google Scholar 

  159. Hollick, J. B. Paramutation and Development. Annu. Rev. Cell Dev. Biol. 26, 557–579 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Dedicated in memory of Mary Alleman and her advancements of paramutation research. Comments from K. Slotkin, J. Claycomb, C. Wedeles, M. Wu and N. Deans were greatly appreciated. Preparation supported by the US National Science and The Ohio State University Foundations. The views, and any errors, expressed herein are solely those of the author. Apologies are extended to those whose work remained uncited owing to space constraints.

Author information

Authors and Affiliations

  1. Department of Molecular Genetics, Center for RNA Biology, The Ohio State University, 105 Biological Sciences Building, 484 West 12th Avenue, Columbus, 43210, Ohio, USA

    Jay B. Hollick

  2. 500 Aronoff Laboratory, 318 West 12th Avenue, Columbus, 43210, Ohio, USA

    Jay B. Hollick

Authors
  1. Jay B. Hollick
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jay B. Hollick.

Ethics declarations

Competing interests

The author is an inventor on U.S. Patents 07264970 and 8134047, which have been assigned to The Regents of the University of California.

Supplementary information

Supplementary information S1 (table)

Efficiency, stability, and genetic requirements of paramutation behaviors (PDF 232 kb)

PowerPoint slides

Glossary

Paramutation

A locus-dependent process in which meiotically heritable changes in allele regulatory behaviour are influenced by trans-homologue interactions. Originally proposed by Alexander Brink to be applied to this invariable and directed “phenomenon distinct from, but not wholly unlike, mutation”.

Epigenetic

Mitotically or meiotically heritable regulatory information found adjunct to, or separate from, DNA.

Non-Mendelian inheritance

Examples in which sexual transmission ratios for alleles or specific regulatory states of alleles deviate from those expected from Mendel's first law of genetics, which states that genetic factors at a defined locus are transmitted unchanged and in equal frequencies to offspring.

Hybrid vigour

(Also known as heterosis). Refers to the observation of increased vigour or the enhancement of traits among offspring of genetically dissimilar parents.

Transgenerational inheritance

Refers to the persistence of a meiotically heritable trait through the second or third generation when originating in males or pregnant females, respectively. In this Review, the term is used in reference to an epigenetic rather than a genetic source for the trait.

Small RNA

(sRNA). Refers to a diverse set of ∼19–36-nucleotide RNAs implicated in eukaryotic gene regulation through association with Argonaute-type proteins.

Argonaute

A class of RNaseH-type proteins targeted to specific RNAs through small, bound RNA guide molecules.

RNA interference

(RNAi). Small RNA-associated gene inactivation based on directing Argonaute functions to cytoplasmic or nascent RNAs to effect post-transcriptional or transcriptional silencing, respectively.

Parent-of-origin transmission

Differential manifestation of genetic information displayed in offspring is determined by the specific sex of the parent that contributes, or transmits, the information.

Transmission ratio distortions

(TRDs). A broad category of chromosome transmission biases based on either preferential segregation during meiosis, gametic competition or zygotic lethality.

Intron homing

A transposon-like behaviour of group II introns targeting specific genomic sequences.

Neocentromeres

Chromosome regions that are distinct from a reference centromere but in certain cases can serve as sites of kinetochore assembly and centromere function.

Haplotypes

A haplotype is a group of alleles that tend to be inherited together from a given parent because of their physical association along a length of chromosome.

Gametophytes

Male or female multicellular haploid entities derived from either microspores or megaspores that produce sperm and egg cells, respectively.

Megaspores

The direct products of female meiosis in plants.

Microspores

The direct products of male meiosis in plants.

Coenocyte

A multinucleated cell derived from nuclear divisions occurring in the absence of cytokinesis.

Central cell

The large binucleate cell of the female gametophyte that serves as the maternal source of the triploid endosperm following fertilization.

Imprinting

A parent-of-origin-dependent process imposing a regulatory behaviour on alleles that are transmitted to offspring.

Long non-coding RNA

A general class of RNAs greater than 200 nucleotides neither encoding proteins nor representing known structural RNAs.

Piwi-interacting RNAs

(piRNAs). Mostly germline-specific small RNAs in metazoans associated with Piwi-clade Argonautes.

MicroRNAs

(miRNAs). Small RNAs processed from a hairpin RNA precursor and used by specific Argonautes to affect the stability and/or translation of cytoplasmic mRNAs.

Nurse cells

Accessory cells that provide nourishment to developing oocytes, spermatocytes or gametes.

Ovariole

A constituent tube of insect ovaries in which oocytes develop.

Balancer chromosomes

Specialized chromosomes containing multiple nested inversions from which recombinant products are not passed to offspring. They are useful for identifying specific heterozygous genotypes when they carry a dominant allele that confers a unique morphological phenotype.

P granules

Non-membrane-bound perinuclear concentrations of ribonucleoproteins appearing during germ cell development. P granules are the Caenorhabditis elegans germ granule equivalent of the perinuclear nuage in Drosophila melanogaster, Mus musculus and Homo sapiens.

Episomes

Nucleic acids that may replicate autonomously (for example, bacterial plasmids) from chromosomal DNA.

Transvection

A homologue-pairing-dependent regulatory behaviour.

Cytoplasmic inheritance

Traits that are determined by the sexual transmission of non-chromosomal factors such as organelles, episomes, RNAs and proteins.

Meristem

A stem cell niche of plants that determines patterns of vegetative and reproductive growth.

Gynogenetic

Derived exclusively from a genome of maternal origin.

Endosperms

The triploid nutritive tissue of a seed derived from the fertilization of the central cell with one sperm cell contributed by a given pollen grain.

Nullisomic

An aneuploid condition in which an otherwise balanced complement consisting of a multiple of the haploid chromosome content is devoid of a given chromosome or chromosome segment (segmental nullisomic).

Non-disjunctions

Conditions in which paired homologous chromosomes or sister chromatids fail to separate, or dis-join, at anaphase.

Disomic

A condition in which an otherwise balanced complement consisting of a multiple of the haploid chromosome content has a pair of homologous chromosomes or chromosome segments (segmental disomic).

Tetrasomic

An aneuploid condition in which an otherwise balanced complement consisting of a multiple of the haploid chromosome content has four homologous chromosomes or chromosome segments (segmental tetrasomic).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hollick, J. Paramutation and related phenomena in diverse species. Nat Rev Genet 18, 5–23 (2017). https://doi.org/10.1038/nrg.2016.115

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg.2016.115

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing