Transcriptional Derepression Uncovers Cryptic Higher-Order Genetic Interactions


Some genetic polymorphisms have phenotypic effects that are masked under most conditions, but can be revealed by mutations or environmental change. The genetic and molecular mechanisms that suppress and uncover these cryptic genetic variants are important to understand. Here, we show that a single mutation in a yeast cross causes a major phenotypic change through its genetic interactions with two specific combinations of cryptic variants in six genes. This result suggests that in some cases cryptic variants themselves play roles in revealing their own phenotypic effects through their genetic interactions with each other and the mutations that reveal them. We also demonstrate that most of the genes harboring cryptic variation in our system are transcription factors, a finding that supports an important role for perturbation of gene regulatory networks in the uncovering of cryptic variation. As a final part of our study, we interrogate how a mutation exposes combinations of cryptic variants and obtain evidence that it does so by disrupting the silencing of one or more genes that must be expressed for the cryptic variants to exert their effects. To prove this point, we delete the transcriptional repressor that mediates this silencing and demonstrate that this deletion reveals a similar set of cryptic variants to the ones that were discovered in the initial mutant background. These findings advance our understanding of the genetic and molecular mechanisms that reveal cryptic variation.


Vyšlo v časopise: Transcriptional Derepression Uncovers Cryptic Higher-Order Genetic Interactions. PLoS Genet 11(10): e32767. doi:10.1371/journal.pgen.1005606
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1005606

Souhrn

Some genetic polymorphisms have phenotypic effects that are masked under most conditions, but can be revealed by mutations or environmental change. The genetic and molecular mechanisms that suppress and uncover these cryptic genetic variants are important to understand. Here, we show that a single mutation in a yeast cross causes a major phenotypic change through its genetic interactions with two specific combinations of cryptic variants in six genes. This result suggests that in some cases cryptic variants themselves play roles in revealing their own phenotypic effects through their genetic interactions with each other and the mutations that reveal them. We also demonstrate that most of the genes harboring cryptic variation in our system are transcription factors, a finding that supports an important role for perturbation of gene regulatory networks in the uncovering of cryptic variation. As a final part of our study, we interrogate how a mutation exposes combinations of cryptic variants and obtain evidence that it does so by disrupting the silencing of one or more genes that must be expressed for the cryptic variants to exert their effects. To prove this point, we delete the transcriptional repressor that mediates this silencing and demonstrate that this deletion reveals a similar set of cryptic variants to the ones that were discovered in the initial mutant background. These findings advance our understanding of the genetic and molecular mechanisms that reveal cryptic variation.


Zdroje

1. Gibson G, Dworkin I. Uncovering cryptic genetic variation. Nature reviews Genetics. 2004;5(9):681–90. 15372091

2. Paaby AB, Rockman MV. Cryptic genetic variation: evolution's hidden substrate. Nature reviews Genetics. 2014;15(4):247–58. doi: 10.1038/nrg3688 24614309

3. Hermisson J, Wagner GP. The population genetic theory of hidden variation and genetic robustness. Genetics. 2004;168(4):2271–84. 15611191

4. Queitsch C, Sangster TA, Lindquist S. Hsp90 as a capacitor of phenotypic variation. Nature. 2002;417(6889):618–24. 12050657

5. Sangster TA, Salathia N, Lee HN, Watanabe E, Schellenberg K, Morneau K, et al. HSP90-buffered genetic variation is common in Arabidopsis thaliana. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(8):2969–74. doi: 10.1073/pnas.0712210105 18287064

6. Sangster TA, Salathia N, Undurraga S, Milo R, Schellenberg K, Lindquist S, et al. HSP90 affects the expression of genetic variation and developmental stability in quantitative traits. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(8):2963–8. doi: 10.1073/pnas.0712200105 18287065

7. Felix MA. Cryptic quantitative evolution of the vulva intercellular signaling network in Caenorhabditis. Current biology: CB. 2007;17(2):103–14. 17240335

8. Milloz J, Duveau F, Nuez I, Felix MA. Intraspecific evolution of the intercellular signaling network underlying a robust developmental system. Genes & development. 2008;22(21):3064–75. 18981482

9. Duveau F, Felix MA. Role of pleiotropy in the evolution of a cryptic developmental variation in Caenorhabditis elegans. PLoS biology. 2012;10(1):e1001230. doi: 10.1371/journal.pbio.1001230 22235190

10. Waddington CH. Genetic assimilation of an acquired character. Evolution. 1953;7(2):118–26.

11. Rutherford SL, Lindquist S. Hsp90 as a capacitor for morphological evolution. Nature. 1998;396(6709):336–42. 9845070

12. Gibson G, Hogness DS. Effect of polymorphism in the Drosophila regulatory gene Ultrabithorax on homeotic stability. Science. 1996;271(5246):200–3. 8539619

13. Gibson G, Wemple M, van Helden S. Potential variance affecting homeotic Ultrabithorax and Antennapedia phenotypes in Drosophila melanogaster. Genetics. 1999;151(3):1081–91. 10049924

14. Dworkin I, Palsson A, Birdsall K, Gibson G. Evidence that Egfr contributes to cryptic genetic variation for photoreceptor determination in natural populations of Drosophila melanogaster. Current biology: CB. 2003;13(21):1888–93. 14588245

15. Tirosh I, Reikhav S, Sigal N, Assia Y, Barkai N. Chromatin regulators as capacitors of interspecies variations in gene expression. Molecular systems biology. 2010;6:435. doi: 10.1038/msb.2010.84 21119629

16. Halfmann R, Jarosz DF, Jones SK, Chang A, Lancaster AK, Lindquist S. Prions are a common mechanism for phenotypic inheritance in wild yeasts. Nature. 2012;482(7385):363–8. doi: 10.1038/nature10875 22337056

17. Jarosz DF, Lindquist S. Hsp90 and environmental stress transform the adaptive value of natural genetic variation. Science. 2010;330(6012):1820–4. doi: 10.1126/science.1195487 21205668

18. True HL, Lindquist SL. A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature. 2000;407(6803):477–83. 11028992

19. True HL, Berlin I, Lindquist SL. Epigenetic regulation of translation reveals hidden genetic variation to produce complex traits. Nature. 2004;431(7005):184–7. 15311209

20. Ledon-Rettig CC, Pfennig DW, Crespi EJ. Diet and hormonal manipulation reveal cryptic genetic variation: implications for the evolution of novel feeding strategies. Proceedings of the royal society. 2010;277(1700):3569–78. doi: 10.1098/rspb.2010.0877 20573627

21. Lauter N, Doebley J. Genetic variation for phenotypically invariant traits detected in teosinte: implications for the evolution of novel forms. Genetics. 2002;160(1):333–42. 11805068

22. Rohner N, Jarosz DF, Kowalko JE, Yoshizawa M, Jeffery WR, Borowsky RL, et al. Cryptic variation in morphological evolution: HSP90 as a capacitor for loss of eyes in cavefish. Science. 2013;342(6164):1372–5. doi: 10.1126/science.1240276 24337296

23. Rosas U, Barton NH, Copsey L, Barbier de Reuille P, Coen E. Cryptic variation between species and the basis of hybrid performance. PLoS biology. 2010;8(7):e1000429. doi: 10.1371/journal.pbio.1000429 20652019

24. Suzuki Y, Nijhout HF. Evolution of a polyphenism by genetic accommodation. Science. 2006;311(5761):650–2. 16456077

25. Berger D, Bauerfeind SS, Blanckenhorn WU, Schafer MA. High temperatures reveal cryptic genetic variation in a polymorphic female sperm storage organ. Evolution. 2011;65(10):2830–42. doi: 10.1111/j.1558-5646.2011.01392.x 21967425

26. Kienle S, Sommer RJ. Cryptic variation in vulva development by cis-regulatory evolution of a HAIRY-binding site. Nature communications. 2013;4:1714. doi: 10.1038/ncomms2711 23591881

27. Moczek AP. On the origins of novelty in development and evolution. BioEssays. 2008;30(5):432–47.

28. Le Rouzic A, Carlborg O. Evolutionary potential of hidden genetic variation. Trends in ecology & evolution. 2008;23(1):33–7. 18079017

29. Ehrenreich IM, Pfennig DW. Genetic assimilation: a review of its potential proximate causes and evolutionary consequences. Annals of botany. 2015.

30. Gibson G. Decanalization and the origin of complex disease. Nature reviews Genetics. 2009;10(2):134–40. doi: 10.1038/nrg2502 19119265

31. Bergman A, Siegal ML. Evolutionary capacitance as a general feature of complex gene networks. Nature. 2003;424(6948):549–52. 12891357

32. Sangster TA, Lindquist S, Queitsch C. Under cover: causes, effects and implications of Hsp90-mediated genetic capacitance. BioEssays. 2004;26(4):348–62.

33. Richardson JB, Uppendahl LD, Traficante MK, Levy SF, Siegal ML. Histone variant HTZ1 shows extensive epistasis with, but does not increase robustness to, new mutations. PLoS genetics. 2013;9(8):e1003733. doi: 10.1371/journal.pgen.1003733 23990806

34. Sollars V, Lu X, Xiao L, Wang X, Garfinkel MD, Ruden DM. Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for morphological evolution. Nature genetics. 2003;33(1):70–4. 12483213

35. Cowen LE, Lindquist S. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science. 2005;309(5744):2185–9. 16195452

36. Jarosz DF, Taipale M, Lindquist S. Protein homeostasis and the phenotypic manifestation of genetic diversity: principles and mechanisms. Annual review of genetics. 2010;44:189–216. doi: 10.1146/annurev.genet.40.110405.090412 21047258

37. Blount ZD, Borland CZ, Lenski RE. Historical contingency and the evolution of a key innovation in an experimental population of Escherichia coli. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(23):7899–906. doi: 10.1073/pnas.0803151105 18524956

38. Dworkin I. Towards a genetic architecture of cryptic genetic variation and genetic assimilation: the contribution of K. G. Bateman. Journal of genetics. 2005;84(3):223–6. 16385156

39. Taylor MB, Ehrenreich IM. Higher-order genetic interactions and their contribution to complex traits. Trends in genetics. 2015;31(1):34–40. doi: 10.1016/j.tig.2014.09.001 25284288

40. Chandler CH, Chari S, Dworkin I. Does your gene need a background check? How genetic background impacts the analysis of mutations, genes, and evolution. Trends in genetics. 2013;29(6):358–66. doi: 10.1016/j.tig.2013.01.009 23453263

41. Dowell RD, Ryan O, Jansen A, Cheung D, Agarwala S, Danford T, et al. Genotype to phenotype: a complex problem. Science. 2010;328(5977):469. doi: 10.1126/science.1189015 20413493

42. Taylor MB, Ehrenreich IM. Genetic interactions involving five or more genes contribute to a complex trait in yeast. PLoS genetics. 2014;10(5):e1004324. doi: 10.1371/journal.pgen.1004324 24784154

43. Chandler CH, Chari S, Tack D, Dworkin I. Causes and consequences of genetic background effects illuminated by integrative genomic analysis. Genetics. 2014;196(4):1321–36. doi: 10.1534/genetics.113.159426 24504186

44. Tanaka K, Nakafuku M, Satoh T, Marshall MS, Gibbs JB, Matsumoto K, et al. S. cerevisiae genes IRA1 and IRA2 encode proteins that may be functionally equivalent to mammalian ras GTPase activating protein. Cell. 1990;60(5):803–7. 2178777

45. Tanaka K, Nakafuku M, Tamanoi F, Kaziro Y, Matsumoto K, Toh-e A. IRA2, a second gene of Saccharomyces cerevisiae that encodes a protein with a domain homologous to mammalian ras GTPase-activating protein. Molecular and cellular biology. 1990;10(8):4303–13. 2164637

46. Liti G, Carter DM, Moses AM, Warringer J, Parts L, James SA, et al. Population genomics of domestic and wild yeasts. Nature. 2009;458(7236):337–41. doi: 10.1038/nature07743 19212322

47. Schacherer J, Shapiro JA, Ruderfer DM, Kruglyak L. Comprehensive polymorphism survey elucidates population structure of Saccharomyces cerevisiae. Nature. 2009;458(7236):342–5. doi: 10.1038/nature07670 19212320

48. Kobayashi O, Suda H, Ohtani T, Sone H. Molecular cloning and analysis of the dominant flocculation gene FLO8 from Saccharomyces cerevisiae. Molecular & general genetics. 1996;251(6):707–15. 8757402

49. Gagiano M, Bester M, van Dyk D, Franken J, Bauer FF, Pretorius IS. Mss11p is a transcription factor regulating pseudohyphal differentiation, invasive growth and starch metabolism in Saccharomyces cerevisiae in response to nutrient availability. Molecular microbiology. 2003;47(1):119–34. 12492858

50. Benedetti H, Raths S, Crausaz F, Riezman H. The END3 gene encodes a protein that is required for the internalization step of endocytosis and for actin cytoskeleton organization in yeast. Molecular biology of the cell. 1994;5(9):1023–37. 7841519

51. Tang HY, Xu J, Cai M. Pan1p, End3p, and S1a1p, three yeast proteins required for normal cortical actin cytoskeleton organization, associate with each other and play essential roles in cell wall morphogenesis. Molecular and cellular biology. 2000;20(1):12–25. 10594004

52. Pedrajas JR, Kosmidou E, Miranda-Vizuete A, Gustafsson JA, Wright AP, Spyrou G. Identification and functional characterization of a novel mitochondrial thioredoxin system in Saccharomyces cerevisiae. The Journal of biological chemistry. 1999;274(10):6366–73. 10037727

53. Pan X, Heitman J. Protein kinase A operates a molecular switch that governs yeast pseudohyphal differentiation. Molecular and cellular biology. 2002;22(12):3981–93. 12024012

54. Robertson LS, Fink GR. The three yeast A kinases have specific signaling functions in pseudohyphal growth. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(23):13783–7. 9811878

55. Lorenz MC, Heitman J. Regulators of pseudohyphal differentiation in Saccharomyces cerevisiae identified through multicopy suppressor analysis in ammonium permease mutant strains. Genetics. 1998;150(4):1443–57. 9832522

56. Fujita A, Kikuchi Y, Kuhara S, Misumi Y, Matsumoto S, Kobayashi H. Domains of the SFL1 protein of yeasts are homologous to Myc oncoproteins or yeast heat-shock transcription factor. Gene. 1989;85(2):321–8. 2697640

57. Conlan RS, Tzamarias D. Sfl1 functions via the co-repressor Ssn6-Tup1 and the cAMP-dependent protein kinase Tpk2. Journal of molecular biology. 2001;309(5):1007–15. 11399075

58. Michelmore RW, Paran I, Kesseli RV. Identification of markers linked to disease-resistance genes by bulked segregant analysis: a rapid method to detect markers in specific genomic regions by using segregating populations. Proceedings of the National Academy of Sciences of the United States of America. 1991;88(21):9828–32. 1682921

59. Ehrenreich IM, Torabi N, Jia Y, Kent J, Martis S, Shapiro JA, et al. Dissection of genetically complex traits with extremely large pools of yeast segregants. Nature. 2010;464(7291):1039–42. doi: 10.1038/nature08923 20393561

60. Lo WS, Dranginis AM. FLO11, a yeast gene related to the STA genes, encodes a novel cell surface flocculin. Journal of bacteriology. 1996;178(24):7144–51. 8955395

61. Bruckner S, Mosch HU. Choosing the right lifestyle: adhesion and development in Saccharomyces cerevisiae. FEMS microbiology reviews. 2012;36(1):25–58. doi: 10.1111/j.1574-6976.2011.00275.x 21521246

62. Liu H, Styles CA, Fink GR. Saccharomyces cerevisiae S288C has a mutation in FLO8, a gene required for filamentous growth. Genetics. 1996;144(3):967–78. 8913742

63. Halme A, Bumgarner S, Styles C, Fink GR. Genetic and epigenetic regulation of the FLO gene family generates cell-surface variation in yeast. Cell. 2004;116(3):405–15. 15016375

64. Wu J, Suka N, Carlson M, Grunstein M. TUP1 utilizes histone H3/H2B-specific HDA1 deacetylase to repress gene activity in yeast. Molecular cell. 2001;7(1):117–26. 11172717

65. Gjuvsland AB, Hayes BJ, Omholt SW, Carlborg O. Statistical epistasis is a generic feature of gene regulatory networks. Genetics. 2007;175(1):411–20. 17028346

66. Sherman F. Guide to Yeast Genetics and Molecular. In: Guthrie C, Fink GR, editors. Methods in enzymology. San Diego, California: Elsevier Academic Press; 1991. p. 3–21.

67. Tong AH, Evangelista M, Parsons AB, Xu H, Bader GD, Page N, et al. Systematic genetic analysis with ordered arrays of yeast deletion mutants. Science. 2001;294(5550):2364–8. 11743205

68. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754–60. doi: 10.1093/bioinformatics/btp324 19451168

69. Erdeniz N, Mortensen UH, Rothstein R. Cloning-free PCR-based allele replacement methods. Genome research. 1997;7(12):1174–83. 9414323

70. Matsui T, Linder R, Phan J, Seidl F, Ehrenreich IM. Regulatory Rewiring in a Cross Causes Extensive Genetic Heterogeneity. Genetics. 2015. 26232408

71. Storici F, Lewis LK, Resnick MA. In vivo site-directed mutagenesis using oligonucleotides. Nature biotechnology. 2001;19(8):773–6. 11479573

72. Gietz RD, Woods RA. Transformation of yeast by lithium acetate/single-stranded carrier DNA/polyethylene glycol method. Methods in enzymology. 2002;350:87–96. 12073338

73. Fichtner L, Schulze F, Braus GH. Differential Flo8p-dependent regulation of FLO1 and FLO11 for cell-cell and cell-substrate adherence of S. cerevisiae S288c. Molecular microbiology. 2007;66(5):1276–89. 18001350

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2015 Číslo 10
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz

Betablokátory a Ca antagonisté z jiného úhlu
Autori: prof. MUDr. Michal Vrablík, Ph.D., MUDr. Petr Janský

Autori: doc. MUDr. Petr Čáp, Ph.D.

Farmakoterapie akutní a chronické bolesti

Získaná hemofilie - Povědomí o nemoci a její diagnostika

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Nemáte účet?  Registrujte sa

Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa