Large-scale chromosomal changes and associated fitness consequences in pathogenic fungi

Current Fungal Infection Reports

Volumn 8, Issue 2, 2014, Pages 163-170

  Forche, Anja ^a  

^a BOWDOIN COLLEGE   (United States)

Author keywords

Adaptation; Aneuploidy; Candida; Cryptococcus; Fitness; Fluconazole resistance; Fungal pathogens; Genome plasticity; Loss of heterozygosity

Indexed keywords

FLUCONAZOLE;

ANEUPLOIDY; ANTIFUNGAL RESISTANCE; CANDIDA ALBICANS; CANDIDA GLABRATA; CRYPTOCOCCUS NEOFORMANS; DIPLOIDY; FUNGAL GENOME; FUNGUS; HETEROZYGOSITY LOSS; HUMAN; NONHUMAN; PHENOTYPIC PLASTICITY; REPRODUCTIVE FITNESS; REVIEW;

EID: 84905739964     PISSN: 19363761     EISSN: 1936377X     Source Type: Journal    
DOI: 10.1007/s12281-014-0181-2     Document Type: Review

References (98)

1. Hube B. Extracellular proteinases of human pathogenic fungi. Contrib Microbiol. 2000;5:126-37.
2. Casadevall A. Amoeba provide insight into the origin of virulence in pathogenic fungi. Adv Exp Med Biol. 2012;710:1-10.
3. Waechtler B, Wilson D, Haedicke K, Dalle F, Hube B. From attachment to damage: defined genes of Candida albicans mediate adhesion, invasion and damage during interaction with oral epithelial cells. PLoS One. 2011;6:e17046.
4. Brown AJP, Budge S, Kaloriti D, Tillmann A, Jacobsen MD, Yin Z, et al. Stress adaptation in a pathogenic fungus. J Exp Biol. 2014;217:144-55.
5. Noble SM. Candida albicans specializations for iron homeostasis: from commensalism to virulence. Curr Opin Microbiol. 2013;16:708-15.
6. Hube B, Monod M, Schofield DA, Brown AJ, Gow NA. Expression of seven members of the gene family encoding secretory aspartyl proteinases in Candida albicans. Mol Microbiol. 1994;14:87-99. (Pubitemid 24312822)
7. Fradin C, Kretschmar M, Nichterlein T, Gaillardin C, d'Enfert C, Hube B. Stage-specific gene expression of Candida albicans in human blood. Mol Microbiol. 2003;47:1523-43. (Pubitemid 36363337)
8. Setiadi ER, Doedt T, Cottier F, Noffz C, Ernst JF. Transcriptional response of Candida albicans to hypoxia: linkage of oxygen sensing and Efg1p-regulatory networks. J Mol Biol. 2006;361:399-411. (Pubitemid 44118339)
9. Lorenz MC, Bender JA, Fink GR. Transcriptional response of Candida albicans upon internalization by macrophages. Eukaryot Cell. 2004;3:1076-87. (Pubitemid 39385215)
10. Upadhya R, Campbell LT, Donlin MJ, Aurora R, Lodge JK. Global transcriptome profile of Cryptococcus neoformans during exposure to hydrogen peroxide induced oxidative stress. PLoS One. 2013;8:e55110.
11. Derengowski LS, Paes HC, Albuquerque P, Tavares AH, Fernandes L, Silva-Pereira I, et al. The transcriptional response of Cryptococcus neoformans to ingestion by Acanthamoeba castellanii and macrophages provides insights into the evolutionary adaptation to the mammalian host. Eukaryot Cell. 2013;12:761-74.
12. Brown SP, Cornforth DM, Mideo N. Evolution of virulence in opportunistic pathogens: generalism, plasticity, and control. Trends Microbiol. 2012;20:336-42.
13. Martin R, Albrecht-Eckardt D, Brunke S, Hube B, Hünniger K, Kurzai O. A core filamentation response network in Candida albicans is restricted to eight genes. PLoS One. 2013;8:e58613.
14. Rustchenko EP, Howard DH, Sherman F. Variation in assimilating functions occurs in spontaneous Candida albicans mutants having chromosomal alterations. Microbiology. 1997;143:1765-78. (Pubitemid 27230767)
15. Coyle S, Kroll E. Starvation induces genomic rearrangements and starvation-resilient phenotypes in yeast. Mol Biol Evol. 2008;25:310-8. (Pubitemid 351231602)
16. Forche A, Magee PT, Selmecki A, Berman J, May G. Evolution in Candida albicans populations during single passage through a mouse host. Genetics. 2009;182:799-811.
17. Forche A, Abbey D, Pisithkul T, Weinzierl MA, Ringstrom T, Bruck D, et al. Stress alters rates and types of loss of heterozygosity in Candida albicans. mBio. 2011;2:e00129-11. First detailed study on the effect of different physiologically relevant stresses on LOH rates and types in C. albicans. In vitro exposure to oxidative stress, febrile temperature, or fluconazole stress increased LOH rates up to several orders of magnitude. The proportion/extent of LOH was dependent on the type of stress, presumably reflecting the nature of the different stresses.
18. Polakova S, Blume C, Zárate JA, Mentel M, Jørck-Ramberg D, Stenderup J, et al. Formation of new chromosomes as a virulence mechanism in yeast Candida glabrata. Proc Natl Acad Sci U S A. 2009;106:2688-93.
19. Hickman M, Zeng G, Forche A, Hirakawa MP, Abbey D, Harrison BD, et al. The 'obligate diploid' Candida albicans forms mating-competent haploids. Nature. 2013;494:55-9. This is the first report and detailed description of haploids in C. albicans. Haploids were recovered in vitro and in vivo, possess most characteristics of diploids including hyphal and chlamydospore formation and mating. Haploids and diploid mating products were out-competed by their heterozygous diploid progenitor suggesting that it is not cell ploidy but rather the level of heterozygosity that determines fitness.
20. Selmecki A, Forche A, Berman J. Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science. 2006;313:367-70. (Pubitemid 44480964)
21. Tang Y-C, Amon A. Gene copy-number alterations: a cost-benefit analysis. Cell. 2013;152:394-405.
22. Torres EM, Sokolsky T, Tucker CM, Chan LY, Boselli M, Dunham MJ, et al. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science. 2007;317:916-24. (Pubitemid 47301313)
23. Zhu J, Pavelka N, Bradford WD, Rancati G, Li R. Karyotypic determinants of chromosome instability in aneuploid budding yeast. PLoS Genet. 2012;8:e1002719.
24. Torres EM, Dephoure N, Panneerselvam A, Tucker CM, Whittaker CA, Gygi SP, et al. Identification of aneuploidy-tolerating mutations. Cell. 2010;143:71-83.
25. Selmecki AM, Dulmage K, Cowen LE, Anderson JB, Berman J. Acquisition of aneuploidy provides increased fitness during the evolution of antifungal drug resistance. PLoS Genet. 2009;5:e1000705.
26. Pavelka N, Rancati G, Zhu J, Bradford WD, Saraf A, Florens L, et al. Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast. Nature. 2010;468:321-5.
27. Yona AH, Manor YS, Herbst RH, Romano GH, Mitchell A, Kupiec M, et al. Chromosomal duplication is a transient evolutionary solution to stress. Proc Natl Acad Sci U S A. 2012;109:21010-5.
28. Rancati G, Pavelka N, Fleharty B, Noll A, Trimble R, Walton K, et al. Aneuploidy underlies rapid adaptive evolution of yeast cells deprived of a conserved cytokinesis motor. Cell. 2008;135:879-93.
29. Ni M, Feretzaki M, Li W, Floyd-Averette A, Mieczkowski P, Dietrich FS, et al. Unisexual and heterosexual meiotic reproduction generate aneuploidy and phenotypic diversity de novo in the yeast Cryptococcus neoformans. PLoS Biol. 2013;11:e1001653. This study showed that a-α and α-α sexual reproduction in C. neoformans generates phenotypic diversity, and that aneuploidy is responsible for the observed phenotypic changes, as chromosome loss restored wild-type phenotypes.
30. Li W, Averette AF, Desnos-Ollivier M, Ni M, Dromer F, Heitman J. Genetic diversity and genomic plasticity of Cryptococcus neoformans AD hybrid strains. G3. 2012;2:83-97.
31. Lin X, Litvintseva AP, Nielsen K, Patel S, Floyd A, Mitchell TG, et al. Alpha AD hybrids of Cryptococcus neoformans: evidence of samesex mating in nature and hybrid fitness. PLoS Genet. 2007;3:e186.
32. Lengeler KB, Cox GM, Heitman J. Serotype AD strains of Cryptococcus neoformans are diploid or aneuploid and are heterozygous at the mating-type locus. Infect Immun. 2001;69:115-22. (Pubitemid 32038306)
33. Forche A, Alby K, Schaefer D, Johnson AD, Berman J, Bennett RJ. The parasexual cycle in Candida albicans provides an alternative pathway to meiosis for the formation of recombinant strains. PLoS Biol. 2008;6:e110.
34. Llorente B, Smith C, Symington L. Break-induced replication: what is it and what is it for? Cell Cycle. 2008;7:859-64. (Pubitemid 351573777)
35. Kraus E, Leung WY, Haber JE. Break-induced replication: a review and an example in budding yeast. Proc Natl Acad Sci U S A. 2001;98:8255-62. (Pubitemid 32678021)
36. Covo S, Puccia CM, Argueso JL, Gordenin DA, Resnick MA. The sister chromatid cohesion pathway suppresses multiple chromosome gain and chromosome amplification. Genetics. 2014;196:373-84.
37. Andersen MP, Nelson ZW, Hetrick ED, Gottschling DE. A genetic screen for increased loss of heterozygosity in Saccharomyces cerevisiae. Genetics. 2008;179:1179-95.
38. Legrand M, Chan CL, Jauert PA, Kirkpatrick DT. Role of DNA mismatch repair and double-strand break repair in genome stability and antifungal drug resistance in Candida albicans. Eukaryot Cell. 2007;6:2194-205.
39. Selmecki A, Bergmann S, Berman J. Comparative genome hybridization reveals widespread aneuploidy in Candida albicans laboratory strains. Mol Microbiol. 2005;55:1553-65. (Pubitemid 40342079)
40. Morrow CA, Fraser JA. Ploidy variation as an adaptive mechanism in human pathogenic fungi. Semin Cell Dev Biol. 2013;24:339-46.
41. Sionov E, Chang YC, Kwon-Chung KJ. Azole heteroresistance in Cryptococcus neoformans: emergence of resistant clones with chromosomal disomy in the mouse brain during fluconazole treatment. Antimicrob Agents Chemother. 2013;57:5127-30.
42. Ngamskulrungroj P, Chang Y, Hansen B, Bugge C, Fischer E, Kwon-Chung KJ. Characterization of the chromosome 4 genes that affect fluconazole-induced disomy formation in Cryptococcus neoformans. PLoS One. 2012;7:e33022.
43. Sionov E, Lee H, Chang YC, Kwon-Chung KJ. Cryptococcus neoformans overcomes stress of azole drugs by formation of disomy in specific multiple chromosomes. PLoS Pathog. 2010;6:e1000848.
44. Tan Z, Hays M, Cromie GA, Jeffery EW, Scott AC, Skupin A, et al. Aneuploidy underlies a multicellular phenotypic switch. Proc Natl Acad Sci U S A. 2013;110:12367-72. Identification of S. cerevisiae strains able to reversibly switch between "fluffy" and "smooth" colony-forming states. The switch is correlated with a change in chromosomal copy number. Loss of aneuploid chromosomes correlates with reversion to "smooth" morphology.
45. Rustchenko E. Chromosome instability in Candida albicans. FEMS Yeast Res. 2007;7:2-11. (Pubitemid 46122025)
46. Perepnikhatka V, Fischer FJ, Niimi M, Baker RA, Cannon RD, Wang YK, et al. Specific chromosome alterations in fluconazole-resistant mutants of Candida albicans. J Bacteriol. 1999;181:4041-9. (Pubitemid 29295923)
47. Janbon G, Sherman F, Rustchenko E. Monosomy of a specific chromosome determines L-sorbose utilization: a novel regulatory mechanism in Candida albicans. Proc Natl Acad Sci U S A. 1998;95:5150-5. (Pubitemid 28208566)
48. Bouchonville K, Forche A, Tang KE, Selmecki A, Berman J. Aneuploid chromosomes are highly unstable during DNA transformation of Candida albicans. Eukaryot Cell. 2009;8:1554-66.
49. Pavelka N, Rancati G. Never in neutral: a systems biology and evolutionary perspective on how aneuploidy contributes to human diseases. Cytogenet Genome Res. 2013;139:193-205.
50. Bennett RJ, Johnson AD. Completion of a parasexual cycle in Candida albicans by induced chromosome loss in tetraploid strains. EMBO J. 2003;22:2505-15. (Pubitemid 36604989)
51. Butler G, Rasmussen MD, Lin MF, Santos MA, Sakthikumar S, Munro CA, et al. Evolution of pathogenicity and sexual reproduction in eight Candida genomes. Nature. 2009;459:657-62.
52. van Het Hoog M, Rast TJ, Martchenko M, Grindle S, Dignard D, Hogues H, et al. Assembly of the Candida albicans genome into sixteen supercontigs aligned on the eight chromosomes. Genome Biol. 2007;8:R52.
53. Gräser Y, Volovsek M, Arrington J, Schönian G, Presber W, Mitchell TG, et al. Molecular markers reveal that population structure of the human pathogen Candida albicans exhibits both clonality and recombination. Proc Natl Acad Sci U S A. 1996;93:12473-7.
54. Xu J, Mitchell TG, Vilgalys R. PCR-restriction fragment length polymorphism (RFLP) analyses reveal both extensive clonality and local genetic differences in Candida albicans. Mol Ecol. 1999;8:59-73. (Pubitemid 29032676)
55. Forche A, Schönian G, Gräser Y, Vilgalys R, Mitchell TG. Genetic structure of typical and atypical populations of Candida albicans from Africa. Fungal Genet Biol. 1999;28:107-25. (Pubitemid 30025758)
56. Balloux F, Lehmann L, de Meeus T. The population genetics of clonal and partially clonal diploids. Genetics. 2003;164:1635-44. (Pubitemid 37102223)
57. Xu J, Vilgalys R, Mitchell TG. Lack of genetic differentiation between two geographically diverse samples of Candida albicans isolated from patients infected with human immunodeficiency virus. J Bacteriol. 1999;181:1369-73. (Pubitemid 29119583)
58. Magwene PM, Kayikci O, Granek JA, Reininga JM, Scholl Z, Murray D. Outcrossing, mitotic recombination, and life-history trade-offs shape genome evolution in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 2011;108:1987-92.
59. Berman J, Hadany L. Does stress induce (para)sex? Implications for Candida albicans evolution. Trends Genet. 2012;28:197-203.
60. Diogo D, Bouchier C, d'Enfert C, Bougnoux ME. Loss of heterozygosity in commensal isolates of the asexual diploid yeast Candida albicans. Fungal Genet Biol. 2009;46:159-68.
61. Coste A, Turner V, Ischer F, Morschhäuser J, Forche A, Selmecki A, et al. A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans. Genetics. 2006;172:2139-56.
62. Dunkel N, Blaß J, Rogers PD, Morschhäuser J. Mutations in the multi-drug resistance regulator MRR1, followed by loss of heterozygosity, are the main cause of MDR1 overexpression in fluconazole-resistant Candida albicans strains. Mol Microbiol. 2008;69:827-40. (Pubitemid 352033303)
63. White TC. The presence of an R467K amino acid substitution and loss of allelic variation correlate with an azole-resistant lanosterol 14alpha demethylase in Candida albicans. Antimicrob Agents Chemother. 1997;41:1488-94. (Pubitemid 27289673)
64. Heilmann CJ, Schneider S, Barker KS, Rogers PD, Morschhäuser J. An A643T mutation in the transcription factor Upc2p causes constitutive ERG11 upregulation and increased fluconazole resistance in Candida albicans. Antimicrob Agents Chemother. 2010;54:353-9.
65. Chen X, Magee BB, Dawson D, Magee PT, Kumamoto CA. Chromosome 1 trisomy compromises the virulence of Candida albicans. Mol Microbiol. 2004;51:551-65. (Pubitemid 38142140)
66. Abbey D, Hickman M, Gresham D, Berman J. High-resolution SNP/CGH microarrays reveal the accumulation of loss of heterozygosity in commonly used Candida albicans strains. G3 (Bethesda). 2011;1:523-30.
67. Dunham MJ, Badrane H, Ferea T, Adams J, Brown PO, Rosenzweig F, et al. Characteristic genome rearrangements in experimental evolution of Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 2002;99:16144-9. (Pubitemid 35462763)
68. Rustchenko-Bulgac EP, Sherman F, Hicks JB. Chromosomal rearrangements associated with morphological mutants provide a means for genetic variation of Candida albicans. J Bacteriol. 1990;172:1276-83. (Pubitemid 20085947)
69. Rustchenko EP, Howard DH, Sherman F. Chromosomal alterations of Candida albicans are associated with the gain and loss of assimilating functions. J Bacteriol. 1994;176:3231-41. (Pubitemid 24166714)
70. Janbon G, Sherman F, Rustchenko E. Appearance and properties of L-sorbose-utilizing mutants of Candida albicans obtained on a selective plate. Genetics. 1999;153:653-64. (Pubitemid 29482323)
71. Selmecki AM, Gerami-Nejad M, Paulsen C, Forche A, Berman J. An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1. Mol Microbiol. 2008;68:624-41. (Pubitemid 351490182)
72. Sionov E, Chang YC, Garraffo HM, Kwon-Chung KJ. Heteroresistance to fluconazole in Cryptococcus neoformans is intrinsic and associated with virulence. Antimicrob Agents Chemother. 2009;53:2804-15.
73. Mondon P, Petter R, Amalfitano G, Luzzati R, Concia E, Polacheck I, et al. Heteroresistance to fluconazole and voriconazole in Cryptococcus neoformans. Antimicrob Agents Chemother. 1999;43:1856-61. (Pubitemid 29395175)
74. Roetzer A, Gabaldón T, Schüller C. From Saccharomyces cerevisiae to Candida glabrata in a few easy steps: important adaptations for an opportunistic pathogen. FEMS Microbiol Lett. 2011;314:1-9.
75. Dodgson AR, Pujol C, Pfaller MA, Denning DW, Soll DR. Evidence for recombination in Candida glabrata. Fungal Genet Biol. 2005;42:233-43. (Pubitemid 40222105)
76. Ahmad KM, Ishchuk O, Hellborg L, Jørgensen G, Skvarc M, Stenderup J, et al. Small chromosomes among Danish Candida glabrata isolates originated through different mechanisms. Antonie Van Leeuwenhoek. 2013;104:111-22.
77. Bader O, Schwarz A, Kraneveld EA, Tangwattanchuleeporn M, Schmidt P, Jacobsen MD, et al. Gross karyotypic and phenotypic alterations among different progenies of the Candida glabrata CBS138/ATCC2001 reference strain. PLoS One. 2012;7:e52218.
78. Muller H, Thierry A, Coppée J-Y, Gouyette C, Hennequin C, Sismeiro O, et al. Genomic polymorphism in the population of Candida glabrata: gene copy-number variation and chromosomal translocations. Fungal Genet Biol. 2009;46:264-76.
79. Warnock DW, Burke J, Cope NJ, Johnson EM, Von Fraunhofer NA, Williams EW. Fluconazole resistance in Candida glabrata. Lancet. 1988;332:1310.
80. vanden Bossche H, Marichal P, Odds FC, Le Jeune L, Coene MC. Characterization of an azole-resistant Candida glabrata isolate. Antimicrob Agents Chemother. 1992;36:2602-10.
81. Marichal P, Vanden Bossche H, Odds FC, Nobels G, Warnock DW, Timmerman V, et al. Molecular biological characterization of an azole-resistant Candida glabrata isolate. Antimicrob Agents Chemother. 1997;41:2229-37. (Pubitemid 27422218)
82. Ghannoum MA. Potential role of phospholipases in virulence and fungal pathogenesis. Clin Microbiol Rev. 2000;13:122-43. (Pubitemid 30039346)
83. Naglik JR, Rodgers CA, Shirlaw PJ, Dobbie JL, Fernandes-Naglik LL, Greenspan D, et al. Differential expression of Candida albicans secreted aspartyl proteinase and phospholipase B genes in humans correlates with active oral and vaginal infections. J Infect Dis. 2003;188:469-79. (Pubitemid 36960660)
84. Dromer F, Salamero J, Contrepois A, Carbon C, Yeni P. Production, characterization, and antibody specificity of a mouse monoclonal antibody reactive with Cryptococcus neoformans capsular polysaccharide. Infect Immun. 1987;55:742-8. (Pubitemid 17021970)
85. Viviani MA, Cogliati M, Esposto MC, Lemmer K, Tintelnot K, Valiente MF, et al. Molecular analysis of 311 Cryptococcus neoformans isolates from a 30-month ECMM survey of Cryptococcosis in Europe. FEMS Yeast Res. 2006;6:614-9. (Pubitemid 43725745)
86. Lin X, Nielsen K, Patel S, Heitman J. Impact of mating type, serotype, and ploidy on the virulence of Cryptococcus neoformans. Infect Immun. 2008;76:2923-38.
87. Hu G, Liu I, Sham A, Stajich JE, Dietrich FS, Kronstad JW. Comparative hybridization reveals extensive genome variation in the AIDS-associated pathogen Cryptococcus neoformans. Genome Biol. 2008;9:R41.
88. Cogliati M, Barchiesi F, Spreghini E, Tortorano AM. Heterozygosis and pathogenicity of Cryptococcus neoformans AD-hybrid isolates. Mycopathologia. 2012;173:347-57.
89. Okagaki LH, Strain AK, Nielsen JN, Charlier C, Baltes NJ, Chrétien F, et al. Cryptococcal cell morphology affects host cell interactions and pathogenicity. PLoS Pathog. 2010;6:e1000953.
90. Zaragoza O, Nielsen K. Titan cells in Cryptococcus neoformans: cells with a giant impact. Curr Opin Microbiol. 2013;16:409-13. Cryptococcus neoformans has the ability to form 'titan cells' that can possess as many as 64 genomes per cell. Titan cells are most frequently isolated during asymptomatic pulmonary infection. This study suggests a role of titan cells in latent persistence within the host until conditions become favorable for infection.
91. Garcia-Rodas R, Casadevall A, Rodriguez-Tudela JL, Cuenca-Estrella M, Zaragoza O. Cryptococcus neoformans capsular enlargement and cellular gigantism during Galleria mellonella infection. PLoS One. 2011;6:e24485.
92. Zaragoza O, Garcia-Rodas R, Nosanchuk JD, Cuenca-Estrella M, Rodriguez-Tudela JL, Casadevall A. Fungal cell gigantism during mammalian infection. PLoS Pathog. 2010;6:e1000945.
93. Crabtree JN, Okagaki LH, Wiesner DL, Strain AK, Nielsen JN, Nielsen K. Titan cell production enhances the virulence of Cryptococcus neoformans. Infect Immun. 2012;80:3776-85.
94. Marichal P, Koymans L, Willemsens S, Bellens D, Verhasselt P, Luyten W, et al. Contribution of mutations in the cytochrome P450 14alpha-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans. Microbiology. 1999;145:2701-13. (Pubitemid 29485885)
95. Cowen LE, Lindquist S. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science. 2005;309:2185-9. (Pubitemid 41396062)
96. Orni-Wasserlauf R, Izkhakov E, Siegman-Igra Y, Bash E, Polacheck I, Giladi M. Fluconazole-resistant Cryptococcus neoformans isolated from an immunocompetent patient without prior exposure to fluconazole. Clin Infect Dis. 1999;29:1592-3. (Pubitemid 30022776)
97. Ngamskulrungroj P, Chang Y, Hansen B, Bugge C, Fischer E, Kwon-Chung KJ. Cryptococcus neoformans Yop1, an endoplasmic reticulum curvature-stabilizing protein, participates with Sey1 in influencing fluconazole-induced disomy formation. FEMS Yeast Res. 2012;12:748-54. This study identified Chr4as a common aneuploidy in heteroresistance C. neoformans isolates. Chr4 contains a GTPase and two GTPase activating proteins important for the regulation of endoplasmic reticulum (ER) morphogenesis and trafficking. These results establish an important link between ER integrity and aneuploid formation under fluconazole stress.
98. Semighini CP, Averette AF, Perfect JR, Heitman J. Deletion of Cryptococcus neoformans AIF ortholog promotes chromosome aneuploidy and fluconazole-resistance in a metacaspase-independent manner. PLoS Pathog. 2011;7:e1002364.