Molecular markers reveal that population structure of the human pathogen Candida albicans exhibits both clonality and recombination.

Gräser, Yvonne; Volovsek, Miguel; Arrington, Jennifer M.; Schönian, Gabriele; Presber, W; Mitchell, Thomas G.; Vilgalys, Rytas

doi:10.1073/pnas.93.22.12473

Cited by 208 publications

(199 citation statements)

References 36 publications

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“…Our initial data showing that a decrease in susceptibility and resistance to 5FC were exclusive characteristics of clade I, and the data presented here showing that a mutant allele of the FUR1 gene was dispersed throughout one clade but absent in non-clade I strains, suggest that if mating does occur, it happens only between members of the same clade. These results are consistent with studies suggesting that the population structure of C. albicans is mainly clonal (4,17). The results presented here reinforce previous concerns (18,24) that not all strains, or clades, of C. albicans are equal, and that representative strains should be selected from each of the five C. albicans clades in future studies of drug resistance or phenotypes of clinical relevance.…”

Section: Discussionsupporting

confidence: 81%

“…Furthermore, it was demonstrated that 72% of clade I isolates exhibited reduced susceptibility to 5FC (5FC MIC Ն 0.5 g/ml) compared to 2% of non-clade I isolates (18). The fact that clades maintain their integrity side by side in the same geographical locale, combined with the observation that the majority of clade I isolates are less susceptible to 5FC, indicates that while recombination may occur within a clade, it may be a rare event between different clades (18,24), an interpretation consistent with earlier studies indicating that the population structure of C. albicans is primarily clonal (4,17).…”

supporting

confidence: 75%

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Clade-Specific Flucytosine Resistance Is Due to a Single Nucleotide Change in the FUR1 Gene of Candida albicans

Dodgson¹,

Dodgson

Pujol³

et al. 2004

Antimicrob Agents Chemother

121

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Population studies have indicated that natural resistance to flucytosine (5FC) in Candida albicans is limited to one of the five major clades, clade I. In addition, while 73% of clade I isolates are less susceptible to 5FC (MIC > 0.5 g/ml), only 2% of non-clade I isolates are less susceptible. In order to determine the genetic basis for this clade-specific resistance, we sequenced two genes involved in the metabolism of 5FC that had previously been linked to resistance (cytosine deaminase and uracil phosphoribosyltransferase), in 48 isolates representative of all clades. Our results demonstrate that a single nucleotide change from cytosine to thymine at position 301 in the uracil phosphoribosyltransferase gene (FUR1) of C. albicans is responsible for 5FC resistance. The mutant allele was found only in group I isolates. The 5FC MICs for strains without copies of the mutant allele were almost exclusively <0.25 g/ml, those for strains with one copy of the mutant allele were >0.5 g/ml, and those for strains with two copies of the mutant allele were >16 g/ml. Thus, the two alleles were codominant. The presence of this allele is responsible for clade I-specific resistance to 5FC within the C. albicans population and thus by inference is likely to be the major underlying 5FC resistance mechanism in C. albicans. This represents the first description of the genetic mutation responsible for 5FC resistance.Analyses of the population structure of Candida albicans have revealed five major clades (I, II, III, SA, and E), each exhibiting a degree of geographical specificity (1,19,20,24). Recently, it was demonstrated that natural isolates that had been identified as resistant to flucytosine (5FC) were all members of clade I (18). Furthermore, it was demonstrated that 72% of clade I isolates exhibited reduced susceptibility to 5FC (5FC MIC Ն 0.5 g/ml) compared to 2% of non-clade I isolates (18). The fact that clades maintain their integrity side by side in the same geographical locale, combined with the observation that the majority of clade I isolates are less susceptible to 5FC, indicates that while recombination may occur within a clade, it may be a rare event between different clades (18,24), an interpretation consistent with earlier studies indicating that the population structure of C. albicans is primarily clonal (4,17).Although it has been demonstrated that natural resistance to 5FC is confined to isolates in clade I, the genetic basis of 5FC resistance has not been identified. 5FC enters a cell through the action of cytosine permease (15). Inside the cell, 5FC is converted to 5-fluorouracil (5FU) by cytosine deaminase, encoded by the gene FCY1 (7, 16). 5FU is then converted to 5-fluorouridine monophosphate by uracil phosphoribosyltransferase (UPRTase), encoded by the gene FUR1 (7, 16). 5-Fluorouridine monophosphate is then converted to 5-fluorouridine triphosphate, which, when incorporated into RNA in place of UTP, disrupts protein synthesis (7, 16). In addition, 5FU, when converted to 5-fluorodeoxyuridine monophosphat...

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Section: Discussionsupporting

confidence: 81%

supporting

confidence: 75%

Clade-Specific Flucytosine Resistance Is Due to a Single Nucleotide Change in the FUR1 Gene of Candida albicans

Dodgson¹,

Dodgson

Pujol³

et al. 2004

Antimicrob Agents Chemother

121

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“…C. albicans has retained a large number of genes required for mating, and the mating process is elaborate. However, the role of mating in C. albicans continues to be a topic of debate, particularly as the population structure of C. albicans is largely clonal, indicating a predominantly asexual mode of reproduction (Graser et al, 1996;Tibayrenc, 1997). Because the existence of an elaborate mating apparatus is difficult to reconcile with the population structure, we felt it necessary to resolve whether nuclear fusion normally occurs when two C. albicans cells mate.…”

Section: Discussionmentioning

confidence: 99%

Nuclear fusion occurs during mating in Candida albicans and is dependent on the KAR3 gene

Bennett

Miller

Chua

et al. 2005

Molecular Microbiology

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SummaryIt is now well established that mating can occur between diploid a and a a a a cells of Candida albicans . There is, however, controversy over when, and with what efficiency, nuclear fusion follows cell fusion to create stable tetraploid a/ a a a a cells. In this study, we have analysed the mating process between C. albicans strains using both cytological and genetic approaches. Using strains derived from SC5314, we used a number of techniques, including time-lapse microscopy, to demonstrate that efficient nuclear fusion occurs in the zygote before formation of the first daughter cell. Consistent with these observations, zygotes micromanipulated from mating mixes gave rise to mononuclear tetraploid cells, even when no selection for successful mating was applied to them. Mating between different clinical isolates of C. albicans revealed that while all isolates could undergo nuclear fusion, the efficiency of nuclear fusion varied in different crosses. We also show that nuclear fusion in C. albicans requires the Kar3 microtubule motor protein. Deletion of the CaKAR3 gene from both mating partners had little or no effect on zygote formation but reduced the formation of stable tetraploids more than 600-fold, as determined by quantitative mating assays. These findings demonstrate that nuclear fusion is an active process that can occur in C. albicans at high frequency to produce stable, mononucleate mating products.

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“…Because of the effect of genetic recombination shuffling alleles, the multilocus genotypes of pathogens undergoing random genetic exchange will typically not match those in fingerprint databases, unless by chance alone. Such considerations are paramount in the medically important fungi where estimates show that 75% are morphologically sexual, and where several of the morphologically asexual species (which include C. immitis and C. posadasii) have been shown to undergo cryptic recombination in nature (3,22,23). Within Coccidioides, the rate of recombination is high enough that in the two populations that have been extensively surveyed for single nucleotide polymorphisms, only three instances of genetically identical isolates have been found (of which two could have occurred by chance alone), and tests consistently confirm the occurrence of panmixia and linkage equilibrium among markers (17,18).…”

Section: Discussionmentioning

confidence: 99%

Disease surveillance in recombining pathogens: Multilocus genotypes identify sources of humanCoccidioidesinfections

Fisher

Rannala

Chaturvedi

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Molecular surveillance of pathogenic microbes works by genotyping isolates with DNA fingerprinting techniques and then using these genotypes to assign individuals to populations. Clonality is assumed in many fingerprinting studies, although this assumption has been shown to be false for many organisms. To accommodate recombining organisms into surveillance programs, methods using population allele frequencies in combination with individual multilocus genotypes are necessary. Here, we develop a statistical method appropriate for haploid recombining microbes that allows individuals to be assigned to populations. We illustrate the usefulness of this technique by inferring the source populations for Coccidioides isolates recovered from patients treated outside the endemic area of Coccidioides sp., the etiological agents of human coccidioidomycosis, but with a travel history including visits to one or more endemic areas.

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Molecular markers reveal that population structure of the human pathogen Candida albicans exhibits both clonality and recombination.

Abstract: The life history of Candida albicans presents an enigma: this species is thought to be exclusively asexual, yet strains show extensive phenotypic variation. To

Cited by 208 publications

References 36 publications

Clade-Specific Flucytosine Resistance Is Due to a Single Nucleotide Change in the FUR1 Gene of Candida albicans

Clade-Specific Flucytosine Resistance Is Due to a Single Nucleotide Change in the FUR1 Gene of Candida albicans

Nuclear fusion occurs during mating in Candida albicans and is dependent on the KAR3 gene

Disease surveillance in recombining pathogens: Multilocus genotypes identify sources of humanCoccidioidesinfections

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