The evolution of drug resistance in clinical isolates of Candida albicans.
Open accessAbstract
Candida albicans is both a member of the healthy human microbiome and a major pathogen in immunocompromised individuals. Infections are typically treated with azole inhibitors of ergosterol biosynthesis often leading to drug resistance. Studies in clinical isolates have implicated multiple mechanisms in resistance, but have focused on large-scale aberrations or candidate genes, and do not comprehensively chart the genetic basis of adaptation. Here, we leveraged next-generation sequencing to analyze 43 isolates from 11 oral candidiasis patients. We detected newly selected mutations, including single-nucleotide polymorphisms (SNPs), copy-number variations and loss-of-heterozygosity (LOH) events. LOH events were commonly associated with acquired resistance, and SNPs in 240 genes may be related to host adaptation. Conversely, most aneuploidies were transient and did not correlate with drug resistance. Our analysis also shows that isolates also varied in adherence, filamentation, and virulence. Our work reveals new molecular mechanisms underlying the evolution of drug resistance and host adaptation.
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TL;DR
Genome sequencing of 43 serial Candida albicans isolates from 11 oral candidiasis patients shows that loss-of-heterozygosity events, not aneuploidies, are commonly associated with acquired azole resistance. The study also identifies 240 recurrently mutated genes and evolved changes in adhesion, filamentation, and virulence.
Key findings
- LOH events were detected in all series, were often persistent and recurrent, and coincided with increased fluconazole MIC; highly recurrent LOH occurred on chromosome 3 right arm (Patients 1, 9, 14, 16, 42, 59; p < 5 × 10−4) and chromosome 5 left arm (Patients 1, 14, 15, 43; p < 0.01), regions containing CDR1/CDR2/MRR1 and ERG11/TAC1.
- Aneuploidies appeared in at least one isolate from 80% (8/10) of clonal patient series, most often chromosome 5 (6 of 8 patients with an aneuploid isolate), but were mostly transient and did not consistently correlate with MIC changes.
- Persistent nonsynonymous SNPs outside LOH tracts occurred in 1470 genes; applying recurrence across three or more patient series identified 240 polymorphic genes, enriched for fungal-type cell wall (18 genes, p < 0.0012) and cell surface genes (24 genes, p < 0.00012). Polymorphisms in 166 of the 240 genes appeared with an increase in MIC.
- Isolates varied in adherence, filamentation, and virulence; increased in vitro fitness generally correlated with virulence traits, but drug resistance often initially reduced fitness in the absence of drug while increasing fitness in its presence.
Methods
- Illumina paired-end sequencing of 43 colony-purified serial clinical isolates from 11 HIV-infected patients with oropharyngeal candidiasis, plus reference strain SC5314; coverage was 53–283X (103X average). SNP calls were validated by Sequenom iPLEX: 1853/1973 calls concordant (93.9%).
- Genetic analyses included GATK SNP calling, sliding-window LOH detection, copy-number/ploidy analysis with flow cytometry, maximum-parsimony phylogenetics in PAUP*, persistence/recurrence filtering, and NMF clustering of co-occurring mutations.
- Phenotypic assays included fluconazole E-test MICs, in vitro competition fitness with and without fluconazole, C. elegans survival, filamentation on Spider agar, and adhesion; 23 recurrently mutated loci with available homozygous deletion mutants were profiled for MIC and fitness.
Limitations
- Stated: because each clinical sample was purified from a single colony, the study cannot assess population structure at any single time point; formally distinguishing de novo mutation followed by selection from selection on pre-existing variation is not possible with the samples and data at hand; ordering of events cannot be definitively inferred from singly sampled isolates; substantial additional sampling per time point is required to fully interpret fitness patterns.
- Stated: some endpoint-only changes were treated as persistent because several time courses had only two or three isolates.
- Evident: the clonal analysis rests on 10 patient series and 43 isolates, with some series containing only two isolates; deletion-mutant testing covered only 23 loci and used loss-of-function mutants, whereas known fluconazole resistance mechanisms are often gain-of-function.
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- Findingown data
Co-occurrence of nonsynonymous substitutions across isolates reveals functional clusters.
“Co-occurrence of nonsynonymous substitutions across isolates reveals functional clusters.”
Quote in the paperSubstantial claim - Findingown data
The distance between isolates indicated significant genetic diversity within each patient series, typically with each isolate differing by several thousand SNPs from its progenitor isolate.
“Despite these clonal relationships, the distance between isolates indicated significant genetic diversity within each patient series (Figure 2B), typically with each isolate differing by several thousand SNPs from its ‘progenitor’ isolate (Figure 2—source data 1).”
Quote in the paperSubstantial claim - Findingown data
We clustered the patient-by-gene matrix using NMF clustering to reveal five coherent clusters.
“We clustered the resulting patient-by-gene matrix using NMF clustering to reveal five coherent clusters (correlation matrix of the clusters left; red: positive correlation; blue: negative correlation; white: no correlation).”
Quote in the paperSubstantial claim - Findingown data
Persistent aneuploidies were rarer than persistent LOH events.
“In contrast to the persistence of most LOH events, persistent aneuploidies were rarer”
Quote in the paperSubstantial claim - Findingcitation
The persistent and recurrent LOH on the right arm of chromosome 3 in Patients 9 and 16 was associated with the presence of a homozygous mutation in MRR1, a regulator of MDR1 expression.
“In another example, the persistent and recurrent LOH on the right arm of chromosome 3 in Patients 9 and 16 (Figure 4A,D) was associated with the presence of a homozygous mutation in MRR1 (Schubert et al., 2011), a regulator of MDR1 expression.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Schubert et al., 2011 source
Not checked in the free run.
- Findingown data
The progenitor isolates were more sensitive to fluconazole than subsequent isolates, as defined by the minimum inhibitory concentration (MIC).
“The progenitor isolates were more sensitive to fluconazole than subsequent isolates, as defined by the minimum inhibitory concentration (MIC) (Table 1, ‘Materials and methods’).”
Quote in the paperSubstantial claim - Findingown data
iPlex base calls matched 1853 (93.9%) of the calls from our computational analysis of the sequencing data.
“We interrogated 1973 SNPs in 27 isolates from nine clinical series and found that the iPlex base calls matched 1853 (93.9%, Figure 1—figure supplement 1A, Table 2) of the calls from our computational analysis of the sequencing data.”
Quote in the paperSubstantial claim - Findingown data
There were 131 such mutations in 86 ORFs from 18 LOH regions from the 10 clonal patient series.
“There were 131 such mutations in 86 ORFs from 18 LOH regions from the 10 clonal patient series (Table 1 and Figure 5; Figure 5—source data 1B,C).”
Quote in the paperSubstantial claim - Findingown data
We detected newly selected mutations, including single-nucleotide polymorphisms (SNPs), copy-number variations and loss-of-heterozygosity (LOH) events.
“We detected newly selected mutations, including single-nucleotide polymorphisms (SNPs), copy-number variations and loss-of-heterozygosity (LOH) events.”
Quote in the paperSubstantial claim - Findingown data
Aneuploidies, either whole chromosomal or segmental, were present in at least one isolate from 80% (8/10) of the clonal patient series.
“Aneuploidies, either whole chromosomal or segmental, were evident in at least one isolate from 80% (8/10) of the clonal patient series”
Quote in the paperSubstantial claim - Findingown data
The most prevalent aneuploidies involved Chromosome 5, occurring in 6 of 8 patients with at least one aneuploid isolate.
“with the most prevalent aneuploidies involving Chromosome 5 (6 of 8 patients with at least one aneuploid isolate; Figure 3A and Figure 4B–G, green).”
Quote in the paperNot a substantial claim - Findingown data
Persistent aneuploidies were not consistently associated with adaptive increases in MIC levels.
“and were not consistently associated with adaptive increases in MIC levels (Figures 3 and 4).”
Quote in the paperSubstantial claim - Findingown data
Filtering for both persistence and recurrence across at least three series reduced the number of polymorphisms for patient 1 from 13,562 polymorphisms in 5022 genes to 23 recurrent genes.
“For example, filtering for both persistence and recurrence across at least three series reduced the number of polymorphisms for patient 1 from 13,562 polymorphisms in 5022 genes to 23 recurrent genes (Figure 2—source data 1, Figure 5—source data 1A).”
Quote in the paperSubstantial claim - Findingown data
In three of the cases with Chromosome 5 LOH and trisomy, ERG11, located on the region of Chromosome 5 with LOH, was mutated.
“In three of these cases, ERG11, located on the region of Chromosome 5 with LOH, was mutated.”
Quote in the paperNot a substantial claim - Findingown data
When MIC increases first appeared, they were usually accompanied by a decrease in fitness in the absence of drug (Patient 1, isolates 2, 13, and 16, Patients 9, 14, 15 16, and 59).
“When MIC increases first appeared, they were usually accompanied by a decrease in fitness in the absence of drug (Patient 1, isolates 2, 13, and 16, Patients 9, 14, 15 16, and 59, Figure 7A).”
Quote in the paperSubstantial claim - Findingown data
Seven members of the FGR genes, involved in filamentous growth and specifically expanded in C. albicans, are among the 240 genes.
“In addition, seven members of the FGR genes (Uhl et al., 2003), involved in filamentous growth and specifically expanded in C. albicans (Butler et al., 2009), are also among the 240 genes”
Quote in the paperNot a substantial claim0 of 2 sources checked - Findingown data
Initially in a series, drug resistance (MIC) and in vitro fitness (in the absence of drug) were inversely related.
“Initially in a series, drug resistance (MIC) and in vitro fitness (in the absence of drug) were inversely related”
Quote in the paperSubstantial claim - Findingown data
We found substantial variation in many virulence-associated phenotypes between isolates in the same series.
“We found substantial variation in many of these phenotypes between isolates in the same series (Figure 6 and Figure 7)”
Quote in the paperSubstantial claim - Findingown data
Applying the recurrence filter identified 240 polymorphic genes that are more likely to have contributed to adaptation.
“Applying the recurrence filter (i.e., persistent nonsynonymous SNPs that appeared in the same ORFs in three or more patient series), we identified 240 polymorphic genes that are more likely to have contributed to adaptation (Figure 5—source data 1A).”
Quote in the paperSubstantial claim - Findingown data
Isolates in 2 of 7 patients with a Chromosome 3 LOH were trisomic for this chromosome.
“Additionally, isolates in 2 of the 7 patients with a Chromosome 3 LOH were trisomic for this chromosome.”
Quote in the paperNot a substantial claim - Findingown data
In patient 59, fitness in vitro decreased while virulence phenotypes increased in a later isolate.
“A notable exception was patient 59, where fitness in vitro decreased while virulence phenotypes increased in a later isolate (Figures 6D and Figure 7).”
Quote in the paperNot a substantial claim - Findingown data
These correlations are significantly higher than expected in a null model (p < 5.2 × 10−182, permutation test).
“These correlations are significantly higher than expected in a null model (p < 5.2 × 10−182, permutation test, ‘Materials and methods’).”
Quote in the paperSubstantial claim - Findingown data
The most recurrently mutated gene outside of an LOH region was AXL1, encoding a putative endoprotease.
“The most recurrently mutated gene outside of an LOH region was AXL1 that encodes a putative endoprotease”
Quote in the paperNot a substantial claim - Findingown data
The number of 240 recurrently polymorphic genes is higher than expected by chance (empirical p < 10−4 based on a Poisson model of background mutation).
“This number of genes is higher than expected by chance (empirical p < 10−4 based on a Poisson model of background mutation, ‘Materials and methods’).”
Quote in the paperSubstantial claim - Findingown data
Ten genes were mutated in seven series.
“followed by ten genes mutated in seven series (Figure 5—source data 1A).”
Quote in the paperNot a substantial claim - Findingown data
The enriched set includes several members in each of three cell wall gene families important for biofilm formation and virulence: Hyr/Iff proteins, ALS adhesins, and PGA-30-like proteins.
“including several members in each of three cell wall gene families important for biofilm formation and virulence (Hoyer et al., 2008): the Hyr/Iff proteins (HYR1 and 3, IFF8 and 6), the ALS adhesins (ALS1-4,7,9), and the PGA-30-like proteins (seven genes)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hoyer et al., 2008 source
Not checked in the free run.
- Findingown data
In general, increased fitness in vitro (in the absence of drug) correlated with an increase in traits associated with virulence (adhesion, filamentation, and virulence in nematode).
“In general, increased fitness in vitro (in the absence of drug) correlated with an increase in traits associated with virulence (adhesion, filamentation, and virulence in nematode).”
Quote in the paperSubstantial claim - Findingown data
Polymorphisms in 166 of the 240 genes appeared together with an increase in MIC.
“Finally, polymorphisms in 166 of the 240 genes appeared together with an increase in MIC”
Quote in the paperSubstantial claim - Findingown data
5 of the 22 deletion mutants reduced in vitro fitness in a culture medium thought to approximate in vivo conditions.
“Consistent with a role in host adaptation, 5 of the 22 deletion mutants reduced in vitro fitness in a culture medium thought to approximate in vivo conditions (Figure 8, ‘Materials and methods’).”
Quote in the paperSubstantial claim- Rests on an assumption: The culture medium used for in vitro fitness assays approximates in vivo conditions.
- Findingown data
The coding sequence for the 240 recurrent genes is longer than average (2.21 ± 1.53 kb vs 1.83 ± 1.29 kb for non-recurrent persistent genes, p < 3.68 × 10−5, t-test).
“Though the coding sequence for these 240 recurrent genes is longer than average (2.21 ± 1.53 kb vs 1.83 ± 1.29 kb for non-recurrent persistent genes, p < 3.68 × 10−5, t-test)”
Quote in the paperNot a substantial claim - Findingcitation
Among the least fit deletion mutants were cell wall protein genes (HYR1, HYR3, and PIR1).
“Among the least fit were cell wall protein genes (HYR1, HYR3, and PIR1; De Groot et al., 2003).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites De Groot et al., 2003 source
Not checked in the free run.
- Findingown data
A decrease in fitness in isolate 13 of patient 1 was accompanied by a decrease in virulence.
“whereas, a decrease in fitness in isolate 13 of patient 1 was accompanied by a decrease in virulence (Figures 6C and Figure 7).”
Quote in the paperNot a substantial claim - Findingreasoning
Isolates from later time points were often more fit than those from earlier time points (measured in vitro, in the absence of drug) without further changes in MIC, with notable exceptions.
“Consistent with subsequent selection of strains with compensatory variations, isolates from later time points were often more fit than those from earlier time points (measured in vitro, in the absence of drug) without further changes in MIC (e.g., patient 1, isolates 5-7, isolate 14, Figure 7A), with notable exceptions (e.g., isolates 8 and 11).”
Quote in the paperSubstantial claim - Findingown data
In 4 of 6 patients with a Chromosome 5 LOH, the isolate with an LOH event also harbors a Chromosome 5 trisomy or is preceded by an isolate with a Chromosome 5 trisomy.
“in 4 of the 6 patients with a Chromosome 5 LOH, the isolate with an LOH event also harbors a Chromosome 5 trisomy or is preceded by an isolate with a Chromosome 5 trisomy.”
Quote in the paperSubstantial claim - Findingown data
The 240 recurrently mutated genes partition into 5 co-occurrence clusters based on correlation in their mutation occurrence patterns.
“Next, we partitioned the 240 recurrently mutated genes into 5 ‘co-occurrence clusters’ based on the correlation in their mutation occurrence patterns (Figure 5, Figure 5—source data 1A).”
Quote in the paperSubstantial claim - Findingown data
These isolates with elevated MIC exhibited increased relative fitness in the presence of the drug.
“Consistent with the elevated MIC, these isolates exhibited increased relative fitness in the presence of the drug (Figure 7B).”
Quote in the paperSubstantial claim - Findingnone given
The addition of the YFP marker reduced the fitness of the strain relative to the unaltered one.
“The addition of the YFP marker reduced the fitness of the strain relative to the unaltered one”
Quote in the paperNot a substantial claim - Findingown data
Strains 3731 and 3733 from patient 42 have a higher MIC than isolate 3795.
“There were two strains from patient 42 (3731 and 3733) with a higher MIC”
Quote in the paperSubstantial claim - Findingown data
The cell wall deletion mutants (HYR1, HYR3, and PIR1) were among the least fit in vitro.
“Notably, the cell wall deletion mutants (HYR1, HYR3, and PIR1) were among the least fit in vitro (Figure 8).”
Quote in the paperNot a substantial claim - Findingcitation
Aneuploidies appeared frequently within the drug-resistant isolates.
“Aneuploidies appeared frequently within the drug-resistant isolates, consistent with previous reports (Selmecki et al., 2006).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Selmecki et al., 2006 source
Not checked in the free run.
- Findingcitation
There was strong enrichment for cell wall gene families thought to be critical determinants of the transition from commensalism to pathogenesis.
“In particular, there was strong enrichment for cell wall gene families thought to be critical determinants of the transition from commensalism to pathogenesis (Gow and Hube, 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gow and Hube, 2012 source
Not checked in the free run.
- Interpretationown data
The large number of SNPs detected suggests that isolates from later time points in a series are not simply direct descendants of the earlier isolate.
“The large number of SNPs detected suggests that isolates from later time points in a series are not simply direct descendants of the earlier isolate; however, since mutation and mitotic recombination rates can be elevated under stressful conditions (e.g., drug treatment Galhardo et al., 2007; Forche et al., 2011), we cannot rule out the possibility that some of the variation may be due to de novo”
Quote in the paperSubstantial claim - Premisecitation
Genomes of drug-resistant strains isolated following clinical treatment often exhibit large-scale changes, such as loss of heterozygosity, copy-number variation, and whole chromosome aneuploidy accompanied by point mutations.
“Indeed, the genomes of drug-resistant strains isolated following clinical treatment often exhibit large-scale changes, such as loss of heterozygosity (LOH) (Coste et al., 2006; Dunkel and Morschhauser, 2011), copy-number variation (CNV), including short segmental CNV, and whole chromosome aneuploidy (Selmecki et al., 2010) accompanied by point mutations.”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
The recurrence of LOH events that coincide with changes in MIC suggests that they have been positively selected to rise in frequency relative to the progenitor strain.
“The recurrence of LOH events that coincide with changes in MIC suggests that they have been positively selected to rise in frequency relative to the progenitor strain.”
Quote in the paperSubstantial claim - Study design and conductcitation
We validated our pipeline for detection of point mutations using Sequenom iPlex genotyping.
“We validated our pipeline for detection of point mutations using Sequenom iPlex genotyping (Storm et al., 2003) (‘Materials and methods’).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Storm et al., 2003
Not checked in the free run.
- Premisecitation
Increased activity or level of the enzymes of the ergosterol pathway (e.g., ERG11) reduces direct impact of the drug on its target.
“First, increased activity or level of the enzymes of the ergosterol pathway (e.g., ERG11) reduces direct impact of the drug on its target (Asai et al., 1999; Oliver et al., 2007).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Drug resistance can increase during an infection through the acquisition of aneuploidies due to genomic plasticity and rapid evolutionary selection during infection.
“Studies of clinical isolates of C. albicans suggest that drug resistance can increase during an infection through the acquisition of aneuploidies (Selmecki et al., 2009) due to genomic plasticity and rapid evolutionary selection during infection.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Selmecki et al., 2009 source
Not checked in the free run.
- Interpretationown data
Putative driver mutations in these regions are suggestive of a point mutation followed by an LOH of the mutant allele that confers an advantage.
“Putative driver mutations (defined above as non-synonymous SNPs that were homozygous for a genotype not found in the progenitor strain that persisted in the subsequent isolates; e.g., G/T > A/A) in these regions are suggestive of a point mutation followed by an LOH of the mutant allele that confers an advantage.”
Quote in the paperSubstantial claim - Interpretationown data
A population of related but divergent genotypes of the same lineage exists within a given patient.
“Thus, we conclude that a population of related but divergent genotypes of the same lineage exists within a given patient.”
Quote in the paperSubstantial claim - Premisecitation
Increased efflux of the drug from cells by ABC transporters (encoded by CDR1 and CDR2) or by the major facilitator superfamily efflux pump (encoded by MDR1) reduces the effective intracellular drug concentration.
“Second, increased efflux of the drug from cells by ABC transporters (encoded by CDR1 and CDR2) (Coste et al., 2006) or by the major facilitator superfamily efflux pump (encoded by MDR1) (Dunkel et al., 2008) reduces the effective intracellular drug concentration.”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
Our work reveals new molecular mechanisms underlying the evolution of drug resistance and host adaptation.
“Our work reveals new molecular mechanisms underlying the evolution of drug resistance and host adaptation.”
Quote in the paperSubstantial claim - Premisecitation
Epidemiological data suggest that the intensity of fluconazole use is driving the appearance of resistant isolates.
“Epidemiological data suggest that the intensity of fluconazole use is driving the appearance of resistant isolates (Pfaller et al., 1998).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Pfaller et al., 1998 source
Not checked in the free run.
- Interpretationown data
Compensatory mutations may subsequently arise to offset the major fitness cost of mutations conferring drug resistance.
“suggesting that compensatory mutations may subsequently arise to offset the major fitness cost of mutations conferring drug”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Exposure to a mammalian host results in elevated frequencies of LOH and aneuploidy.
“and exposure to a mammalian host results in elevated frequencies of LOH and aneuploidy (Forche et al. 2009).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Forche et al. 2009 source
Not checked in the free run.
- Interpretationcitation
C. albicans, like S. cerevisiae, generates large scale genetic variation as a means of adaptation.
“Thus, C. albicans like S. cerevisiae (Gresham et al., 2008; Pavelka et al., 2010; Yona et al., 2012; Chang et al., 2013) generates large scale genetic variation as a means of adaptation.”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
Drug resistance and in vitro fitness in the absence of drug are competing selective pressures.
“suggesting that these are competing selective pressures.”
Quote in the paperSubstantial claim - Interpretationown data
The analysis of clinical isolates identified a range of new candidate genes that may affect drug resistance, fitness, and/or virulence.
“The analysis of clinical isolates identified a range of new candidate genes that may affect drug resistance, fitness, and/or virulence.”
Quote in the paperSubstantial claim - Interpretationown data
The isolates are samples from a broad range of genetic variants within clonal (single infection) populations.
“supporting the notion that the isolates are samples from a broad range of genetic variants within clonal (single infection) populations.”
Quote in the paperSubstantial claim - Premisecitation
C. albicans lab isolates likely undergo a stress-induced elevation of mutation and mitotic recombination rates.
“Third, C. albicans lab isolates likely undergo a stress-induced elevation of mutation and mitotic recombination rates (Ponder et al., 2005; Forche et al., 2011; Rosenberg, 2011)”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning
It is possible that C. albicans isolates within the human host also undergo elevated levels of LOH and of point mutations to generate a wider range of diversity.
“Thus, it is possible that C. albicans isolates within the human host also undergo elevated levels of LOH and of point mutations to generate a wider range of diversity.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The absence of the extra chromosomes in isolate 14 resulted in improved overall fitness.
“the absence of the extra chromosomes resulted in improved overall fitness.”
Quote in the paperSubstantial claim - Interpretationown data
The 166 genes whose polymorphisms appeared with an increase in MIC are stronger candidates for making a significant functional contribution to resistance.
“and are thus stronger candidates for making a significant functional contribution to resistance (Figure 5—figure supplement 1, Figure 5—source data 1D, empirical p < 10−5 based a binomial model, ‘Materials and methods’).”
Quote in the paperSubstantial claim - Premisecitation
Resistance conferred in C. albicans by gain-of-function mutations in transcription factors Mrr1, Tac1, and Upc2 is associated with reduced fitness under non-selective conditions in vitro and in vivo during colonization of a mammalian host.
“This is also consistent with a recent study (Sasse et al., 2012) showing that resistance conferred in C. albicans by gain-of-function mutations in the transcription factors Mrr1, Tac1, and Upc2 is associated with reduced fitness under non-selective conditions in vitro as well as in vivo during colonization of a mammalian host.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sasse et al., 2012 source
Not checked in the free run.
- Premisecitation
In vitro fitness is not always a reflection of virulence.
“This is consistent with the observations of Noble and co-workers that in vitro fitness is not always a reflection of virulence (Noble et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Noble et al., 2010 source
Not checked in the free run.
- Interpretationcitation
Aneuploidies, while largely transient, may be an important intermediate giving rise to more stable adaptive genotypes in some cases.
“In this context, it appears that aneuploidies (Figure 7A, green), while largely transient, may be an important intermediate giving rise to more stable adaptive genotypes in some cases”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Yona et al., 2012 source
Not checked in the free run.
- Premisecitation
Mutations can be more readily assimilated in a diploid than in a haploid organism, since deleterious mutations are potentially buffered by a functional version.
“Mutations can be more readily assimilated in a diploid than in a haploid organism, since deleterious mutations are potentially buffered by a functional version (Thompson et al., 2006).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Thompson et al., 2006 source
Not checked in the free run.
- Premisecitation
Previously identified mechanisms of fluconazole resistance are gain-of-function, resulting in increase in amount or activity level of Erg11 or efflux of drug transporters.
“whereas the previously identified mechanisms of fluconazole resistance are ‘gain of function’, resulting in the increase in the amount or activity level of Erg11 (Asai et al., 1999; Oliver et al., 2007) or the efflux of drug transporters (Coste et al., 2006; Dunkel et al., 2008).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation
The evolution of drug resistance in C. albicans has many parallels with the somatic evolution of cancer cells undergoing chemotherapy or treated with specific inhibitors.
“The evolution of drug resistance in C. albicans has many parallels with the somatic evolution of cancer cells undergoing chemotherapy or treated with specific inhibitors.”
Quote in the paperNot a substantial claim - Premisecitation
Several recent studies have shown a similar spectrum of genetic alterations to those observed here during the somatic evolution of cancers in patients undergoing chemotherapy or treated with specific inhibitors.
“Indeed, several recent studies have shown a similar spectrum of genetic alterations to those observed here during the somatic evolution of cancers in patients undergoing chemotherapy (Podlaha et al., 2012; Landau et al., 2013) or treated with specific inhibitors (Ding et al., 2012) to those observed here.”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationown data
A substantial number of persistent and recurrent SNPs, and clusters of co-occurring SNPs, implicate a broad range of pathways and functions that likely provide some growth advantage in the presence of the complex selective pressures found in the host.
“In addition, a substantial number of persistent and recurrent SNPs, and clusters of co-occurring SNPs, implicate a broad range of pathways and functions that likely provide some growth advantage in the presence of the complex selective pressures found in the host.”
Quote in the paperSubstantial claim
- May combine two claims. 51
- Classified as probably not a substantial claim. 18
May combine two claims.
FindingcitationA nonsynonymous homozygous change in the fluconazole drug target ERG11 was associated with the formation of the persistent LOH on the left arm of chromosome 5 in Patient 1, consistent with previous reports, as was TAC1 in Patient 42.
“For example, a nonsynonymous homozygous change in the fluconazole drug target ERG11 was associated with the formation of the persistent LOH on the left arm of chromosome 5 in Patient 1 (Figure 3A), consistent with previous reports (White, 1997b), as was TAC1 in Patient 42.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites White, 1997b
Not checked in the free run.
May combine two claims.
Findingown dataAt least one non-clonal C. albicans isolate was detected in three of the remaining ten patient series (PT 9, 16, 42), indicating that at least ∼36% of the 11 patients sampled carried more than one unrelated Candida strain.
“Additionally, we detected at least one non-clonal C. albicans isolate in three of the remaining ten patient series (PT 9,16, 42; Figure 2B, red), indicating that at least ∼36% of the 11 patients sampled carried more than one unrelated Candida strain.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMost aneuploidies were transient and did not correlate with drug resistance.
“Conversely, most aneuploidies were transient and did not correlate with drug resistance.”
- Also stated in: § Introduction · hedged
“aneuploidies were prevalent in the isolates, yet they were more likely to be transient, and aneuploidy, per se, did not correlate with changes in drug resistance.”
Quote in the paperSubstantial claim- Also stated in: § Introduction · hedged
May combine two claims.
Findingown dataThe extent of persistence and recurrence of these two LOH events is statistically significant under a naïve binary model (p < 5 × 10−4 for the Chr3R LOH; p < 0.01 for the Chr5L LOH).
“The extent of persistence and recurrence of these two LOH events is statistically significant under a naïve binary model (p < 5 × 10−4 for the Chr3R LOH; p < 0.01 for the Chr5L LOH).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSNPs in 240 genes recurrently contain persistent SNPs and may be related to host adaptation and antifungal exposure.
“SNPs in 240 genes may be related to host adaptation.”
- Also stated in: § Introduction · hedged
“We found 240 genes that recurrently contain persistent SNPs, many of which may be related not only to antifungal exposure but also to the complex process of adaptation to the host and antifungal exposure.”
Quote in the paperSubstantial claim- Also stated in: § Introduction · hedged
May combine two claims.
Findingown dataThree of four LOH events in Patient 1 were persistent and associated with an increase in MIC and both of these events were recurrent.
“For example, three of four LOH events in Patient 1 were persistent and associated with an increase in MIC and both of these events were recurrent, such that LOH events in these genomic regions coincided with increases in MIC in other patients.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataDifferent isolates collected on the same day from the same patient (patient 14 [2440 and 2501] and patient 16 [3107 and 3119]) differed by 9668 and 18,291 SNPs, respectively, and had very different fluconazole MIC levels and different fitness phenotypes.
“However, the role of pre-existing diversity is supported by the observation that different isolates collected on the same day from the same patient (patient 14 [2440 and 2501] and patient 16 [3107 and 3119]) differed by 9668 and 18,291 SNPs, respectively (Figure 2—source data 1) and had very different fluconazole MIC levels (Table 1) and different fitness phenotypes (see below), although in each”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataWe have overlaid recurrent driver mutations (n = 17) occurring outside of LOH regions and inside LOH regions.
“We have overlaid recurrent driver mutations (e.g., G/T > A/A) (n = 17) occurring outside of LOH regions (yellow circle, green box) and inside LOH regions (yellow circle, white box).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataLOH events were detected in all series, were often persistent and recurrent across patients' series, and were associated with increased drug resistance.
“LOH events were commonly associated with acquired resistance”
- Also stated in: § Introduction · plain
“we found that LOH events were recurrent across patients' series and were associated with increased drug resistance”
- Also stated in: § LOH events are commonly associated with increased resistance · plain
“LOH events were detected in all of the series and were often persistent, recurrent, and associated with increased drug resistance”
Quote in the paperSubstantial claim- Also stated in: § Introduction · plain
May combine two claims.
Findingown dataMost isolates from each individual patient were highly related, suggesting a clonal population structure and a single primary infection source.
“Most isolates from each individual patient were highly related, suggesting a clonal population structure and facilitating the identification of variation.”
- Also stated in: § Most series are clonal, but there is significant genetic diversity between isolates · hedged
“isolates within most series were clonally related, suggesting a single (primary) infection source”
Quote in the paperSubstantial claim- Also stated in: § Most series are clonal, but there is significant genetic diversity between isolates · hedged
May combine two claims.
Findingown dataHighly recurrent LOH events occurred on the right arm of chromosome 3 (in Patients 1, 9, 14, 16, 42, and 59) and on the left arm of chromosome 5 (in Patients 1, 14, 15, and 43).
“Highly recurrent LOH events occurred on the right arm of chromosome 3 (in Patients 1, 9, 14, 16, 42, and 59; Figure 3A, Figure 4A,B,D,F,H, Figure 3—source data 1) and on the left arm of chromosome 5 (in Patients 1, 14, 15, and 43; Figure 3A, Figure 4B,C,G, Figure 3—source data 1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIsolates varied in adherence, filamentation, and virulence.
“Our analysis also shows that isolates also varied in adherence, filamentation, and virulence.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data17 persistent recurrently polymorphic genes also had driver-like polymorphisms, eight of which were also homozygosed in an LOH tract in at least one patient series.
“Notably, 17 persistent recurrently polymorphic genes also had driver-like polymorphisms, eight of which were also homozygosed in an LOH tract in at least one patient series (Figure 5, Figure 5—source data 1A,B,C).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataHYR3, a known virulence gene, was persistently mutated in nine of the patients, three of which occurred in LOH tracts, including one in which a new allele was homozygosed.
“Likewise HYR3, a known virulence gene, was persistently mutated in nine of the patients, three of which occurred in LOH tracts, including one in which a new allele was homozygosed”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataOur study identified substantial genetic diversity in each series, in contrast to the report of only 26 SNPs detected in a single clinical series of Candida glabrata isolates that spanned a 10-month period.
“Our study identified substantial genetic diversity in each series, in contrast to the report of only 26 SNPs detected in a single clinical series of Candida glabrata isolates that spanned a 10-month period (Singh-Babak et al., 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Singh-Babak et al., 2012 source
Not checked in the free run.
May combine two claims.
Findingown dataThe sequencing of serial clinical isolates and comparison of consecutive isolates from one patient allowed distinguishing and removing non-clonal isolates and estimating that at least ∼30% of patients (3/10) carried at least one non-clonal strain of C. albicans.
“This approach allowed us to distinguish (and remove from further analysis) isolates that were non-clonal and to estimate that at least ∼30% of the patients (3/10) carried at least one non-clonal strain of C. albicans.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDeletion of one gene (orf19.4658) caused a twofold decrease in MIC, whereas the other 22 mutants tested had no significant effect on MIC.
“Deletion of one gene (orf19.4658) caused a twofold decrease in MIC, whereas the other 22 mutants tested did have no significant effect on MIC (data not shown).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe later isolates in the series from patients 30 and 43 had increased fitness and higher virulence by all three measures.
“For example, the later isolates in the series from patients 30 and 43 had increased fitness and higher virulence by all three measures (Figure 6A,B, Figure 7)”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataWe identified persistent nonsynonymous coding SNPs within 1470 genes outside LOH tracts, 167 of them harboring 336 driver-like polymorphisms.
“We identified persistent nonsynonymous coding SNPs within 1470 genes outside LOH tracts, 167 of them harboring 336 driver-like polymorphisms (Figure 5—source data 1B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn Patient 1 isolate 13, an increase in MIC and a trisomy of 5 of 8 chromosomes accompanies a large decrease in fitness (in the absence of drug) relative to the preceding isolate 12 but has increased fitness in the presence of drug.
“For example, in Patient 1 isolate 13, an increase in MIC and a trisomy of 5 of 8 chromosomes accompanies a large decrease in fitness (in the absence of drug) relative to the preceding isolate 12 (Figure 7A) but has increased fitness in the presence of drug (Figure 7B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataERG11 was affected in 70% (7/10) of the patient series, with persistent SNPs in four series (Patients 9, 14, 30, and 59) and mutations in the LOH events in three series (Patients 1, 15, and 43).
“ERG11, which encodes the drug target of fluconazole, was affected in 70% (7/10) of the patient series with persistent SNPs in four series (Patients 9, 14, 30, and 59) and mutations in the LOH events in three series (Patients 1, 15, and 43)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe set of 240 recurrently mutated genes was enriched for fungal-type cell wall genes (18 genes, p < 0.0012) and cell surface genes (24 genes, p < 0.00012).
“The set of 240 recurrently mutated genes was enriched for fungal-type cell wall (18 genes, p < 0.0012) and cell surface genes (24 genes, p < 0.00012)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThree deletion mutants were significantly more fit than the WT parental strain (SN250), including CCN1 and orf19.4471.
“Three were significantly more fit than the WT parental strain (SN250, red, Figure 8), including CCN1, that encodes a G1 cyclin required for hyphal growth maintenance (Loeb et al., 1999) and orf19.4471, an ortholog of Saccharomyces cerevisiae VPS64”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Loeb et al., 1999 source
Not checked in the free run.
May combine two claims.
Findingown dataAXL1 is persistently mutated in eight series, three of which were driver mutations.
“The gene is persistently mutated in eight series, (three of which were driver mutations)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe characterized genes in most of the clusters have coherent functions: Cluster 1 is enriched for cell wall and cell surface genes, Cluster 2 for cell cycle and stress genes, Cluster 3 for genes involved in drug response, and Cluster 5 for carbohydrate binding.
“The characterized genes in most of the clusters have coherent functions. Cluster 1 is enriched for cell wall and cell surface genes, Cluster 2 for cell cycle and stress genes, Cluster 3 for genes involved in drug response, and Cluster 5 for carbohydrate binding”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThese persistent SNPs include ERG11 in patients 9, 14, 30, and 59 and TAC1 in patients 1, 7, 14, 15, 30 and 43.
“These again include ERG11 in patients 9, 14, 30, and 59 and TAC1 in patients 1, 7, 14, 15, 30 and 43 (Figure 5).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data171 of the 240 genes were also mutated in an LOH tract in at least one additional patient (15/171 in three or more additional patients and 34/171 in two additional patients).
“More generally, 171 of the 240 genes were also mutated in an LOH tract in at least one additional patient (15/171 in three or more additional patients and 34/171 in two additional patients).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIsolate 14 has a similar MIC phenotype to isolate 13 but is euploid and is much more fit.
“Isolate 14 has a similar MIC phenotype to isolate 13 but is euploid (Figure 3) and is much more fit (Figure 7A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the ten patients studied here, LOH was commonly observed and was associated with changes in MIC.
“In the ten patients studied here, LOH was commonly observed and was associated with changes in MIC.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe addition of the YFP marker slightly reduced the fluconazole MIC as measured by the E-strip test.
“and slightly reduced the fluconazole MIC as measured by the E-strip test.”
Quote in the paperNot a substantial claimMay combine two claims.
FindingreasoningIsolate 3795 is a euploid strain with the highest MIC.
“This strain was chosen since it was a euploid strain with the highest MIC.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIsolate 3795 from patient 9 is fluconazole-resistant with a MIC of 128 μg/ml.
“a derivative of the fluconazole-resistant (128 μg/ml) isolate 3795 from patient 9 (Table 1)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Table 1
Not checked in the free run.
May combine two claims.
Findingown dataWe cataloged many genetic alterations found in intergenic regions, some of which could affect gene regulation.
“While our analysis focused on recurrent SNPs in ORFs, we nonetheless cataloged the many genetic alterations found in intergenic regions (Figure 2—source data 1), some of which could affect gene regulation.”
Quote in the paperNot a substantial claimMay combine two claims.
FindingcitationThe evolved isolate 4617 in patient 59 had a dramatic increase in filamentation relative to the progenitor, concomitant with the appearance of persistent SNPs in genes associated with filamentous growth: CHO1, MNN2, and 7 different FGR genes.
“For example, the evolved isolate 4617 in patient 59 had a dramatic increase in filamentation relative to the progenitor, which was concomitant with the appearance of persistent SNPs in genes associated with filamentous growth: CHO1, MNN2, and 7 different FGR (filamentous growth regulator) genes (Uhl et al., 2003).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Uhl et al., 2003 source
Not checked in the free run.
May combine two claims.
Findingnone givenStrains 3731 and 3733 are aneuploid.
“but these strains are aneuploid”
Quote in the paperSubstantial claimMay combine two claims.
FindingreasoningUnlike LOH events, aneuploidies were often transient and not consistently correlated to increases in drug resistance.
“Unlike LOH events, aneuploidies were often transient and not consistently correlated to increases in drug resistance.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationC. albicans infections are typically treated with azole inhibitors of ergosterol biosynthesis, often leading to drug resistance.
“Infections are typically treated with azole inhibitors of ergosterol biosynthesis often leading to drug resistance.”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationThese regions include key genes implicated in drug resistance: on Chromosome 3, genes encoding the Cdr1 and Cdr2 efflux pumps and the Mrr1 transcription factor that regulates the Mdr1 major facilitator superfamily efflux pump, and on Chromosome 5, genes encoding the drug target Erg11, and Tac1, a transcription factor that positively regulates expression of CDR1 and CDR2.
“These regions include key genes implicated in drug resistance: on Chromosome 3, genes encoding the Cdr1 and Cdr2 efflux pumps and the Mrr1 transcription factor that regulates the Mdr1 major facilitator superfamily efflux pump (Schubert et al., 2011), and on Chromosome 5, genes encoding the drug target Erg11, and Tac1, a transcription factor that positively regulates expression of CDR1 and CDR2 (”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Interpretationown dataThese data are consistent with two different evolutionary scenarios: accumulation of de novo mutations followed by selection, or selection acting on pre-existing variation to vary the frequency of different genotypes in the population.
“These data are consistent with two different evolutionary scenarios: accumulation of de novo mutations followed by selection (Figure 1B), or selection acting on pre-existing variation to vary the frequency of different genotypes in the population (Figure 1C).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
InterpretationreasoningPersistent changes will include those variants that were driven to sufficiently high frequency by selection to ensure repeated sampling, whereas non-persistent (transient) ones do not.
“We reasoned that such persistent changes will include those variants that were driven to sufficiently high frequency by selection to ensure repeated sampling (Figure 1B,C, yellow lightning bolt), whereas non-persistent (transient) ones do not (Figure 1B,C, pink lightning bolt).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationStudies in clinical isolates have implicated multiple mechanisms in resistance, but have focused on large-scale aberrations or candidate genes, and do not comprehensively chart the genetic basis of adaptation.
“Studies in clinical isolates have implicated multiple mechanisms in resistance, but have focused on large-scale aberrations or candidate genes, and do not comprehensively chart the genetic basis of adaptation.”
- Also stated in: § Introduction · plain
“Studies in evolved isolates have implicated multiple mechanisms in drug resistance, but have focused on large-scale aberrations such as aneuploidies and LOH (Selmecki et al., 2008; 2009) or candidate genes (Perea et al., 2001; White et al., 2002), and do not comprehensively chart the genetic basis of adaptation.”
Quote in the paperSubstantial claim0 of 3 sources checked- Also stated in: § Introduction · plain
May combine two claims.
Interpretationown dataThe detection of known genes involved in drug resistance confirms the approach works and that detection of genes involved in processes implicated in virulence, suggests that these process are co-evolving.
“Thus, the detection of known genes involved in drug resistance confirms the approach works and that detection of genes involved in processes implicated in virulence, suggests that these process are co-evolving.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
InterpretationreasoningIt is possible that the recurrent non-synonymous coding SNPs in the new loci identified in the clinical isolates confer resistance.
“Therefore, it is possible that the recurrent non-synonymous coding SNPs in the new loci, we identified in the clinical isolates confer resistance.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningAlternatively, these loci may not be involved in fluconazole resistance per se and may have a more general role in adaptation to the complex host environment.
“Alternatively, these loci may not be involved in fluconazole resistance per se and may have a more general role in adaptation to the complex host environment.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Interpretationown dataThe additional copy may increase the likelihood of an LOH event on that chromosome.
“Thus, the additional copy may increase the likelihood of an LOH event on that chromosome.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAll three cell wall gene families are specifically expanded in the genomes of pathogenic Candida species.
“All three families are specifically expanded in the genomes of pathogenic Candida species (Butler et al., 2009).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Butler et al., 2009 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationLOH in several genes important for fluconazole resistance has been reported previously for ERG11, TAC1, and MRR1.
“LOH in several genes important for fluconazole resistance has been reported previously for ERG11 (Oliver et al., 2007), TAC1 (Coste et al., 2006), and MRR1 (Schubert et al., 2011)”
Quote in the paperSubstantial claim0 of 3 sources checkedClassified as probably not a substantial claim.
Study design and conductreasoningThe simulation accounts for gene length.
“and thus a larger target for mutation, our simulation accounts for gene length.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationAneuploidy generally has a negative effect on fitness.
“Consistent with the general negative effect of aneuploidy on fitness (Tang and Amon, 2013)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Tang and Amon, 2013
Not checked in the free run.
May combine two claims.
PremisecitationAXL1 transcript is upregulated in an RHE model of oral candidiasis and in clinical isolates from HIV+ patients with oral candidiasis.
“whose transcript is upregulated in an RHE model of oral candidiasis and in clinical isolates from HIV+ patients with oral candidiasis (Zakikhany et al., 2007).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zakikhany et al., 2007 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningAneuploidy chromosomes are reversible or unstable, unlike LOH events, which are irreversible in the absence of mating.
“This is consistent with the irreversibility of LOH events in the absence of mating highlights the reversible nature (instability) of aneuploidy chromosomes.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningMost of the genes in these clusters are not well characterized and represent new candidates involved in drug resistance and adaptation to the host environment.
“Most of the genes in these clusters are not well characterized and represent new candidates involved drug resistance and adaptation to the host environment.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataIsolate 4380 aligned poorly to the SC5314 genome; however, this sequence aligned at high identity to the C. dubliniensis genome and was therefore removed from further analysis.
“Isolate 4380 aligned poorly to the SC5314 genome; however, this sequence aligned at high identity to the C. dubliniensis genome and was therefore removed from further analysis.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Interpretationnone givenAneuploidies may cause increased frequencies of LOH events through whole chromosome loss, as well as by increasing the likelihood of recombination events.
“Nevertheless, aneuploidies may cause increased frequencies of LOH events through whole chromosome loss, as well as by increasing the likelihood of recombination events.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA transient role for aneuploidy is consistent with recent findings from in vitro evolution studies in S. cerevisiae in which a transient aneuploidy was responsible for fitness at elevated temperature, but was eventually replaced by a more stable mutation.
“A transient role for aneuploidy is consistent with recent findings from in vitro evolution studies in S. cerevisiae (Yona et al., 2012) in which a transient aneuploidy was responsible for fitness at elevated temperature, but was eventually replaced by a more stable mutation.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Yona et al., 2012 source
Not checked in the free run.
May combine two claims.
Study design and conductown data1,853 predictions were confirmed as correct by Sequenom genotyping and 120 were discordant, to a calling accuracy of 93.9%.
“1,853 predictions were confirmed as correct by Sequenom genotyping and 120 were discordant (Table 2), to a calling accuracy of 93.9%.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductnone givenIsolates were colony purified at collection and represent a single clone.
“Isolates were colony purified at collection and represent a single clone.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
Interpretationown dataOur results suggest there may be complex population dynamics during the transition from commensal to pathogen and across the course of treatment.
“Our results suggest there may be complex population dynamics during the transition from commensal to pathogen and across the course of treatment.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationVariation in intragenic repeat number modulates phenotypic diversity in adhesion and biofilm formation.
“Variation in intragenic repeat number modulates phenotypic diversity in adhesion and biofilm formation (Verstrepen et al., 2005).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Verstrepen et al., 2005 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThis functional diversity of cell surface antigens has been proposed to allow rapid adaptation to the environment as well as evasion of the host immune system in fungi and other pathogens.
“This functional diversity of cell surface antigens has been proposed to allow rapid adaptation to the environment as well as evasion of the host immune system in fungi and other pathogens (Gemayel et al., 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Gemayel et al., 2010 source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
InterpretationreasoningThe potential loss of additional chromosomes during competition could alter fitness and confound results for aneuploid strains.
“and thus the potential loss of additional chromosomes during the course of the competition could alter fitness and confound our results.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataMany of the isolates evolved additional phenotypes, including changes in in vitro fitness, filamentation, adhesion, and in vivo virulence, and the data points to candidate genes that underlie some of these evolved traits.
“Indeed, many of the isolates evolved additional phenotypes, including changes in in vitro fitness, filamentation, adhesion, and in vivo virulence, and the data presented here points to candidate genes that underlie some of these evolved traits.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Fluconazole is fungistatic, such that many cells exposed to the drug arrest their growth but do not die.
“First, fluconazole, the antifungal drug used to treat the patients in our series, is fungistatic, such that many cells exposed to the drug arrest their growth but do not die.”
The paper relies on this without support.
C. albicans is a highly heterozygous diploid whereas C. glabrata is haploid.
“Second, C. albicans is a highly heterozygous diploid whereas C. glabrata is haploid.”
The paper relies on this without support.
The culture medium used for in vitro fitness assays approximates in vivo conditions.
“5 of the 22 deletion mutants reduced in vitro fitness in a culture medium thought to approximate in vivo conditions (Figure 8, ‘Materials and methods’).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Over the past 20 years, these strains have been extensively investigated at the genomic and transcriptomic levels to elucidate the mechanisms of resistance, revealing a combination of various resistance mechanisms among the resistant strains.
“Over the past 20 years, these strains have been extensively investigated at the genomic and transcriptomic levels to elucidate the mechanisms of resistance (25–35), revealing a combination of various resistance mechanisms among the resistant strains (Table 1).”
From Potential role of lysine acetylation in the stepwise adaptation of <i>Candida albicans</i> to fluconazole (2025) · cites this paper as [32]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThese LOH events included homozygosis of a chromosome 5 left-arm region containing an ERG11 point mutation.
“These LOH events included homozygosis of a region of the left arm of chromosome 5 that includes a point mutation in ERG1155.”
From Drug resistance and tolerance in fungi. (2020) · cites this paper as [55]
This ERG11 allele's homozygosis persisted in the infecting population for over 8 months, supporting the idea that ERG11 mutations help pathogens survive drug selection.
“Homozygosis of this ERG11 allele was persistent (retained in the infecting population for more than 8 months55), consistent with the notion that mutations in ERG11 promote pathogen survival under drug selection56.”
From Drug resistance and tolerance in fungi. (2020) · cites this paper as [55]
In clinical C. albicans isolates from one HIV patient on fluconazole, LOH events kept in all later isolates appeared alongside acquired bona fide resistance.
“For example, in a series of clinical C. albicans isolates from the same patient with HIV treated with fluconazole54,55, LOH events that were retained in all subsequent isolates arose concomitant with the acquisition of bona fide resistance.”
From Drug resistance and tolerance in fungi. (2020) · cites this paper as [55]
There exists significant variation within C. albicans samples, suggesting that selection to become more resistant to drugs can shape the genetic variation of infecting populations.
“Despite the usually clonal nature of clinical isolates obtained from the same patient, it is known that there exist significant variation within C. albicans samples, suggesting that selection to become more resistant to drugs can shape the genetic variation of infecting populations (Ford et al., 2015; Hirakawa et al., 2015).”
From Genome Comparisons of Candida glabrata Serial Clinical Isolates Reveal Patterns of Genetic Variation in Infecting Clonal Populations (2019) · cites this paper as Ford et al., 2015
Extra copies of Chr3, Chr4, and Chr5 have previously been shown to confer increased resistance to FLC.
“Extra copies of hr3 (Perepnikhatka et al. 1999; Ford et al. 2015), Chr4 (Perepnikhatka et al. 1999; Anderson et al. 2017), and Chr5 (Coste et al. 2006; Selmecki et al. 2006, 2008; Ford et al. 2015; Todd et al. 2019) have previously been shown to confer increased resistance to FLC”
From Acquisition of cross-azole tolerance and aneuploidy in <i>Candida albicans</i> strains evolved to posaconazole (2022) · cites this paper as Ford et al. 2015
In 43 clinical C. albicans isolates, loss-of-heterozygosity events were persistent and often associated with resistance, while aneuploidies were often transient and did not correlate with drug resistance.
“Recent analysis of large-scale genomic changes in 43 clinical isolates of C. albicans showed that, while loss-of-heterozygosity events were persistent and often associated with resistance, aneuploidies in clinical isolates were often transient and did not correlate with drug resistance.”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus<i>Candida albicans</i> (2020) · cites this paper as [156]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Fitness-assay reference strain changes from 4639 to 3795
MajorThe Methods first identify a derivative of isolate 4639 as the reference for competitions with and without fluconazole, then identify a derivative of isolate 3795 for those same assays. Figure 7B also names 4639 as its reference.
“the reference strain used was a derivative of the drug-resistant isolate 4639 from patient 59 (Table 1) expressing ENO1::YFP”
“we constructed a derivative of the fluconazole-resistant (128 μg/ml) isolate 3795 from patient 9 (Table 1) that expresses ENO1::YFP to use as the reference for competitive fitness assays in the presence and absence of fluconazole”
Recurrence threshold is stated as both more than three and at least three patients
MinorThe Figure 5 caption requires mutations in more than three patients, whereas the Results and Methods define the filter as three or more patient series.
“genes in which nonsynonymous persistent SNPs appear in more than three patients and are not within an LOH region”
“persistent nonsynonymous SNPs that appeared in the same ORFs in three or more patient series”
Phylogenetic tree method is described two different ways
MinorThe Results say a neighbor-joining algorithm constructed the tree, while the figure caption and Methods say maximum parsimony was used.
“used as a heuristic a neighbor-joining algorithm to construct a phylogenetic tree from this distance metric”
“A distance based tree was estimated using maximum parsimony with PAUP* (4.0)”
Patient 14 isolates described as collected on the same day have different dates
MinorThe text says isolates 2440 and 2501 were collected on the same day, but Table 1 dates them January 3 and January 4, 1996, respectively.
“different isolates collected on the same day from the same patient (patient 14 [2440 and 2501] and patient 16 [3107 and 3119])”
“| | | 2440 | 1/3/96 | Fluconazole | 800 | 1.5 | 82.93 | 15,446,882 | 85.69% | | | | 2501* | 1/4/96 | Fluconazole | 800 | 96 | 88.59 | 17,480,274 | 81.98% |”
Count of genes with persistent nonsynonymous SNPs differs by one
MinorThe Results report 1470 genes with persistent nonsynonymous coding SNPs outside LOH tracts, but the Methods use 1471 as the number of ORFs with such SNPs in a model explicitly described as excluding LOH regions.
“We identified persistent nonsynonymous coding SNPs within 1470 genes outside LOH tracts”
“To determine if the number of persistent non-synonymous SNPs (nsSNPs) occurring in conjunction with changes in MIC was greater than expected, we developed a simple model to simulate the occurrence of nsSNPs outside of LOH regions at each time point. For each time point (i), a random variable Xi ∼ Pois(λi) was assigned, where λi represents the Poisson parameter for each time point:λi = m/T × ti;m = 1471, the number of ORFs with persistent nsSNP”
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PAUP^* : Phylogenetic Analysis Using Parsimony (and other methods) 4.0b8
Swofford, D. L. (2001) · Cited by 12,789 · see citing works
Metagenes and molecular pattern discovery using matrix factorization
Brunet, J.-P., Tamayo, P., Golub, T. R., & Mesirov, J. P. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308531101 · Cited by 2,183 · see citing works
The impact of next-generation sequencing technology on genetics
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Self-citationBakers' Yeast, a Model for Fungal Biofilm Formation
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Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast
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Regulation of Cell-Surface Genes and Biofilm Formation by the C. albicans Transcription Factor Bcr1p
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Resistance Mechanisms in Clinical Isolates of <i>Candida albicans</i>
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Chromosomal duplication is a transient evolutionary solution to stress
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Self-citationGenomic Screen for Vacuolar Protein Sorting Genes inSaccharomyces cerevisiae
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Functional and Structural Diversity in the Als Protein Family of Candida albicans
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“Other mutations were in genes not previously related to fluconazole resistance, including cell adhesion (ALS3,5 and 7 and HYR3; [Hoyer et al., 1998; Sheppard et al., 2004; Hoyer et al., 2008]), filamentous growth (FGR14, FGR28, and EFH, [Uhl et al., 2003; Connolly et al., 2013]), and biofilm formation (BCR1 and YAK1;…”
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The ‘obligate diploid’ Candida albicans forms mating-competent haploids
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Genome-wide identification of fungal GPI proteins.
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Genomic Plasticity of the Human Fungal Pathogen Candida albicans
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Self-citationCandida albicans ALS3 and insights into the nature of the ALS gene family
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ALTERNATIVECANDIDA ALBICANSLIFESTYLES: Growth on Surfaces
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Stress Alters Rates and Types of Loss of Heterozygosity in Candida albicans
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Self-citationGlobal Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata
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“Our study identified substantial genetic diversity in each series, in contrast to the report of only 26 SNPs detected in a single clinical series of Candida glabrata isolates that spanned a 10-month period (Singh-Babak et al., 2012).”
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Evolution of the cancer genome
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The cost of antibiotic resistance from a bacterial perspective
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MALDI-TOF Mass Spectrometry-Based Snp Genotyping
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MATING IN CANDIDA ALBICANS AND THE SEARCH FOR A SEXUAL CYCLE
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MALDI-TOF Mass Spectrometry-Based SNP Genotyping
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Evolution of Drug Resistance in <i>Candida Albicans</i>
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Driving change: the evolution of alternative genetic codes
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Evolution in<i>Candida albicans</i>Populations During a Single Passage Through a Mouse Host
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Self-citationDynamic Large-Scale Chromosomal Rearrangements Fuel Rapid Adaptation in Yeast Populations
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Stress-Induced Phenotypic Switching in Candida albicans
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Candidemia in critically ill patients: difference of outcome between medical and surgical patients
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A G<sub>1</sub> Cyclin Is Necessary for Maintenance of Filamentous Growth in <i>Candida albicans</i>
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Formation of Azole-Resistant <i>Candida albicans</i> by Mutation of Sterol 14-Demethylase P450
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Ploidy controls the success of mutators and nature of mutations during budding yeast evolution
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Genome-Wide Single-Nucleotide Polymorphism Map for Candida albicans
Forche, A., Magee, P. T., Magee, B. B., & May, G. (2004) · Eukaryotic Cell · doi:10.1128/ec.3.3.705-714.2004 · Cited by 62 · see citing works
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Self-citationThe Yak1 Kinase Is Involved in the Initiation and Maintenance of Hyphal Growth inCandida albicans
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Self-citationThe role ofCandida albicansAP-1 protein against host derived ROS in in vivo models of infection
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Gene Ontology and the annotation of pathogen genomes: the case of Candida albicans
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Drug resistance and tolerance in fungi.
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Self-citationMolecular Evolution of Antifungal Drug Resistance
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Candidiasis and Mechanisms of Antifungal Resistance
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The genomic consequences of hybridization
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Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens
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The importance of antimicrobial resistance in medical mycology
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Self-citationGeometric deep learning enables 3D kinematic profiling across species and environments
Dunn, T., Marshall, J. D., Severson, K. S., Aldarondo, D. E., Hildebrand, D. G. C., Chettih, S. N., Wang, W. L., Gellis, A., Carlson, D., Aronov, D., et al. (2021) · Nature Methods · doi:10.1038/s41592-021-01106-6 · Cited by 199 · see citing works
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- Authors
- Ford, C. B., Funt, J. M., Abbey, D., Issi, L., Guiducci, C., Martinez, D. A., Delorey, T., Li, B. Y., White, T. C., Cuomo, C., Rao, R. P., Berman, J., Thompson, D. A., & Regev, A.
- Affiliations
- Broad Institute (US)
- University of Minnesota (US)
- Worcester Polytechnic Institute (US)
- University of Missouri–Kansas City (US)
- Corresponding author
- Thompson, Dawn A
- Regev, Aviv
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2015-02-03
- Volume
- 4
- Pages
- e00662-e00662
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC4383195
- OpenAlex
- W2089758228
- Semantic Scholar
- 874a0ac2f4bc41d9b2662f76f63140c6c7e49a5d
- Cited by
- 348
- References
- 91
- Citations by year
- 2026: 15 · 2025: 32 · 2024: 26 · 2023: 36 · 2022: 30 · 2021: 35 · 2020: 30 · 2019: 39 · 2018: 39 · 2017: 38 · 2016: 15 · 2015: 12
- FWCI
- 26.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital WPI (submittedVersion, cc-by)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation (Graduate Student Fellowship)
- Howard Hughes Medical Institute (Full investigator)
- Helen Hay Whitney Foundation (Postdoctoral Fellowship)
- National Institutes of Health (8DP1CA174427, 2R01CA119176-01)
- Alfred P. Sloan Foundation
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Yeasts and Rust Fungi Studies
- Keywords
- Candida albicans, drug resistance, azole resistance, ergosterol biosynthesis, oral candidiasis, loss of heterozygosity, copy number variation, single nucleotide polymorphisms, aneuploidy, host adaptation, fungal virulence, filamentation, cell adhesion, clinical isolates
- MeSH terms
- Adhesiveness, Aneuploidy, Candida albicans, Candidiasis, Humans, Microbial Sensitivity Tests, Mutation, Phenotype, Virulence, Fluconazole, Genome, Human, Sequence Analysis, DNA, Evolution, Molecular, Loss of Heterozygosity, Polymorphism, Single Nucleotide, Drug Resistance, Fungal, Host-Pathogen Interactions, Genetic Fitness
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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