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The evolution of drug resistance in clinical isolates of Candida albicans.

Ford CB, Funt JM, Abbey D, Issi L, Guiducci C, Martinez DA, Delorey T, Li BY, White TC, Cuomo C, Rao RP, Berman J, Thompson DA, Regev A - Elife (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Broad Institute of MIT and Harvard, Cambridge, United States.

ABSTRACT
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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Related in: MedlinePlus

Null distributions of (a) the expected number of persistent, recurrent nonsynonymous SNPs outside of LOH regions, and (b) persistent non-synonymous SNPsassociated with MIC changes outside of LOH regions.
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fig9: Null distributions of (a) the expected number of persistent, recurrent nonsynonymous SNPs outside of LOH regions, and (b) persistent non-synonymous SNPsassociated with MIC changes outside of LOH regions.


The evolution of drug resistance in clinical isolates of Candida albicans.

Ford CB, Funt JM, Abbey D, Issi L, Guiducci C, Martinez DA, Delorey T, Li BY, White TC, Cuomo C, Rao RP, Berman J, Thompson DA, Regev A - Elife (2015)

Null distributions of (a) the expected number of persistent, recurrent nonsynonymous SNPs outside of LOH regions, and (b) persistent non-synonymous SNPsassociated with MIC changes outside of LOH regions.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383195&req=5

fig9: Null distributions of (a) the expected number of persistent, recurrent nonsynonymous SNPs outside of LOH regions, and (b) persistent non-synonymous SNPsassociated with MIC changes outside of LOH regions.
Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Broad Institute of MIT and Harvard, Cambridge, United States.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus