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Adaptation on a Genomic Scale INSIGHT elifesciences.org MICROBIAL EVOLUTION Adaptation on a genomic scale Sequencing the genome of Candida albicans as it evolves in a patient reveals the genetic changes that allow the yeast to adapt to its environment. ISTVÁN BARTHA AND JACQUES FELLAY C. albicans is found in a large fraction of the Related research article Ford CB, Funt JM, human population. Normally, it does not affect Abbay D, Issi L, Guiducci C, Martinez DA, its host, but it can become pathogenic in peo- Delorey T, Li BY, White TC, Cuomo C, Rao RP, ple with weakened immune systems (Mayer Berman J, Thompson DA and Regev A. et al., 2013). C. albicans has a diploid genome— 2015. The evolution of drug resistance in a common feature of sexually reproducing spe- clinical isolates of Candida albicans. eLife cies, featuring two sets of each chromosome—but has a predominantly asexual life cycle (Diogo et al., 4:e00662 doi: 10.7554/eLife.00662 2009). These genetic features are very similar to Image Candida albicans cells taken from a those of cancer cells (Landau et al., 2013). patient before treatment with an antifungal To shed light on the development of drug drug (left), and after adapting to resist the resistant strains in vivo, Ford, Funt et al. studied drug (right) samples from HIV-infected individuals diagnosed with a fungal infection called oral candidiasis and treated with fluconazole. This drug works by pre- daptation to new environments is of fun- venting C. albicans making a molecule called ergos- damental importance in ecology. Infectious terol that is incorporated into the cell membrane: Aagents and cancer cells also relentlessly without this molecule the yeast cell can't grow. adapt to escape detection by the immune system Ford, Funt et al. analyzed 43 fungal isolates and to avoid being killed by drugs targeted at collected from 11 individuals, with several sam- them. The nature and extent of adaptive changes ples taken from each individual over a period in various human pathogens have been studied of several months. Using deep-sequencing tech- under well-controlled conditions in the laboratory nology, they obtained a whole genome sequence (Foll et al., 2014; Szamecz et al., 2014), and also of C. albicans from each sample, which allowed in clinical samples (Mukherjee et al., 2011; Poon them to produce a comprehensive catalogue of et al., 2012). Several mutations leading to drug the different genetic variants of the fungus. These resistance in Candida albicans, a species of yeast variants range from single nucleotide mutations that causes oral and genital infections in humans, in the DNA of the cells to large-scale genetic have been identified through targeted gene changes such as loss of heterozygosity (where one sequencing or large-scale genotyping approaches of the two copies of a chromosomal region is lost) (MacCallum et al., 2010; Dhamgaye et al., 2012). and aneuploidies (where the cell contains either Now, in eLife, Dawn Thompson and Aviv Regev more or fewer chromosomes than normal). Of note, Copyright Bartha and Fellay. This of the Broad Institute of MIT and Harvard and co- all sequencing data have been made publicly avail- article is distributed under the terms of workers—including Christopher Ford and Jason able, which is an unprecedented resource for the the Creative Commons Attribution Funt as joint first authors—describe the genomic research community. License, which permits unrestricted use and redistribution provided that the adaptation of C. albicans when it is exposed to a The first isolate, collected before treatment original author and source are credited. common antifungal compound (Ford et al., 2015). started, provided a snapshot of pre-existing Bartha and Fellay. eLife 2015;4:e06193. DOI: 10.7554/eLife.06193 1 of 3 Insight Microbial evolution | Adaptation on a genomic scale genetic variation and was used to filter out non- The work by Ford, Funt et al. provides a global drug-related mutations. To identify the genes description of the genetic processes underlying that are under selection pressure during flucon- drug resistance and adaptation in C. albicans. azole therapy, Ford, Funt et al. searched for What else could now be learned about microbial mutations called ‘non-synonymous coding sin- evolution using deep sequencing technology? gle nucleotide polymorphisms’ that emerged First, the analysis of multiple strains collected and persisted in at least three of the patients simultaneously in the same infected patient under treatment. These mutations alter a single has the potential to reveal population structure, DNA nucleotide, which subsequently changes dynamics and diversity. Second, mechanistic and the identity of an amino acid in one of the pro- temporal details governing the emergence of teins produced by the cell. Such mutations escape mutations will certainly be gained from in were observed in a total of 240 genes, notably vitro experiments, including the characterization including genes encoding proteins involved in of single colonies over time. Finally, the sequenc- fungal cell wall formation or in the regulation of ing of paired host and pathogen genomes opens the efflux pumps that move toxic substances out the door to innovative studies of host-specific of the cell. adaptation. Among the larger-scale genetic variants, loss of heterozygosity events were significantly associ- István Bartha is in the School of Life Sciences, École ated with higher drug resistance, whereas most Polytechnique Fédérale de Lausanne, Lausanne, aneuploidies were transient and had no detectable Switzerland and Host-pathogen genomics group, Swiss impact. However, aneuploidies may still indirectly Institute of Bioinformatics, Lausanne, Switzerland help resistance to develop by increasing the like- Jacques Fellay is in the School of Life Sciences, École lihood that loss of heterozygosity events occur Polytechnique Fédérale de Lausanne, Lausanne, following the loss of a chromosome. Measurement Switzerland and Host-pathogen genomics group, Swiss of the in vitro fitness of the sequenced strains Institute of Bioinformatics, Lausanne, Switzerland, convincingly demonstrated that C. albicans had [email protected] adapted to fluconazole: the measured fitness of Competing interests: The authors declare that no the last isolate was indeed higher in the presence competing interests exist. of the drug than without it. Published 03 February 2015 Because a single colony was sequenced at each time point, it was not possible to distinguish References between the appearance of new mutations and Dhamgaye S, Bernard M, Lelandais G, Sismeiro O, the selection of pre-existing minority variants in Lemoine S, Coppée JY, Le Crom S, Prasad R, Devaux F. 2012. RNA sequencing revealed novel response to drug pressure. Most isolates from actors of the acquisition of drug resistance in each individual were highly related, suggesting Candida albicans. BMC Genomics 13:396. that samples collected in the same patient doi: 10.1186/1471–2164-13–396. share the same common ancestor. Despite this Diogo D, Bouchier C, d'Enfert C, Bougnoux ME. 2009. clonal relationship, significant within-host diver- Loss of heterozygosity in commensal isolates of the asexual diploid yeast Candida albicans. Fungal sity was present, as various isolates of the same Genetics and Biology 46:159–168. doi: 10.1016/j. patient differed by thousands of single nucleo- fgb.2008.11.005. tide polymorphisms. Foll M, Poh Y-P, Renzette N, Ferrer-Admetlla A, Bank C, A remaining open question is whether pre- Shim H, Malaspinas A-S, Ewing G, Liu P, Wegmann D, existing genetic variation is maintained at low et al. 2014. Influenza virus drug resistance: a time- sampled population genetics perspective. PLOS Genetics levels in the C. albicans population throughout the 10:e1004185. doi: 10.1371/journal.pgen.1004185. treatment period, or if only drug-selected strains Ford C, Funt J, Abbay D, Issi L, Guiducci C, Martinez D, are conserved. To address this, more in-depth Delorey T, Li BY, White T, Cuomo C, et al. 2015. genomic analyses of fungal sub-populations are The evolution of drug resistance in clinical isolates needed. An obvious first step would be to study of Candida albicans. eLife 4:e00662. doi: 10.7554/ eLife.00662. the loss of heterozygosity events in greater detail, Landau DA, Carter SL, Stojanov P, McKenna A, because such mutations are irreversible in clonal Stevenson K, Lawrence MS, Sougnez C, Stewart C, populations with a purely asexual life cycle. Sivachenko A, Wang L, et al. 2013. Evolution and Therefore, valuable insights into the diversity of impact of subclonal mutations in chronic lymphocytic C. albicans inside a single host could be gained leukemia. Cell 152:714–726. doi: 10.1016/j. cell.2013.01.019. by investigating whether any of the resistance- MacCallum DM, Coste A, Ischer F, Jacobsen MD, inducing loss of heterozygosity events reverses Odds FC, Sanglard D. 2010. Genetic dissection of after fluconazole treatment has ended. azole resistance mechanisms in Candida albicans Bartha and Fellay. eLife 2015;4:e06193. DOI: 10.7554/eLife.06193 2 of 3 Insight Microbial evolution | Adaptation on a genomic scale and their validation in a mouse model of disseminated Poon AF, Swenson LC, Bunnik EM, Edo-Matas D, infection. Antimicrobial Agents and Chemotherapy Schuitemaker H, van 't Wout AB, Harrigan PR. 54:1476–1483. doi: 10.1128/AAC.01645-09. 2012. Reconstructing the dynamics of HIV evolution Mayer FL, Wilson D, Hube B. 2013. Candida albicans within hosts from serial deep sequence data. PLOS pathogenicity mechanisms. Virulence 4:119–128. Computational Biology 8:e1002753. doi: 10.1371/ doi: 10.4161/viru.22913. journal.pcbi.1002753. Mukherjee R, Jensen ST, Male F, Bittinger K, Hodinka RL, Szamecz B, Boross G, Kalapis D, Kovács K, Fekete G, Miller MD, Bushman FD. 2011. Switching between Farkas Z, Lázár V, Hrtyan M, Kemmeren P, Groot raltegravir resistance pathways analyzed by deep Koerkamp MJ, et al. 2014. The Genomic Landscape of sequencing.
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