systemic candidiasis in adult patients. Genome analysis of 68 isolates from 8
hospitals across Scotland, together with 83 global isolates, revealed insights into the population genetics and evolution of C. glabrata. Clinical isolates of C. glabrata from across Scotland are highly-genetically diverse, including at least separate sequence types (STs) that have been recovered previously in globally diverse locations, and one newly discovered ST. Several STs had evidence for ancestral recombination, suggesting transmission between distinct geographical regions has coincided with genetic exchange arising in new clades. Three isolates were missing MAT1, potentially representing a second mating type. Signatures of positive selection were identified in every ST including enrichment for Epithelial Adhesins (EPA) thought to facilitate fungal adhesion to human epithelial cells. In patent microevolution was identified from seven sets of recurrent cases of candidiasis, revealing an enrichment for non-synonymous and frameshift indels in cell surface proteins. Microevolution within patients also affected EPA genes, and several genes involved in drug resistance including the ergosterol synthesis gene ERG4 and the echinocandin target FKS1/2, the latter coinciding with a marked drop in fluconazole MIC. In addition to nuclear genome diversity, the C. glabrata mitochondrial genome was particularly diverse, appearing reduced in size and with fewer conserved protein encoding genes in all non-reference ST15 isolates. Together, this study highlights the genetic diversity present within the C. glabrata population that may impact virulence and drug resistance, and two major mechanisms generating this diversity: microevolution and genetic exchange/recombination.
R.A.F, D.W., T.W., and A.W. are supported by the Medical Research Council
Centre for Medical Mycology MR/N006364/2. R.A.F. is supported by a Wellcome
Trust Seed Award (215239/Z/19/Z). D.W. is supported by a Wellcome Trust Senior Research Fellowship (214317/Z/18/Z). C.A.M is funded by the European Union's Horizon 2020, Innovative Training Network: FunHoMic (grant N° 812969) and consortium ‘Host-Directed Medicine in invasive FUNgal infections’—HDM-FUN (Grant Agreement 847507). The authors thank Zeynab Heidari and Elaina Collie725 Duguid of the Centre for Genome-Enabled Biology and Medicine , University of Aberdeen for their support and assistance in this work. We would also like to thank Dr. Lucy van Dorp for valuable suggestions for running ADMIXTURE, and Prof. Ian Stansfield for useful discussions.
- Candida glabrata
- genome sequencing