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The yeast Candida glabrata is an opportunistic human fungal pathogen whose incidence has increased in the last two decades. Despite its name, this yeast is only distantly related to the model fungal pathogen C. albicans, and more closely related to Saccharomyces cerevisiae and other yeasts that underwent an ancient whole-genome duplication. Understanding what specific traits make C. glabrata a successful opportunistic pathogen within a clade of mostly innocuous yeasts, and how these compare to virulence traits in distant pathogens such as C. albicans is a focus of intense research. From an evolutionary perspective, uncovering how the ability to infect humans has emerged multiple, independent times in different lineages may reveal new disease mechanisms and provide us with the capacity to predict which genomic features in a clade may confer a higher potential to develop virulence against humans. ; TG group acknowledges support of the Spanish Ministry of Economy and Competitiveness grants, 'Centro de Excelencia Severo Ochoa 2013–2017' SEV-2012-0208, and BIO2012-37161 cofounded by European Regional Development Fund (ERDF); from the European Union and ERC Seventh Framework Programme (FP7/2007-2013) under grant agreements FP7-PEOPLE-2013-ITN-606786 and ERC-2012-StG-310325, and grant from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No H2020-MSCA-ITN-2014-642095.

SUMMARY: An increasing number of phased (i.e. with resolved haplotypes) reference genomes are available. However, the most genetic variant calling tools do not explicitly account for haplotype structure. Here, we present HaploTypo, a pipeline tailored to resolve haplotypes in genetic variation analyses. HaploTypo infers the haplotype correspondence for each heterozygous variant called on a phased reference genome. AVAILABILITY AND IMPLEMENTATION: HaploTypo is implemented in Python 2.7 and Python 3.5, and is freely available at https://github.com/gabaldonlab/haplotypo, and as a Docker image. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. ; This work was supported by the European Union's Horizon 2020 research and innovation programme under the grant agreement ERC-2016-724173 and Marie Sklodowska-Curie grant agreements N° 642095, and 747607; the Spanish Ministry of Economy, Industry, and Competitiveness (MEIC) for the EMBL partnership, and grants 'Centro de Excelencia Severo Ochoa' SEV-2012-0208, and BFU2015-67107 co-founded by European Regional Development Fund (ERDF); the CERCA Programme/Generalitat de Catalunya; from the Catalan Research Agency (AGAUR) SGR857; and INB Grant (PT17/0009/0023—ISCIII-SGEFI/ERDF).

Candida glabrata is an opportunistic fungal pathogen that currently ranks as the second most common cause of candidiasis. Although the mechanisms underlying virulence and drug resistance in C. glabrata are now starting to be elucidated, we still lack a good understanding of how this yeast adapts during the course of an infection. Outstanding questions are whether the observed genomic plasticity of C. glabrata plays a role during infection, or what levels of genetic variation exist within an infecting clonal population. To shed light onto the genomic variation within infecting C. glabrata populations, we compared the genomes of 11 pairs and one trio of serial clinical isolates, each obtained from a single patient. Our results provide a catalog of genetic variations existing within clonal infecting isolates, and reveal an enrichment of non-synonymous changes in genes encoding cell-wall proteins. Genetic variation and the presence of non-synonymous mutations and copy number variations accumulated within the host, suggest that clonal populations entail a non-negligible level of genetic variation that may reflect selection processes that occur within the human body. As we show here, these genomic changes can underlie phenotypic differences in traits that are relevant for infection. ; TG group acknowledges support from the Spanish Ministry of Economy, Industry, and Competitiveness (MEIC) for the EMBL partnership, and grants "Centro de Excelencia Severo Ochoa 2013–2017" SEV-2012-0208, and BFU2015-67107 cofunded by European Regional Development Fund (ERDF), from the CERCA Programme/Generalitat de Catalunya; from the Catalan Research Agency (AGAUR) SGR857, and grant from the European Union's Horizon 2020 research and innovation programme under the grant agreement ERC-2016-724173 the Marie Sklodowska-Curie grant agreement No. H2020-MSCA-ITN-2014-642095. This project received support from the INB Grant (PT17/0009/0023 – ISCIII-SGEFI/ERDF).

Candida glabrata is an opportunistic fungal pathogen that ranks as the second most common cause of systemic candidiasis. Despite its genus name, this yeast is more closely related to the model yeast Saccharomyces cerevisiae than to other Candida pathogens, and hence its ability to infect humans is thought to have emerged independently. Moreover, C. glabrata has all the necessary genes to undergo a sexual cycle but is considered an asexual organism due to the lack of direct evidence of sexual reproduction. To reconstruct the recent evolution of this pathogen and find footprints of sexual reproduction, we assessed genomic and phenotypic variation across 33 globally distributed C. glabrata isolates. We cataloged extensive copy-number variation, which particularly affects genes encoding cell-wall-associated proteins, including adhesins. The observed level of genetic variation in C. glabrata is significantly higher than that found in Candida albicans. This variation is structured into seven deeply divergent clades, which show recent geographical dispersion and large within-clade genomic and phenotypic differences. We show compelling evidence of recent admixture between differentiated lineages and of purifying selection on mating genes, which provides the first evidence for the existence of an active sexual cycle in this yeast. Altogether, our data point to a recent global spread of previously genetically isolated populations and suggest that humans are only a secondary niche for this yeast. ; The T.G. group acknowledges the support of the Spanish Ministry of Economy and Competitiveness grants "Centro de Excelencia Severo Ochoa 2013–2017" SEV-2012-0208 and BFU2015-67107 cofunded by the European Regional Development Fund (ERDF); European Union and ERC Seventh Framework Programme (FP7/2007–2013) under grant agreement ERC-2012-StG-310325; Catalan Research Agency (AGAUR) SGR857; CERCA Programme/Generalitat de Catalunya; and a grant from the European Union's Horizon 2020 research and innovation programme under Marie Sklodowska-Curie grant agreement H2020-MSCA-ITN-2014-642095. C.F.'s and T.G.'s groups acknowledge support from the GDRI "iGenolevures" of the French CNRS for travel and meeting funds. T.G., O.B., and E.G.-M. acknowledge funding from the European Unionunder grant agreement FP7-PEOPLE-2013-ITN-606786 "ImresFun."