Cryptococcus neoformans (Cn) and Cryptococcus gattii (Cg) are closely related pathogenic yeasts that may cause meningo-encephalitis, which is fatal if left untreated. Cn and Cg differ in host range and geographic occurrence. Cn mainly infects immunocompromised people and occurs worldwide, whereas Cg may cause infections in otherwise healthy people and is found predominantly in (sub)tropical regions. Six major haploid genotypic groups have consistently been distinguished in molecular studies of Cn and Cg. Two of them correspond to the varieties of Cn: var. grubii and var. neoformans. Within Cg four major genotypic groups have consistently been found, but these groups have not been described as separate taxa. The taxonomic status of the major genotypic groups within the Cn - Cg species complex and the interactions between the genotypic groups were studied. Six major monophyletic lineages, which correspond to the previously described genotypic groups could be identified when six nuclear regions were analyzed. In addition, the isolates clustered in the same major monophyletic lineage for all regions studied, which indicates that recombination between the monophyletic lineages has not occurred. Surprisingly, some isolates of one of the Cg genotypic groups possessed mitochondrial sequences (partially) identical to those of another Cg genotypic group. The identification of Cg isolates which possess a nuclear genome belonging to one genotypic group and a mitochondrial genome (partially) belonging to another genotypic group suggests that mating or somatic fusion has occurred between these two genotypic groups. Diploid or aneuploid hybrid isolates have been found which result from mating between the two varieties. Hybrids between Cn and Cg had never been isolated from a patient or the environment. Surprisingly, three clinical isolates were discovered that were hybrids between Cn var. neoformans and Cg. In addition, one clinical isolate was found that was a hybrid between Cn var. grubii and Cg. These four hybrids probably result from mating between isolates of Cn and Cg. Our results combined with results from other studies suggest that Cn and Cg have almost completed speciation. Cn and Cg are morphologically and physiologically different and formed sister groups for all studied regions. Hybrids between Cn and Cg are rare, suggesting that most hybrids are inviable. Therefore, the current two species status of Cn and Cg is probably justified. The two varieties within Cn started to diverge more recently. The two varieties have physiological differences and formed monophyletic lineages for all regions studied. However, Cn hybrids are found often and mating experiments have generated fertile progeny and haploid recombinants, indicating that the two varieties are not yet species. The Cg genotypic groups started to diverge even more recently. The genotypic groups do not differ physiologically, but can be distinguished by differences in the nuclear genome using, e.g. Luminex xMAP technology. Analyses of nuclear regions distinguished four monophyletic lineages, but the identification of Cg isolates which possess a nuclear genome belonging to one genotypic group and a mitochondrial genome (partially) belonging to another genotypic group suggests that mating has occurred between two Cg genotypic groups. These results indicate that the Cg genotypic groups might be described as varieties
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