Cryptococcus
neoformans is a ubiquitous human fungal pathogen that causes meningoencephalitis in predominantly immunocompromised
hosts. The fungus is typically haploid, and sexual reproduction involves two individuals with opposite mating types/sexes, and a. However, the overwhelming predominance of mating type (MAT) over a in C.
neoformans populations limits a mating in nature. Recently it was discovered that C. neoformans can undergo same-sex mating under laboratory conditions, especially between isolates. Whether same-sex mating occurs in nature and contributes to the current population structure was unknown. In this study, natural AD
hybrids that arose by fusion between two cells of different serotypes (A and D) were identified and characterized, providing definitive evidence that same-sex mating occurs naturally. A novel truncated allele of the mating-type-specific cell identity determinant SXI1 was also identified as a genetic factor likely involved in this process. In addition, laboratory-constructed AD strains exhibited hybrid vigor both in vitro and in vivo, providing a plausible explanation for their relative abundance in nature despite the fact that AD hybrids are inefficient in meiosis/sporulation and are trapped in the diploid state. These findings provide insights on the origins, genetic mechanisms, and fitness impact of unisexual hybridization in the Cryptococcus population.