Genomic hallmarks of parasexual reproduction in three hybrid groups of the human pathogen Cryptococcus neoformans
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Hybridization is a major driver of fungal evolution, yet knowledge of the molecular mechanisms underpinning hybridization and its genomic impact remain limited. Here, we analyse 197 Cryptococcus neoformans genomic sequences, including 13 newly sequenced strains, identifying three genetically clustered and distinct hybrid groups (H1, H2 and H3) each with unique parental origins and ecological associations. Using phylogenomics, population structure analyses, and long-read genome assemblies, we identified hybrid genomes with chromosome-wide loss of heterozygosity (LOH), inheritance of large intact parental haplotype blocks and widespread aneuploidy within and across genomes. These patterns are also observed when progeny were generated with spo11 Δ parents, indicating these features are a result of a meiotic-independent process such as parasex. This is further underscored by discovery of haploid and near-haploid recombinants in both spo11 Δ mutant progeny and reanalysed the wild-type hybrid progeny. We hypothesise these haploid and near-haploid recombinants are generated through ploidy reduction via independent chromosome assortment because of concerted chromosomal loss, which is a key feature of the parasexual cycle. Phenotypic assays demonstrated that several hybrid isolates have diverse growth and virulence patterns, underscoring functional consequences of genome plasticity. Together, our work suggests a non-meiotic reproductive process contributes to shape the genotypic and phenotypic diversity of Cryptococcus neoformans .
Significance statement
Hybridisation in fungal pathogens has been linked to novel genotypes, some of which have enhanced virulence. Cryptococcus is a human pathogen responsible for approximately 180,000 deaths annually worldwide. However, the mechanisms by which Cryptococcus generates genotypic diversity remains understudied. By analysing 197 C. neoformans genome sequences, we identified three distinct groups of hybrids, defined by their ancestral inheritance. In each of these 3 groups, we discovered novel features of hybrid isolates including uneven chromosome numbers in most but not all hybrids, chromosome-wide loss of heterozygosity consistent with whole chromosome inheritance from a single parent, and whole-chromosome-wide haplotype inheritance. These genomic features are consistent with a parasexual form of reproduction, which is a non-meiotic process involving cell and nuclear fusion, followed by gradual chromosome loss and sometimes mitotic recombination. Surprisingly, similar genomic patterns were observed in spo11 Δ mutant crosses, supporting the hypothesis that a non-canonical process such as parasex is facilitating cryptococcal hybridisation. Our results expand our understanding of fungal reproduction and highlight new routes for the emergence of virulence and antifungal resistance.
