Cross-subgenus hybridization between Leishmania and Sauroleishmania informs on parasite genomic compatibility and transcriptomic adaptation.

Leishmania parasites can enter a cryptic sexual reproductive cycle generating hybrid genotypes that can lead to unpredictable clinical outcomes and transmission cycles. Despite the importance of hybrids in Leishmania epidemiology, the mechanisms involved in their formation - including the impact of parental genetic distance - remain poorly understood. We report the in vitro generation of a hybrid between Leishmania (Leishmania) infantum and Leishmania (Sauroleishmania) tarentolae, two species from sister phylogenetic clades circulating across Southern Italy, providing evidence of genomic compatibility. Whole-Genome Sequencing indicates that, while the hybrid is largely tetraploid, its genome is not just the sum of its parental content. RNA-seq analysis of the hybrid transcriptome uncovers significant differences in the abundance of orthologous transcripts expressed from both parental genomes, driven by either parent-specific gene copy number variations or differential mRNA turnover. These results demonstrate that, beyond genomic restructuring, post-transcriptional regulation may serve as an additional mechanism shaping viable hybrid phenotypes, potentially enhancing parasite adaptability and fitness.