Discussion

Natural selection is an important driver of microbial pathogenesis. Infectious agents have evolved various bet hedging strategies to constantly generate genetic diversity that allows for selection of the fittest in changing host environments. As part of the LeiSHield consortium we discovered a novel strategy of evolutionary adaptation in the protozoan parasite Leishmania relying on chromosomal amplification and allelic variation. Drawing from the sequenced genomes of 204 L. donovani field isolates and conducting evolutionary experiments we uncover highly dynamic and regulated karyotype changes in vitro and in vivo that allow for the development and selection of beneficial alleles. We demonstrate that haplotype selection regulates transcript abundance and generates considerable phenotypic variability causing fitness gains in culture and infected hamsters in a tissue-specific manner.  We further show that allelic diversity is higher for those chromosomes that undergo frequent amplification thus linking aneuploidy to genome evolution and the generation of new haplotypes. Our data unravel a new microbial bet hedging strategy based on genome instability that drives parasite fitness and its long-term evolution, which may be broadly applicable to other eukaryotic pathogens and questions current approaches towards Leishmania epidemiology and drug discovery.