Discussion
Genome instability plays a central yet poorly understood role in human disease. Iterations between genetic amplification and environmental selection drive cancer development, microbial infection and therapeutic failure, thus increasing human mortality. The molecular mechanisms that harness the deleterious effects of genome instability to generate beneficial phenotypes in these pathogenic systems are largely unknown. An ideal disease model to address this important open question is provided by the protozoan pathogen Leishmania that causes devastating human and veterinary infections and exploits a wide variety of genetically heterogenous animal and insect hosts, thus undergoing constant adaptation. In the absence of transcriptional regulation, these early-branching eukaryotes exploit frequent variations in chromosome and gene copy number to regulate expression levels. We apply ecological genomics and experimental evolution approaches to assess how Leishmania genome instability generates genetic heterogeneity, how this is translated into selectable phenotypes, and how comparative systems analyses can inform on molecular markers underlying parasite fitness gain. Our results draw a complex picture of Leishmania evolutionary adaptation in the field and in culture that relies (i) on co-amplification of functionally related genes that establish complex fitness phenotypes, (ii) on frequent gene deletion and post-transcriptional, compensatory responses that significantly increase the parasite fitness landscape, and (iii) on dynamic changes of small nucleolar (sno) RNAs that can program epitranscriptomic and translational regulation, thereby providing proteomic robustness to genetically heterogenous parasite populations [1]- [5]. This complex adaptation process allows to maintain genetic heterogeneity and thus evolvability of the parasite population despite continuous selection inside equally heterogenous vertebrate and invertebrate hosts. Data will be presented that investigate the link between Leishmania genome instability and fitness gain in relevant animal models conducting Experimental Evolution in hamsters and sand flies. Novel insight into Leishmania adaptation will be likely applicable to other fast evolving eukaryotic systems with unstable genomes, such as fungi or cancer cells.
Keywords Leishmania; Genome instability; fitness gain; phenotypic adaptation References [1] Prieto Barja et al., Nat Ecol Evol. 2017 [2] Bussotti et al., MBio, 2018 [3] Bussotti et al., PNAS USA. 2021 [4] Spath and Bussotti, NAR 2021 [5] Piel et al., PLoS Pathog. 2022
Acknowledgements This work was supported by a grants from the Institut Pasteur International Direction to the LeiSHield consortium, the EU H2020 project LeiSHield-MATI-REP-778298-1, the Institut Pasteur ‘Programmes Transversaux de Recherche’ (PTR 425-21), the Agence Nationale pour la Recherche Labex ‘Integrative Biology of Emerging Infectious Diseases’ contract ANR-10-LABX-62-IBEID and Labex
