Comparative 3D Genome Organization in Apicomplexan Parasites

Evelien Bunnik⁰, Aarthi Venkat¹, Ferhat Ay¹, Karine Le Roch²
(0) University of Texas Health San Antonio, Long school of Medicine
(1) La Jolla Institute for Immunology.
(2) University of California, Riverside

Abstract
The malaria parasite, Plasmodium falciparum, is a major cause of mortality in young children and pregnant women living in endemic areas. The spread of drug-resistant parasites is alarming and calls for the development of novel antimalarial drugs. However, the development of novel antimalarials is hampered by our lack of understanding about how the parasite controls its development and gene expression profiles through the different stages of its life cycle. Increasing amounts of evidence points towards a role for chromatin structure and three-dimensional (3D) nuclear organization to regulate gene expression throughout the parasite life cycle. In eukaryotic cells, the positioning of chromosomes in the nucleus is highly organized and has been showed to have a complex and dynamic relationship with gene expression. In the human malaria parasite Plasmodium falciparum, the clustering of genes involved in virulence and pathogenicity correlates with their coordinated silencing and has a strong influence on the overall genome organization. To identify conserved and species-specific principles of genome organization, we performed Hi-C experiments and generated 3D genome models for five Plasmodium species and two related apicomplexan parasites. Plasmodium species mainly showed clustering of centromeres, telomeres, and virulence genes. In P. falciparum, the heterochromatic virulence gene cluster had a strong repressive effect on the surrounding nuclear space, while this was less pronounced in Plasmodium vivax and Plasmodium berghei, and absent in Plasmodium yoelii. In Plasmodium knowlesi, telomeres and virulence genes while still interacting were more dispersed throughout the nucleus, and its 3D genome showed a strong correlation with gene expression. The Babesia microti genome showed a classical Rabl organization with colocalization of subtelomeric virulence genes, while the Toxoplasma gondii genome was dominated by clustering of the centromeres and lacked virulence gene clustering. Collectively, our results demonstrate that spatial genome organization in most Plasmodium species is constrained by the colocalization of virulence genes. P. falciparum and P. knowlesi, the only two Plasmodium species with gene families involved in antigenic variation, are unique in the effect of these genes on chromosome folding, indicating a potential link between genome organization and gene expression in more virulent pathogens.