Proteome size reduction in Apicomplexans is linked with loss of DNA repair and host redundant pathways.

Abstract

Apicomplexans are alveolate parasites which include Plasmodium falciparum, the main cause of malaria, one of the world's biggest killers from infectious disease. Apicomplexans are characterized by a reduction in proteome size, which appears to result from metabolic and functional simplification, commensurate with their parasitic lifestyle. However, other factors may also help to explain gene loss such as population bottlenecks experienced during transmission, and the effect of reducing the overall genomic information content. The latter constitutes an 'informational constraint', which is proposed to exert a selective pressure to evolve and maintain genes involved in informational fidelity and error correction, proportional to the quantity of information in the genome (which approximates to proteome size). The dynamics of gene loss was examined in 41 Apicomplexan genomes using orthogroup analysis. We show that loss of genes involved in amino acid metabolism and steroid biosynthesis can be explained by metabolic redundancy with the host. We also show that there is a marked tendency to lose DNA repair genes as proteome size is reduced. This may be explained by a reduction in size of the informational constraint and can help to explain elevated mutation rates in pathogens with reduced genome size. Multiple Sequentially Markovian Coalescent (MSMC) analysis indicates a recent bottleneck, consistent with predictions generated using allele-based population genetics approaches, implying that relaxed selection pressure due to reduced population size might have contributed to gene loss. However, the non-randomness of pathways that are lost challenges this scenario. Lastly, we identify unique orthogroups in malaria-causing Plasmodium species that infect humans, with a high proportion of membrane associated proteins. Thus, orthogroup analysis appears useful for identifying novel candidate pathogenic factors in parasites, when there is a wide sample of genomes available.