Functional Profiling of a Plasmodium Genome Reveals an Abundance of Essential Genes

Ellen Bushell,Ana Rita Gomes,Theo Sanderson,Burcu Anar,Gareth Girling,Colin Herd,Tom Metcalf,Katarzyna Modrzynska,Frank Schwach,Rowena E Martin,Michael W Mather,Geoffrey I Mcfadden,Leopold Parts,Gavin G Rutledge,Akhil B Vaidya,Kai Wengelnik,Julian C Rayner,Oliver Billker

doi:10.1016/j.cell.2017.06.030

Abstract

SummaryThe genomes of malaria parasites contain many genes of unknown function. To assist drug development through the identification of essential genes and pathways, we have measured competitive growth rates in mice of 2,578 barcoded Plasmodium berghei knockout mutants, representing >50% of the genome, and created a phenotype database. At a single stage of its complex life cycle, P. berghei requires two-thirds of genes for optimal growth, the highest proportion reported from any organism and a probable consequence of functional optimization necessitated by genomic reductions during the evolution of parasitism. In contrast, extreme functional redundancy has evolved among expanded gene families operating at the parasite-host interface. The level of genetic redundancy in a single-celled organism may thus reflect the degree of environmental variation it experiences. In the case of Plasmodium parasites, this helps rationalize both the relative successes of drugs and the greater difficulty of making an effective vaccine.

Highlights

Throughout the tree of life, the evolution of parasitism has been accompanied by drastic reductions in genome size and gene numbers (Jackson et al, 2016; Vivares et al, 2002; Wolf and Koonin, 2013)
The Apicomplexa include important parasites of livestock and human pathogens, such as Toxoplasma gondii, which infects approximately one-third of the human population and causes pathology in immunodeficient individuals and malaria parasites, among which P. falciparum remains the biggest killer of all parasites, leading to an estimated 214 million clinical cases and 438,000 deaths annually (WHO, 2015)
We estimate that almost two-thirds of parasite genes contribute to normal asexual growth of the blood stage in vivo, an unexpectedly large number for a single phase of a complex life cycle, which we propose is a consequence of genomic reduction during the evolution of parasitism

Summary

Introduction

Throughout the tree of life, the evolution of parasitism has been accompanied by drastic reductions in genome size and gene numbers (Jackson et al, 2016; Vivares et al, 2002; Wolf and Koonin, 2013). In free-living organisms such as Escherichia coli, Saccharomyces cerevisiae, Drosophila melanogaster, or Caenorhabditis elegans, the majority of genes have no loss-of-function phenotypes when tested under laboratory conditions (Dietzl et al, 2007; Gerdes et al, 2003; Giaever et al, 2002; Kamath et al, 2003; Winzeler et al, 1999), even though many genes are highly conserved in evolution and must fulfil important functions. Functions for almost all genes were found by varying the conditions under which growth assays were conducted, supporting an alternative concept that most genes in single-celled eukaryotes contribute to survival only in specific environments (Hillenmeyer et al, 2008)

Methods

Results

Discussion

Conclusion