Sequencing for Malaria Diversity

RESEARCH HIGHLIGHTS PATHOGEN GENOMICS the data by clustering the cells according to transcriptome similarity showed clusters of distinct cell Sequencing for malaria diversity states representing the different life-cycle stages, as well as transitions The advancing capabilities and barriers, different genetic ancestries of between various stages. For example, reduced costs of sequencing human hosts and different species the intra-erythrocytic developmental de novo technologies are enabling a deeper of Anopheles mosquito vectors, as cycle (IDC) indeed formed a appreciation of the genotypic and well as wider climate differences. artemisinin ring shape in the displayed data, phenotypic variability of infectious One major motivation for representing all cell stages and their resistance disease pathogens. Two new studies P. falciparum genomic analyses transition states. alleles in the in Science survey diversity in malarial is to monitor the emergence of Beyond illustrating the diversity Plasmodium species, assessing antimalarial drug resistance, pfap2mu gene of cell states, the transcriptome data genetic diversity across Africa, as well especially in response to recent in Ghana and expanded the range of genes that as transcriptomic diversity through interventions with modern drugs are known to be upregulated at key Malawi the pathogen life cycle. such as artemisinin. The sequencing life-cycle stages, such as host liver cell In their study, Amambua-Ngwa data enabled a genome-wide view invasion. As ~40% of Plasmodium et al. carried out whole-genome of loci under recent selection. genes are still of unknown function, sequencing of 2,263 isolates of The authors searched for ‘identical- these data may assist in assigning Plasmodium falciparum, which is a by-descent’ regions, which are gene functions and increasing the single-celled protozoan that is the regions showing a significant lack of number of potential targets for cause of the most lethal form of recombination (which is otherwise therapeutic intervention. malaria. Samples were collected from rife throughout the P. falciparum The authors further enhanced the 15 countries across sub-Saharan genome) and is indicative of positive cell atlas with data from additional Africa, spanning the entire continent selection retaining intact alleles. models and RNA-seq technologies. from west-to-east, as well as the It is widely thought that the main They characterized P. falciparum island of Madagascar. threat for developing artemisinin and Plasmodium knowlesi cultured Analysis of genetic diversity was resistance in Africa is through spread in human blood to capture the largely consistent with the model of existing resistance alleles from IDC stages. Overall, 15,858 cells of human-infectious P. falciparum Southeast Asia. However, the authors were processed by droplet-based originating from a great-ape-tropic found likely de novo artemisinin scRNA-seq technology, which offers P. falciparum species that crossed into resistance alleles in the pfap2mu gene lower transcriptomic depth but humans ~10,000 years ago in central in Ghana and Malawi. This finding increased cellular throughput at Africa, as ancestral genome segments indicates that African-origin artemis- lower cost than Smart-seq2. of likely central African origin inin resistance is possible and that the Finally, as support that the atlas were found to contribute to derived prevalence and spread of such alleles has wide applicability, including P. falciparum populations throughout should be closely monitored. clini cally, the team showed that the continent. In a separate study, Howick, samples from three infected humans However, clustering analysis Russell et al. used single-cell RNA in Kenya could be preserved locally, showed that populations were not sequencing (scRNA-seq) as part of a then subsequently processed and continuous throughout Africa: six Malaria Cell Atlas project. Cell Atlas mapped onto the atlas to reveal the population subgroups localized to approaches have typically been applied cellular transcriptional diversity particular geographical regions. to analyse intercellular pheno typic in natural infections, including a Reasons for this population diversity across multicellular organ- mixed-species infection in one stratification are likely to be isms, but here the authors applied of the donors. multifactorial, including geographical it to characterize the diversity of These studies thus provide Plasmodium parasites during the valuable resources for the malaria complex life cycle stages between community to further understand mosquitoes and mammalian hosts. pathogen diversity. They initially used a mosquito and mouse model of Plasmodium berghei Darren J. Burgess infection sampled throughout the life ORIGINAL ARTICLES Amambua-Ngwa, A. et al. Major subpopulations of Plasmodium falciparum in cycle and generated 1,787 single-cell sub-Saharan Africa. Science 365, 813–816 (2019) | transcriptomes using a Smart-seq2 Howick, V. M. et al. The Malaria Cell Atlas: single scRNA-seq protocol adapted for parasite transcriptomes across the complete Plasmodium life cycle. Science 365, eaaw2619 (2019) Credit: Sebastian Kaulitzki/Alamy Plasmodium RNAs. Visualizing NATURE REVIEWS | GENETICS VOLUME 20 | NOVEMBER 2019 | 629.

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