Genomes of all known members of a Plasmodium subgenus reveal paths to virulent human malaria

Abstract

Plasmodium falciparum, the most virulent agent of human malaria, shares a recent 25 common ancestor with the gorilla parasite P. praefalciparum. Little is known about the other gorilla 26 and chimpanzee-infecting species in the same (Laverania) subgenus as P. falciparum but none of 27 them are capable of establishing repeated infection and transmission in humans. To elucidate 28 underlying mechanisms and the evolutionary history of this subgenus, we have generated multiple 29 genomes from all known Laverania species. The completeness of our dataset allows us to conclude 30 that interspecific gene transfers as well as convergent evolution were important in the evolution of 31 these species. Striking copy number and structural variations were observed within gene families 32 and one, stevor shows a host specific sequence pattern. The complete genome sequence of the 33 closest ancestor of P. falciparum enables us to estimate confidently for the first time the timing of 34 the beginning of speciation to be 40,000-60,000 years ago followed by a population bottleneck 35 around 4,000-6,000 years ago. Our data allow us also to search in detail for the features of P. 36 falciparum that made it the only member of the Laverania able to infect and spread in humans. 37 39Main Text: 40The evolutionary history of Plasmodium falciparum, the most common and deadliest human 41 malaria parasite, has been the subject of uncertainty and debate 1,2 . Recently it has become clear that 42 P. falciparum is derived from a group of parasites infecting African Great Apes and known as the 43Laverania subgenus 2 . Until 2009, the only other species known in this subgenus was a parasite of 44 chimpanzees known as P. reichenowi, for which only one isolate was available 3 . It is now clear that 45 there are a total of at least seven species in Great Apes that naturally infect chimpanzees (P. gaboni, 46 P. billcollinsi and P. reichenowi), gorillas (P. praefalciparum, P. blacklocki and P. adleri) 4,5 , or 47 humans (P. falciparum) ( Fig. 1a). Within this group, P. falciparum is the only parasite that has 48 successfully adapted to humans after a transfer from gorillas and subsequently spread all over the 49 world 2 . 50Over time there have been various estimates concerning the evolutionary history of P. 51 falciparum with the speciation event having been estimated to be anywhere between 10,000 to 5.5 52 million years ago, the latter falsely based on the date of the chimpanzee-human split 6,7 . Others 53 report a bottleneck less than 10,000 years ago 8 , but suggest a drop to a single progenitor parasite. 54The latter seems unlikely due to the presence of allelic dimorphisms that predate speciation events 55 and therefore could not have both been transmitted if a new species were founded by a single 56 individual infection. Also, the dating of the speciation cannot be accurately estimated without the 57 genome sequence of P. praefalciparum, the closest living sister species to P. falciparum. 58The absence of in vitro culture or a usable animal mode...

Molecular interactions governing host-specificity of blood stage malaria parasites

“…Recently, non-invasive sampling of non-human primate fecal samples from across equatorial Africa has revealed that the origin of P. falciparum is traceable to a sub-genus of African great ape malaria parasites, known as the Laverania [5,6] (Figure 1). Global P. falciparum isolates form a monophyletic clade embedded within the diversity of P. praefalciparum , strongly suggesting that this pandemic resulted from a single gorilla to-human cross-species transmission event [5], which occurred ~50,000 years ago [23], coinciding with the expansion of humans out of Africa.…”

“…For example, it is conceivable that while Rh5-BSG forms the foundation for Laveranian host tropism, invasion is enhanced by other receptor-ligand interactions. The recently sequenced genomes of the ape Laverania [23,35] are likely to offer additional insights. In particular, the hypothesis that pseudogenization of the Pf Rh3 and Pf EBA165 ligands and/or duplication of Pf Rh2 were necessary prerequisites for expression of alternative, human-permissive invasion pathways warrants further investigation.…”

Plasmodium vivax-like genome sequences shed new insights into Plasmodium vivax biology and evolution

“…Among the eleven samples, ten presented mixed infections with other Plasmodium species ( Supplementary Table 1). Four samples containing P. gaboni or P. malariae-like co-infections were used in other studies (see Supplementary Table 1) 13,14 . In order to obtain the P. vivax-like genotypes, sequencing reads were extracted based on their similarity to the reference genome sequence of P. vivax, PvP01 15 .…”

“…G-PhoCS uses a Bayesian MCMC approach to infer, based on the information provided by multiple loci, the divergence time between species. This method has been applied in two recent studies for Plasmodium parasites: one aiming at estimating the relative split times between the two P. ovale sub-species and between P. malariae and P. malariae-like 14 ; the other to estimate the divergence time within the Laverania subgenus, a subgenus including P. falciparum and all its closest aperelatives 13 . The Silva method is based on the estimate of the sequence divergence in different proteins and comparison of this divergence measured between different lineages 29 .…”

Natural selection contributed to immunological differences between human hunter-gatherers and agriculturalists

“…Agriculturalists and pastoralists also lived in proximity with their domesticated animals, providing opportunity for novel or expanded zoonotic transmission 4 of pathogens potentially including rotavirus, measles virus, and influenza [9][10][11] . Finally, agriculturists performed extensive modifications to the landscape, including clearing fields and constructing irrigation systems, which may have led to an increase in the incidence of vector-borne diseases, such as Plasmodium falciparum malaria 12,13 .…”