For decades, the origin of the deadliest of the four Plasmodium parasites that cause malaria has been an enigma.

One view is that P. falciparum has been the constant nemesis of humans and their early ancestors for millions of years.

But DNA evidence hinted that, like the viral agents of SARS and AIDS, it might be a relatively recent recruit to the ranks of human pathogens, possibly a fly-by-night scion of Plasmodium gallinaceum, acquired from the wild ancestor of modern chickens, the red jungle fowl, Gallus gallus, somewhere in Asia in the past 8000 years.

Dr Toby Sargeant, a member Professor Terry Speed’s bioinformatics research group at WEHI, has effectively eliminated P. gallinaceum as the progenitor of P. falciparum.

Sargeant’s powerful new statistical techniques for retracing evolutionary relationships between taxa hints that the host-switch may been in the opposite direction: the avian clade, including P. gallinaceum, may have been founded by a Plasmodium species that evolved in primates.

Plasmodium does have an ability to host-switch. Occasional cases of presumed P. malariae infection in Malaysia have recently been reassigned to a non-lethal Plasmodium species that infects rhesus macaques, P. knowlesii.

Malaria’s vertebrate hosts are an oddly eclectic lot: some 200 Plasmodium species form clades that specialise in parasitising rodents, birds, reptiles, and primates; two clades are primate specialists, infecting taxa as diverse as lemurs, macaques, gibbons, tamarins, and all the African and Asian great apes, including humans. Most infect more than one host species.

“If you look at the hosts’ phylogeny, there are large gaps that don’t appear to have been filled,” Sargeant says. “Ancient host-switching events seem to have been involved.

“Over the past 20 years, two questions remained unresolved. One was whether the two primate-infecting clades are closely or distantly related. Another is how the avian and reptilian malarias are related to the falciparum clade. My approach was to bring to bear as much data as possible to resolve that phylogeny.”

Sargeant began by analysing protein domains: short amino acid sequences that fold into evolutionarily conserved 3-D configurations.

“It’s not easy to say a particular gene in one species is the same as one present in another species,” he says. “You simplify the problem by looking at protein domains, for which the evolutionary origin is simpler to ascertain.

“The assumption underlying all these phylogenetic methods is that the triplet codons for amino acids are incompletely constrained, which allows changes to accumulate almost at random.

“So as related species accumulate unshared differences, we can use the relative differences to get an idea of how distantly related they are. The good thing about protein domains is that they tend to be constrained by function, so they change slowly relative to the DNA sequences that encode them.