The acquired
prion disease kuru was restricted to the Fore and neighbouring linguistic groups of the Papua New Guinea highlands and largely affected children and adult women. Oral history documents the onset of the epidemic in the early twentieth century, followed by a peak in the mid-twentieth century and subsequently a well-documented decline in frequency. In the context of these strong associations (gender, region and time), we have considered the genetic factors associated with susceptibility and resistance to
kuru. Heterozygosity at
codon 129 of the human
prion protein gene (PRNP) is known to confer relative resistance to both sporadic and acquired
prion diseases. In
kuru, heterozygosity is associated with older patients and longer incubation times. Elderly survivors of the
kuru epidemic, who had multiple exposures at mortuary feasts, are predominantly PRNP
codon 129 heterozygotes and this group show marked Hardy-Weinberg disequilibrium. The deviation from Hardy-Weinberg equilibrium is most marked in elderly women, but is also significant in a slightly younger cohort of men, consistent with their exposure to
kuru as boys. Young Fore and the elderly from populations with no history of
kuru show Hardy-Weinberg equilibrium. An increasing cline in 129V allele frequency centres on the
kuru region, consistent with the effect of selection in elevating the frequency of resistant genotypes in the exposed population. The genetic data are thus strikingly correlated with exposure. Considering the strong coding sequence conservation of primate
prion protein genes, the number of global coding polymorphisms in man is surprising. By intronic resequencing in a European population, we have shown that haplotype diversity at PRNP comprises two major and divergent clades associated with 129M and 129V.
Kuru may have imposed the strongest episode of recent human balancing selection, which may not have been an isolated episode in human history.