Genetic susceptibility, evolution and the kuru epidemic

Abstract

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.

Epidemiological mechanisms of genetic resistance to kuru

“…If the different villages that experienced the travelling wave at different times comprised individuals of different genotype frequencies prior to the epidemic, our conclusions would be affected. However, recent genotyping of young modern Fore and young individuals from the East Highland Papua New Guinea region that was not affected by kuru did not show a significant deviation from the 25/50/25% MM/MV/VV genotype frequency [16], suggesting that it was unlikely that there were differences in the genotype frequencies between villages initially. Additionally, there is evidence that the age of onset of kuru is strongly correlated with the probability that the patient is heterozygote [12,33].…”

“…genotypes was 50 per cent [16]. All genotype models described the kuru mortality incidence data equally well, yielding similar corrected Akaike information criteria (AICc) values.…”

“…Therefore, the genotype models could not be distinguished by the incidence data alone. However, these models could be distinguished in terms of their consistency with the population genetics data [16,33,34] (figure 2). The suite of eight models assumed resistance to kuru for heterozygotes or homozygotes manifested via either transmission rate (models Ti or Tii, respectively), or incubation period (Ii or Iii, respectively) or both mechanisms (Bi, Bii, Biii, Biv) with combinations of resistance/susceptibility for the heterozygotes and homozygotes.…”

Routes of Transmission in the Food Chain

“…Studies that examined the molecular genetic basis of susceptibility to kuru found that homozygotes for methionine at codon 129 were overrepresented in the younger age group, while valine homozygotes and heterozygotes were overrepresented in the much older age group, and survivors were almost never carried homozygotes for methionine at this position (Liberski, 2013). Heterozygosity at this codon was associated with older patients and with longer incubation times (Mead et al, 2008). It is thought that heterozygotes were protected from disease by the more difficult interactions between the protein heterodimers, while the homologous protein-protein interactions made homozygotes more susceptible to disease (Palmer et al, 1991).…”

Kuru: A Journey Back in Time from Papua New Guinea to the Neanderthals’ Extinction

“…At the beginning, it was demonstrated that 2 kuru cases were 129 Met Met [ 149 ]. Further studies found that individuals of 129 Val Val and 129 Met Val genotype were susceptible to kuru, but those of 129 Met Met genotype were overrepresented in the younger age group while those of 129 Val Val 129 Met Val were overrepresented in much older age group [ 53 , 95 , 150 , 151 , 152 , 153 ]. In contrast, those people who survived the epidemic were characterized by almost the total absence of 129 Met Met homozygotes.…”