Balancing Selection at the Prion Protein Gene Consistent with Prehistoric Kurulike Epidemics

  title={Balancing Selection at the Prion Protein Gene Consistent with Prehistoric Kurulike Epidemics},
  author={Simon Mead and Michael P. H. Stumpf and J T Whitfield and Jonathan Beck and Mark Poulter and Tracy A. Campbell and James B. Uphill and David Goldstein and Michael P. Alpers and Elizabeth M. C. Fisher and John Collinge},
  pages={640 - 643}
Kuru is an acquired prion disease largely restricted to the Fore linguistic group of the Papua New Guinea Highlands, which was transmitted during endocannibalistic feasts. Heterozygosity for a common polymorphism in the human prion protein gene (PRNP) confers relative resistance to prion diseases. Elderly survivors of the kuru epidemic, who had multiple exposures at mortuary feasts, are, in marked contrast to younger unexposed Fore, predominantly PRNP 129 heterozygotes. Kuru imposed strong… 
Genetic susceptibility, evolution and the kuru epidemic
Kuru may have imposed the strongest episode of recent human balancing selection, which may not have been an isolated episode in human history.
A novel protective prion protein variant that colocalizes with kuru exposure.
Variants at codons 127 and 129 of PRNP demonstrate the population genetic response to an epidemic of prion disease and represent a powerful episode of recent selection in humans.
Epidemiological mechanisms of genetic resistance to kuru
A model that combines the dynamics of kuru transmission and the population genetics of human resistance indicates that human resistance arises from a combination of both a longer incubation period and reduced susceptibility to infection.
Prion genotypes in Central America suggest selection for the V129 allele
Using the well‐characterized, human diversity sample series, we show that the V129 prion allele has a very high frequency in South American populations relative to the East Asian populations from
Molecular evolution of the sheep prion protein gene
  • J. Slate
  • Biology
    Proceedings of the Royal Society B: Biological Sciences
  • 2005
The molecular evolution of PRNP in ruminants is examined and it is shown that variation in sheep appears to have been maintained by balancing selection, a profoundly different process from that seen in other ruminant.
Genotyping of PRNP coding region for scrapie in Indian sheep
Polymorphisms of the prion protein gene at the codons responsible for the susceptibility and resistance of the scrapie disease in the sheep are identified and absence of ARR allele in the Mandya sheep should be taken into consideration for the implementation of a preventive selection programme to avoid erosion of the genetic stock.
Negative Purifying Selection Drives Prion and Doppel Protein Evolution
Overall, the results clearly indicate that both proteins are under strong selective constraints with relaxed selection on amino acid residues connecting α-helices 1 and 2.
The prion protein gene in humans revisited: lessons from a worldwide resequencing study.
The analyses reveal the worldwide pattern of variation at the PRNP gene to be inconsistent with neutral expectations, indicating instead an excess of low-frequency variants, a footprint of the action of either positive or purifying selection.
Kuru: Genes, Cannibals and Neuropathology
Kuru was the first human transmissible spongiform encephalopathy or prion disease identified, occurring in the Fore linguistic group of Papua New Guinea, and formed a background against which the recent epidemics of iatrogenic and variant Creutzfeldt-Jakob disease could be studied.


Haplotype Diversity and Linkage Disequilibrium at Human G6PD: Recent Origin of Alleles That Confer Malarial Resistance
The hypothesis that malaria has had a major impact on humans only since the introduction of agriculture within the past 10,000 years is supported and the locus of “A−” and ”Med” mutations provides a striking example of the signature of selection on the human genome.
Prion protein gene variation among primates.
To examine the species barriers between non-human primates and humans, sequenced the open reading frames (ORF) of 25 PrP genes from apes and monkeys to suggest that codons between 90 and 130 have a profound influence on the transmissibility of prions from one species to another.
Phenotype-genotype studies in kuru: implications for new variant Creutzfeldt-Jakob disease.
If nvCJD behaves like kuru, future cases may begin to occur in older individuals with heterozygous codon 129 genotypes and signal a maturing evolution of the nv CJD "epidemic," which may have less (or at least less readily identified) amyloid plaque formation.
Sporadic--but not variant--Creutzfeldt-Jakob disease is associated with polymorphisms upstream of PRNP exon 1.
A quantitative-trait-locus study of prion incubation periods in mice has demonstrated an important factor that is close to Prnp but is independent of its coding sequence or that of the nearby prion-like doppel gene (Prnd), and analyzed the PRNP locus for such tightly linked susceptibility factors.
Homozygous prion protein genotype predisposes to sporadic Creutzfeldt–Jakob disease
It is argued that homozygosity predisposes towards sporadic CJD and that this directly supports the hypothesis that interaction between prion protein molecules underlies the disease process.
Codon 219 lys allele of PRNP is not found in sporadic Creutzfeldt‐Jakob disease
The codon 219Glu/Lys heterozygous polymorphism might be uniquely excluded from sporadic CJD, as it was found in the general Japanese population with 6% allele frequency.
Species-barrier-independent prion replication in apparently resistant species.
The existence of subclinical forms of prion infection with important public health implications are demonstrated, both with respect to iatrogenic transmission from apparently healthy humans and dietary exposure to cattle and other species exposed to bovine spongiform encephalopathy prions.
Genetic perspectives on human origins and differentiation.
The issue of whether or not a population size bottleneck occurred among the authors' ancestors is under debate among geneticists as well as among anthropologists, and the Garden of Eden model of the origin of modern humans is confirmed.
Novel proteinaceous infectious particles cause scrapie.
A new term "prion" is proposed to denote a small proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids.