Genetic susceptibility, evolution and the kuru epidemic.

Area of Science:

• Neuroscience
• Genetics
• Anthropology

Background:

• Kuru, an acquired prion disease, primarily affected Fore and neighboring groups in Papua New Guinea, with documented incidence peaks and declines.
• Strong associations between kuru and gender, region, and time prompted an investigation into genetic susceptibility factors.

Purpose of the Study:

• To investigate genetic factors influencing susceptibility and resistance to kuru.
• To analyze the role of prion protein gene (PRNP) codon 129 polymorphisms in kuru.
• To explore evidence of natural selection related to kuru exposure.

Main Methods:

• Analysis of PRNP codon 129 genotypes in kuru-affected individuals and control populations.
• Assessment of Hardy-Weinberg equilibrium in relation to kuru exposure and demographics.
• Examination of allele frequency clines for PRNP codon 129 variants.
• Intronic resequencing of the PRNP gene in a European population.

Main Results:

• PRNP codon 129 heterozygosity was associated with older kuru patients and longer incubation periods.
• Elderly kuru survivors, predominantly heterozygotes, exhibited significant Hardy-Weinberg disequilibrium.
• A cline in 129V allele frequency centered on the kuru region indicated selection.
• Haplotype diversity at PRNP revealed two major clades associated with 129M and 129V alleles.

Conclusions:

• Genetic data strongly correlate with kuru exposure, particularly PRNP codon 129 heterozygosity conferring resistance.
• Kuru likely represents a significant episode of recent human balancing selection.
• Balancing selection at the PRNP locus may have occurred multiple times in human history.