One position in one gene dominates susceptibility to every form of human prion disease — and the reason it is still common is that a Papua New Guinean epidemic spread by eating the dead selected against both homozygotes.
Prion diseases are caused by a protein that misfolds and then persuades other copies of itself to misfold the same way. There is no genetic material in the infectious agent at all. Creutzfeldt–Jakob disease is the human form: rapidly progressive dementia with movement disorder, and invariably fatal.
It arrives in three ways. Most cases are sporadic, with no identified cause. A minority are inherited, from mutations in PRNP itself. A small number were acquired — from contaminated surgical instruments or human growth hormone, or, in the variant form, from eating beef from cattle with BSE.
rs1799990 is PRNP codon 129, where the protein carries either methionine or valine. It is not rare, it is not a mutation, and everyone has two copies of something here.
A genome-wide study of variant CJD, replicated across 929 samples spanning every category of human prion disease against 4,254 controls from the UK and Papua New Guinea, found PRNP strongly associated with risk across all of them. The best single-SNP association in variant CJD reached p = 2.5 × 10⁻¹⁷, and the best haplotypic association p = 1 × 10⁻²⁴. The main contribution came from codon 129.
Being heterozygous — one methionine, one valine — confers relative resistance. Homozygotes at either letter are more susceptible. The mechanism is intuitive for once: misfolding propagates most efficiently between identical molecules, and a mixed pair is a worse template.
This is where the subject stops being ordinary genetics.
Kuru was a prion disease largely confined to the Fore people of the Papua New Guinea Highlands, transmitted at mortuary feasts where the dead were eaten. It killed on an epidemic scale in the twentieth century.
Elderly survivors of that epidemic — people with multiple exposures at those feasts — are predominantly codon 129 heterozygotes, in marked contrast to younger, unexposed Fore. Kuru imposed strong balancing selection on that population, essentially eliminating the homozygotes.
And the pattern is not confined to them: worldwide PRNP haplotype diversity and coding allele frequencies suggest strong balancing selection at this locus during the evolution of modern humans.
The straightforward reading of that is uncomfortable and is what the authors wrote: something like kuru happened before, more than once, widely enough to leave a mark on the whole species.
Beyond PRNP, a position upstream of RARB — the retinoic acid receptor beta gene — reached nominal genome-wide significance (p = 1.9 × 10⁻⁷), and retinoic acid regulates prion protein expression in cultured cells. A region upstream of STMN2 was associated with acquired prion disease, with kuru incubation time, and with resistance to kuru.
Those are leads rather than conclusions, and the paper says so.
In practice, for almost everyone: nothing you can act on.
Prion disease is extraordinarily rare. Being homozygous at codon 129 is common — a large share of the population is — and the overwhelming majority of those people will never encounter a prion. Susceptibility to an exposure you will not have is not a risk you can do anything about.
There is no preventive treatment, no screening programme, and no clinical use for this genotype in an asymptomatic person. What it is genuinely useful for is understanding: it explains why an epidemic of a fatal disease with no DNA left a signature in the human genome.
Sources. Mead et al. (Lancet Neurol 2009) conducted a genome-wide association study of variant CJD risk with replication across 929 samples covering many categories of human prion disease and 4,254 control samples from the UK and Papua New Guinea, including UK controls genotyped by the Wellcome Trust Case Control Consortium. The PRNP locus was strongly associated with risk across several markers and all categories of prion disease (best single SNP in vCJD p = 2.5 × 10⁻¹⁷; best haplotypic association p = 1 × 10⁻²⁴), with the main contribution conferred by polymorphic codon 129 and an additional nearby SNP conferring increased vCJD risk. An SNP upstream of RARB reached nominal genome-wide significance (p = 1.9 × 10⁻⁷), with a similar association in a small iatrogenic CJD sample (p = 0.030) but not in sporadic CJD or kuru; a region upstream of STMN2 was associated with acquired prion disease (vCJD p = 5.6 × 10⁻⁵), kuru incubation time (p = 0.017) and resistance to kuru (p = 2.5 × 10⁻⁴), and Stmn2 expression fell 30-fold after infection in a mouse cellular model.
Balancing selection. Mead et al. (Science 2003) reported that elderly survivors of the kuru epidemic with multiple exposures at mortuary feasts are predominantly PRNP 129 heterozygotes, in marked contrast to younger unexposed Fore, and concluded that kuru imposed strong balancing selection essentially eliminating 129 homozygotes. Worldwide PRNP haplotype diversity and coding allele frequencies were interpreted as evidence of strong balancing selection at this locus during the evolution of modern humans.
Position listed here. rs1799990, PRNP codon 129 (M129V).
Clinical use. Codon 129 genotype has no established role in the assessment of an asymptomatic person. Sporadic CJD is diagnosed clinically with support from MRI, EEG and CSF markers including RT-QuIC; inherited prion disease is diagnosed by PRNP sequencing in the appropriate clinical context, which is a different test from a codon 129 genotype and is done through clinical genetics. There is no disease-modifying therapy.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Creutzfeldt–Jakob Disease and Prion Disease comes down to these specific, well-studied positions — not a diagnosis.
No, in any practical sense. Homozygosity is common, prion disease is extraordinarily rare, and susceptibility to an exposure you are almost certainly never going to have is not a risk you can act on. There is no screening and no preventive treatment.
Because heterozygotes are the resistant ones, and selection that favours heterozygotes keeps both alleles in a population rather than removing either. Kuru did this visibly to the Fore within living memory, and the worldwide pattern of PRNP diversity suggests it happened before, during the evolution of modern humans.
No, and the distinction matters. Inherited prion disease is caused by pathogenic mutations in PRNP and is found by sequencing the gene, through clinical genetics, usually because of a family history. Codon 129 is a common polymorphism that everybody has a version of. A consumer file showing your codon 129 letters has not tested you for inherited prion disease.
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