A heterozygote advantage.

Abstract

The evidence for balancing selection at the prion protein gene ( PRNP ) due to kuru in the Fore group of the Papua New Guinea Highlands is compelling (“Balancing selection at the prion protein gene consistent with prehistoric kurulike epidemics,” S. Mead et al. , Reports, 25 April, p. [640][1]). That is, their analysis of worldwide haplotype diversity and sequence analysis demonstrates that the major alleles at the PRNP locus are maintained by selective factors favoring the maintenance of heterozygotes. In addition, the extent of the “heterozygote advantage” in the Fore in terms of their viability in the present generation can be calculated from Mead et al. 's genotypic data (provided by S. Mead). In 30 women over the age of 50 that had a history of multiple exposures to mortuary feasts, 4 were homozygous MM , 23 were heterozygous MV , and 3 were homozygous VV ( M and V indicate methonine and valine at position 129), a large deviation from Hardy-Weinberg proportions. In another sample of unexposed Fore individuals, the genotypes were in Hardy-Weinberg proportions (31 MM , 72 MV , and 37 VV ). Using these two groups as the frequencies of the genotypes after (indicated by primes below) and before selection, the viability of genotype MM relative to genotype MV can be estimated ([1][2]) as VMM = ( P' MMPMV )/( P' MVPMM ) = (0.133)(0.514)/(0.767)(0.221) = 0.403, and the viability of genotype VV relative to genotype MV can be estimated as VVV = ( P' VVPMV )/( P' MVPVV ) = (0.100)(0.514)/(0.767)(0.264) = 0.254. In other words, the relative viabilities of the genotypes MM , MV , and VV are 0.403, 1.0, and 0.254, respectively, a very strong heterozygote advantage in the face of kuru. Because adult males participated little at feasts, this heterozygote advantage acts primarily in females. Therefore, the average selection coefficient ( s = 1 − V ) against MM homozygotes is approximately- sMM = (1 − VMM )/2 = 0.299, and against VV homozygotes, it is − sVV = (1 − VVV )/2 = 0.373. The expected equilibrium frequency of the V allele is therefore qV = − sMM /(− sMM + − sVV ) = 0.45, not very different from the observed frequency of 0.55. Although it is not known whether selection has been this strong in previous generations, the strength of balancing selection in this one generation appears to be the strongest yet documented in any human population. 1. 1.[↵][3] 1. P. W. Hedrick , Genetics of Populations, ed. 2 (Jones & Bartlett, Boston, 2000). [1]: /lookup/doi/10.1126/science.1083320 [2]: #ref-1 [3]: #xref-ref-1-1 View reference 1. in text