A population threshold for functional polymorphisms
Wong, GKS; Yang, ZY; Passey, DA; Kibukawa, M; Paddock, M; Liu, CR; Bolund, L; Yu, J
We sequenced 114 genes (for DNA repair, cell cycle arrest, apoptosis, and detoxification) in a mixed human population and observed a sudden increase in the number of functional polymorphisms below a minor allele frequency of similar to6%. Functionality is assessed by considering the ratio in the number of nonsynonymous single nucletide polymorphisms (SNPs) to the number of synonymous or intron SNPs. This ratio is steady from below 1% in frequency-that regime traditionally associated with rare Mendelian diseases-all the way up to about 6% ill frequency, after which it falls precipitously. We consider possible explanations for this threshold effect. There are four candidates as follows: (1) deleterious variants that have yet to be purified from the Population, (2) balancing selection, in which a selective advantage accrues to the heterozygotes, (3) population-specific functional polymorphisms, and (4) adaptive variants that are accumulating in the population as a response to the dramatic environmental changes of the last 7,000similar to17,000 years.