Dichotomy of single-nucleotide polymorphism haplotypes in olfactory receptor genes and pseudogenes

Substantial efforts are focused on identifying single-nucleotide polymorphi sms (SNPs) throughout the human genome, particularly in coding regions (cSN Ps), for both linkage disequilibrium and association studies(1,2). Less att ention, however, has been directed to the clarification of evolutionary pro cesses that are responsible for the variability in nucleotide diversity amo ng different regions of the genome(3). We report here the population sequen ce diversity of genomic segments within a 450-kb cluster(4,5) of olfactory receptor (OR) genes(6,7) on human chromosome 17. We found a dichotomy in th e pattern of nucleotide diversity between OR pseudogenes and introns on the one hand and the closely interspersed intact genes on the other. We sugges t that weak positive selection is responsible for the observed patterns of genetic variation. This is inferred from a lower ratio of polymorphism to d ivergence in genes compared with pseudogenes or introns, high non-synonymou s substitution rates in OR genes. and a small but significant overall reduc tion in variability in the entire OR gene cluster compared with other genom ic regions. The dichotomy among functionally different segments within a sh ort genomic distance requires high recombination rates within this OR clust er. Our work demonstrates the impact of weak positive selection on human nu cleotide diversity, and has implications for the evolution of the olfactory repertoire.