Step-wise analysis of polymorphisms in the human dopamine D2 receptor gene

Evolutionary analysis of neurotransmitter receptor systems has previously focused on interspecies differentiation. Recently, emphasis has shifted to intragenic evolution within a single species and the functional relevance associated with intraspecies variations. For example, multiple polymorphisms have been identified within the human dopamine D2 receptor (DRD2) gene, many of which have been used in clinical association studies. In an attempt to evaluate the intragenic evolution of the DRD2 gene, genotypes from 116 humans were determined using five biallelic markers which reside within a 30 kb span of the DRD2 gene, that are non-polymorphic in other higher order primates. Only seven different haplotypes, out of a theoretical maximum of 32, were present in the study group of 232 chromosomes. Moreover, five of the seven haplotypes accounted for 99% (n = 230/232) of the human haplotypes. A phylogenetic tree was generated from the haplotypic data using a maximum parsimony algorithm. The relationship of the haplotypes within the phylogenetic tree is consistent with a progressive step-wise nucleotide conversion within the human gene. These data indicate that specific haplotypic subtypes of the human DRD2 gene exist within the human population and allow for the possibility that functional differences may exist between the DRD2 subtypes. Therefore, future studies focused on a functional analysis of the entire human DRD2 haplotype, as opposed to individual polymorphisms, may provide important insights into the functional relevance of molecular variations within the human DRD2 gene.