Genetic variability and evolution of two pharmacologically important classes of genes.

Abstract

We have studied the human genetic variability of single nucleotide polymorphisms (SNPs) and haplotypes in two pharmaceutically important classes of genes that might be expected to experience different evolutionary pressures: antigen presentation and processing (APP) and nuclear hormone receptor (NHR) genes. We compared the variation pattern in these two classes of genes with 5119 reference (REF) genes. We assessed this variability by sequencing and discovering SNPs in 5'-upstream, 5'-untranslated region (5'UTR), exon, intron, 3'UTR and 3'-downstream regions of all these genes in 79 unrelated humans from diverse ethnic backgrounds, one chimpanzee (Pan troglodytes) and a gorilla (Gorilla gorilla). SNP density and nucleotide diversity were higher in the APP genes than the REF genes. Relative to the REF genes, APP SNP density was significantly higher in the coding and 3'UTR regions. Higher variation in the coding region of the APP genes was due specifically to having more non-synonymous changes, which suggests that natural selection may be acting to promote change or diversity in these proteins. In contrast, the NHR genes showed lower SNP density and diversity relative to REF genes. The NHR genes consistently showed lower nucleotide diversity in all the genomic regions except in the 3'downstream region. SNP frequency data on the non-synonymous SNPs also suggested that the coding region in the NHR genes is conserved to a higher degree than the coding region in the REF genes. Significantly lower SNP density was observed in the 5'-upstream and 5'UTR regions of the NHR genes, perhaps reflecting selective conservation of these regions. Heterozygosity in the APP genes was significantly higher than in the NHR genes in each of the three species tested. Moreover, between species there were more fixed differences in the APP genes than in the NHR genes. Substantial variability exists in these two classes of genes. It is important to consider this interindividual variability pattern while developing drugs that act on such targets.