Concurrent action of purifying selection and gene conversion results in extreme conservation of the major stress-inducible Hsp70 genes in mammals

Several evolutionary mechanisms alter the fate of mutations and genes within populations based on their exhibited functional effects. To understand the underlying mechanisms involved in the evolution of the cellular stress response, a very conserved mechanism in the course of organismal evolution, we studied the patterns of natural genetic variation and functional consequences of polymorphisms of two stress-inducible Hsp70 genes. These genes, HSPA1A and HSPA1B, are major orchestrators of the cellular stress response and are associated with several human diseases. Our phylogenetic analyses revealed that the duplication of HSPA1A and HSPA1B originated in a lineage proceeding to placental mammals, and henceforth they remained in conserved synteny. Additionally, analyses of synonymous and non-synonymous changes suggest that purifying selection shaped the HSPA1 gene diversification, while gene conversion resulted in high sequence conservation within species. In the human HSPA1-cluster, the vast majority of mutations are synonymous and specific genic regions are devoid of mutations. Furthermore, functional characterization of several human polymorphisms revealed subtle differences in HSPA1A stability and intracellular localization. Collectively, the observable patterns of HSPA1A-1B variation describe an evolutionary pattern, in which purifying selection and gene conversion act simultaneously and conserve a major orchestrator of the cellular stress response.