Compromised Function of the Pancreatic Transcription Factor PDX1 in a Lineage of Desert Rodents

Abstract

Gerbils are a subfamily of rodents living in arid regions of Asia and Africa. Recent studies have shown that several gerbil species have unusual amino acid changes in the PDX1 protein, a homeodomain transcription factor essential for pancreatic development and β-cell function. These changes were linked to strong GC-bias in the genome that may be caused by GC-biased gene conversion, and it has been hypothesized that this caused accumulation of deleterious changes. Here we use two approaches to examine if the unusual changes are adaptive or deleterious. First, we compare PDX1 protein sequences between 38 rodents to test for association with habitat. We show the PDX1 homeodomain is almost totally conserved in rodents, apart from gerbils, regardless of habitat. Second, we use ectopic gene overexpression and gene editing in cell culture to compare functional properties of PDX1 proteins. We show that the divergent gerbil PDX1 protein inefficiently binds an insulin gene promoter and ineffectively regulates insulin expression in response to high glucose in rat cells. The protein has, however, retained the ability to regulate some other β-cell genes. We suggest that during the evolution of gerbils, the selection-blind process of biased gene conversion pushed fixation of mutations adversely affecting function of a normally conserved homeodomain protein. We argue these changes were not entirely adaptive and may be associated with metabolic disorders in gerbil species on high carbohydrate diets. This unusual pattern of molecular evolution could have had a constraining effect on habitat and diet choice in the gerbil lineage.