Genome sequence of a diabetes-prone rodent reveals a mutation hotspot around the ParaHox gene cluster

Abstract

The sand rat Psammomys obesus is a gerbil species native to deserts of North Africa and the Middle East, and is constrained in its ecology because high carbohydrate diets induce obesity and type II diabetes that, in extreme cases, can lead to pancreatic failure and death. We report the sequencing of the sand rat genome and discovery of an unusual, extensive, and mutationally biased GC-rich genomic domain. This highly divergent genomic region encompasses several functionally essential genes, and spans the ParaHox cluster which includes the insulin-regulating homeobox gene Pdx1. The sequence of sand rat Pdx1 has been grossly affected by GC-biased mutation, leading to the highest divergence observed for this gene across the Bilateria. In addition to genomic insights into restricted caloric intake in a desert species, the discovery of a localized chromosomal region subject to elevated mutation suggests that mutational heterogeneity within genomes could influence the course of evolution.

Keywords: Pdx1; desert rodent; gene conversion; homeobox; type 2 diabetes.

Fig. 1.

The sand rat and its genomic hotspot of mutation. (A) Juvenile sand rat P. obesus. (B) Cladogram of representative murid rodents indicating the phylogenetic position of sand rat. (C) GC content of genes around the ParaHox cluster of sand rat and other rodents (Mus musculus, Rattus norvegicus, Chinchilla lanigera) revealing a chromosomal hotspot of GC skew in sand rat (shaded in gray). Genes shown in inferred ancestral gene order; parentheses around Rfc3 indicate this gene has been transposed to a different genomic location in sand rat. Sand rat GC values based on transcriptome and genome sequences; when partial only alignable sequence is compared. (D) Unrooted phylogenetic trees inferred from synonymous changes (dS) only from concatenated alignments of 26 genes in the mutational hotspot (Upper) and 100 random genes (Lower).

Fig. 2.

Molecular divergence of sand rat Pdx1. (A) Alignment of Pdx1 hexapeptide domain and homeodomain sequences across vertebrates. (B) Maximum likelihood tree of ParaHox proteins showing divergent P. obesus Pdx1; species included are sand rat, mouse, zebra finch, spotted gar, amphioxus (full tree in SI Appendix, Fig. S6). (C) Histogram of PDI values for 1:1:1 mammalian orthologs of the sand rat predicted proteins: Pdx1 is marked by an arrow, other genes within the GC-rich region are marked by arrowheads.

Fig. 3.

Molecular modeling of sand rat Pdx1 binding. (A) Molecular model of sand rat Pdx1 homeodomain bound to DNA. The two amino acid changes indicated are the largest contributors to altered enthalpy of binding. (B) Probability distributions of the enthalpy of binding of homeodomain protein–DNA interactions among hamster (normal vertebrate) Pdx1/mouse insulin A1 DNA element (black), sand rat Pdx1/sand rat A1 element (red), hamster Pdx1/sand rat A1 (green), and sand rat Pdx1/mouse A1 (blue) inferred by molecular dynamics simulations and MM-PBSA; sand rat Pdx1 homeodomain has the lowest enthalpy of binding (higher affinity) for each DNA target. (C) Per-site enthalpy of binding comparison between hamster and sand rat Pdx1 revealing contribution of amino acid changes at homeodomain positions 13 and 36 to reduced enthalpy of binding (higher affinity).