Significance A core question in evolutionary biology is how mutation and selection adapt and constrain species to specialized habitats. We sequenced the genome of the sand rat, a desert rodent susceptible to nutritionally induced diabetes, and discovered an unusual chromosome region skewed toward G and C nucleotides. This region includes the Pdx1 homeobox gene, a transcriptional activator of insulin , which has undergone massive sequence change, likely contributing to diabetes and adaptation to low caloric intake. Our results imply that mutation rate varies within a genome and that hotspots of high mutation rate may influence ecological adaptation and constraint. In addition, we caution that divergent regions can be omitted by conventional short-read sequencing approaches, a consideration for existing and future genome sequencing projects.