Adaptive Evolution of the Insulin Two-Gene System in Mouse

Meng-Shin Shiao^*^,^,1, Ben-Yang Liao^*^,3, Manyuan Long^,2 and Hon-Tsen Yu^*^,2^,4

^* Institute of Zoology and Department of Life Science, National Taiwan University, Taipei 106, Taiwan, Republic of China and Department of Ecology and Evolution, University of Chicago, Chicago, Illinois 60637

^⁴ Corresponding author: Institute of Zoology and Department of Life Science, National Taiwan University, Taipei 106, Taiwan, Republic of China.
E-mail: ayu{at}ntu.edu.tw

Insulin genes in mouse and rat compose a two-gene system inwhich Ins1 was retroposed from the partially processed mRNAof Ins2. When Ins1 originated and how it was retained in genomesstill remain interesting problems. In this study, we used genomicapproaches to detect insulin gene copy number variation in rodentspecies and investigated evolutionary forces acting on bothIns1 and Ins2. We characterized the phylogenetic distributionof the new insulin gene (Ins1) by Southern analyses and confirmedby sequencing insulin genes in the rodent genomes. The resultsdemonstrate that Ins1 originated right before the mouse–ratsplit ( $~$ 20 MYA), and both Ins1 and Ins2 are under strong functionalconstraints in these murine species. Interestingly, by examininga range of nucleotide polymorphisms, we detected positive selectionacting on both Ins2 and Ins1 gene regions in the Mus musculusdomesticus populations. Furthermore, three amino acid siteswere also identified as having evolved under positive selectionin two insulin peptides: two are in the signal peptide and oneis in the C-peptide. Our data suggest an adaptive divergencein the mouse insulin two-gene system, which may result fromthe response to environmental change caused by the rise of agriculturalcivilization, as proposed by the thrifty-genotype hypothesis.