Giant island mice exhibit widespread gene expression changes in key metabolic organs

Abstract

Island populations repeatedly evolve extreme body sizes, but the genomic basis of this pattern remains largely unknown. To understand how organisms on islands evolve gigantism, we compared genome-wide patterns of gene expression in Gough Islandmice, the largestwild housemice in theworld, andmainlandmice fromtheWSB/EiJwild-derived inbred strain.We used RNA-seq to quantify differential gene expression in three keymetabolic organs: Gonadal adipose depot, hypothalamus, and liver. Between 4,000 and 8,800 genes were significantly differentially expressed across the evaluated organs, representing between 20% and 50% of detected transcripts, with 20% or more of differentially expressed transcripts in each organ exhibiting expression fold changes of at least 2x.Aminimumof 73 candidate genes for extreme size evolution, including Irs1 and Lrp1, were identified by considering differential expression jointly with other data sets: 1) genomic positions of published quantitative trait loci for body weight and growth rate, 2) whole-genome sequencing of 16 wild-caught Gough Island mice that revealed fixed single-nucleotide differences between the strains, and 3) publicly available tissue-specific regulatory elements. Additionally,patternsof differential expression across three time points inthe liver revealed thatArid5b potentially regulateshundreds of genes. Functional enrichment analyses pointed to cell cycling,mitochondrial function, signaling pathways, inflammatory response, and nutrient metabolism as potential causes of weight accumulation in Gough Island mice. Collectively, our results indicate that extensive gene regulatory evolution inmetabolic organs accompanied the rapid evolution of gigantismduring the short time house mice have inhabited Gough Island.