GSE135007
Giant island mice exhibit widespread gene regulatory evolution in key metabolic organs
Background: Island populations repeatedly evolve extreme body sizes, but the genomic basis of this morphological pattern remains largely unknown. To understand how organisms on islands evolve gigantism, we compared genome-wide patterns of gene expression in Gough Island mice, the largest wild house mice in the world, and mice from the WSB/EiJ wild-derived inbred strain. In a highly replicated experiment, we used RNASeq to quantify differences in gene expression in three key metabolic organs:  gonadal adipose depot, hypothalamus, and liver. Results: We discovered pervasive evidence of transcriptional evolution, with 20% or more of differentially regulated transcripts in each organ exhibiting expression fold changes of at least 2X. By considering differential expression jointly with the genomic positions of quantitative trait loci for body size and single nucleotide differences located within established tissue-specific regulatory elements, we nominated 66 candidate genes for extreme size evolution, including Irs1 and Lrp1. Patterns of differential expression across three developmental time points in the liver revealed that Arid5b potentially regulates tens of co-regulated gene groups. Functional enrichment analyses on thousands of differentially expressed genes pointed to cell cycling, mitochondrial function, signaling pathways, immune reactivity, and nutrient metabolism as potential causes of weight accumulation in Gough Island mice. Conclusion: Collectively, our results suggest that extensive regulatory evolution in metabolic organs contributed to the rapid evolution of gigantism during the short time house mice have inhabited Gough Island. Overall design: mRNA profiles were generated for 5 females and 5 males for two mouse strains in each of 5 conditions: 28-day-old gonadal adipose depot, 28-day-old hypothalamus, Theiler stage 24-25 (E16.5) liver, 14-day-old liver, and 28-day-old liver.