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. 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.背景：岛屿种群反复演化出极端体型，但该形态模式的基因组基础仍在很大程度上未知。为解析岛屿生物如何演化出巨型体型，我们对全球体型最大的野生家鼠——戈夫岛小鼠，与WSB/EiJ野生来源近交品系小鼠的全基因组基因表达模式进行了比较。在一项高度重复的实验中，我们采用RNA测序（RNASeq）对三种关键代谢器官的基因表达差异进行定量分析：性腺脂肪垫、下丘脑与肝脏。结果：我们发现了广泛存在的转录演化证据，每个器官中20%及以上的差异调控转录本的表达倍数变化至少为2倍。通过将差异表达与体型相关数量性状基因座（quantitative trait loci, QTL）的基因组位置，以及位于已验证组织特异性调控元件内的单核苷酸差异相结合分析，我们筛选出66个极端体型演化的候选基因，包括Irs1与Lrp1。对肝脏三个发育时间点的差异表达模式分析显示，Arid5b可能调控数十个共调控基因簇。对数千个差异表达基因的功能富集分析表明，细胞周期、线粒体功能、信号通路、免疫反应性与营养代谢可能是戈夫岛小鼠体重积累的潜在诱因。结论：综上，本研究结果表明，在家鼠定居戈夫岛的短短时间内，代谢器官中广泛的调控演化推动了巨型体型的快速演化。本研究为两个小鼠品系的5只雌性与5只雄性个体生成了mRNA表达谱，涵盖5种实验条件：28日龄性腺脂肪垫、28日龄下丘脑、泰氏分期24-25期（胚胎16.5天）肝脏、14日龄肝脏及28日龄肝脏。