Adaptive methylation regulation of p53 pathway in sympatric speciation of blind mole rats, Spalax

Abstract

p53 has been shown to play important roles in environmental adaptive evolution. Here we show that p53 and its target genes express differentially between two abutting populations of the blind mole rat Spalax galili during its sympatric speciation caused by sharply divergent abutting ecologies of chalk and basalt. Remarkably, the differential expression of p53 is due to differing methylation on sites –1446, –1204, and –1086 of the p53 promoter, which plays a key role in regulating the binding of several transcription factors including Cut-Like Homeobox 1, paired box 4 (Pax 4), Pax 6, and activator protein 1. Different expressions of S. galili p53 selectively changed adaptive cell-cycle arrest. This article provides evidence supporting the sympatric speciation of S. galili , demonstrating the importance of epigenetic modifications in adaptive evolution. Epigenetic modifications play significant roles in adaptive evolution. The tumor suppressor p53 , well known for controlling cell fate and maintaining genomic stability, is much less known as a master gene in environmental adaptation involving methylation modifications. The blind subterranean mole rat Spalax eherenbergi superspecies in Israel consists of four species that speciated peripatrically. Remarkably, the northern Galilee species Spalax galili (2 n = 52) underwent adaptive ecological sympatric speciation, caused by the sharply divergent chalk and basalt ecologies. This was demonstrated by mitochondrial and nuclear genomic evidence. Here we show that the expression patterns of the p53 regulatory pathway diversified between the abutting sympatric populations of S. galili in sharply divergent chalk–basalt ecologies. We identified higher methylation on several sites of the p53 promoter in the population living in chalk soil (chalk population). Site mutagenesis showed that methylation on these sites linked to the transcriptional repression of p53 involving Cut-Like Homeobox 1 (Cux1), paired box 4 (Pax 4), Pax 6, and activator protein 1 (AP-1). Diverse expression levels of p53 between the incipiently sympatrically speciating chalk–basalt abutting populations of S. galili selectively affected cell-cycle arrest but not apoptosis. We hypothesize that methylation modification of p53 has adaptively shifted in supervising its target genes during sympatric speciation of S. galili to cope with the contrasting environmental stresses of the abutting divergent chalk–basalt ecologies.