Coding and non-coding mutations in DNA contribute significantly to phenotypic variability during evolution. However, less is known about the role of epigenetics in this process. Although previous studies have identified eye development genes associated with the loss-of-eyes phenotype in the Pachón blind cave morph of the Mexican tetra Astyanax mexicanus, no inactivating mutations have been found in any of these genes. Here, we show that excess DNA methylation-based epigenetic silencing promotes eye degeneration in blind cave A. mexicanus. By performing parallel analyses in A. mexicanus cave and surface morphs, and in the zebrafish Danio rerio, we have discovered that DNA methylation mediates eye-specific gene repression and globally regulates early eye development. The most significantly hypermethylated and downregulated genes in the cave morph are also linked to human eye disorders, suggesting that the function of these genes is conserved across vertebrates. Our results show that changes in DNA methylation-based gene repression can serve as an important molecular mechanism generating phenotypic diversity during development and evolution.
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We thank members of the Weinstein and Jeffery laboratories for support, help and suggestions. We thank staff at the NICHD's Molecular Genomics Laboratory for bisulfite and RNA-Seq assistance. We also thank members of the zebrafish and cavefish communities for sharing reagents and protocols. We thank K. Sampath for comments on the manuscript. We thank S. McGaugh for suggestions on cavefish sequence alignments and M. Goll for providing the zebrafish tet2,3 double mutant line. Work in the Weinstein and Jeffery laboratories is supported by the intramural programme of the NICHD and by R01EY024941, respectively.
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figures 1–7
Differentially up and down regulated genes from surface and cavefish eyes at 54 hpf by RNA seq analysis
Cavefish genes with significant promoter hypermethylation and reduced gene expression
Cavefish genes with substantial promoter hypermethylation and reduced gene expression and their linked human disease phenotypes
Primer sequences used in this study
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Gore, A.V., Tomins, K.A., Iben, J. et al. An epigenetic mechanism for cavefish eye degeneration. Nat Ecol Evol 2, 1155–1160 (2018). https://doi.org/10.1038/s41559-018-0569-4
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