@article {Shen004119, author = {Xia Shen and Jennifer De Jonge and Simon Forsberg and Mats Pettersson and Zheya Sheng and Lars Hennig and {\"O}rjan Carlborg}, title = {Natural CMT2 variation is associated with genome-wide methylation changes and temperature adaptation}, elocation-id = {004119}, year = {2014}, doi = {10.1101/004119}, publisher = {Cold Spring Harbor Laboratory}, abstract = {As Arabidopsis thaliana has colonized a wide range of habitats across the world it is an attractive model for studying the genetic mechanisms underlying environmental adaptation. Here, we used public data from two collections of A. thaliana accessions to associate genetic variability at individual loci with differences in climates at the sampling sites. We use a novel method to screen the genome for plastic alleles that tolerate a broader climate range than the major allele. This approach reduces confounding with population structure and increases power compared to standard genome-wide association methods. Sixteen novel loci were found, including an association between Chromomethylase 2 (CMT2) and variability in seasonal temperatures where the plastic allele had reduced genome-wide CHH methylation. Cmt2 mutants were more tolerant to heat-stress, suggesting genetic regulation of epigenetic modifications as a likely mechanism underlying natural adaptation to variable temperatures, potentially through differential allelic plasticity to temperature-stress.AUTHOR SUMMARY A central problem when studying adaptation to a new environment is the interplay between genetic variation and phenotypic plasticity. Arabidopsis thaliana has colonized a wide range of habitats across the world and it is therefore an attractive model for studying the genetic mechanisms underlying environmental adaptation. Here, we used publicly available data from two collections of A. thaliana accessions, covering the native range of the species, to identify loci associated with differences in climates at the sampling sites. To address the confounding between geographic location, climate and population structure, a new genome-wide association analysis method was developed that facilitates detection of potentially adaptive loci where the alternative alleles display different tolerable climate ranges. Sixteen novel such loci, many of which contained candidate genes with amino acid changes, were found including a strong association between Chromomethylase 2 (CMT2) and variability in seasonal temperatures. The reference allele dominated in areas with less seasonal variability in temperature, and the alternative allele, which disrupts genome-wide CHH-methylation, existed in both stable and variable regions. We have experimentally shown that plants with a defective CMT2 gene tolerate heat-stress better than plants with a functional gene. Our results thus link natural variation in CMT2, and differential genome-wide CHH methylation, to the distribution of A. thaliana accessions across habitats with different seasonal temperature variability and show that disruption of CMT2 function improves heat-stress tolerance. The results therefore also suggest a role for genetic regulation of epigenetic modifications in natural adaptation to temperature, potentially through differential allelic plasticity, and illustrate the importance of re-analyses of existing data using new analytical methods to obtain a more complete understanding of the mechanisms contributing to adaptation.BLURB Disrupted Chromomethylase 2 (CMT2) is associated with plasticity to seasonal temperature variability, decreased CHH-methylation and improved heat-stress tolerance, suggesting a role for genetic regulation of epigenetic modifications in natural adaptation.}, URL = {https://www.biorxiv.org/content/early/2014/04/10/004119}, eprint = {https://www.biorxiv.org/content/early/2014/04/10/004119.full.pdf}, journal = {bioRxiv} }