Assessing the Impact of Transgenerational Epigenetic Variation on Complex Traits

Abstract

Loss or gain of DNA methylation can affect gene expression and is sometimes transmitted across generations. Such epigenetic alterations are thus a possible source of heritable phenotypic variation in the absence of DNA sequence change. However, attempts to assess the prevalence of stable epigenetic variation in natural and experimental populations and to quantify its impact on complex traits have been hampered by the confounding effects of DNA sequence polymorphisms. To overcome this problem as much as possible, two parents with little DNA sequence differences, but contrasting DNA methylation profiles, were used to derive a panel of epigenetic Recombinant Inbred Lines (epiRILs) in the reference plant Arabidopsis thaliana. The epiRILs showed variation and high heritability for flowering time and plant height (∼30%), as well as stable inheritance of multiple parental DNA methylation variants (epialleles) over at least eight generations. These findings provide a first rationale to identify epiallelic variants that contribute to heritable variation in complex traits using linkage or association studies. More generally, the demonstration that numerous epialleles across the genome can be stable over many generations in the absence of selection or extensive DNA sequence variation highlights the need to integrate epigenetic information into population genetics studies.

Author Summary

DNA methylation is defined as an epigenetic modification because it can be inherited across cell division. Since variations in DNA methylation can affect gene expression and be inherited across generations, they can provide a source of heritable phenotypic variation that is not caused by changes in the DNA sequence. However, the extent to which this type of phenotypic variation occurs in natural or experimental populations is unknown, partly because of the difficulty in teasing apart the effect of DNA methylation variants (epialleles) from that of the DNA sequence variants also present in these populations. To overcome this problem, we have derived a population of epigenetic recombinant inbred lines in the plant Arabidopsis thaliana, using parents with few DNA sequence differences but contrasting DNA methylation profiles. This population showed variation and a high degree of heritability for two complex traits, flowering time and plant height. Multiple parental DNA methylation differences were also found to be stably inherited over eight generations in this population. These findings reveal the potential impact of heritable DNA methylation variation on complex traits and demonstrate the importance of integrating epigenetic information in population genetics studies.