Response to Kalchhauser et al.: Inherited Gene Regulation Is not Enough to Understand Nongenetic Inheritance.

In their Opinion Adrian-Kalchhauser et al. [ 1. Adrian-Kalchhauser I. et al. Understanding ‘Non-genetic’ inheritance: insights from molecular-evolutionary crosstalk. Trends Ecol. Evol. 2020; 35: 1078-1089 Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar ] discussed the diverse molecular mechanisms underlying certain forms of nongenetic inheritance (see Box 1 for terminology). They proposed embracing these mechanisms under the unifying concept of inherited gene regulation (IGR). We think the article provides a valuable overview of several forms of nongenetically inherited gene regulation and their interactions with genetic variation. However, we are concerned that this article might lead readers to conclude that all forms of nongenetic inheritance boil down to IGR – a conclusion that we regard as inconsistent with known features of many forms of nongenetic inheritance. In the following text, we clarify our concerns, and explain why we believe that nongenetically inherited variation cannot be understood solely in terms of variation in gene expression. Box 1Genetic and Nongenetic Inheritance TerminologyWe use inheritance to mean the transmission of something from parent to offspring, contributing to parent–offspring resemblance. Genetic inheritance is the transmission of DNA sequence during reproduction. Nongenetic inheritance is then the transmission of anything else from parent to offspring. This might also occur during reproduction (e.g., small RNAs present in gametes), but other aspects like behaviour, microbiomes, and physical structures can be transmitted after reproduction and without the involvement of gametes. Epigenetic inheritance has historically been used in many different ways. We adhere to the predominating narrow-sense use that refers to certain inherited molecular factors that regulate gene expression. However, as explained above and in the text, these molecular factors are only a subset of the kinds of elements that can mediate nongenetic inheritance. Thus, the IGR framework encompasses only those forms of nongenetic inheritance that involve parent–offspring transmission of narrow-sense epigenetic factors, and leaves out other nongenetically inherited elements. Nongenetic inheritance is broader than IGR. We use inheritance to mean the transmission of something from parent to offspring, contributing to parent–offspring resemblance. Genetic inheritance is the transmission of DNA sequence during reproduction. Nongenetic inheritance is then the transmission of anything else from parent to offspring. This might also occur during reproduction (e.g., small RNAs present in gametes), but other aspects like behaviour, microbiomes, and physical structures can be transmitted after reproduction and without the involvement of gametes. Epigenetic inheritance has historically been used in many different ways. We adhere to the predominating narrow-sense use that refers to certain inherited molecular factors that regulate gene expression. However, as explained above and in the text, these molecular factors are only a subset of the kinds of elements that can mediate nongenetic inheritance. Thus, the IGR framework encompasses only those forms of nongenetic inheritance that involve parent–offspring transmission of narrow-sense epigenetic factors, and leaves out other nongenetically inherited elements. Nongenetic inheritance is broader than IGR.