The study of the signals and mechanisms that shape our life’s trajectory has been a topic of fascination for centuries. The discovery that epigenetic variation — changes in gene expression or cellular phenotype that occur without alterations in the DNA sequence — can be inherited across generations suggested a molecular basis for how experiences in one generation might be relayed to subsequent generations. As a result, research has increasingly focused on unravelling the relative contribution and potential impact of transgenerational epigenetic inheritance on phenotype development.

In a seminal 2011 paper, Greer et al. discovered in Caenorhabditis elegans that wild-type descendants of animals with mutations in ash-2, wdr-5 and set-2 — genes that encode components of the histone 3 lysine 4 (H3K4)-methylating complex COMPASS — displayed the same increase in lifespan previously reported for their mutant ancestors. This longevity phenotype was observed up to the fourth generation (F4), making it a truly transgenerational example of inheritance of a complex trait, as the effect on lifespan was seen in descendants that did not directly arise from germ cells present in the mutant ancestor.