A human genome-wide screen for transgenerational epigenetic inheritance

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During the last 50 years, several studies have challenged the view that DNA is the sole biological unit of heredity in multi-cellular organisms such as mammals. In these studies, inter-individual phenotypic differences were observed that could not be explained by genetic or environmental heterogeneity and yet, surprisingly, were passed on to the offspring. We are now beginning to realize that the biological mechanisms at the heart of these phenomena are epigenetic. Epigenetic modifications, such as the addition of methyl groups to the DNA, occur naturally and stably influence genome function without changing the underlying DNA sequence. Specifically, epigenetic modifications play central roles in regulating gene expression, and therefore it is not surprising that the cell carefully controls when and where in the genome epigenetic modifications are established. However, recent evidence suggests that epigenetic modifications in mammals can be perturbed by environmental or stochastic factors, in some cases correlating with altered phenotypes in the individual. But could such epigenetic variants, be transmitted to the offspring? Theoretically, such epigenetic variants should not be passed on to the next generation as they might interfere with embryonic development of the offspring. Indeed, during normal mammalian development, epigenetic modifications are reprogrammed during early embryogenesis. However, studies in mouse models show that occasionally epigenetic variants escape this reprogramming event and persist in the cells of the offspring i.e. epigenetic inheritance - biological inheritance that is not encoded strictly in the DNA sequence. If common, epigenetic inheritance could have a significant impact on phenotypic outcomes in the context of both health and disease. However, conclusive evidence of this phenomenon in humans is still lacking. To date, only three single-gene studies have claimed transgenerational epigenetic inheritance-like effects in humans, and even these have been controversial. The main stumbling blocks have been access to: (i) suitable human cohorts in which epigenetic inheritance can be distinguished from the effects of genetics or environment; (ii) technologies for performing relatively unbiased experiments to search for these epigenetic variants. We intend to perform the first-ever systematic large-scale study of epigenetic inheritance in humans. The experimental design uses a powerful approach that integrates a cohort of identical twins and their offspring, cutting-edge genomics technologies, and custom computational biology methodologies. The results of our study will yield crucial insights into the phenomenon of epigenetic inheritance, thereby significantly impacting on our understanding of the biological basis of heritable phenotypic variation in humans.