Transgenerational inheritance” models, mechanisms of non-DNA-sequence based inheritance

Heritability was traditionally thought to be a characteristic feature of the genetic material of an organismnotably, its DNA sequence. During the past several decades, however, it has become clear that inheritance that is independent of DNA sequence exists in the form of epigenetic effects (DNA methylation, RNA-interference (RNAi silencing), histone modifications, and chromatin remodeling). Environmental factors can influence both genetics (via DNA damage, mutations) and epigenetics. In addition, there is this mysterious phenomenon called “transgenerational inheritance” in which life style or environmental pressures on one generation can affect not only the offspring but those in the F2 and F3 generations.

A fascinating anecdotal story about a small community near the coast in Sweden [Pembrey, Eur J Hum Genet  2oo2; 10:669–671] has been featured on Nova or the Discovery Channel. A local physician had recorded for more than a century births and deaths of the town’s citizens and annual weather (e.g. abundant harvest vs famine conditions). He noted that famine at the time a male is entering puberty … sends an unknown transgenerational message to his grandson, resulting in a 4-fold less risk of type-2 diabetes (T2D), whereas famine in the same population, at the time a female’s oocytes are forming in utero, increases the risk of obesity and T2D 4-fold in that baby’s granddaughter. There are many similar observations found in microbes, plants, and invertebrate and vertebrate animals other than humans.

In mammals, the molecular mechanisms have been challenging to elucidate, in part due to difficulties in designing robust models and approaches. Authors [see attached] review some of the evidence, concepts, and potential mechanisms of nonDNA sequencebased transgenerational inheritance. They have highlighted particular model systems, and they discuss whether phenotypes are replicated or reconstructed over successive generations––as well as whether mechanisms appear to operate at transcriptional and/or posttranscriptional levels. Finally, they explore the short- and long-term implications of nonDNA sequencebased inheritance. Understanding the effects of nonDNA sequencebased mechanisms is key to appreciating gene-environment interactions and to a full appreciation of heritability in health and disease.

Science  7 Oct 2o16; 354: 59–63

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