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Transgenerational Epigenetic Effects ANRV353-GG09-13 ARI 25 July 2008 16:32 ANNUAL Transgenerational Epigenetic REVIEWS Further Click here for quick links to Annual Reviews content online, Effects including: • Other articles in this volume • Top cited articles Neil A. Youngson and Emma Whitelaw • Top downloaded articles Department of Population Studies and Human Genetics, Queensland Institute of Medical • Our comprehensive search Research, Brisbane 4006, Australia; email: [email protected] Annu. Rev. Genomics Hum. Genet. 2008. 9:233–57 by University of California - San Diego on 01/24/09. For personal use only. Key Words First published online as a Review in Advance on non-Mendelian inheritance, soft inheritance, parental effects, June 3, 2008 resistance to reprogramming The Annual Review of Genomics and Human Genetics Annu. Rev. Genom. Human Genet. 2008.9:233-257. Downloaded from arjournals.annualreviews.org is online at genom.annualreviews.org Abstract This article’s doi: Transgenerational epigenetic effects include all processes that have 10.1146/annurev.genom.9.081307.164445 evolved to achieve the nongenetic determination of phenotype. There Copyright c 2008 by Annual Reviews. has been a long-standing interest in this area from evolutionary biolo- All rights reserved gists, who refer to it as non-Mendelian inheritance. Transgenerational 1527-8204/08/0922-0233$20.00 epigenetic effects include both the physiological and behavioral (intel- lectual) transfer of information across generations. Although in most cases the underlying molecular mechanisms are not understood, modi- fications of the chromosomes that pass to the next generation through gametes are sometimes involved, which is called transgenerational epi- genetic inheritance. There is a trend for those outside the field of molec- ular biology to assume that most cases of transgenerational epigenetic effects are the result of transgenerational epigenetic inheritance, in part because of a misunderstanding of the terms. Unfortunately, this is likely to be far from the truth. 233 ANRV353-GG09-13 ARI 25 July 2008 16:32 INTRODUCTION rounds of mitosis. Recent evidence shows that the establishment of epigenetic state can be in- Transgenerational epigenetic effects and trans- fluenced by environmental factors (33, 40, 129). Transgenerational generational epigenetic inheritance are not the To ensure the totipotency of the zygote and epigenetic effects: same, but a novice to the discipline would to prevent perpetuation of abnormal epigenetic phenotypes present in find this hard to understand. The situation successive generations states, most gene regulatory, i.e., epigenetic, in- has arisen because the word epigenetic has that are not genetically formation is not transferred between genera- changed its meaning over the past fifty years. determined tions. Several mechanisms have evolved to erase In the phrase ‘transgenerational epigenetic ef- Transgenerational the marks, including germline and somatic re- fects,’ epigenetic is being used in its broader epigenetic programming of DNA methylation and chro- inheritance or (and original) sense to include all processes that matin proteins. However, we know that at some gametic epigenetic have evolved to achieve the nongenetic de- loci the epigenetic marks are not cleared. Ex- inheritance: a termination of phenotype. Waddington, who phenotype present in amples of this include genomic imprinting in coined the word epigenetics, was interested successive generations mammals, mating type switching in yeast, and in how gene expression patterns are modi- that is nongenetically paramutation in plants. Although exceptional determined and results fied during differentiation and development. with respect to their resistance to reprogram- from epigenetic He was a developmental biologist, with no ming, these examples can be considered part of modifications passed particular interest in transgenerational events. via the gametes that normal development, and they are not depen- However, evolutionary biologists have stud- escape reprogramming dent on environmental cues. Twoissues that we ied the transgenerational nongenetic determi- Hard inheritance: now need to address are firstly, the extent of nation of phenotype for centuries. This has essentially Mendelian; this resistance to transgenerational epigenetic been termed soft inheritance, non-Mendelian hereditary material reprogramming and secondly, whether or not remains constant inheritance, parental effects, and fetal pro- epigenetic marks established in response to en- between generations gramming, among others. Although in many vironmental cues are also resistant. (except for rare instances these phrases refer to different phe- random mutations) There is a current trend for those outside nomena, including both physiological and be- the field of molecular biology to assume that Soft inheritance: the havioral (intellectual) processes, they all involve generation of a new all cases of transgenerational epigenetic effects a transfer of nongenetic information across phenotype is less are the result of transgenerational epigenetic in- rigidly determined and generations; i.e., they are transgenerational epi- by University of California - San Diego on 01/24/09. For personal use only. heritance, in part because of a misunderstand- shows a more rapid genetic effects. Although in most cases the un- ing of the terms. This is misleading. When response to derlying molecular mechanisms are not under- discussing transgenerational epigenetic effects, environment stood, modifications to the chromosomes that care must be taken not to make assumptions Annu. Rev. Genom. Human Genet. 2008.9:233-257. Downloaded from arjournals.annualreviews.org Parental effects: pass to the next generation through the gametes about the underlying mechanisms. In an at- effects on the are sometimes involved. The latter has to-date phenotype of offspring tempt to improve this situation, we propose that been called ‘transgenerational epigenetic inher- that are not the term ‘transgenerational epigenetic inheri- itance.’ Here, the word epigenetic refers to mi- determined by the tance’ be replaced by ‘gametic epigenetic inher- offspring’s own totically and/or meiotically heritable changes itance,’ which is a more precise description of genotype but by the in gene function that cannot be explained the event. In this review we discuss the current genotype or by changes in gene sequence. This narrower environmental knowledge in the broad area of non-Mendelian definition of epigenetics has recently become experience of its inheritance and attempt to highlight those cases widely accepted among molecular biologists. parents where gametic epigenetic inheritance is known We have learned a considerable amount Paramutation: an to occur. interaction between about epigenetic (in its more recent sense) mod- two alleles of a locus, ifications, including both the methylation of resulting in a heritable the cytosine residue of DNA and the modifica- epigenetic change of tion of the chromatin proteins that package the SOFT INHERITANCE one allele induced by DNA. In general these marks are established Mendelian genetics is built on the inheritance the other allele in early development and are stable through of stable traits and the evolution of such traits 234 Youngson · Whitelaw ANRV353-GG09-13 ARI 25 July 2008 16:32 occurs slowly as a result of rare genetic muta- tion of germline and soma and the gametes are tion, selection, and drift. The slow reactivity of derived from vegetative tissue after most devel- this ‘hard inheritance’ is not ideal for an organ- opment is complete. This may provide plants Adaptation: a ism or population to thrive in a dynamic envi- with a greater opportunity for soft inheritance phenotypic change ronment. Another more pliable system, which than mammals. that is ultimately fine tunes the next generation to their future en- It should be emphasized that the examples beneficial to the vironment, would be an advantage. Ernst Mayr of soft inheritance described in this review, reproductive success of (1904–2005) (77, 78) first proposed the term although Lamarckian in their environmental an organism ‘soft inheritance’ to describe this type of sys- determination, involve short-term adaptations tem. Soft inheritance would be especially suited that supplement the evolutionary processes of to adaptation to fluctuations in nutrition, pre- Darwin and Mendel. Thus, they are distinct dation, or disease, which occur relatively un- from Lamarck’s proposed overall mechanism of predictably and may endure for more than one evolution. generation. Soft inheritance is adaptive in the sense used by evolutionary biologists, i.e., ad- vantageous to the individual or species. The Adaptive Parental Effects ability of epigenetic mechanisms to perpetuate in Plants and Insects gene expression patterns relatively stably, and Parental effects are defined as effects on the to retain the capacity to react to environmen- phenotype of offspring that are not determined tal cues, makes them ideal for facilitating soft by the offspring’s genotype but instead are de- inheritance. The largest barrier to such a sys- termined by the genotype or environmental ex- tem is the resetting of epigenetic marks between perience of the parents. These effects can be generations. paternal or maternal and have been reported The notion of soft inheritance is still viewed in a range of multicellular organisms. Such ef- by some as controversial. This is mainly due fects fit within the confines of transgenerational to its association
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