International Journal of Epidemiology, 2015, Vol. 44, No. 4 1109 International Journal of Epidemiology, 2015, 1109–1112 Commentary: Far-reaching doi: 10.1093/ije/dyv024 hypothesis or a step too far: Advance Access Publication Date: 7 April 2015 the inheritance of acquired characteristics Luke Isbel and Emma Whitelaw* LaTrobe Institute of Molecular Science, LaTrobe University, Melbourne, VIC, Australia *Corresponding author. LaTrobe Institute of Molecular Science, LaTrobe University Bundoora, Melbourne, VIC, Australia 3086. E-mail: [email protected] Downloaded from https://academic.oup.com/ije/article/44/4/1109/669284 by guest on 29 September 2021 A quarter of a century ago, Eva Jablonka and Marion J Does it ever happen? Lamb put forward a model (reprinted in this issue of IJE) Putting aside the question of mechanism, one of the con- to explain how the functional history of a gene might influ- tinuing problems with the hypothesis is the scant evidence 1 ence its expression in subsequent generations. They were for the inheritance of acquired characteristics. Although particularly interested in the idea that an environmental the authors propose a phenomenon that occurs across all stimulus acting on the parent could alter the behaviour of a phyla, they acknowledge that there is greater opportunity gene in the offspring. The model is simple and is depicted for the inheritance of acquired epigenetic marks in organ- in Figure 1. The environment stimulates a change in tran- isms such as plants, in which the germ cells arise from som- scription that is associated with chemical modifications to atic cells. In contrast, the mammalian germ line segregates the DNA or to the proteins that package the DNA.These early in development, providing less opportunity. Indeed, modifications are inherited via the germ line and influence putative examples in plants are numerous but recent re- transcriptional activity in the next generation. In other views conclude that few satisfy careful scrutiny.7,8 Of those words, epigenetic marks, generally considered to be cleared that do, most, if not all, involve the fluctuating transcrip- between generations, are retained at some loci and convey tional activity of genes adjacent to transposons and recip- a memory of the altered activity state to the offspring. rocal changes in DNA methylation.9 This model emerged in conjunction with the developing In the past, it has been difficult to rule out the possibil- interest among biologists in epigenetics, in particular the ity that acquired epigenetic changes are inherited in finding that demethylation of DNA could result in gene ac- 2,3 some instances because they are associated with a new tivation and that, at least in cell culture, the addition of an environmental stimulus, 5-azacytidine, could change genetic change. For example, in one study carried out in the level of DNA methylation.4 Patterns of DNA methyla- Arabidopsis, reduced DNA methylation did result in a tion had already been shown to be mitotically heritable phenotypic change that was inherited, but it turned out 10 in vitro.2 At the same time, observations that the expres- to be the result of the integration of a transposon. sion of some autosomal genes is dependent on the sex of Whole-genome sequencing provides a feasible way to test the parent from which they are inherited, termed genomic this in the future. imprinting, were being made.5,6 The latter requires that Early examples in mammals include the major urinary ‘epigenetic marks’ be inherited across meiosis to enable the proteins, inserted transgene arrays and genes driven by up- 11 zygote (fertilized egg) to discriminate between the paternal stream retroviral elements, as reviewed. Whereas the ear- and maternal alleles. From these and other findings, Eva lier studies were carried out in mixed genetic backgrounds, Jablonka and Marion J Lamb speculated on the existence in which genetic differences can confound the interpret- of a form of ‘Lamarckian’ inheritance that involved an ation, the agouti viable yellow(Avy) and axin fused(Axinfu) adaptive response to the environment based on epigenetic experiments used inbred colonies, reducing the chance of variations. This bold hypothesis has generated a great deal underlying genetic explanations. The Avy mouse has been of interest and has driven experiments in the field for the the most studied mammalian model. Inbred colonies of last couple of decades. Here we review the current evidence this strain show a range of coat-colour phenotypes, from for and against the inheritance of acquired characteristics. yellow, through mottled (yellow and brown patches) to VC The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association 1110 International Journal of Epidemiology, 2015, Vol. 44, No. 4 Downloaded from https://academic.oup.com/ije/article/44/4/1109/669284 by guest on 29 September 2021 Figure 1. The model of transgenerational inheritance put forward by Jablonka and Lamb.1 1. Environmental stimulus induces a phenotypic change to an organism: in this case, reduced size. 2. The associated epigenetic mark (star) is replicated faithfully during meiosis and mitosis. The epigenetic mark escapes the epigenetic reprogramming that occurs during early development. 3. The epigenetic state, which influences transcription of the A locus, is inherited by progeny and recapitulates the altered phenotype (blue). pseudoagouti (brown).The phenotype is linked to the epi- offspring is influenced by the coat colour of the dam.13 genetic state of a retrotransposon upstream of the agouti Yellow females produce a higher proportion of yellow off- locus. Alleles that behave in this stochastic manner spring than pseudoagouti females do, suggesting that the are referred to as metastable epialleles.12 In the case of Avy, epigenetic state is sometimes passed through the female the coat colour (and DNA methylation) range in the gamete. International Journal of Epidemiology, 2015, Vol. 44, No. 4 1111 There is now robust evidence for transgenerational epi- Escape from erasure genetic inheritance in C.elegans. Worms have an intrinsic Importantly, for an epigenetic mark to be transmitted ability to resist viral infection, mediated by a pathway that through the germ line it must escape global epigenetic involves small RNA molecules passed via the gametes. reprogramming events that occur during the development This is an adaptive response to an environmental stimulus of gametes and during the early stages of embryonic devel- that can be passed on to the offspring. Knocking out this opment. It is now well documented that imprinted loci ac- pathway results in a loss of resistance after a number of quire DNA methylation during germ cell development generations.14 Further studies have identified some of the and that this is refractory to later global reprogramming molecular machinery responsible, which includes factors events.19 As these regions re-establish methylation state involved in both the RNAi and chromatin pathways.15 every generation in the gametes, they cannot be considered This is one of the few examples of transgenerational epi- to undergo transgenerational epigenetic inheritance in the genetic inheritance in which the changes are likely to be Downloaded from https://academic.oup.com/ije/article/44/4/1109/669284 by guest on 29 September 2021 true sense. It is now generally accepted that some loci, par- adaptive. Most of the cases reported in plants and mam- ticularly repetitive elements, are able to resist reprogram- mals, discussed above, appear to be driven by stochastic ming of DNA methylation in the germ line and the early events. embryo.11 However, it remains to be seen if any these loci are responsive to the environment. Is DNA methylation the epigenetic mark involved? Lack of evidence for transgenerational DNA methylation state inversely correlates with transcrip- epigenetic effects on evolution tional activity at metastable epialleles in mammals, but there is no evidence so far that these methylation states are A major theme of Jablonka and Lamb’s hypothesis was the retained in the gametes or early embryo.11 In plants it is possibility of non-Mendelian inheritance providing an also well established that DNA methylation is involved in adaptive and evolutionary advantage. However, despite 25 suppression of transcription at epialleles but, again, evi- years of intense research across a range of organisms, the dence that this mark is driving the inheritance of changes influence of epigenetic inheritance on evolution remains in transcription across generations is lacking. Recent re- speculative. views emphasize the potential role for RNA as a transge- Conflict of interest: None declared. nerational messenger.8,11 References 1. Jablonka E, Lamb MJ. The inheritance of acquired epigenetic Environmental actions on the epigenome variations. J Theor Biol 1989;139:69–83. For the model to apply, the environment must be able to 2. Holliday R. The inheritance of epigenetic defects. Science change an organism’s epigenome. At the cellular level, we 1987;238:163–70. know that treatment with various chemicals, such as 5-aza- 3. Razin A, Riggs A. DNA methylation and gene function. Science 1980;210:604–10. cytidine, can change epigenetic state and transcriptional 4. Razin A, Cedar H. DNA methylation in eukaryotic cells. Int Rev activity but there are few robust cases involving whole or- Cytol 1984;92:26. ganisms. In the Avy mouse strain, in utero exposure to a 5. Cattanach BM, Kirk M. Differential activity of maternally and methyl-supplemented diet results in an increase in the pro- paternally derived chromosome regions in mice. Nature vy 16 portion of offspring with a methylated A locus. Many 1985;315:496–98. subsequent studies have been conducted to search for 6. Monk M, Boubelik M, Lehnert S. Temporal and regional transgenerational effects after exposure to toxins or changes in DNA methylation in the embryonic, extraembryonic stresses in multiple model organisms, as reviewed.17 Most and germ cell lineages during mouse embryo development.