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A new take on the epigenetic signatures of prenatal stress

The conditions encountered in the womb can have life-long impact on health. It is usually assumed that this is because embryos respond to adverse conditions by programming their gene expression. In collaboration with Bas Heijmans and others, we propose that these effects also can be caused by selection on stochastic epigenetic variation. The paper is published in Cell Reports and there is also a press release.

The concept of fetal programming is based on the idea that embryos modify their physiology in response to the uterine environment. This may be good if conditions stay as predicted. But it may have negative health effects later in life if the conditions change. The concept of programming has been backed up by associations between adverse prenatal conditions and patterns of DNA methylation – an epigenetic mark that regulates gene expression.

Our simple insight is that the uterine environment does not need to induce changes in DNA methylation for this association between adverse prenatal conditions and DNA methylation to arise. In the early embryo, stochastic differences in gene expression can become stabilized by DNA methylation, resulting in embryos with different epigenomic profiles. Not programmed by the environment, these random differences in gene expression (and hence DNA methylation) may nevertheless provide some embryos with a survival advantage when conditions are harsh. In other words, adverse maternal conditions may impose selection on random variation in DNA methylation.

Human embryo at 8-cell stage. (C) Yorgos Nikas/Science Photo Library

We used a mechanistic simulation model to illustrate how selection reduce DNA methylation variance at loci that influence implantation success. The prediction fits very well with empirical data from offspring conceived during the Dutch Hunger Winter, a famine at the end of World War II. This makes selection on stochastic epigenetic variation a reasonable explanation for the epigenetic signatures of prenatal exposure to adverse conditions.

This new hypothesis is not only of academic interest. Fetal programming implies that the behaviour or physiology of the mother causes the offspring phenotype to change. In contrast, a selective process does not bring new phenotypes into being, it changes the distribution of already existing variants. This difference may influence which preventive strategies and treatments that are most likely to be effective. That different mechanisms can be responsible for the same pattern is also relevant to society. As Sarah Richardson has pointed out, careless discussion of epigenetic research on how early life affects health across generations could be harmful.



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Developmental Bias and Evolution at Santa Fe

The third and final workshop funded by our EES grant took on the role of developmental bias in evolution. Like the meeting in February, Santa Fe greeted us with snow, jetlag, and huevos rancheros for breakfast.

The workshop showcased the extraordinary breadth of approaches used to understand if, and how, developmental processes direct evolution. Ecologists, developmental biologists, and palaeontologists explained what data are out there and what they mean. Theoretical biologists and computer scientists convincingly showed that the role of development not only can be formulated in precise terms, but that there are predictions ready to be tested. Judging from the work presented, we can look forward to some very interesting studies doing just that in the near future.

As there should be, there was both unity and spirited disagreement – with views ranging from development as constraint to development as the main driver of evolution. History and philosophy of biology again proved useful to understand this diversity. While debate over the role of development in evolution is as old as evolutionary science, contemporary research really does seem to bring new insights – conceptually, theoretically and empirically.

One way to think of developmental bias is through the use of morphospaces. The morphospace of several groups of reptiles (including dinosaurs) that lived around 230-200 million year ago, using two (undefined) shape characters. Reproduced from the Palaeobiology Research Group of the University of Bristol, UK

Origin-Of-Life researcher Wim Hordijk kindly summarized his views of the meeting on this blog. The Lund crew – Tobias, Alfredo, Nathalie, Reinder, and Illiam – are very grateful to the SFI for hosting, and the organisers for giving us a lot of things to think of. Next up – the Evolution Evolving meeting at Cambridge. See you there!

 

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Another bad day for anticipatory maternal effects

A new study on water fleas, headed by Reinder and Alex, suggests that a classic example of adaptive maternal effects is not as adaptive as we might have thought.

Some years ago, Tobias, Sinead and Shinichi did a meta-analysis that seemed to undermine the idea that maternal effects are designed to transfer information about the local environment. Reviewers and editors did not really want to hear that, and the paper proved somewhat difficult to publish (but has been well received and cited). But one ‘anticipatory maternal effects’ appeared well supported: water fleas exposed to toxic cyanobacteria produced offspring that were more tolerant to the toxin.

So, to understand how this maternal effect evolves, Reinder and Alex challenged water flea mothers and offspring with cyanobacteria that produce the toxin microcystin. But rather than just expose the animals throughout their lives, they also exposed mothers at different times during her life. The rationale is that maternal effects that have been selected to transmit information are expected to behave like signals – triggered and delivered by a system well designed to pass on information with limited cost to the receiver.

It turned out that offspring indeed were somewhat better able to handle the toxin when their mothers had been exposed late in their lives. In other words, tolerance or resistance can be transmitted to the next generation through non-genetic means. But there was not much to suggest that the mechanism has been selected to transmit information about the presence of cyanobacteria. Instead, our experimental evidence – along with a meta-analysis of Daphnia research – fits better with a model of passive transfer of tolerance rather than an anticipatory maternal effect. Again, reviewers and editors were not very happy to hear this, and this paper also proved somewhat difficult to publish.

We should not be too surprised of these results, however. Not all plastic responses that allow organisms to cope with stress are properly seen as adaptations to cope with the stressor.

Genetically identical sisters, raised in two different environments. Daphnia raised in the microcystin treatment (on the right) displays smaller body size and carries less eggs than her sister from the control treatment

We can think of these maternal effects as – in Mary-Jane West-Eberhard terms – examples of phenotypic accommodation that have not yet been followed by genetic accommodation.

But while our results question if there really has been selection for maternal transfer of information about microcystin exposure, the study is still not quite conclusive. Two kinds of follow-up studies would be particularly informative.

Endless replications

The first is to contrast responses of populations of water fleas with different evolutionary histories of exposure. This kind of comparison can effectively reveal if plastic responses in naïve animals become fine-tuned over evolutionary time (see a nice example from house finches here).

The second is to reveal the mechanism of the maternal effect. This would not only tell us ‘how it works’, but – keeping the comparison with signals in mind – whether or not the mechanism has properties that we expect of systems designed to transmit information.

We have our ideas about what is going on, and Alex has just completed a set of experiments that can tell us more. In the meantime, we hope that this paper will inspire more studies to look at maternal effects as a window into the evolutionary transition from stress-induced responses to local adaptation. To get started, please see here and here.

 

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Lund workshop on the evolutionary origins of individuality

The evolutionary process is itself evolving. Perhaps the best example is the origin of new reproductive organizations that are capable of evolving by natural selection. Single celled organisms evolved into multicellular organisms, some of which – leaf cutter ants, for example – appear to have evolved into collectives that deserve the label superorganism.

Last week our group hosted a small workshop to bring together researchers that use different approaches to tackle how and why such transitions in individuality happens. The aim was to share insights from projects within our Templeton-funded grant, and to spread ideas to local Lund researchers.

The presentations generated a lot of great discussions, which continued over dinner and at the pub. Richard Watson showed how learning theory bring clarity to the conditions that are necessary for transitions in individuality to happen. Andy Gardner explained how focusing on lower-level evolutionary individuals – genes – can help to understand how conflicts between cells within bodies arise, evolve and become resolved. Charlie Cornwallis and Maria Coelho-Svensson discussed how one can put theory to the test using green algae that come together in groups. Social insects provide another interesting example, and Heikki Helanterä showed how they can shed light on the transition from solitary to collective life cycles.

Evolutionary transitions in individuality is fundamentally about explaining how a developmental organization evolves from social or ecological interactions between the lower-level individuals. This is difficult to address without paying attention to mechanism. Miguel Brun-Usan showed how mechanistic models of cell behaviour provide a window into the conditions that promote transitions in individuality. Some of the order comes from self-organization, a topic theoretically explored by Edith Invernizzi in the context of nest building in social insects.  Finally, Jonathan Birch discussed another evolving relationship between the organism and its surroundings – the evolutionary route towards organisms that are capable of conscious thought.

Thanks to all the speakers and the many Lund researchers and students that attended the workshop. It was great fun and we cannot wait to see more from all of these projects.

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Developmental Bias and Evolution


A recurrent theme in evolutionary biology is to contrast natural selection and developmental constraint – two forces pitted against each other as competing explanations for organismal form. A recent Perspective in the journal Genetics explains why this juxtaposition is deeply misleading. There is also a blog about the paper here.

Our starting point is that characters often evolve through changes in how genes, cells, and tissues regulate each other. Once we study the evolution of such regulatory interactions, it turns out that they do not only limit evolution, but also may facilitate the capacity to adapt and diversify. The paper gives an introduction to recent theoretical and empirical research, and explains how this work is now beginning to reveal how evolution of the evolutionary process itself contributes to diversification and adaptation.

 

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Three new papers on thermal biology of reptile embryos

Most reptiles lay eggs in sand or soil, under logs or in rock crevices. These are places where the temperature often fluctuates, sometimes becoming dangerously high or low. The pervasive effects of temperature on biological systems begs the question how embryos respond in the short term, and how populations adapt in the long term. This question is now thoroughly explored in a theme issue of the Journal of Experimental Zoology, with contributions from our group.

In a study on wall lizards led by Nathalie Feiner, we reveal a pervasive effect of temperature on gene expression in early embryos. The strongest responses were found for genes involved in transcriptional and translational regulation and chromatin remodelling, suggesting possible epigenetic mechanisms underlying thermal acclimation. In another paper, ploughing through 50 years of experimental studies, Dan Noble, Geoff While, and colleagues summarize research on thermal plasticity in reptile embryos, and demonstrate how future progress can be made through meta-analytic and comparative work. The data are accessible to everyone through a paper in the journal Scientific Data, and can be downloaded through this online data base. More papers in this special issue are available through the Journal of Experimental Zoology online early.

 

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