Bubbling beyond the barrier: exosomal RNA as a vehicle for soma–germline communication

Abstract

Abstract‘Weismann's barrier’ has restricted theories of heredity to the transmission of genomic variation for the better part of a century. However, the discovery and elucidation of epigenetic mechanisms of gene regulation such as DNA methylation and histone modifications has renewed interest in studies on the inheritance of acquired traits and given them mechanistic plausibility. Although it is now clear that these mechanisms allow many environmentally acquired traits to be transmitted to the offspring, how phenotypic information is communicated from the body to its gametes has remained a mystery. Here, we discuss recent evidence that such communication is mediated by somatic RNAs that travel inside extracellular vesicles to the gametes where they reprogram the offspring epigenome and phenotype. How gametes learn about bodily changes has implications not only for the clinic, but also for evolutionary theory by bringing together intra‐ and intergenerational mechanisms of phenotypic plasticity and adaptation. image

The physiology of evolution

“…They also conclude by paying homage to Darwin's gemmule theory: 'because GEI [germline epigenetic inheritance] may use a soma-germline vehicle so close to Darwin's 'gemmule' , this ought to remind us that, in science, 'progress [is] often achieved by a 'criticism from the past' … Theories are abandoned and superseded by more fashionable accounts long before they have had an opportunity to show their 'virtues.' A letter to The Journal (Sun & Liu, 2024) commenting on this article confirms what Darwin and Romanes were aiming to achieve in their research together and highlights the role of DNA in soma-germline communication.…”

Reply from Daniel Phillips and Denis Noble

“…Accordingly, whilst we are quick to acknowledge that somatic EV DNAs indeed reach the germline, we believe it ought to be acknowledged that whether they have any regulatory effect is a separate question which has not yet gained adequate support. Furthermore, we are aware of no evidence to demonstrate a role for EV DNA in the inheritance of parental phenotypes, but we are nonetheless supportive of the characteristically bold style of Liu and Sun (2024) in anticipating where this field might be heading, and would not be too surprised if they were eventually proved correct.…”

“…In our recent article 'Bubbling beyond the barrier: exosomal RNA as a vehicle for soma-germline communication' published in The Journal of Physiology (Phillips & Noble, 2023) we provided an updated review for the multifaceted evidence that RNA packaged inside extracellular vesicles (EVs) and released from somatic cells can be transported to the germline wherein they cause the recapitulation of acquired parental phenotypes in offspring. We were pleased to read the positive comments about our paper submitted by Liu and Sun (2024), not least because it was the dedicated writings of Dr Yongsheng Liu that contributed to one of us beginning to explore the topic and its association with Darwin's theory of Pangenesis in the first place -in particular, the wonderful article 'Has Darwin's pangenesis been rediscovered?'…”

“…In our recent article ‘Bubbling beyond the barrier: exosomal RNA as a vehicle for soma–germline communication’ published in The Journal of Physiology (Phillips & Noble, 2023) we provided an updated review for the multifaceted evidence that RNA packaged inside extracellular vesicles (EVs) and released from somatic cells can be transported to the germline wherein they cause the recapitulation of acquired parental phenotypes in offspring. We were pleased to read the positive comments about our paper submitted by Liu and Sun (2024), not least because it was the dedicated writings of Dr Yongsheng Liu that contributed to one of us beginning to explore the topic and its association with Darwin's theory of Pangenesis in the first place – in particular, the wonderful article ‘Has Darwin's pangenesis been rediscovered?’ (Liu & Li, 2014), and much shorter ‘150 years of Darwin's theory of intercellular flow of hereditary information’ (Liu & Chen, 2018), which we strongly recommend to readers interested in the historical precedent behind these very modern discoveries. In their letter, Liu and Sun (2024) propose that it is not only EV RNA but also EV DNA that can be shuttled from the soma to the germline to mediate inheritance, and that such cases can be viewed as instances of gene transfer which provide further evidence for Darwin's theory of pangenesis.…”

Speciation by physiological selection of environmentally acquired traits

“…What emerged was not new experimental results, but new thinking about the physiology of a 'Lamarckian' origin of species. This now appears fortuitous, because modern evidence for the old idea of pangenesis is beginning to emerge, the details of which are dealt with in an accompanying article (Phillips & Noble, 2023) and centre around the communication of extracellular RNAs (exRNAs) from the body to its gametes wherein they reprogram offspring development. The reality of the inheritance of acquired traits and underlying gemmule-like mediator is now acknowledged by even the most mainstream voices and genetic societies and goes to 'illustrate that inheritance can be entirely non-genetic' (Wolf et al, 2022, p. 2).…”