Epigenetics and the Social World: Why DNA Sequence May Still Have the Final Say

Few ideas in modern biology have captured the public imagination quite like epigenetics. The promise is seductive: chemical marks on DNA that respond to diet, stress, pollution, and poverty, potentially recording the social environment directly onto our genomes. If true, epigenetics could become what some scholars call a biosocial science, a field capable of tracing how social circumstances become embodied in molecules. But a pointed correspondence published in Epigenetics Communications by Silvio Zaina of the University of Guanajuato argues that this vision rests on a shaky foundation. Writing in reply to an earlier exchange by Luca Chiapperino and Francesco Paneni in Clinical Epigenetics, Zaina contends that the field’s central premise, that epigenetic marks operate independently of DNA sequence, is largely a historical illusion, and that its persistence may derail attempts to connect biology with the social world.

The debate began when Chiapperino and Paneni highlighted a fundamental technical obstacle: epigenetic studies are largely unable to incorporate fine-grained mapping data of an individual’s surrounding social milieu. The same limitation, they noted, afflicts genomics. Zaina accepts this diagnosis and praises the authors for elevating questions of scientific epistemology into public debate. His response, however, goes a step further. He argues that because epigenetic marks are tightly coupled to DNA sequence, epigenetics is structurally doomed to reproduce the very shortcomings of genomics that Chiapperino and Paneni identified. If the sequence sets the stage for most methylation patterns, then no amount of interdisciplinary ingenuity will allow epigenetics to serve as a clean molecular record of social experience.

To understand why, Zaina insists, one must revisit the history of the concept. The term epigenetics traces back to Conrad Waddington’s definition of epigenesis in the 1940s, a description of molecular development that, in Zaina’s view, sits awkwardly with the modern scientific community’s intuition of what the field does. Epigenetics remained poorly understood until genomic imprinting revived it, because DNA methylation offered a mechanism to explain that clearly non-genetic phenomenon. The next breakthrough came with the demonstration that epigenetic marks can be modified by exogenous factors, notably through studies showing that early nutrition could alter methylation of transposable elements. From these milestones emerged the definition now taught in textbooks: a DNA sequence-independent, environmentally sensitive mode of gene regulation, widely adopted as a tool to hunt for markers of non-communicable diseases, particularly in light of genetics’ notorious missing heritability problem.

That definition, Zaina argues, can be dismantled with the field’s own data. The decisive evidence comes from methylation quantitative trait loci, or methylation QTL, first documented by Tycko’s group in 2008. These are genetic variants that predict methylation states at nearby or distant sites, and subsequent surveys show they account for the vast majority of DNA methylation variation in humans. A comprehensive analysis of human tissues found roughly twice as many methylation QTL as expression QTL colocalizing with genetic variants identified by genome-wide association studies. Even a textbook example of sequence dependence has long been available but rarely stated: mammalian CpG islands, the GC-rich regions surrounding many gene promoters, remain generally unmethylated precisely because of their peculiar sequence composition. The genetic grip on epigenetics is further tightened by methodology. Mendelian randomization, which exploits genetic variants as instruments, is currently the best available tool for assessing whether any given DNA methylation profile causally influences a phenotype, a dependence on genetics that Zaina finds telling.

There is also a quantitative prediction that follows from this tight coupling. If methylation is largely sequence-driven, then individual differentially methylated CpG sites should exert comparatively small phenotypic effects, echoing the missing heritability problem that has frustrated geneticists for decades. The available evidence, Zaina notes, suggests that this prediction is correct. He also flags a conceptual confusion at the heart of the field’s self-description: independence from changes in DNA sequence is often cited as the main difference between epigenetics and genetics, yet genetics deals with sequence variation in populations rather than sequence changes, mutations being a relatively minor topic. The distinction, in other words, is less clean than the standard rhetoric implies.

The second pillar of the popular narrative, the idea that the epigenome is an open book on which the environment can freely write, erase, or rewrite information, fares no better in Zaina’s assessment. He points to the controversy surrounding a famous New Yorker article that proposed epigenetics as the mechanism underlying phenotypic divergence between identical twins, an interpretation that drew sharp criticism from prominent epigeneticists. Even more contentious is the hypothesis of epigenetic transgenerational inheritance in humans, the notion that methylation patterns altered by a grandparent’s environment could be transmitted across generations. Reviews of the evidence describe it as highly controversial, with mechanisms in mammals poorly established and human data difficult to disentangle from genetic and cultural confounding.

What remains, once these assumptions are stripped away? In Zaina’s formulation, epigenetics describes a highly sequence-dependent and comparatively weakly environmentally sensitive mode of transcriptional regulation, functionally closer to the activity of transcription factors or DNA-binding long non-coding RNAs than to a free-floating environmental ledger. He even suggests the field might be more accurately renamed paragenetics. Adding micro-RNAs and non-coding RNAs to the definition, he argues, has only deepened the confusion. The counterfactual he poses is striking: had methylation QTL been documented forty years ago rather than in 2008, the current enthusiasm for epigenetics might never have taken hold. Had the higher affinity of DNA methyltransferases for RNA relative to DNA been appreciated earlier, textbooks might describe those enzymes as RNA-binding proteins that modify DNA chemistry.

The stakes of this conceptual housekeeping extend well beyond taxonomy. Zaina’s central concern is that biosocial epigenetics, the quest to find molecular signatures of adverse social environments, whether politically or economically adverse, is likely to uncover genetics-related phenomena rather than pure environmental imprints. Researchers searching for DNA methylation profiles written exclusively by an adverse milieu to explain how social circumstances create and maintain disadvantaged groups will, on his reading, inevitably bump into sequence-dependent variation. Such findings would be highly controversial if they appeared to clash with dominant views in identity politics or social constructivism. The devils of genetics when applied to social sciences and economics are obvious, he writes, but hidden ones may lurk in epigenetics, precisely because the field’s environmental framing can mask its genetic dependencies.

Zaina is careful not to dismiss the enterprise entirely. Reducing the daylight between epigenetics and fine-grained mapping of the social milieu remains, in his words, a noble and useful pursuit, and he credits Chiapperino and Paneni with correctly identifying the problem and acknowledging its difficulty even for the best interdisciplinary research and technological advances. But he insists that the hurdles will only be overcome after a correct understanding of the essence of epigenetics, however dynamic that essence proves to be. His closing question is deliberately uncomfortable: this territory feels remote from pipettes and tubes, and scientists must decide whether they should walk that far at all. The reply, published open access in Epigenetics Communications, ensures that the debate over whether epigenetics can ever truly bridge biology and society will continue, and that any future biosocial science will have to reckon with the sequence it inherits along with the environment it measures.

Subject of Research: The debate over whether epigenetics can function as a biosocial science given its dependence on DNA sequence

Article Title: Will epigenetics ever be a biosocial science? A reply to Chiapperino and Paneni

Article References: Zaina, S. (2023). Will epigenetics ever be a biosocial science? A reply to Chiapperino and Paneni. Epigenetics Communications, 3(1), Article 2. https://doi.org/10.1186/s43682-023-00018-0

Image Credits: AI Generated

DOI: 10.1186/s43682-023-00018-0

Keywords: epigenetics, DNA methylation, methylation QTL, biosocial science, genomics, social epigenomics, transgenerational inheritance, Mendelian randomization, gene regulation, missing heritability, Waddington, CpG islands