In a recent post I summarize the May 2014 article “Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder.” This article details the gathering and analysis of genetic data in order to determine whether ASD has genetic or epigenetic causes. One of the causes associated with ASD is advanced maternal age (AMA), although the reasons for this association between the increased risk of ASD and AMA are unknown. What is known is that the eggs of older women are more prone to chromosomal abnormalities, so these genetic mutations have been suggested as a likely reason for this association between AMA and ASD. However, as the authors write, “age is also associated with a loss of control of epigenetic regulatory patterns that govern gene expression,” which suggests epigenetic dysregulation as a second potential mechanism.
To test whether increased risks of ASD associated with AMA are genetic or epigenetic in origin, the authors tested specific cell types from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of that were 35 years or older at the time of birth. Using a variety of sophisticated methods, the authors find that while the genes previously associated with ASD are still implicated in ASD, the causes of ASD associated with AMA operate through epigenetic dysregulation rather than through mutations in DNA sequences as commonly thought.
Besides the isolation of epigenetic mechanisms—and not genetic mutations—as the likely cause for the increased risk of ASD, there are a number of other aspects of the impact of epigenetics suggested by this article.
First, to test these competing hypotheses the authors utilized both genome-wide and epigenome-wide analyses on the same data. In doing so they were able to disqualify the genetic explanation for ASD and provide evidence to support an epigenetic cause. In other posts I have written about the benefits of combining genomic and epigenomic analyses. Gene sequencing processes are the preferred methods for analyzing genetic material for diagnostic and predictive purposes, but for however much these processes reveal about gene sequence they reveal nothing about the three-dimensional structure of the gene.
As discussed in more depth in this post, the physical structure of the gene can serve important regulatory functions because genes can be distant from each other in sequence but genes which are sequentially distant can actually be close to each other in three-dimensional space, which then allows them to interact in ways which are not detectable using conventional sequencing. As shown in this video, this three-dimensional structure is determined and manipulable through epigenetic mechanisms; therefore, this structure and its regulatory effects cannot be revealed through analyses of genetic sequence alone, but must include considerations of structure as well.
One practical area in which the combination of genomics and epigenetics would yield substantial results is in drug discovery, which currently relies almost exclusively on gene sequencing. As discussed in this post, epigenetic data can also be used to identify biological pathways linking a disease phenotype to an approved drug therapy. The article cited above provides yet another example of the benefits which can come from combining both genomics—for gene sequence—and epigenetics—for gene structure.
Another interesting point revealed by this article on the epigenetic dysregulation in ASD is one I also talk about in a series of posts about the challenges epigenetics pose not just to contemporary genetics but to contemporary ethics as well. Our contemporary ethics are based upon a very culturally specific and historically contingent conception of the self as distinct from the environment and from other selves. What is not well-known, though, is that the scientific concept of the modern genome as isolated from its environment has its own roots in this same cultural and historical history.
As discussed in more depth in this post, an important historical moment in this common history is the development of the concept of the ‘soul’ via Thomas Aquinas. In his conception of the soul, which eventually becomes our modern concept of the self and the genome, Aquinas relies heavily upon Aristotle’s ontogeny of form and matter. An important aspect of this historical moment is the emphasis both Aristotle and Aquinas place on substance versus accidents in the formation of things—substances are the pure expression of the combination of form (the soul) and matter; accidents are those things which accrue to substances but which are not those substances, and which therefore are not carried on by the soul after the death of the body.
The corollary of this ontogeny in genetics involves the central ‘dogma’ of molecular biology as enunciated by Francis Crick and discussed in this post which details how information only emanates out of but not back into DNA. One of the fundamental challenges of epigenetics to conventional genetics involves the inheritance of environmental ‘accidents’ which is fundamentally not allowed by Crick’s principle. While conventional genetics allows that environmental influences may affect the expression of the genes, except in rare cases these accidents (i.e., mutations) do not become part of the genome and are supposedly discarded via processes such as genomic imprinting, thereby rendering a pristine copy of the form (or soul) of the species to individuals of the next generation. However, as discussed in the article on epigenetic dysregulation and ASD above, it appears that these environmental ‘accidents’ may actually constitute an integral part of the ‘soul’ which is passed on to subsequent generations. This is one of the fundamental challenges of epigenetics to both conventional genetics and contemporary ethics.
An article recently published in Nature magazine titled “Society: Don’t Blame the Mothers” also discusses these ethical challenges from epigenetics. In this article, the authors warn that “careless discussion of epigenetic research on how early life affects health across generations could harm women.” The issue the authors have with the findings from research in epigenetics is how much emphasis is placed on women during maternity which could stigmatize women “making scapegoats of mothers, and could even increase surveillance and regulation of pregnant women.”
The main worry expressed in this article is that mothers will be held to unreasonable standards of behavior because of their close biological connection to the infant via the uterine environment. However, as discussed in epigenetics research too numerous to list, not just the environmental conditions and the choices of mothers are implicated by epigenetics but also those of fathers; and not just of the immediate parents but of grandparents, great grandparent and so on.
All this presents a prime example of the significant complications introduced into conventional ethics by epigenetics. Given our contemporary perception of self as an autonomous center of action, combined with the belief that we are all born with a genetic slate wiped clean of past environmental influences, humans are assumed to be largely responsible for their own individual choices and behaviors; this is the root of the justification we feel for punishing individuals for their actions. If humans were not autonomous, and actually owed significant aspects of their current constitution to the choices and environmental circumstances of parents and grandparents, then how justified is punishment or even stigmatization of the current individual? If such important aspects of self can be traced back and linked directly to the choices and behaviors of parents and grandparents and possibly even great-grandparents, how far back is it justifiable to locate credit or blame for contemporary outcomes? Likewise, how much regulation and even punishment of contemporary choices or behaviors is justified if these links to the health and well-being of two or three subsequent generations down the line can be scientifically demonstrated?
In other words, to truly incorporate the implications of epigenetics requires not only a fundamental reconceptualizing of many aspects of contemporary genetics and biology, but also a fundamental reconceptualization of not only just our ethics but also our political and legal systems to reflect these changes in ethics. For example, the authors of the Nature article recommend that to truly incorporate the findings from epigenetics in a reasonable manner would require acknowledging the complexities involved in human development—that just as intrauterine exposures “can raise or lower disease risk…so too can a plethora of other intertwined genetic, lifestyle, socio-economic and environmental factors that are poorly understood”—as well as recognizing the role of society as a whole in these conditions, as many of the intrauterine stressors identified as having adverse intergenerational effects are also correlated with social gradients of class, race and gender, which “points to the need for societal changes rather than individual solutions.”
These are not minor changes; these are sweeping conceptual, societal and political changes, which is an indication of just how much epigenetics challenges the basic conventions and institutions of contemporary life. As I discuss in one series of posts on the history of epigenetics and another series of posts on its implications for our ethical structures, this magnitude of the challenges of epigenetics to these fundamental social institutions is one reason for the entrenched resistance to epigenetics, though few realize it as such. Most base their objections to epigenetics on scientific grounds, but these kinds of disputes are or at least should be resolvable through scientific methods; what is interesting—as pointed out in this brief history of epigenetics—is how much effort has been and still is devoted to keeping these challenges from epigenetics from ever reaching the arena of dispute on scientific grounds. There is no real scientific basis for these efforts to exclude legitimately scientific treatments of epigenetics, which again suggests that these objections to epigenetics may have their roots in issues even deeper than science.
Am I completely off-base? Or is there something to what I’ve written? Are most of the objections to epigenetics reasonable and science-based, or might there be something more? I am curious to hear what you think. Leave your comments below and I will respond.
Also, if you find these thoughts I’ve shared interesting and worthwhile, Like this post, Reblog it, or Tweet about it using the buttons below.