Epigenetics research and evolution

This 2017 UK essay was a longish review of how epigenetics and other research has informed evolutionary theory:

“There are several processes by which directed evolutionary change occurs—targeted mutation, gene transposition, epigenetics, cultural change, niche construction and adaptation.

Evolution is an ongoing set of iterative interactions between organisms and the environment..Directionality is introduced by the agency of organisms themselves.”

A few takeaway items concerned:

“It is of course the functional phenotype that is ‘seen’ by natural selection. DNA sequences are not directly available for selection other than through their functional consequences.

..the comparative failure of genome-wide association studies to reveal very much about the genetic origins of health and disease. This is one of the most important empirical findings arising from genome sequencing.

Environmental epigenetic impacts on biology and disease include:

  • Worldwide differences in regional disease frequencies
  • Low frequency of genetic component of disease as determined with genome wide association studies (GWAS)
  • Dramatic increases in disease frequencies over past decades
  • Identical twins with variable and discordant disease frequency
  • Environmental exposures associated with disease
  • Regional differences and rapid induction events in evolution

The above list was from the cited 2016 review “Developmental origins of epigenetic transgenerational inheritance” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933018


I was especially interested in the points about behavior’s role in evolution:

“Differential mutation rates are not essential to enable organisms to guide their own evolution.

If organisms have agency and, within obvious limits, can choose their lifestyles, and if these lifestyles result in inheritable epigenetic changes, then it follows that organisms can at least partially make choices that can have long-term evolutionary impact.”

These discussions provided support for the central question of The PRice “equation” for individually evolving: Which equation describes your life?:

“Applying the “How does a phenotype influence its own change?” question to a person:

How can a person remedy their undesirable traits – many of which are from their ancestral phenotype – and acquire desirable traits?”

http://www.mdpi.com/2079-7737/6/4/47/htm “Was the Watchmaker Blind? Or Was She One-Eyed?”

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The pain societies instill into children

The human subjects of this 2017 Swiss study had previously been intentionally traumatized by Swiss society:

“Swiss former indentured child laborers (Verdingkinder) were removed as children from their families by the authorities due to different reasons (poverty, being born out of wedlock) and were placed to live and work on farms. This was a practice applied until the 1950s and many of the Verdingkinder were subjected to childhood trauma and neglect during the indentured labor.

DNA methylation modifications indicated experiment-wide significant associations with the following complex posttraumatic symptom domains: dissociation, tension reduction behavior and dysfunctional sexual behavior.”


Imagine being taken away from your family during early childhood for no other reason than your parents weren’t married.

Imagine just a few of the painful feelings such a child had to deal with then and ever since. I’m unloved. Alone. No one can help me.

Imagine some of the ways a child had to adapt during their formative years because of this undeserved punishment. How fulfilling it would be to believe that they were loved, even by someone they couldn’t see, touch, or hear. How fulfilling it would be to get attention from someone, anyone. How a child became conditioned to do things by themself without asking for help.

The study described a minute set of measurements of the subjects’ traumatic experiences and their consequential symptoms. The researchers tried to group this tiny sample of the subjects’ symptoms into a new invented category.

https://bmcresnotes.biomedcentral.com/articles/10.1186/s13104-017-3082-y “A pilot investigation on DNA methylation modifications associated with complex posttraumatic symptoms in elderly traumatized in childhood”


Another example was provided in Is IQ an adequate measure of the quality of a young man’s life?:

“During this time period [between 1955 and 1990], because private adoptions were prohibited by Swedish law, children were taken into institutional care by the municipalities shortly after birth and adopted at a median age of 6 mo, with very few children adopted after 12 mo of age.”

Swedish society deemed local institutional care the initial destination for disenfranchised infants, regardless of whether suitable families were willing and able to adopt the infants. What happened to infants who weren’t adopted by age 1?

Did Swedish society really need any further research to know that an adoptive family’s care would be better for a child than living in an institution?


A third example of the pain instilled into children by societies was related to me last year by two sisters. During the Chinese Cultural Revolution, 1966-1976, among other things, parents were required to be out of their households from dawn to late night, leaving the children to fend for themselves.

One of the daily chores for the sisters at ages 6 and 7, after attending school, was to buy food for dinner and the next day’s breakfast and lunch with ration coupons, and prepare the family’s evening meal. They never knew their four grandparents, who had died in ways the sisters either didn’t know or weren’t willing to express to me.

It wasn’t difficult to infer that traumatic childhood events still impacted the women’s lives 50 years later. My empathetic understanding of their histories, though, didn’t improve their current situations. I’ll highlight one of their many affected areas – accepting other people’s assistance.

One of the younger sister’s adaptations at ages 6 to 16 was – and still is – that she feels compelled to do everything herself. Her initial reaction is to reject help, no matter the circumstances. Her thoughts, feelings, and behavior impacted by childhood trauma have also included the opposite reaction of forcing family members – at their prolonged inconvenience and discomfort – to help others.

The older sister, on the other hand, accepts other people’s assistance, maybe too readily. She also lives alone, and sometimes has trouble providing for herself without excessive prompting from her sister. Her societal experiences apparently either taught her or reinforced helplessness.


It’s a challenge for each of us to recognize when our thoughts, feelings, and behavior are evidence of our own continuing responses to childhood pain that’s still with us, influencing our biology.

Let’s not develop hopes and beliefs that the societies we live in will resolve any adverse effects of childhood trauma its members caused. Other people may guide us, but each of us has to individually get our life back.

Europe, Asia, Africa, Australia, North and South America: every society has its horror stories, and there are people still living who can document last century’s events and circumstances. What evidence can be presented to show that traumatic effects on children from societal policies have ceased?

A review of biological variability

This 2017 UK/Spanish review subject was biological variability:

“No two cells in a cellular population are the same, and no two individuals of a multi-cellular species are identical—not even if they share the same genetic makeup like monozygotic twins or cloned animals.

Epigenetic and gene expression variability are key contributors to phenotypic differences..There are many possible sources of epigenetic and transcriptional variability, which can be divided into three main categories:

  1. individual-intrinsic factors;
  2. environmental factors; and
  3. random fluctuations, also referred to as stochasticity.”

Most of the review cited cell studies. The reviewers cited their own studies in the Introduction section, for example:

“These studies were among the first to classify disease status or aggressiveness based on variability, where the classical comparison of mean DNA methylation or gene expression levels was not informative.”

to help support a later observation:

“It is critical to obtain a measurement of variability that is independent of the mean to ensure to not confound changes in variability with shifts in mean.”


The review didn’t cover a pertinent aspect of the subject: how standard research approaches miss detecting biological variability.

For example, from Changing an individual’s future behavior even before they’re born that referred to the methodology of genome-wide association studies (GWAS):

“When phenotypic variation results from alleles that modify phenotypic variance rather than the mean, this link between genotype and phenotype will not be detected.”

Another omission was the point made in A study of DNA methylation and age:

“Due to the methods applied in the present study, not all the effects of DNA methylation on gene expression could be detected; this limitation is also true for previously reported results.

The textbook case of DNA methylation regulating gene expression (the methylation of a promoter and silencing of a gene) remains undetected in many cases because in an array analysis, an unexpressed gene shows no signal that can be distinguished from background and is therefore typically omitted from the analysis.”


The reviewers also didn’t cover variability in phenotypic behaviors. I’ll repeat my thoughts from A limited study of parental transmission of anxiety/stress-reactive traits:

“How did parental behavioral transmission of behavioral traits and epigenetic changes become a subject not worth investigating? These traits and effects can be seen everyday in real-life human interactions, and in every human’s physiology.

Perhaps these omissions reflected the reviewers’ focus on their specialties?

Perhaps it isn’t politically correct to discuss or fund research on aspects of biological variability that would advance science by falsifying preferred previous findings? Or advance science by measuring the extent of parental involvement in shaping their offspring’s behavioral and biological variability?

What do you think?

http://onlinelibrary.wiley.com/doi/10.1002/bies.201700148/full “Epigenetic and Transcriptional Variability Shape Phenotypic Plasticity”

What is a father’s role in epigenetic inheritance?

The agenda of this 2017 Danish review was to establish a paternal role in intergenerational and transgenerational epigenetic inheritance of metabolic diseases:

“There are four windows of susceptibility which have major importance for epigenetic inheritance of acquired paternal epigenetic changes:

  1. paternal primordial germ cell (PGC) development,
  2. prospermatogonia stages,
  3. spermatogenesis, and
  4. during preimplantation.”

The review was a long read as the authors discussed animal studies. When it came to human studies near the paper’s end, though, the tone was of a “we know this is real, we just have to find it” variety. The authors acknowledged:

“To what extent the described DNA methylation changes influence the future health status of offspring by escaping remodeling in the preimplantation period as well as in future generations by escaping remodeling in PGC remodeling has yet to be determined.

These studies have not yet provided an in-depth understanding of the specific mechanisms behind epigenetic inheritance or exact effect size for the disease risk in offspring.

Pharmacological approaches have reached their limits..”

before presenting their belief that a hypothetical series of future CRISPR-Cas9 experiments will demonstrate the truth of their agenda.


The review focused on 0.0001% of the prenatal period for what matters with the human male – who he was at the time of a Saturday night drunken copulation – regarding intergenerational and transgenerational epigenetic inheritance of metabolic diseases. The human female’s role – who she was at conception AND THEN what she does or doesn’t do during the remaining 99.9999% of the prenatal period to accommodate the fetus and prevent further adverse epigenetic effects from being intergenerationally and transgenerationally transmitted  – wasn’t discussed.

Who benefits from this agenda’s narrow focus?

If the review authors sincerely want to:

“..raise societal awareness of behavior to prevent a further rise in the prevalence of metabolic diseases in future generations..”

then earn it! Design and implement human studies to test what’s already known from epigenetic inheritance animal studies per Experience-induced transgenerational programming of neuronal structure and functions.

http://jme.endocrinology-journals.org/content/early/2017/12/04/JME-17-0189.full.pdf “DNA methylation in epigenetic inheritance of metabolic diseases through the male germ line”

An update on brain zapping

This 2017 general-audience article entitled Ultrasound for the brain provided a hyped update on brain zapping:

“Ultrasound could potentially treat other movement disorders, as well as depression, anxiety and a host of intract­able neuropsychiatric disorders..

This could be a breakthrough..

Researchers hope one day to help people with neuropsychiatric conditions by repairing or resetting the relevant neural pathways..

The potential advantages, especially for deep brain areas, are huge..”

Though not the main thrust of the article, another potential use of ultrasound would be to activate drugs delivered to a specific area, as this image portrays:


Vanderbilt University was again at the forefront of brain zapping, as noted in What’s an appropriate control group for a schizophrenia study? for example. I hope the disclaimers for subjects participating in Vanderbilt’s brain-zapping studies made it clear that:

“At high intensities, such as those used to relieve essential tremor, ultrasound’s effects are largely thermal: the tissue heats up and cells die.”

Epigenetic mechanisms regulate bone growth

This 2017 Baltimore/China rodent study found:

“MSPC [Mesenchymal stem/progenitor cell] senescence is epigenetically controlled by the polycomb histone methyltransferase enhancer of zeste homolog 2 (Ezh2) and its trimethylation of histone H3 on Lysine 27 (H3K27me3) mark. Ezh2 maintains the repression of key cell senescence inducer genes through H3K27me3.

Our work establishes the role of Ezh2-H3K27me3 as a key epigenetic regulator that controls the onset and progression of MSPC senescence during the transition of fast- to slow-growing phase of long bones.

The self-renewal and proliferative capacity of cells in primary spongiosa of fast-growing bones are maintained by a high level of Ezh2-H3K27me3, whereas loss of Ezh2-H3K27me3 during late puberty leads to cell senescence.”

One of the experiments led to this note in the Discussion section:

“An epidemiologic study demonstrated that 60% of the risk of osteoporosis can be explained by the bone mineral acquired by early adulthood.

Our finding that deletion of Ezh2 in nestin+ cells during early puberty increases the risk of osteoporosis in later adulthood suggests that premature cellular senescence in the primary spongiosa region during the prepubertal or early pubertal phase may also be a major cause of osteoporosis/bone loss in later life.”


The study was short of explanations in several areas. For example, causes for the effect of “loss of Ezh2-H3K27me3 during late puberty” weren’t specified.

In another example, this statement referenced nestin-positive cells:

“Because these cells are likely no longer required in this particular region during adulthood, they stop proliferating and undergo senescence during late puberty.”

but what caused the cells to be “no longer required” wasn’t specified.

The “programmed” and “fate” words were used in the Abstract:

“Our data reveals a programmed cell fate change in postnatal skeleton..”

but not explained until the Discussion section:

“The senescence process is program[m]ed by a conserved mechanism because it restricts in a particular region of long bone and follows a specific time course.”

https://www.nature.com/articles/s41467-017-01509-0 “Programmed cell senescence in skeleton during late puberty”

Does a societal mandate cause DNA methylation?

This 2017 worldwide meta-analysis of humans of recent European ancestry found:

“Here we provide evidence on the associations between epigenetic modifications-in our case, CpG methylation and educational attainment (EA), a biologically distal environmental factor that is arguably among the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study [EWAS] meta-analysis of EA based on data from 27 cohort studies with a total of 10,767 individuals.”

No association was found between the societal mandate of educational attainment and the most widely studied epigenetic mark found in individuals.


The authors preregistered the analysis plan. This discouraged the fishing expeditions that researchers are so often tempted to go on when the study data find for the null hypothesis, as this meta-analysis did.

I was puzzled that the researchers described part of the preregistered analysis plan to be:

“..hypothesis-free as it is performed genome-wide without an expected direction of effect for individual CpG loci.”

The abstract, though, declared:

“If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.”

Was the meta-analysis “hypothesis-free” or did it have “the hypothesis that such factors have large effects on the epigenome”?


Society mandates year after year of school attendance. The mandate continues on to require a four-year degree just to get an entry-level job in many lines of work.

The researchers stated:

“..our EWAS associations are small in magnitude relative to the EWAS associations reported for more biologically proximal environmental factors.”

These factors – BMI, smoking, alcohol consumption, and maternal smoking – all had detrimental effects. What about the effects of educational attainment?

Would a study categorize it as detrimental when an individual breaks from expectations about what they should do, and terminates their educational attainment? One individual I know didn’t go to graduate school after Princeton although they were capable of quality graduate and doctorate work. It would be detrimental to their life if they stopped a career that pays several hundred thousands of dollars a year to go back to school.

Would a study evaluate it as beneficial when an individual lengthens their educational attainment past society’s thirteen-year educational requirement? Would the extra four years still be considered beneficial when they – after foregoing four years of income, and accumulating tens of thousands of dollars of nondischargeable debt – achieve the expected outcome of an entry-level job, and then can’t unassistedly provide for their basic needs?

Are further epigenetic studies of educational attainment as an environmental factor really worthwhile? How about using research funds and efforts on more promising topics like human transgenerational epigenetic inheritance? Suitable subjects may already be selected for the researcher, as several of the “27 cohort studies” that provided data for this meta-analysis included at least three human generations.

http://www.nature.com/mp/journal/vaop/ncurrent/full/mp2017210a.html “An epigenome-wide association study meta-analysis of educational attainment”


Here’s 48 minutes of Brian Nosek, a co-founder of the Open Science Framework (where this meta-analysis was preregistered), explaining why science needs openness like the coordination displayed here:

http://rationallyspeakingpodcast.org/show/rs-172-brian-nosek-on-why-science-needs-openness.html