Genetic imprinting, sleep, and parent-offspring conflict

This 2016 Italian review subject was the interplay of genetic imprinting and sleep regulation:

“Sleep results from the synergism between at least two major processes: a homeostatic regulatory mechanism that depends on the accumulation of the sleep drive during wakefulness, and a circadian self-sustained mechanism that sets the time for sleeping and waking throughout the 24-hour daily cycle.

REM sleep apparently contravenes the restorative aspects of sleep; however, the function of this ‘paradoxical’ state remains unknown. Although REM sleep may serve important functions, a lack of REM sleep has no major consequences for survival in humans; however, severe detrimental effects have been observed in rats.

Opposite imprinting defects at chromosome 15q11–13 are responsible for opposite sleep phenotypes as well as opposite neurodevelopmental abnormalities, namely the Prader-Willi syndrome (PWS) and the Angelman syndrome (AS). Whilst the PWS is due to loss of paternal expression of alleles, the AS is due to loss of maternal expression.

Maternal additions or paternal deletions of alleles at chromosome 15q11–13 are characterized by temperature control abnormalities, excessive sleepiness, and specific sleep architecture changes, particularly REM sleep deficits. Conversely, paternal additions or maternal deletions at chromosome 15q11–13 are characterized by reductions in sleep and frequent and prolonged night wakings.

The ‘genomic imprinting hypothesis of sleep’ remains in its infancy, and several aspects require attention and further investigation.” “Genomic Imprinting: A New Epigenetic Perspective of Sleep Regulation”

A commenter to the review referenced a 2014 study Troubled sleep: night waking, breastfeeding, and parent–offspring conflict that received several reactions, including one by the same commenter. Here are a few quotes from the study author’s consolidated response:

“‘Troubled sleep’ had two major purposes. The first was to draw attention to the oppositely perturbed sleep of infants with PWS and AS and explore its evolutionary implications. The involvement of imprinted genes suggests that infant sleep has been subject to antagonistic selection on genes of maternal and paternal origin with genes of maternal origin favoring less disrupted sleep.

My second major purpose was a critique of the idea that children would be happier, healthier and better-adjusted if we could only return to natural methods of child care. This way of thinking is often accompanied by a belief that modern practices put children at risk of irrevocable harm. The truth of such claims is ultimately an empirical question, but the claims are sometimes presented as if they had the imprimatur of evolutionary biology. This appeal to scientific authority often seems to misrepresent what evolutionary theory predicts: that which evolves is not necessarily that which is healthy.

Why should pregnancy not be more efficient and more robust than other physiological systems, rather than less? Crucial checks, balances and feedback controls are lacking in the shared physiology of the maternal–fetal unit.

Infant sleep may similarly lack the exquisite organization of systems without evolutionary conflict. Postnatal development, like prenatal development, is subject to difficulties of evolutionarily credible communication between mothers and offspring.”

The author addressed comments related to attachment theory:

“Infants are classified as having insecure-resistant attachment if they maintain close proximity to their mother after a brief separation while expressing negative emotions and exhibiting contradictory behaviors that seem to both encourage and resist interaction. By contrast, infants are classified as having insecure-avoidant attachment if they do not express negative emotion and avoid contact with their mother after reunion.

Insecure-avoidant and insecure-resistant behaviors might be considered antithetic accommodations of infants to less responsive mothers; the former associated with reduced demands on maternal attention, the latter with increased demands. A parallel pattern is seen in effects on maternal sleep. Insecure-avoidant infants wake their mothers less frequently, and insecure-resistant infants more frequently, than securely attached infants.

Parent–child interactions are transformed once children can speak. Infants with more fragmented sleep at 6 months had less language at 18 and 30 months. Infants with AS have unconsolidated sleep and never learn to speak. The absence of language in the absence of expression of one or more MEGs [maternally expressed imprinted genes] is compatible with a hypothesis in which earlier development of language reduces infant demands on mothers.”

Regarding cultural differences:

“China, Taiwan and Hong Kong have both high rates of bed-sharing and high rates of problematic sleep compared with western countries. Within this grouping, however, more children sleep in their own room but parents report fewer sleep problems in Hong Kong than in either China or Taiwan. Clearly, cultural differences are significant, and the causes of this variation should be investigated, but the differences cannot be summarized simply as ‘west is worst’.

The fitness [genetic rather than physical fitness] gain to mothers of an extra child and the benefits for infants of longer IBIs [interbirth intervals] are substantial. These selective forces are unlikely to be orders of magnitude weaker than the advantages of lactase persistence, yet the selective forces associated with dairying have been sufficient to result in adaptive genetic differentiation among populations. The possibility of gene–culture coevolution should not be discounted for behaviors associated with infant-care practices.”

Regarding a mismatch between modern and ancestral environments:

“I remain skeptical of a tendency to ascribe most modern woes to incongruence between our evolved nature and western cultural practices. We did not evolve to be happy or healthy but to leave genetic descendants, and an undue emphasis on mismatch risks conflating health and fitness.

McKenna [a commenter] writes ‘It isn’t really nice nor maybe even possible to fool mother nature.’ Here I disagree. Our genetic adaptations often try to fool us into doing things that enhance fitness at costs to our happiness.

Our genes do not care about us and we should have no compunction about fooling them to deliver benefits without serving their ends. Contraception, to take one obvious example, allows those who choose childlessness to enjoy the pleasures of sexual activity without the fitness-enhancing risk of conception.

Night waking evolved in environments in which there were strong fitness costs from short IBIs and in which parents lacked artificial means of birth-spacing. If night waking evolved because it prolonged IBIs, then it may no longer serve the ends for which it evolved.

Nevertheless, optimal infant development might continue to depend on frequent night feeds as part of our ingrained evolutionary heritage. It could also be argued that when night waking is not reinforced by feeding, and infants sleep through the night, then conflict within their genomes subsides. Infants would then gain the benefit of unfragmented sleep without the pleiotropic costs of intragenomic conflict. Plausible arguments could be presented for either hypothesis and a choice between them must await discriminating evidence.”

Commenters on the 2014 study also said:

[Crespi] The profound implications of Haig’s insights into the roles of evolutionary conflicts in fetal, infant and maternal health are matched only by the remarkable absence of understanding, appreciation or application of such evolutionary principles among the research and clinical medical communities, or the general public.

[Wilkins] A mutation may be selected for its effect on the trait that is the basis of the conflict, but that mutation also likely affects other traits. In general, we expect that these pleiotropic effects to be deleterious: conflict over one trait can actually drive other traits to be less adapted. Natural selection does not necessarily guarantee positive health outcomes.

[McNamara] Assuming that AS/REM is differentially influenced by genes of paternal origin then both REM properties and REM-associated awakenings can be better explained by mechanisms of genomic conflict than by traditional claims that REM functions as an anti-predator ‘sentinel’ for the sleeping organism.

[Hinde] Given this context of simultaneous coordination and conflict between mother and infant, distinguishing honest signals of infant need from self-interested, care-extracting signals poses a challenge.


The persistence of epigenetic marks in Type 1 diabetes

This 2016 California human study found:

“A persistency of DNA methylation over time at key genomic loci associated with diabetic complications. Two sets of DNAs collected at least 16–17 years apart from the same participants are used to show the persistency of DNA-me over time.

Twelve annotated differentially methylated loci were common in both WB [whole blood] and Monos [blood monocytes], including thioredoxin-interacting protein (TXNIP), known to be associated with hyperglycemia and related complications.

The top 38 hyperacetylated promoters in cases included 15 genes associated with the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inflammatory pathway, which is strongly associated with diabetic complications.”

The researchers built on a series of studies that showed how subjects with early intensive interventions didn’t develop further complications, whereas subjects with later intensive interventions:

“Continued to develop complications, such as nephropathy, retinopathy, and macrovascular diseases, at significantly higher rates.

This persistence of benefit from early application of intensive therapy, called ‘metabolic memory,’ is an enigma.”

I’d say that the researchers needed to also consider a point of Enduring memories? Or continuous toxic stimulation? that:

“The lasting epigenomic effect would not be due to memory, but continuous stimulation by persistent pathogens or persistent components.”

Other studies that involved specific genes of this study include: “Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort”


A study of genetic imprinting and neurodevelopmental disorders

This 2016 UK human study assessed the roles of genetic imprinting on diseases that may originate from a certain interval on chromosome 15:

“The 15q11.2-q13.3 region contains a cluster of imprinted genes, which are expressed from one parental allele only as a consequence of germline epigenetic events.

The importance of epigenetic status of duplications at this interval was further underlined by analysis of a number of families. Duplications in two unaffected mothers had a DNA-methylation pattern indicative of being paternally derived, whereas their offspring, who possessed a maternally derived duplication, suffered from psychotic illness.

We clearly implicate 15q11.2-q13.3 interstitial duplications of paternal origin in the aetiology of DD [developmental delay], but do not find them at increased rates in SZ [schizophrenia], which is significantly associated only with duplications of maternal origin.

This study refines the distinct roles of maternal and paternal duplications at 15q11.2-q13.3, underlining the critical importance of maternally active imprinted genes in the contribution to the incidence of psychotic illness.”

The researchers analyzed other studies for better estimates of paternal involvement:

“We show for the first time that paternal duplications are pathogenic. One reason why paternal duplications have been regarded as non-pathogenic in the past is their rare occurrence in patients. Here we demonstrate that they are also rare in the general population as a whole.

Paternal duplications should be less efficiently eliminated from the population by negative selection pressure, due to their lower penetrance for neurodevelopmental disorders. Secondly, some maternal duplications will change to paternal when transmitted from male carriers.

We now suggest one further explanation for their rarity: male patients with SZ and other neurodevelopmental disorders have lower fecundity. Men suffering with SZ have only half the number of offspring compared to women with SZ.”

I would have liked further discussion of the “germline epigenetic events” that apparently contribute to the studied problems. These epigenetic abnormalities may have the potential to be prevented or treated, or at least used as early biomarkers.

The reviewers instead focused on:

“This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.” “Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders”

Why drugs aren’t ultimately therapeutic

This 2016 Oregon review’s concept was the inadequacy of drug-based therapies, explored with the specific subject of epilepsy:

“Currently used antiepileptic drugs:

  • [aren’t] effective in over 30% of patients
  • [don’t] affect the comorbidities of epilepsy
  • [don’t] prevent the development and progression of epilepsy (epileptogenesis).

Prevention of epilepsy and its progression [requires] novel conceptual advances.”

The overall concept that current drug-based therapies poorly address evolutionary biological realities was illustrated by a pyramid, with the comment that:

“If the basis of the pyramid depicted in Figure 1 is overlooked, it becomes obvious that a traditional pharmacological top-down treatment approach has limitations.”

Why drug ultimately aren't therapeutic

I would have liked the reviewer to further address the “therapeutic reconstruction of the epigenome” point he made in the Abstract:

“New findings based on biochemical manipulation of the DNA methylome suggest that:

  1. Epigenetic mechanisms play a functional role in epileptogenesis; and
  2. Therapeutic reconstruction of the epigenome is an effective antiepileptogenic therapy.”

As it was, the reviewer lapsed into the prevalent belief that the causes of and cures for human diseases will always be found on the molecular level – for example, the base of the above pyramid – and never in human experiences. This preconception leads to discounting human elements – notably absent in the above pyramid – that generate epigenetic changes.

A consequence of ignoring experiential causes of diseases is that the potential of experiential therapies to effect “therapeutic reconstruction of the epigenome” isn’t investigated. “The Biochemistry and Epigenetics of Epilepsy: Focus on Adenosine and Glycine”

Epigenetic remodeling creates immune system memory

Innate immune memory

This 2016 German review was of the memory characteristics of immune cells:

“Innate immune memory has likely evolved as an ancient mechanism to protect against pathogens. However, dysregulated processes of immunological imprinting mediated by trained innate immunity may also be detrimental under certain conditions.

Evidence is rapidly accumulating that innate immune cells can adopt a persistent pro-inflammatory phenotype after brief exposure to a variety of stimuli, a phenomenon that has been termed ‘trained innate immunity.’ The epigenome of myeloid (progenitor) cells is presumably modified for prolonged periods of time, which, in turn, could evoke a condition of continuous immune cell over-activation.”

The reviewers focused on the particular example of atherosclerosis, although other examples were discussed of epigenetic remodeling to acquire immune memory:

“In the last ten years, several novel non-traditional risk factors for atherosclerosis have been identified that are all associated with activation of the immune system. These include chronic inflammatory diseases such as:

as well as infections with bacteria or viruses.”

The reviewers also discussed diet, mainly of various diets’ negative effects. On the positive side, I was interested to see a study referenced that used a common dietary supplement:

“Pathway analysis of the promoters that were potentiated by β-glucan identified several innate immune and signaling pathways upregulated in trained cells that are responsible for the induction of trained immunity.”

Other research into the epigenetic remodeling of immune system memory includes: “Long-term activation of the innate immune system in atherosclerosis”

Lack of oxygen’s epigenetic effects

This 2016 Finnish review’s subject was the epigenetic effects of hypoxia:

“Ever since the Cambrian period, oxygen availability has been in the center of energy metabolism. Hypoxia stabilizes the expression of hypoxia-inducible transcription factor-1α (HIF-1α), which controls the expression of hundreds of survival genes related to enhanced energy metabolism and autophagy.

There are several other signals, mostly related to stresses, which can increase the expression of HIF factors and thus improve cellular survival. However, a chronic activation of HIF factors can have detrimental effects, e.g. stimulate cellular senescence and tissue fibrosis commonly enhanced in age-related diseases.

Stabilization of HIF-1α increases the expression of histone lysine demethylases (KDM). Hypoxia-inducible KDMs support locally the gene transcription induced by HIF-1α, although they can also control genome-wide chromatin landscape, especially KDMs which demethylate H3K9 and H3K27 sites (repressive epigenetic marks).”

Gene areas where HIF-1α is involved include:

  • “angiogenesis
  • autophagy
  • glucose uptake
  • glycolytic enzymes
  • immune responses
  • embryonic development
  • tumorigenesis
  • generation of miRNAs.”

Figure 1 was instructive in that the reviewers pointed out the lack of a feedback mechanism in HIF-1α signaling. A natural lack of feedback to the HIF-1α signaling source contributed to diseases such as:

  • “age-related macular degeneration
  • cancer progression
  • chronic kidney disease
  • cardiomyopathies
  • adipose tissue fibrosis
  • inflammation
  • detrimental effects which are linked to epigenetic changes.”

The point was similar to a study referenced in The PRice “equation” for individually evolving: Which equation describes your life? that:

“Evolution may preferentially mitigate damage to a biological system than reduce the source of this damage.”

The review was complicated primarily because the subject has many interdependencies and timings within a complex network. Contexts are important:

“The cross-talk between NF-κB [nuclear factor kappa B] and HIF-1α in inflammation might be organized in cell type and context-dependent manner.

It seems that ROS [reactive oxygen species] affect the HIF-1α signaling in a context-dependent manner.

Hypoxia stimulated the expression of KDM3A and KDM4B genes in different cellular contexts. Given that KDM3A and KDM4B are the major histone demethylases which remove the repressive H3K9 sites, their role as transcriptional cofactors seems to be important in the activation of HIF-1α signaling..members of KDM4 subfamily have a crucial role in the DNA repair systems, although the responses seem to be enzyme-specific and appear in a context-dependent manner.

Acute hypoxia can stimulate cell-cycle arrest but does not provoke cellular senescence in all contexts.”

It wasn’t mentioned that hypoxia evokes cellular Adaptations to stress encourage mutations in a DNA area that causes diseases.

The review was tailored for the publishing journal Aging and Disease, and the subject was best summed up by:

“HIF-1α can control cellular fate in adult animals, either stimulating proliferation or triggering cellular senescence, by regulating the expression of different KDMs in a context-dependent manner.”

The review covered hypoxic conditions during human development that are clearly the origins of many immediate and later-life diseases. However, the cited remedies only addressed symptoms.

That these distant causes can no longer be addressed is a hidden assumption of research and treatment of effects of health problems. Aren’t such assumptions testable here in 2016? “Hypoxia-Inducible Histone Lysine Demethylases: Impact on the Aging Process and Age-Related Diseases”

Using epigenetic outliers to diagnose cancer

This 2016 Chinese/UK human cancer cell study tested five algorithms and found:

“Most of the novel proposed algorithms lack the sensitivity to detect epigenetic field defects at genome-wide significance. In contrast, algorithms which recognise heterogeneous outlier DNA methylation patterns are able to identify many sites in pre-neoplastic lesions, which display progression in invasive cancer.

Many DNA methylation outliers are not technical artefacts, but define epigenetic field defects which are selected for during cancer progression.”

The usual method of epigenetic studies involves:

“Identify genomic sites where the mean level of DNAm [DNA methylation] differs as much as possible between the two phenotypes. As we have seen however, such an approach is seriously underpowered in cancer studies where tissue availability is a major obstacle.

In addition to allelic frequency, we also need to take the magnitude of the alteration into consideration. As shown here, infrequent but bigger changes in DNAm (thus defining outliers) are more likely to define cancer field defects, than more frequent yet smaller DNAm changes.”

A similar point was made in Genetic statistics don’t necessarily predict the effects of an individual’s genes:

“Epigenomic analyses are limited by averaging of population-wide dynamics and do not inform behavior of single cells.”

One of the five tested algorithms was made freely available by the researchers. The limitations on its use were discussed, and included:

“Studies conducted in a surrogate tissue such as blood are scenarios where DNAm outliers are probably not of direct biological relevance to cancer development.” “Stochastic epigenetic outliers can define field defects in cancer”