Epigenetic effects on genetic diseases

This 2017 review provided evidence for epigenetic effects on a disease widely considered to be of genetic origins:

“..for a T1D [type 1 diabetes] identical twin the concordance rate (both twins affected)..is consistently less than 100%, which implies a non-genetically determined effect. However, the concordance rate declines with age at diagnosis of the index twin, indicating that in adult-onset T1D the genetic impact is limited, and certainly lower than that in childhood-onset disease.

Genes associated with T1D are well-established and have four broad functions..However, T1D is unlikely to be a single disease since there is disease heterogeneity..the incidence of T1D has even increased several-fold in the last 30 years-a timeframe which rules out genetic evolution. In addition, studies of the incidence of T1D in migrant populations have shown a convergence towards the risk of the host population.

Alongside histone modifications and transcription factors, several cis-regulatory elements, including enhancers, promoters, silencers and insulators, are crucial to the function of the genome..There are more than a million enhancers; therefore, many more than there are genes, so that a number of genes are regulated by the same enhancer, which may co-localise with CpGs. Gene enhancers can be found upstream or downstream of genes and do not necessarily act on the closest promoter..Enhancers may be accompanied by insulators, which are located between the enhancers and promoters of adjacent genes and can limit phenotypic gene expression despite genetic activation.”


The review was weak in a few areas. The authors repeated a laughable claim for gross national product as a non-genetic effect for Type 1 diabetes. They also made other hyperbolic statements such as “..this observation illustrates the power of epigenetic analysis to identify those cells which are actively using the genes associated with a given tissue, given that all cells contain every gene..” that were out of place with the review’s evidential bases.

https://link.springer.com/article/10.1007/s11892-017-0916-x “The Role of Epigenetics in Type 1 Diabetes”

Epigenetics account for two-thirds of Alzheimer’s disease

The genetics percentage from a 2017 summary of Alzheimer’s disease research caught my eye:

“Although numerous single nucleotide polymorphisms (SNPs) have now been robustly associated with AD via genome-wide association studies and subsequent meta-analyses, collectively these common SNPs are believed to only account for 33% of attributable risk and the mechanism behind their action remains largely unknown.”

This citation aligned with other studies’ findings per Using twins to estimate the extent of epigenetic effects that on cellular levels, our experiences account for two-thirds of who we are.


The promise of this category of epigenetics research?

“One of the most exciting aspects of identifying disease-associated epigenomic dysfunction is that these mechanisms are potentially reversible.”

Let’s make research on reversing epigenetic changes a priority for funding, and get studies underway here in 2017!

https://www.epigenomicsnet.com/users/27784-katie-lunnon/posts/14634-robust-evidence-for-dna-methylomic-variation-in-alzheimer-s-disease “Robust evidence for DNA methylomic variation in Alzheimer’s disease” (Registration required)

Epigenetics and addiction

Dr. Moshe Szyf of McGill University explains current rodent epigenetic research into addiction in this October 2016 interview.

“What happens during the time when there’s no drug [cocaine] exposure, there’s just the memory of the original drug exposure? And we found huge epigenetics changes during this time, the time of abstinence.

It actually suggests that abstinence cannot cure addiction. It might even aggravate it.

We found out that timing is very important. Pairing the drug [a DNA methylation inhibitor] administration with the cue was critical with reversing the epigenetic effects and the behavioral effects.

Epigenetic treatment should theoretically reprogram the animal to forget or erase the epigenetic consequences of the initial exposure. And therefore the animal should be protected from addiction for a long time if indeed we found what we thought we did with epigenetic reprogramming.”

https://www.epigenomicsnet.com/users/3002-georgia-patey/videos/13003-video2

On Primal Therapy with Drs. Art and France Janov

Experiential feeling therapy addressing the pain of the lack of love.

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.”

http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006004 “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:

http://www.pnas.org/content/113/21/E3002.full “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.”

http://journals.plos.org/plosgenetics/article?id=10.1371%2Fjournal.pgen.1005993 “Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders”