Autism and the methylome

Q: When is an identical twin not an identical twin? A: Pretty much all the time (at least according to some people) as our increasing understanding of the complexity of genetics stretches and modifies long-held beliefs about the building blocks of life and their role in our health and wellbeing.

DNA methylation differences? @ Wikipedia  

Today I'm talking about identical (monozygotic) twins - siblings derived from one fertilised egg - and how the science of epigenetics might have some interesting implications for autism research as per the study by Chloe Wong and colleagues* (open-access). I should perhaps also direct you to some other interesting research recently discussed in this area too (see here) which might be relevant.

Regular readers will probably already know about my amateur interest in epigenetics (see here and here) and how the area of the epigenome - those chemical marks which have the ability to influence the expression of the genome - has started to yield some potentially important observations. At times I'll admit to being slightly too over-excited at the possibilities of epigenetics. Subsequently brought back down to earth by more sobering accounts (see here**) but not yet ready to poo-poo the whole science just yet***.

I don't want to rehash the whole epigenetic story in this one post, so instead am going to concentrate on the particular area covered by Wong et al and their analysis of the methylome (yes, another -ome for you) which is concerned with the addition of methyl groups to various regions of the genome and how that subsequently alters the expression of genes. DNA methylation has been a sort of peripheral topic in relation to cases of autism for quite some time now; brought to the forefront by all that folic acid (see here) and MTHFR research (see here) and the availability of those lovely methyl groups. Suffice to say that we are still very much at the beginning when it comes to looking at the relationship between all these elements and very complicated conditions like autism.

Anyhow, after that very long introduction (I am only an amateur science blogger after all), a few details from the Wong paper might be in order, bearing in mind it is open-access:

• Part of the UK TEDS initiative and partly sponsored by Autism Speaks who were involved in that recent environmental epigenetics symposium (see here), researchers looked at 50 monozygotic (MZ) twin pairs. It wasn't just a case of 25 twin pairs where one twin was diagnosed with an autism spectrum disorder (ASD) compared with 25 twin pairs where both were concordant for ASD. No, instead the authors looked at a variety of phenotypic combinations based on concordance/discordance for ASD and various core traits based on the Childhood Autism Symptom Test (CAST) schedule. Supplementary table 1 shows the combinations (see here).
• A genome-wide analysis of DNA methylation was undertaken on blood samples provided by participants. I can't pretend to intimately know all the techniques that were employed so won't profess to do so. What I can glean from the paper is that both DNA methylation differences between MZ twin pairs discordant for ASD and analyses between groups scoring high and low on the various core symptom areas were completed with "the aim of identifying real, biologically relevant within-twin and between group DNA methylation differences".
• Results: "ASD is not associated with systemic differences in global DNA methylation". In other words, within the twins, there is quite a high degree of similarity when it comes to patterns of DNA methylation. This might tie in with other work looking at methylation in cases of autism and other family members (see here). 
• When looking at DNA methylation patterns between twin pairs discordant for ASD, specific sites of the genome however seemed to show some variability as a function of ASD diagnosis or not. The authors list the top 50 "differentially methylated CpG sites" (see here) showing gene and position, with a combination of hyper- and hypo-methylated regions identified. Top of the methylation differences pops was the NFYC promoter which was "consistently hypermethylated in affected individuals" (see here for some additional papers on this gene). Hypermethylation by the way, generally means gene silencing as per its function when it comes to transposons (think HERVs). 
• Various other data are presented based on either syndrome or trait specific differences across the twins. I'm not going to go through all of these because, well because that's called plagiarism. I will draw your attention to one particular finding which might be important as they identified "one MZ twin pair, concordant for a very severe autistic phenotype, that appear to represent epigenetic outliers at multiple CpG sites across the genome". I'm immediately drawn back to my autism or autisms post and that all-important phenotypic variability as potentially being relevant here too. That and the tie-up with more structural changes to the genome as per the mention of CNVs and hotspots.

I know I've gone on a bit in the post but this is potentially a very important paper. Not only does it put the epigenome, or at least one part of the epigenome, firmly on the autism research map, but it offers something of a partial explanation for [some of] that 'missing heritability' which was talked about not so many years ago (see here).

The fact also that methylation patterns might be variable both intra-twins and intra-ASD is also important; suggesting that as with more traditional genomic findings in relation to autism, there isn't going to be just one epigenomic factor affecting risk or presentation, but rather a plethora of sites which are hyper- or hypo-methylated, potentially also linked to (affecting?) more structural changes to the genome in cases of ASD.

Don't get me wrong, the same questions remain as are seen in other areas of biological functioning with autism in mind: the heterogeneity, the reliance on diagnosis by observation and note-taking, the (elevated) risk of comorbidities, etc. All of which cloud the waters of association. Distinct however from the question of whether there is anything that can be done when structural changes to the genome are observed (outside of gene therapy for example), when talking about methylation, one speculates that this might be something that lends itself to pharmacotherapy as per the already use of DNA methyltransferase inhibitors for example. Yes, going back to that folic acid-autism link work, the possibility also that environment might help shape gene function and some new light on other external factors (noting that I am not advocating anything at the current time).

So endth the lesson for today.

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* Wong CC. et al. Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits. Molecular Psychiatry. April 2013.

** Ptashne M. Epigenetics: core misconcept. PNAS. April 2013.

*** Fraga MF. et al. Epigenetic differences arise during the lifetime of monozygotic twins. PNAS. 2005; 102: 10604-10609.

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Wong, C., Meaburn, E., Ronald, A., Price, T., Jeffries, A., Schalkwyk, L., Plomin, R., & Mill, J. (2013). Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits Molecular Psychiatry DOI: 10.1038/mp.2013.41