Autistic Spectrum Disorder – Nature or Nurture? Aware or beware?

Since April was ‘Autism awareness month’ internationally, this blog is a little different, aiming to raise awareness of autism and how adults with autism and its associated disorders might differ from the neurotypical.

In March 2014, the US government released figures estimating the prevalence of autism as being 1 in 68 boys and 1 in 189 girls (thus creating a ratio of male:female prevalence of almost 3:1)1. This means that in most communities and workplaces, there will be at least one member who has been diagnosed as being ‘on the spectrum’, due to the expression of a ‘complex behavioural phenotype’, which now includes atypical disorders such as Asperger’s Syndrome or High Functioning Autism (those with an IQ higher than 80 and with good verbal skills).

The Nature-nurture debate

It is now commonly accepted that autistic traits run in families. It has even been argued that such traits are cumulative, resulting in children that are more autistic than their parents1. Recent studies have centred on mutations contained within nonsense DNA, that is to say, DNA which does not code for protein-coding genes, per se, but rather molecular modulators of gene expression. Such modulators include ‘enhancers’, of which more than 100 are now known to be present more in the brain than other tissues of the body, resulting in a significant influence over brain development in utero. Traditional gene studies, which focussed upon protein-coding genes, would actually miss more than 95 % of the human genome, therefore it’s of little wonder that our understanding of developmental pathways in neurological disorders lags behind that of more physically symptomatic diseases such as heart disease, or cancer. This is partly due to the phenomenon of ‘environmental fixation’, whereby families (particularly mothers) were blamed for their child’s autistic traits, to the extent of being branded ‘refrigerator mothers’, alluding to the alleged coldness with which they raised their children2. Furthermore, Harlow (1972) described behaviours in his rhesus monkeys, deprived of maternal contact, that were concordant with those of the autistic children carefully described by Kanner3, perpetuating the theory that families were to blame for the atypical behaviour of their child.  Thus, the pendulum of scientific opinion has swung between the two extremes of ‘nature’ versus ‘nurture’. Current models propose that multiple genetic, epigenetic and environmental factors may contribute to the etiology of autism, with the last decade of research revealing a significant genetic heterogeneity4. In summary, no two individuals diagnosed with ASD or Asperger Syndrome are the same!

The vast majority of studies into autism focus on children, as do the strategies designed to enable those diagnosed on the spectrum to cope with ‘day-to-day life’. However, children become adults, raising the challenge of both adaptation to an environment designed for neurotypical adults and also diagnosis for those adults who form the ‘lost generation’, people who were previously excluded from a diagnosis of classic autism either through ‘camouflage strategies’ (particularly prevalent in girls who are more likely to copy peers and thus appear ‘neurotypical’ to the untrained eye) or adaptation strategies, whereby an individual copies the actions of a neurotypical colleague, learning social rules as one might study a recipe, or protocol. A school friend of mine was such a case. She wore the same clothes as her best friend, did the same hobbies and was academically outstanding. Yet she failed to progress in her chosen career and was diagnosed with Asperger’s Syndrome aged 41. Her career choice of course was influenced by that of her peers, rather than her strengths.

So are HFAs and Aspies always doomed to failure in the workplace? Much is made of the drawbacks of HFA/Asperger’s Syndrome – appearing dissociated or uninterested, difficulties with social interaction, inappropriate conversation and lack of eye contact leading to perceptions of not telling the truth or being disinterested in a particular task or employment role to mention but a few – but shouldn’t we focus more on what autism has to offer?

For example, they may have the ability to focus intensely and for long periods on a difficult problem. There is often an enhanced learning ability, although this often is not applied to subjects they are uninterested in – and therefore it may be necessary to play to the strengths of employees or students, rather than attempting to counter-act weaknesses. HFAs and Aspies often present no problems in a supportive, well-resourced educational institution and often do well academically if they can be stimulated by good teachers. People with HFA and Asperger’s often have intense and deep knowledge of an obscure or difficult subject and a passion for pursuing it in an organized and scholarly manner. This makes them more likely to excel in ‘niche’ topics, particularly neglected areas of research. They are usually intelligent, gifted, honest, hard workers when interested in a task and excellent problem solvers. People with high-functioning autism are thought to become excellent scientists and engineers or enter other professions where painstaking, methodical analysis is required.

So should we beware of Autism? Or accept what it has to offer? Besides, what exactly is normal?

Blog written by Diane Lee, who has recently moved to the School of Veterinary Medicine at the Universityof Surrey.

1 Sylvie Goldman, MD, Albert Einstein College of Medicine, Opinion: Sex, Gender and the Diagnosis of Autism – A Biosocial View of the Male Preponderance (p.1-2)

2Judith Miles: Autism spectrum disorders—A genetics review; Genetics in Medicine (2011) 13, 278–294; doi:10.1097/GIM.0b013e3181ff67ba

3Kanner L. (1949). Problems of nosology and psychodynamics of early infantile autism. Am. J. Orthopsychiatry 19, 416–426

4Geschwind D. H. (2008). Autism: many genes, common pathways? Cell 135, 391–39510.1016/j.cell.2008.10.016

ENCODE: A new tool for drug discovery?

Only a small proportion (<2%) of the total genome codes for proteins and the remainder had up to now been termed non-coding or ‘junk DNA’. The aim of the ENCODE (Encyclopaedia of DNA elements) project was to attempt to characterize these undefined regions.  The consortium has recently published 30 papers detailing, amongst much data, regions of transcription and regulatory areas that were previously unreported.

One of these papers by Maurano et al., used a technique to map sites of regulatory elements within the DNA and compare these with noncoding variant polymorphisms associated with common diseases that have been identified through genome-wide association studies (GWAS).

The group examined many different cell types including primary cells, immortalized, malignancy derived or pluripotent cell lines, hematopoietic cells, progenitor cells as well as some fetal tissue samples. They used Deoxyribonuclease 1 (DNase1) hypersensitive sites (DHSs) of increased chromatin accessibility as a marker for binding sites of regulatory elements such as transcription factors and thus mapped the regulatory regions in this material. In total, they identified DHS positions spanning 42.2% of the genome, a higher density of regulatory regions than previously appreciated. They then examined the position of single nucleotide polymorphisms (SNPs) identified by GWAS and found a 40% enrichment of these SNPs in DHSs. This analysis shows that the common genetic variants associated with disease are often located at recognition sequences of transcription factors. The authors also demonstrated that these regulatory regions may control the expression of genes that are distant (>250kb) rather than solely the expression of the nearest gene.

Further interesting data from the consortium was obtained through the study of cancer lines. Over 40 cancer lines of different origin were examined and data obtained showing that cancer lines possess regulatory DNA regions that are not present in normal cells (Stamatoyannopoulous, J. A., 2012).

The new information provided by ENCODE is not yet readily applicable to drug discovery, however, this data could provide a map of transcriptional and regulatory regions that could help to identify novel therapeutic targets. In a recent article in Nature Drug Discovery, Michael Snyder one of the principal investigators of the ENCODE consortium explains that changes in gene expression through a change in regulatory sequence could enable identification of proteins that could make useful drug targets.

Applications that could be useful in drug discovery settings include the use of knockdown technologies to screen for biological effects, or zinc finger nuclease technology that can introduce mutations to regulatory elements to determine if changes in these regulatory regions are causal of disease.

Systematic localization of common disease-associated variation in regulatory DNA.

Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, Reynolds AP, Sandstrom R, Qu H, Brody J, Shafer A, Neri F, Lee K, Kutyavin T, Stehling-Sun S, Johnson AK, Canfield TK, Giste E, Diegel M, Bates D, Hansen RS, Neph S, Sabo PJ, Heimfeld S, Raubitschek A, Ziegler S, Cotsapas C, Sotoodehnia N, Glass I, Sunyaev SR, Kaul R, Stamatoyannopoulos JA.

Science. 2012 Sep 7;337(6099):1190-5. doi: 10.1126/science.1222794. Epub 2012 Sep 5.

What does our genome encode?, Stamatoyannopoulous, J. A. 2012, Genome Research 22: 1602-1611

An audience with Michael Snyder, Nature reviews Drug Discovery Oct 2012. 11: 744

The ENCODE papers are available online at