Sunday, 8 April 2012

Dust settled: autism, de novo mutations and older dads

On purpose I have left it a few days to post about the trio of studies published in Nature by Sanders and colleagues*, O'Roak and colleagues** and Neale and colleagues*** which have created big headlines like this one and this one on quite a few de novo mutations - as in not present in parents but present in children - being linked to the diagnosis of autism. A fourth study picked up by Time magazine (here) by Kerin and colleagues**** on moesin adds to the flavour. This last study coincidentally being in the same publication that contains an article suggesting that the predictive power of personal genome sequencing is likely to be a little bit more limited than many initially suspected. Who'd have thought it?

Back to the Nature articles, I let the dust settle a little for two main reasons: (1) just about everyone has an opinion about this work and its meaning, and (2) my first instinct was to say 'add them to the 2193 genes, 2806 SNPs/VNTRs, 4544 copy number variations, etc' already found and discussed in relation to autism.

I've talked about mutation and genes already quite a bit on this blog and how, whether diagnosed with autism or anything else or nothing at all, we are all a product of mutation and individually carry our own store of genetic mutations. Quite by chance I just saw one of the latest Marvel film adaptations, 'Thor' complete with cameo performance from the magnificent Stan Lee, who has whether knowingly or not, popularised mutation and in some respects relieved it of its quite negative connotations. After all, every kid wants to be Wolverine or Spiderman don't they?

Anyway a very, very short summary of the papers in question:

  • Sanders and colleagues* discussed exome sequencing for nearly a thousand individuals, including 200 people with a diagnosis of autism. Exome sequencing, I am reliably informed, relates to the analysis of exons, the parts of DNA which get translated into functional proteins. There is quite a good background description here. Their results identified several de novo mutations in brain-expressed genes to be present, with one mutation in the same gene present in 2 unrelated participants with autism but not in asymptomatic controls among other findings.
  • O'Roak and colleagues** carried out similar exome analysis for a couple of hundred parent - child trios (trios implying mum, dad and child with autism, N=677). Their analysis suggested quite a few of the 248 de novo mutations, 126 classified as 'severely disruptive', they found were paternal in origin - from dads - and showed a positive correlation with paternal age consistent with other work on older dads perhaps being a risk factor for autism. I was interested in some elements of the last sentence of this paper abstract which talked about 'extreme locus heterogeneity' but at the same time providing ".. a target for future discovery, diagnostics and therapeutics". Make of that what you will.
  • Neale and colleagues*** again sequenced exomes in 175 trios. They reported finding de novo mutations in less than half of their cases (46.3%) stating that ".. the overall rate of mutation is only modestly higher than the expected rate". Nevertheless, some clever proteomics work looking at how these mutation might fit together revealed some interesting interactions between the proteins encoded by the genes being looked at. They also suggested that carrying these mutations might up the risk of autism between 5 - 20 times compared with not having them. I was also interested in one of the gene candidates identified in this study, KATNAL2, which has been tentatively correlated with 'conscientiousness' as a personality trait (assuming you believe that personality is genetic). Dr Ben Neale, the lead author, has also summarised his team's results on a guest blog post here and done to my mind, quite a good job outside of all the hype.

I have probably not been able to do justice to the complexity and obvious work that has gone into these studies with this very short summary. There was some overlap in the genetic areas of interest across the studies which, given the statistical odds involved, might be potentially very important. I must admit that I raised an eyebrow when these papers all came out pretty much simultaneously and only a few days after the CDC reported another increase in their estimates of prevalence of autism in the United States, up from 1 in 110 to 1 in 88 8-year olds - indeed 1 in 32 boys apparently in the State of Utah. I'm sure that the timing was just coincidence though.

I've said it before and will say it again, I am not a molecular biologist or anything related, so am very much an amateur when it comes to decoding the precise meaning of exomes and de novo mutations outside of some background reading. With this in mind, I translate these collective works as suggesting a few things (but don't quote me on this):

  1. The genetics of autism are getting more and more complicated with every study published. It probably doesn't help that the diagnosis of autism is a subjective experience from a clinical viewpoint and autism is often surrounded by other comorbidities which are also likely to exert an effect on results. Exactly how this might change if and when the new 'sliding scale' DSM-V autism diagnostic criteria comes out will be interesting.
  2. These were studies on de novo mutations meaning that they did not originate from parents. I read one comment on a blog (here) by a commentator who drops by this blog now and again, RAJ, asking the very important question: where did all the heritability go? Does this mean that the autism of today is different from the autism of yester-year or is it all a question of technology, participant numbers, etc.?
  3. How and why do these de novo mutations appear is a question that should be on everyone's lips. Random is a word that crops us time and time again in relation to these mutations but with due respect, if we are talking about these mutations showing cause and effect in relation to autism risk, saying they just randomly appear leaves quite a big gap in the knowledge base. Again with my amateur status as a caveat, I do wonder about the involvement of environment and judging by the latest blog from Tom Inset at the NIMH, I'm not the only one. The paternal spotlight and in particular the older dads suggestion from the O'Roak study has put sperm in the cross-hairs, and lets face it, that opens up a myriad of possible environmental factors outside of just 'old sperm' as potentially showing some association (something again that RAJ has commented on in other posts on this blog).
  4. As per other studies on mutation in areas such as ADHD, whilst these are impressive studies utilising some impressive technologies, one perhaps needs to ask how common these mutations were in terms of autism as a whole. Yes, there were some interesting areas coming to light and yes, these should be priorities for future studies. As the paper from Neale and colleagues reported however, the overall rate of mutation was only marginally higher than what would be normally expected and one should perhaps not discount the influence of things like intellectual disability as accounting for at least some results (see here).

With the onset of epigenetics (changes to gene expression without changes to the genome), things are changing in the world of genetics. Autism research at the same time continues its fascination with this area of endeavour. The concept of an 'autism gene' covering everyone with autism (and the BAP?) is a distant memory (as are the millions of pounds/dollars/other currency pumped into this area down the years) to be replaced by an altogether more complicated picture emerging of spontaneous mutations, differing genetic profiles for individuals and genes and environment potentially acting variably but synergistically.

To finish, the UK is awash with Britain's Got Talent at the moment, and aside from asking 'where me keys, where me phone' a group called the Zimmers got me reminiscing about an old Beastie Boys classic... fight for your right to [fill in the blank].

* Sanders SJ. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. April 2012.
DOI: 10.1038/nature10945

** O’Roak BJ. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations Nature. April 2012.
DOI: 10.1038/nature10989

*** Neale BM. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. April 2012.
DOI: 10.1038/nature11011

**** Kerin T. et al. A noncoding RNA antisense to moesin at 5p14.1 in autism. Science Translational Medicine. April 2012.
DOI: 10.1126/scitranslmed.3003479


  1. "my first instinct was to say 'add them to the 2193 genes, 2806 SNPs/VNTRs, 4544 copy number variations, etc' already found and discussed in relation to autism."

    My thoughts exactly. I wonder if any of these genetic researchers have ever heard of Occam's razor.

    Either there are literally thousands of genes that might be involved in some small number of cases of autism, each in an almost unique way or there is an elephant in the room that no one has seen yet.

  2. Thanks MJ.

    There was quite a good post from Micheael Eisen on this collected work and how the results might have been 'hyped':

    That combined with Ben Neale's post for genomes unzipped gives perhaps a more accurate flavour of these combined results saying yes there are some important details from the work, but the underlying issue is that at the moment, no single mutation or group of mutations can account for autism.

    And as for epigenetics... to quote a favourite Star Trek film of mine, the undiscovered country.

  3. Fan of the Beastie Boys too. Several decades ago my wife and I were invited to a taping of the US TV show 'Showtime at the Apollo' by dear friends who at the time owned the Apollo Theater in Harlem. The co-hosts were Run DMC and the Beastie Boys!

  4. This particular version from BGT is a sight to behold (keep watching don't be put off by the first song):