Thursday 23 August 2012

De novo mutations, older dads and autism (again)

Those with an interest in autism (and/or schizophrenia) will have probably already seen the headlines discussing the study by Augustine Kong and colleagues* on  the rate of de novo genetic mutations and a father's age as being potentially important for conditions like autism and schizophrenia. For those like me who are still struggling with all things mutation, quite a nice summary of the current research is offered in this Nature commentary accompanying the study.

I'm going to briefly focus on the potential implications specifically for autism in this post, accepting that (a) de novo mutations have been looked at with schizophrenia in mind (see here) and (b) increasing parental (and grand-parental) age has been linked to an increased risk of schizophrenia (see here).

This is not the first time this year that findings related to de novo mutation and paternal age in relation to autism have surfaced in Nature as discussed in this post. The latest study from Kong and colleagues suggests a few things:

  • The entire genome of 78 families (mum, dad, child) of Icelandic-origin was sequenced.
  • They studied the small genetics changes, SNPs, in and between mums and dads and their children, taking into account the age of the parents. Apparently of the offspring included for study, 44 had received a diagnosis of an autism spectrum disorder and 21 diagnosed with schizophrenia.
  • Their analysis suggested (i) fathers passed on about four times more mutations than mothers, (ii) approximately 2 new mutations were present in children for every year of increase in the father's age at conception - so a father conceiving at 20-years old passed on 25 random mutations compared with a father conceiving at 40-years old who passed on 65 mutations, (iii) mums were reported to pass on about 15 mutations irrespective of age; thought due to the fact that women carry their eggs through life whilst sperm is constantly being produced and therefore potentially subject to the rigours of ageing and environment.

There has, understandably, been some discussion about the implications of this research with regards to autism and more generally about the trend towards couples starting families when they're getting on a bit. Kari Stefansson, lead author on the paper discusses the trend (in Iceland) towards increasing paternal age when conceiving a child - 27.9 years in 1980 to 33 years in 2011 - as a case in point and potentially what implications this may have. That being said, I have to say that I raised a smile when reading about this recent research which suggested that children with older fathers might actually be genetically-programmed to live longer as a function of increasing teleomere length with age in sperm**. I am comparing apples and oranges here but want to show how such things are never straight-forward.

Another debate has also seemingly arisen from the Kong study with regards to the numbers of children with autism being currently diagnosed/estimated, and whether the figures reflect better case ascertainment, etc. or are reflective of a true increase in the numbers of people with autism. To quote from Fred Volkmar (here) "This study provides some of the first solid scientific evidence for a true increase in the condition of autism". Earlier this year I discussed the latest estimates of autism in the United States produced by the CDC and how an estimated 1 in 110 8-year olds with autism became 1 in 88 8-year olds with autism. If accurate, what Dr Volkmar seems to be suggesting is a kind of bridge between the genetics-environment camps which will almost certainly impact on the autism numbers game: older parents, older fathers passing on a greater number of mutations potentially increasing the risk of autism or schizophrenia. I pass no judgement on this proposal by the way.

There are a few final comments to make on this research and the area in general. Regular readers of this blog might already know that I am becoming a bit of a fan of the area of epigentics and the promise that it might hold for conditions like autism. Noting the recent research from Richard Anney and colleagues ("no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level") it's all well and good suggesting that older fathers might increase the risk of autism, but without such details as to which SNPs are consistently and reliably at work, there is likely to be a whole lot more involved in the aetiology of autism than just the structure of the genome. That and my continuing questioning as to whether age is the only factor in causing mutation or whether other environmental 'exposures' might also exert an effect.

Additionally and finally, I've said it before and I'll say it again: autism is not a homogeneous condition. We might talk about autism as being diagnostically homogeneous insofar as a person presents with this triad (soon to be dyad) of symptoms and the autism diagnosis box is ticked, but symptom onset and presentation varies from person to person (endophenotype to endophenotype?) and is further complicated by elevated risk for various comorbidity, psychological, cognitive and also more somatic comorbidity. I see nothing in the current research that rules out the possibility that more mutations passed to offspring as a result of older dads might not also be tied into an increased risk for other things (autoimmune features and conditions, epilepsy, learning disability, depression, anxiety, etc., etc.). Until we can, with some degree of confidence, peel back the diagnostic and risk layers, this issue will be in the background of any autism research.

Don't get me wrong, I am very interesting in the latest results from Kong and the now replicated findings of advancing paternal age and risk in some cases of autism. I do however believe that within the context of all the other research published and on-going in autism, this might be but one small piece of a much larger puzzle on aetiology and underlying pathology.

To finish, Jim Morrison has been on my musical radar of late, so how about some Riders on the Storm?


* Kong A. et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature. 2012; 488: 471-475.

** Eisenberg DTA. et al. Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants. PNAS. 2012; 109: 10251-10256.

---------- Augustine Kong, Michael L. Frigge, Gisli Masson, Soren Besenbacher, Patrick Sulem, Gisli Magnusson, Sigurjon A. Gudjonsson, Asgeir Sigurdsson, Aslaug Jonasdottir, Adalbjorg Jonasdottir, Wendy S. W. Wong, Gunnar Sigurdsson, G. Bragi Walters, Stacy Steinberg, Hannes Helgason, Gudmar Thorleifsson, Daniel F. Gudbjartsson, Agnar Helgason, Olafur Th. Magnusson,, Unnur Thorsteinsdottir, & Kari Stefansson (2012). Rate of de novo mutations and the importance of father’s age to disease risk Nature DOI: 10.1038/nature11396


  1. I have not read the paper yet so maybe this question is answered in it, but how is the relationship made between the genetic mutations (snps, I guess) and a causal mechanism for autism/schizophrenia?

    It is one thing to say that a mutation exists but it is quite another to make the case that the mutation actually played a role in causing the condition.

  2. Thanks MJ.

    The 'causality' side of things is, I think, more inferred by the authors (and media) than overt following the offspring diagnoses of autism and schizophrenia. As per the Richard Anney findings, the whole area of SNPs and autism (and lots of other conditions) is still a work in progress which really does need to start to taking into account the wide ranging presentation of autism and its comorbidities.

    The continued fascination with SNPs, CNVS, etc. in a way reflects that long-running belief that autism 'must' be genetic despite reproducible evidence for the majority not necessarily being forthcoming at the moment. I would dearly love to see a lot more focus on the epigenetics side of things given that there is quite a bit of distance to run in that area and some important focus needed on environmental factors too.

  3. Genome Evolves By Culture, Natural Selection, Not Randomly
    Tags: genetic mutations, RNAs are organisms,

    Rate of de novo mutations and the importance of father’s age to disease risk

    RNA nucleotide genes are ORGANISMS, life’s primal ORGANISMS.
    Genomes are template ORGANISMS evolved by the RNAs for carrying out their - RNAs’ - natural-selection tasks.
    All life’s activities originate and evolve for the survival of the RNAs.
    THIS is Darwinian evolution.

    Modified RNAs expressions are NOT random mutations. Some of them are caused accidents, but not random. Apply Darwinism to them.
    There is no randomness in the universe that evolves from all inert mass, singularity, to all moving mass, energy, and probably back again.
    Now, after a century of strangled Enlightenment, it’s time to restructure science plans, policies and budgets.
    The viable future of humanity is not with natural selection, but with scientism, the follow up of Enlightenment.

    Dov Henis (comments from 22nd century)


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