Interview with Stephen Scherer

11 Jun

Stephen Scherer is co-author on the recent paper ‘Functional impact of global rare copy number variation in autism spectrum disorders‘. I caught up with him via email to ask a few questions:

1) What is the ‘bottom line’ message readers can take away from your work?

I am always frustrated when I hear at the end of most news stories…’and we don’t know what can cause autism’. Data from the past few years including our new study show alterations in genes can cause autism. We have not found all of the genes yet, and not all autism cases can be accounted for (the genetics can be complex) but genes can cause autism. For the specialists, through our new study we show either de novo or rare inherited copy number variations as one form of genetic alteration involved in autism. The genes affected are often linked together in a connected functional pathway and may of these molecules dictate how brain cells (neurons) develop and communicate. Some of the autism genes we found have already been found to cause intellectual disabilities, which is not entirely surprising since many individuals with autism also have these challenges.

2) How does your paper tie in with other gene/autism studies?

We validate many previous findings, but also find dozens and dozens of new autism risk genes. Our data furthers the hypothesis that rare genetic alterations contribute much more relative risk to developing autism than common genetic variations.

3) What should future researchers use your study for in terms of direction to take their own work?

I think one of the most important impacts of the study is the design itself. Nature really wanted us to include the Figure 1, which outlines the design and analysis. CNV studies are still quite tricky to do and the data has to be of the highest quality to make sense of it. I think our study on autism will set the standard for all other studies going forward, so they should follow it. Moreover, many of the functional pathway studies published before may have been either underpowered, flawed by low resolution arrays or high false discovery rates, or incomplete study designs. We spent alot of time thinking of how to best do this properly so if others are interested they should read the Supplementary Information carefully. Use it as a guide. Finally, for the functional biologists look at the long list of genes we present in the Supplementary Information since they may find their favorite gene to be an autism candidate gene!

4) How difficult was it managing the input from such a very large amount of co-authors?

The Autism Genome Project has some 120 scientists from 11 countries involved (see the authorship list). We selected a ‘writing team’ comprised of genome scientists, statisticians, medical geneticists, psychiatrists and developmental pediatricians. Interesting, everyone saw their own story in the data. I pretty much new in advance what I wanted to see in the final manuscript so much of my job was bring focus to the many other good ideas (note that there are five other papers spinning out of this larger study presenting some of these other data and interpretations). In took about 12 solid months of analysis of the data, three months of writing and editing, alot of cursing, and then submission to Nature (with even more cursing). The review time from submission to publication took ~six months. This was the hardest for me (except other than constantly changing the author list….and affiliations). The reviewers were very very thorough and Nature can (rightfully) be very demanding. In the end we are very proud of the manuscript. Dalila Pinto who is the first author and a post-doc in the lab was the driving force behind the analysis and deserved a lions-share of the credit. Would I do it again? I’ve had two Senior Author papers in Nature this year, which have been very draining. But I would do it again!

8 Responses to “Interview with Stephen Scherer”

  1. Laurentius Rex June 12, 2010 at 09:12 #

    I’m still not buying, all it confirms is complexity, the complexity which will continue to and by mathematical imperative must destroy these particular lines of disorganised and top down research.

    I’ll tell you what causes autism.

    The word which defines it, if I were to define something to be called researcher obstreperance, I could easily qauntify and identify real traits and aggregate them.

    No doubt genes would be found for that too, in great profusion and confusion. To create an artificial disorder is an experiment that needs to be done, in the true spirit of science, as a control to test the propensity of all top down studies to artefact.

    genes don’t cause autism, they cause human variety, or to put it another way “neurodiversity” everything that is human. Then humans create categories, and decide which of us they like and which they don’t. I won’t go into the next stage of this human disorder but it is very unpleasant and needs a cure

  2. RAJ June 14, 2010 at 05:41 #


    An interesting study with many qualifiers. Professor Rutter is listed as a co-author. Unfortunatly Professor Rutter has had a serious illness and has been unavailable for comment since last year. Professor Rutter may have disagreed with Scherer’s interpretations. Here is a video of what may have been one of his last presentations a year ago. The video is about 1/2 hour long and he states his evolving concepts about autism etiolgy:

    Rutter discusses his view that ASD etiology is primarily a gene-environment (GXE) multifactorial condition and offers spot on complaints about the resistance of some genetic researchers to the GXE model. Sherer would be one of those who Rutter complains about in his presentation.

    I would pose several quations to Professor Scherer.

    1. The ASD group was taken from families recruited from multiple incidence families (2 or more). Studying largely (over 90%) multi incidence families would bias the result towards inherited CNV’s.

    2. The control groups are not matched for either age, IQ or gender. The failure to control for gender is troubling since:

    “In many instances, there are large sex differences in mutation rates, recombination rates, selection, rates of gene flow, and genetic drift. Mutation rates are often higher in males, a difference that has been estimated both directly and indirectly. The higher male mutation rate appears related to the larger number of cell divisions in male lineages but mutation rates also appear gene- and organism-specific”

    The Multi incidence family ASD group male/ female ratio was male =83%, female = 17%

    The SAGE control group male female ratio was male =31% female= 69%.

    Click to access nature09146-s1.pdf

    3. CNV mutation can be either de novo or inherited. In inherited cases the parents are not normally affected. Previous studies have shown the same CNV mutations in a variety of developmental problems and therefore CNV’s are not specific to autism. De novo mutations are not present in the parents and therefore cannot possible be associated with ‘autistic’ traits in unaffected family members. The GXE model would propose that environmental modifiers are likely to disrupt normal functioning of the gene variation.

    HIV research offers the possibility about how CNV’s operate and how environmental modifiers may disrupt brain development which is the core of ASD etiology.
    HIV researchers have identified a single gene CCL31 where lower copy number variations substantially inrease the risk for infection after exposure to the virus.

    Perhaps you can ask Professor Scherer to answer the questions.

    • Sullivan June 14, 2010 at 05:51 #


      perhaps you could ask Prof. Scherer? Is there something hindering you doing that? I doubt Prof. Scherer would be interested in speaking for Prof. Rutter, as you appear to be doing. You tend to do a lot of putting words into the mouths of experts, then expecting us to accept them.

  3. RAJ June 20, 2010 at 04:41 #


    “perhaps you could ask Prof. Scherer? Is there something hindering you doing that”?

    I tried as I did with Hakonarnson. No response. They only respond to softball questions.

    • Sullivan June 21, 2010 at 02:33 #


      so, that would be a “I didn’t even try in this case”. Right?


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    […] Last week I wrote about press reports on a possible urine test for autism based on the limited findings of a pilot study that had a number of weaknesses. This week a rather more substantial piece of research has caught the attention of the media. Functional impact of global rare copy number variation in autism spectrum disorders by Pinto et al was published online by Nature on 9 June 2010. It is not an easy read for non-scientists like myself but there are some really helpful commentaries online. The NHS has a very readable guide on its NHS Choices site. PZ Myers has summarized the paper for a lay audience on his Science Blog, Pharyngula. Orac is another Science Blogger who offers his reflections on the study at Respectful Insolence. And the corresponding author for study, Stephen Scherer, answers questions from Kev Leitch over at LBRB. […]

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