The idea is this. People with autism have a set of genetic variants that give them a predisposition for developing autism. Straightforward, right? Presumably, the siblings of people with autism carry many of these same genetic variants, but there is some reason why they don't develop the disorder. Of course, one possibility is that they do not, in fact, carry the autism-causing genetic variants. Another possibility, raised by this paper, is that they do have genes that predispose them to autism, but that some compensatory mechanism has maintained normal neural development in the face of this genetic predisposition. This compensation could be developmental – in that some sort of canalization mechanism sets in when it somehow senses that brain development is going off track. Or, it could be genetic, in that the unaffected siblings also possess genetic variants (presumably at other genetic loci) that shift them back towards normal development.
Here's Figure 3 from the paper. The top panel shows the "state" regions. Those are brain regions that show differential activation in the autism group (reduced activity in response to viewing biological motion). The middle panel shows the "trait" regions, which are the regions with reduced activity in both the autism group and the group of unaffected siblings. The bottom panel shows the "compensatory" regions, which show elevated activity specifically in the group of unaffected siblings.
The brain regions identified as "state" regions are those that are typically identified as regions of reduced activity in autism – a nice validation. The two "compensatory" regions are the right posterior superior temporal sulcus (pSTS) and ventromedial prefrontal cortex (vmPFC). Both of these regions have been associated with social perception and cognition. Note that both of these regions also appear in the "state" category.
So what does that mean? Well, that means that there are certain regions within these two structures that show reduced activity in cases of autism. There are other regions within the same two structures that are not impaired in autism, but show enhanced activity in unaffected siblings.
Like much of the most interesting science, this paper raises more questions than it answers, and there are many conceivable explanations of these patterns. The results suggest a number of interesting avenues for future research, however.
The paper can be found here. It is an open-access article, so you don't need a subscription to PNAS to get it.
Update: Full citation
Kaiser MD, Hudac CM, Shultz S, Lee SM, Cheung C, Berken AM, Deen B, Pitskel NB, Sugrue DR, Voos AC, Saulnier CA, Ventola P, Wolf JM, Klin A, Vander Wyk BC, & Pelphrey KA (2010). Neural signatures of autism. Proceedings of the National Academy of Sciences of the United States of America PMID: 21078973
Wow, that third panel pretty much blew my mind. Also, this is probably not relevant and only seems similar due to my moderately-lay relationship with genetics, but have we anything to learn from the bully whippet here, or is that a totally different kind of issue? Do they know if there's a one-v-two chromosome issue here? I would assume so since it's strongly correlated in siblings, but don't know what the data is these days. I do know, though, that the doubling of a sometimes-good trait can be a debilitating trait, - is there any way to quantify this with this range of brain activity?
ReplyDeleteDiana – I suspect that there is something like that going on, but probably even more complex. Of course, one of the difficulties in genetic studies of autism (and a number of other complex diseases) is that even large-scale genetic association studies have proven to be remarkably ineffective at identifying the genetic variants responsible. Probably the leading theory in terms of what is going on is that there are significant non-linearities in the way that genes are contributing.
ReplyDeleteThe phenomenon that you bring up is one form that such a non-linearity could take, where there is some kind of dosage effect for a particular gene. Another possibility is that it involves an interaction between different genes. So, you could have A and be fine, or have B and be fine, but if you have A and B you have autism.
I believe that the current thinking is that reconciling the high heritability of autism, the relatively high rate of incidence, and the failure of the genetic association studies requires there to be highly non-linear interactions involving probably eight or ten different genes, at least. So, it seems likely that there may be dosage effects AND interactions among multiple genes.
I think the real power and benefit of the results of this study might be that they identify a new measurable trait – activity in these "compensatory" regions – that can be the focus of future genetic studies. While the complexity of the genetics underlying autism might lie beyond the reach of our current tools, maybe the genetics of this neural trait will be tractable, and that might give us a window onto the disorder.