Friday, April 6, 2012

Novel mutations = novel conclusions?

As reported in the NYT, the results of three new studies, published (here, here, and here) this week in Nature on the genetics of autism has found novel gene mutations that might explain risk as well as evidence that risk increases with the age of the father.  From the Sanders et al. paper:
Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance.
It explains risk in only a very small fraction of cases.  Though, Sander et al. suggest that the model may well be useful for explaining many more. As the Times story says:
Experts said the new research gave scientists something they had not had: a clear strategy for building some understanding of the disease’s biological basis.
An intensified search for rare mutations could turn up enough of these to account for 15 percent to 20 percent of all autism cases, some experts say, and allow researchers a chance to see patterns and some possible mechanisms to explain what goes awry. 
This would be great, of course.  Any clues to the bigger picture could be extremely helpful.  However, if autism is like every other complex disorder, a finding that's true at one extreme of the distribution of the phenotype will not necessarily apply to any other part of the distribution.  There are high shared fractions of the genome among relatives, usually many coding changes, too.  So it is going to be difficult to 'prove' that the change observed really is causal. Exome sequence assumes coding changes and in a way is vulnerable to identifying a coding change and assuming it's causal, when regulatory changes are not in the search space; is this the drunk looking for his keys under the lamplight?

Indeed, as O'Roak et al. conclude,
Although there is no one major genetic lesion responsible for ASD, it is still largely unknown whether there are subsets of individuals with a common or strongly related molecular aetiology and how large these subsets are likely to be.
O'Roak et al. identified novel mutations in sporadic, non-familial cases, and characterized them as to their severity and type, and they also identified pathways that the affected genes might share.  They conclude that there are likely to be from hundreds to over a thousand genes associated with autism: "Our analysis predicts extreme locus heterogeneity underlying the genetic aetiology of autism."

Of course there must be 'networks', and all of this kind of rhetoric sounds impressive but really is post-facto and in a sense superficial.  Genes interact with other genes, not just in terms of protein-protein interactions but also related to expression level (not assayable by exome sequencing).  So saying that there are hundreds of genes in networks is to some extent big-words to acknowledge that we may find this or that component, but this trait is simply not simple.

Neale et al. report, "Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold."  Again, other functional elements in DNA that greatly outnumber the protein-coding parts, are likely to be at least as important.  Indeed, there are findings that 1% or more of autism is due to copy number variation, which may overall swamp the rare variants in importance, if the results hold up.

Each of these studies looked at a subset of the study population -- because autism is such a wide spectrum of disorders, it's important to reduce possible genetic heterogeneity by narrowing the phenotype in any study -- and found novel, or sporadic mutations to be associated with risk.  Because the idea that new mutations, which we all carry a substantial number of, might be causative can't help predict who is at risk, the hope is that if these mutations are indeed associated with risk, they might give some clues as to which developmental pathways are affected in this disorder.  The hope has been for years that genes for autism will be identified. Now that it's looking like this is a polygenic disorder, if indeed genes are a primary cause, and that sporadic mutations might be significant, it's looking more and more likely that those who have long said that major genes that can predict the disorder will not be found have been right.

The Times quotes a well-known population geneticist on this work:
“This is a great beginning, and I’m impressed with the work, but we don’t know the cause of these rare mutations, or even their levels in the general population,” said Dr. Aravinda Chakravarti of the Institute of Genetic Medicine at the Johns Hopkins University Medical School, who was not involved in the studies. “I’m not saying it’s not worth it to follow up these findings, but I am saying it’s going to be a hard slog.”
If these new results can in fact lead to understanding what goes awry in the developing brain to lead to autism, great.  Whether this will ever be clinically significant is another matter.  And one needs to remember that autism is by far mainly environmentally caused!  The report last week that its prevalence has increased by 78% in the past decade alone shows that this is about environments (that increase is unlikely to all be due to changing definitions of the disorder, or changes in diagnostic practices).  Well, a determined geneticist will argue that rapid environmental change could, in principle, have led to higher disease risk by triggering big responses in a few common genetic variants interacting with the environment.  Not so! We've had he environmental change (whatever it is), and ASD is clearly not due to one or two major genes responding to that change.

The same arguments apply to excessively exuberant claims implying simple genetic adaptation due to natural selection, and for the same reasons.

If biomedical research is about doing something about autism, rather than about forcing genetic thinking onto the problem, we're looking under the wrong lamp-post!

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