Autism clearly has a genetic component, since if one half of a set of identical twins suffers from the disorder, the other generally does as well. But there are also a high number of cases where it seems to appear spontaneously, with affected children being born in families with no history of problems.
In recent years, new molecular tools like DNA chips have allowed researchers to look at these sporadic cases in more detail. The results have suggested that spontaneous mutations may play a large role in causing the disease. But these studies were limited to looking at large changes, the loss or duplication of huge regions of the genome. Technology has marched on, however, and DNA sequencing has reached the point where we're now able to look for small individual changes in the genomes of families with an autistic member. These new studies reinforce the role of spontaneous mutations, but suggest that up to a thousand genes may be behind autistic behavior.
Three studies tackling autism with a similar approach appeared in Nature this week. They all relied on what is called "exome" sequencing. Although a lot of the body's basic biochemistry is performed by proteins, the percentage of the genome that actually encodes these proteins is very small (less than two percent). There are techniques that let us make copies of only the protein-coding portions of the genome, which are termed exons; sequencing them creates what is called an "exome." It won't capture all the genetic variation present—there are still going to be mutations in that other 98 percent, many of them significant—but it's much faster and less expensive than sequencing an entire genome.
And that's a good thing in this case, because the papers collectively sequenced a lot of people. Two of them relied on the Simons Simplex Collection, a set of families that have donated DNA from unaffected parents, affected children, and, in some cases, unaffected siblings. By comparing the exomes of a family, researchers can spot any genetic changes that arose spontaneously and only appear in affected individuals. One study sequenced 238 of these families for a total of over 900 exomes; another sequenced over 700 exomes.
The challenge with sifting through all this data is that spontaneous mutations happen all the time, and you'd expect a certain number of them to occur by chance. To really be certain that one of them was a good candidate, it would have to be mutated specifically in several individuals. Combined, the three studies identified four genes that fit the bill.
That said, a lot of the genes that were mutated only once were very intriguing. Many of them are involved in the development or maintenance of the nervous system. Sets of them clustered on the same biochemical pathways, including a signaling pathway that's essential for a lot of developmental processes. Others had previously been associated with mental disorders. In short, they look a lot like what you might expect would be behind autism, and there are a lot of them.
How many? One of the groups used a statistical analysis to estimate based on the number of genes they had identified so far. The answer they came up with is 1,034 different genes. For context, that's over four percent of the total number of estimated genes. Although there are a lot of uncertainties with this number at the moment, it does look like there are a lot of genes involved. Each one may be mutated only rarely, but it's capable of having a large effect when it is.
Two of the papers use the large and diverse collection of genes to drive home the point that autism isn't a single disorder. There may be set of behaviors and tendencies that are (more or less) common to autistics, but that isn't reflected by the biology. There's a big difference between, say, a mutation that alters how the brain develops, and one that changes the behavior of the ion channels that allow it to function once it has. We may lump those two together via a diagnosis, but we shouldn't expect that there will be a single understanding or treatment for autism.
The other thing to come out in two of the studies is support for something, apparent in epidemiological studies, that hints that the rise in diagnoses of autism isn't only a product of changed diagnoses. In general, the studies found, older fathers tended to pass on more spontaneous mutations to their kids. Since non-inherited autism appears to be a product of spontaneous mutations, a trend towards older parenthood may make autism a bit more common.