Two new studies demonstrate the promise and pitfalls of the industrial-scale gene-processing technologies that define the meaning of the much-ballyhooed Big Data.
Bad news first. One of the two reports published in Nature provided a four-digit estimate of the number of genes involved with autism. [I’m obligated to break here to say that Scientific American is part of the Nature Publishing Group.]
My science skeptic friends would say that this is also the point that I should start trying to bash autism genetics. “A thousand genes?” “Think of the combinatorial mess.” “They’ll never make any progress.”
But what the myriad research teams found was actually pretty cool. The two studies, published Oct. 29, pooled the labor of more than 50 laboratories across the globe. Their results tied more than 100 genes to autism, sixty of which met a “high-confidence” threshold—meaning that a particular gene has more than a 90 percent chance of increasing the risk of autism. Only 11 had met that mark before.
One of the studies looked at 2,515 families from a database maintained by the Simons Foundation Autism Research Initiative. The families had only one child with autism, suggesting the involvement of a rare, spontaneously occurring—writ de novo—mutation.
The researchers then looked for the mutated DNA by sequencing the full protein-coding portion of the affected child’s genes, known as an exome. They used their high-powered, next-generation sequencers to look at the exomes of both parents and, in many cases, at least one sibling—a mind-blowing endeavor for any geneticist who has 15 to 20 years on a CV and remembers when sequencing a single gene was a big deal. De novo mutations of various sorts are estimated to account for at least 30 percent of autism cases.
Of course, the next question is what do you do with all of this information—and how does it lead to treatments? The idea of routinely administering drugs for autism the way physicians do for blood pressure is still quite a ways off.
But pathways that get you from here to there might become a bit clearer from these types of studies. The genes found by the various research groups point to dysfunctions in the communication hubs, or synapses, that connect one neuron to another. Each brain cell typically synapses to thousands of others. Also involved was genetic material (transcription factors or chromatin) that regulates the activity of genes. “Having these genes that you can put in a stem cell or a mouse for research will be transformative in finding what causes autism,” says Stephan Sanders, assistant professor of psychiatry at the University of California San Francisco, and an author on both papers.
In terms of focus, any biologist will tell you that that a list that includes synapses, transcription factors and chromatin still covers a lot of ground. But it does at least provide a starting point of sorts, furnishing a number of intriguing ways to categorize the disorder. “Higher IQ autism,” such as Asperger’s, which affects mostly boys, appears to have different genetics than the “lower IQ” form in which both boys and girls are affected. Autism is characterized by language deficits, social problems and repetitive gesturing.
Nicholas Lange of Harvard, an author for Scientific American whose article on autism I edited last year, was enthusiastic after reading the two papers because some of the newly discovered genes are implicated in other disorders. That raises the possibility that research for, say, schizophrenia or epilepsy treatments might be of use for autism as well. He wrote me: “These findings, and many others like them recently, help us move forward from thinking of autism as a discrete multi-genic disorder toward viewing it more generally as a disability arising from factors shared by many other human impairments, some of whose biological underpinnings are already well known.”
Besides the research that crunched the exome sequencing database, the other study, with contributions from dozens of institutions, came from the Autism Sequencing Consortium, funded by the National Institute of Mental Health as part of its efforts to support collaborations that would be too big for any one lab.
These studies don't represent a clarion call that marks the beginning of the war on autism—nor should they. War analogies and science don’t mix that well. Pace Richard Nixon. But they are a measure of progress, an acknowledgement that the field has moved light years beyond the days of Bettelheim’s “refrigerator mothers.”
Image Source: National Library of Medicine