Free The Autistic Brain: Thinking Across the Spectrum by Temple Grandin, Richard Panek

and one that can lead to autism—is due to a change in the FMR1 gene on the X chromosome.
    By and large, though, the genetics of autism isn’t that simple. Nowhere near.
    After the Human Genome Project and Celera Genomics mapped the human genome in 2001, dozens of institutions in nineteen countries banded together to form the Autism Genome Project, or AGP.Using a database of 1,400 families, these scientists deployed the gene chip, a new technology that worked at a much higher level of resolution than previous methods and that allowed them to look at thousands of DNA variants on a single chip all at once, rather than on a one-by-one basis. The researchers used this technology to look at each subject’s entire genome—all twenty-three pairs of chromosomes—as well as particular areas that earlier research had pinpointed as possibly being of interest.
    When phase one of the Autism Genome Project came to an end, in 2007, the consortium published a paperin
Nature Genetics
that did identify several specific areas of the genome as likely contributors to autism. Among the more promising avenues for further research is a mutation in the gene that codes for a protein called neurexin, which links directly with a protein called neuroligin to control how two brain cells connect across the synapse between them. During development, these interactions are crucial for directing neurons to their proper targets and for forming signaling pathways in the brain. This finding by the AGP reinforced earlier research indicating that mutations in the SHANK3 protein, which interacts with neuroligin protein at the synapse, are associated with an increased risk of ASD and mental retardation.
    But in addition to serving as a direction for further research, the paper demonstrated the effectiveness of the strategy that AGP scientists had used to detect these mutations. They searched for copy number variations, or CNVs—submicroscopic duplications, deletions, or rearrangements of sections of DNA. These variations, which can vary in length and position on the chromosome, have the potential to disrupt gene function.
    Where do these copy number variations come from? Most are inherited. At some point, an irregularity entered the gene pool, and it was passed down through the generations. But some CNVs aren’t hereditary. They arise spontaneously, either in the egg or sperm before fertilization or in the fertilized egg shortly afterward. These are called de novo mutations, from the Latin words for “from the beginning.”
    Many CNVs are benign. And geneticists estimate that each genome—each person’s unique DNA—might contain as many as several dozen de novo mutations. They’re part of what makes each person unique. But might de novo CNVs be associated with autism?
    This is the question that a 2007 studyof 264 families, published in
Science,
set out to answer. The authors concluded that such mutations do pose “a more significant risk factor for ASD than previously recognized.” The study found that 10 percent of autistic children with nonautistic siblings (12 out of 118) had de novo copy number variations, but only 1 percent of controls who had no history of autism (2 out of 196) showed CNVs. In the following five years, this paper, “Strong Association of De Novo Copy Number Mutations with Autism,” would be cited more than 1,200 times.
    The hope that autism could be traced to one or even a few gene variations became less and less realistic. By the time phase two of the Autism Genome Project—drawing on the DNA of 996 elementary-school-age children in the United States and Canada diagnosed with ASD, their parents, and 1,287 controls—came to an end, in 2010,the collaborators had identified dozens of copy number variants potentially associated with ASD. By 2012, geneticists had associated ASD with hundreds of copy number variations.
    Further complicating the research was that many of the CNVs seemed to be, if not unique, at least extremely rare.