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Dozens of Genes Associated with Autism in New Research

Two major genetic studies of autism, led in part by UC San Francisco scientists and involving more than 50 laboratories worldwide, have newly implicated dozens of genes in the disorder. The research shows that rare mutations in these genes affect communication networks in the brain and compromise fundamental biological mechanisms that govern whether, when, and how genes are activated overall.

The two new studies, published in the advance online edition of Nature (1, 2) on October 29, 2014, tied mutations in more than 100 genes to autism. Sixty of these genes met a “high-confidence” threshold indicating that there is a greater than 90 percent chance that mutations in those genes contribute to autism risk.

The majority of the mutations identified in the new studies are de novo (Latin for “afresh”) mutations, meaning they are not present in unaffected parents’ genomes but arise spontaneously in a single sperm or egg cell just prior to conception of a child.

The genes implicated in the new studies fall into three broad classes: they are involved in the formation and function of synapses, which are sites of nerve-cell communication in the brain; they regulate, via a process called transcription, how the instructions in other genes are relayed to the protein-making machinery in cells; and they affect how DNA is wound up and packed into cells in a structure known as chromatin. Because modifications of chromatin structure are known to lead to changes in how genes are expressed, mutations that alter chromatin, like those that affect transcription, would be expected to affect the activity of many genes.

One of the new Nature studies made use of data from the Simons Simplex Collection (SSC), a permanent repository of DNA samples from nearly 3,000 families created by the Simons Foundation Autism Research Initiative. Each SSC family has one child affected with autism, parents unaffected by the disorder and, in a large proportion, unaffected siblings. The second study was conducted under the auspices of the Autism Sequencing Consortium (ASC), an initiative supported by the National Institute of Mental Health that allows scientists from around the world to collaborate on large genomic studies that couldn’t be done by individual labs.

“Before these studies, only 11 autism genes had been identified with high confidence, and we have now more than quadrupled that number,” said Stephan Sanders, PhD, assistant professor of psychiatry at UCSF, co-first author on the SSC study, and co-author on the ASC study. Based on recent trends, Sanders estimates that gene discovery will continue at a quickening pace, with as many as 1,000 genes ultimately associated with autism risk.

“There has been a lot of concern that 1,000 genes means 1,000 different treatments, but I think the news is much brighter than that,” said Matthew W. State, MD, PhD, chair and Oberndorf Family Distinguished Professor in Psychiatry at UCSF. State was co-leader of the Nature study focusing on the SSC and a senior participant in the study organized by the ASC, of which he is a co-founder. ”There is already strong evidence that these mutations converge on a much smaller number key biological functions. We now need to focus on these points of convergence to begin to develop novel treatments.

Autism, which is marked by deficits in social interaction and language development, as well as by repetitive behaviors and restricted interests, is known to have a strong genetic component. But until a few years ago, genomic research had failed to decisively associate individual genes with the disorder.

The two new studies highlight the factors that have radically changed that picture, State said. One is the advent of next-generation sequencing (NGS), which allows researchers to read each of the “letters” in the DNA code at unprecedented speed. Another is the establishment of the SSC; a 2007 study had suggested that de novo mutations would play a significant role in autism risk, and the SSC was specifically designed to help test that idea by allowing for close comparisons between children with autism and their unaffected parents and siblings. Lastly, collaborative initiatives such as the ASC are enabling teams of researchers around the world to work closely together, pooling their resources to create large datasets with sufficient statistical power to draw valid conclusions.

The large research teams behind each of the two new studies used a form of NGS known as “whole-exome” sequencing, a letter-by-letter analysis of just the portion of the genome that encodes proteins.

In November 2013, a study led by A. Jeremy Willsey, a graduate student in State’s lab, showed that the functional roles of the nine high-confidence autism risk genes that had then been discovered all converged on a single cell type in a particular place in the brain at a particular time during fetal development. Willsey is a co-author on both of the new Nature studies, which State believes will further accelerate our understanding of how the myriad of genes involved in autism affect basic biological pathways in the brain.

“These genes carry really large effects,” State said. “That we now have a bounty of dozens of genes, and a clear path forward to find perhaps hundreds more, provides an incredible foundation for understanding the biology of autism and finding new treatments.”


“ But why, Dad, why?! ”

“  You know why, son.  You’re out of control!  Giving that Kryptonian Supernova Wedgie to Lex Luthor, Jr.  You’re lucky his father is a mad genius and will figure out how to fix his spine.  Burning ‘Bat-Dork Lives Here’ in the lawn of Wayne Manor with your heat vision.  You know how old Alfred is?  He can’t be out in the heat with a rake and grass seed fixing that. 

And I’m not stupid, I know why you spend so much time in near-orbit over Paradise Island.  You’re at that age, and Telescopic X-Ray Vision is too great a temptation: I was a Superboy once, too.  There isn’t a birthmark or mole in Smallville I don’t know about.  ”

“ And you’re punishing me for the SAME THING? ”

“ But I wasn’t tweeting that information to the whole world!  Or taking selfies with Catwoman’s stolen jewels and unmentionables draped over your head!  How did you think that made the Bat-Twins feel?  They’re already in therapy because Selina can’t give up crime.  Would it be funny if your friend Atom, Jr. went swimming in your mother’s underwear drawer and took pictures?  You Teen Titans opened up a Boom Tube to Apokolips just to take turns mooning Darkseid and made a Vine out of it! ”

“ Seriously?!  I have super-hearing!  I HEARD you and Uncle Hal and Uncle Barry cracking up!   We’re just kids!  We were just fooling around! ”

“  That’s the problem: you narcissistic super-kids today don’t know how to keep your youthful indiscretions discrete.  It’s not that you get up to any less shenanigans than we did, you just don’t know how to keep your fat mouths shut and your fingers off the record button.  It’s cool now, but the Internet never forgets.  Brainiac built it that way, to be a permanent repository of the catalogued embarrassment of the entire human race.  There’s some things you just remember fondly and chuckle about around the Justice League meeting table with your friends, not digitally immortalize for everyone to throw in your face and judge you for years later. ”

“ I-I promise, Dad, I’ll never do it again.  Don’t take away my powers!  ”

“ Well … okay.  But you’re not completely off the hook. ”

“  Wait, Dad.  What are you doing with that Red Kryptonite? ”

“ Well, son, I’ve specifically altered the atomic weight of this sample of Red K so that it’s random transformative powers aren’t so random: exposure to this will turn you into a giant, delusional, bald-headed, diaper-wearing telepathic super-ape with extremely poor impulse control for 48 hours, then it’ll wear off. Your Teen Titan buddies can help babysit you until then.  But don’t worry, I’ve borrowed a collection of Uncle Jimmy’s cameras, and I’ll be close by.  You can follow all your misadventures later on Instagram. ”

“  Why don’t you just send me to the Phantom Zone and be done with it.  The Internet is right: you are a jerk. ”

Curt Swan & Murphy Anderson, August 1970