Genomic “Hotspots” Offer Clues to Causes of Autism, Other Disorders
An international team, led by researchers from the University of California, San Diego School of Medicine, has discovered that “random” mutations in the genome are not quite so random after all. Their study, to be published in the journal Cell on December 21, shows that the DNA sequence in some regions of the human genome is quite volatile and can mutate ten times more frequently than the rest of the genome. Genes that are linked to autism and a variety of other disorders have a particularly strong tendency to mutate.
Clusters of mutations or “hotspots” are not unique to the autism genome but instead are an intrinsic characteristic of the human genome, according to principal investigator Jonathan Sebat, PhD, professor of psychiatry and cellular and molecule medicine, and chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases at UC San Diego.
“Our findings provide some insights into the underlying basis of autism—that, surprisingly, the genome is not shy about tinkering with its important genes” said Sebat. “To the contrary, disease-causing genes tend to be hypermutable.”
Jonathan Sebat, PhD, assistant professor of psychiatry and cellular and molecular medicine at the UC San Diego School of Medicine has received the 2012 Roche and Nature Medicine Award for Translational Neuroscience. He was honored today at a symposium in Switzerland.
The award highlights young researchers who have made innovative and ground-breaking scientific discoveries in the field of translational neuroscience, especially related to autism spectrum disorders.
Sebat is being recognized for his work in better understanding the genetics of autism. Specifically, he, Michael Wigler of Cold Spring Harbor Laboratory and colleagues discovered that rare spontaneously occurring copy number variants are strongly associated with autism.
“This discovery was a key turning point in autism genetics and has now focused attention squarely on rare genetic variants, and spontaneous mutations in particular,” Sebat said.
Since the 2007 paper, researchers have made rapid progress in identifying individual mutations that confer high risk of disease, including autism.
Sebat, who is also chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases and a member of the Institute for Genomic Medicine, both at UC San Diego, has also made key discoveries in schizophrenia, including the fact that schizophrenia and autism share some of the same genes.
Image using an electron microscope shows a cilium growing from a neuron. (Gleeson lab).
A team led by researchers at the University of California, San Diego School of Medicine reports that newly discovered mutations in an evolved assembly of genes cause Joubert syndrome, a form of syndromic autism.
Joubert syndrome is a rare, recessive brain condition characterized by malformation or underdevelopment of the cerebellum and brainstem. The disease is due specifically to alterations in cellular primary cilia – antenna-like structures found on most cells. The consequence is a range of distinct physical and cognitive disabilities, including poor muscle control, and mental retardation. Up to 40 percent of Joubert syndrome patients meet clinical criteria for autism, as well as other neurocognitive disorders, so it is considered a syndromic form of autism.
The cause or causes of Joubert syndrome are not well-understood. Researchers looked at mutations in the TMEM216 gene, which had previously been linked to the syndrome. However, only half of the expected Joubert syndrome patients exhibit TMEM216 gene mutations; the other half did not. Using genomic sequencing, the research team, led by Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego, broadened their inquiry and discovered a second culprit: mutations in a neighboring gene called TMEM138.
“It is extraordinarily rare for two adjacent genes to cause the same human disease,” said Gleeson. “The mystery that emerged from this was whether these two adjacent, non-duplicated genes causing indistinguishable disease have functional connections at the gene or protein level.”
2011 Science Fellow Alysson Muotri spends his days using stem cells to understand autism, a disorder that affects 1% of all U.S. children. By examining the brain cells of adult patients with Rett syndrome specifically, he’s trying to determine if Autism Spectrum Disorder is permanent or if it’s possible to treat those cells with chemicals, inducing them to revert back to normal conditions. (via poptech)
Dr. Eric Courchesne explains how an over-abundance of neurons in the front cortex of the brain leads to autism. He recently published an important research paper revealing that children with autism have 67 percent more neurons in the frontal cortex. Courchesne explained that scientist must now work to discover why this overgrowth occurrs.