摘要：本周在《神经元》杂志上刊登了三篇有关自闭症的论文。其中，刊登在《神经元》月刊上的两项研究结果描述了增加患孤独症风险的一系列基因变异。孤独症这种发育障碍会在3岁左右显现出来，美国大约1／100的孩子患有这种疾病。 第三项研究阐述了这些缺损基因如何瞄准特定的目标——脑突触的形成。脑突触是信号在神经元之间传递的连接点。 研究人员发现人类基因组的一个区域如果发生改变，往往会要么导致孤独症，要么导致一种完全相反的、友好得过了头的疾病，也就是威廉姆斯综合征。
当基因发生突变且复制的基因多于正常情况时，可能会出现孤独症。但当这个名为7q11．23的基因组区域的某些部分出现缺失，人们可能会患上威廉姆斯综合征，这种疾病的一个特点往往是高度社交型人格。 其中一份研究报告的主要撰写人、耶鲁大学的马修•斯泰特说：“在研究脑部与社交相关区域的发育时，这个基因组区域可以说有着重要的意义。” 患有威廉姆斯综合征的人可能对陌生人极其信任，而且对音乐有着特殊的喜爱，但可能也会表现出发育上的残疾、学习障碍以及手部和面部的畸形。
孤独症的表现存在广泛的差异，从轻微的社交障碍到完全无法正常交流，以及重复性动作、对某些光和声音敏感和行为问题等。
由耶鲁大学和纽约科尔德斯普林实验室研究人员发起的两项研究活动对1000多个家庭的基因组进行了分析，每个家庭都有一名孩子患有孤独症，而其兄弟姐妹和父母则不存在这种问题。 研究人员说，这一发现似乎印证了目前越来越多的证据所支持的一个观点，即孤独症可能是人类基因组数百个不同区域中的任何一个偶然发生的基因突变造成的。
生物探索推荐英文原文：
Autism linked to hundreds of spontaneous genetic mutations
Autistic girls tend to have mutations in more genes than autistic boys.
Analysis suggests that girls are partially shielded from effects of the changes.
The most comprehensive search yet for spontaneous genetic mutations associated with autism spectrum disorders suggests that hundreds of regions in the genome may have a hand in causing such conditions.
Analyses reported in three papers published this week in Neuron dramatically expand the list of known genetic culprits. Two of the studies also shed light on a long-standing mystery: why are boys four times more likely to have autism than girls? The researchers found that girls with autism tend to have many more mutated genes than boys with the disorder, suggesting that it generally takes a larger genomic change to cause autism in girls.
Autism is difficult to pin down. A wide range of symptoms, many involving difficulties in social interactions and communication, are united under the diagnoses of autism spectrum disorders. And although it is estimated that such conditions are more than 90% heritable, quests to find common mutations associated with them have not yet yielded any reproducible hits, says Stephen Scherer, a geneticist at the Hospital for Sick Children in Toronto, Canada, who was not involved in any of the studies.
"Autism is a heterogeneous disease, both clinically and genetically," he notes.
Spontaneity counts
In 2007, Michael Wigler, a geneticist at Cold Spring Harbor Laboratory in New York, and his colleagues showed that spontaneous mutations — those that arise for the first time in an individual, rather than being inherited — are important in about half of all cases of autism (seeNew mutations implicated in half of autism cases). A follow-up study in 2010, of 996 autistic individuals, found that people with autism carry a heavy load of rare duplications or deletions in regions of the genome that contain genes.
Now Wigler and his group, as well as a team headed up by Matthew State, a geneticist at the Yale University School of Medicine in New Haven, Connecticut, have expanded on that search, using higher-resolution techniques to trawl through the genome. The researchers searched the DNA of more than 1,000 individuals with autism and their unaffected family members, looking for rare mutations that duplicate or delete segments of the genetic code. The teams focused largely on spontaneous mutations.
Their results indicate that spontaneous duplications or deletions of at least 130 sites in the genome could contribute to the risk of autism. Wigler believes that in total there are closer to 400 such sites. "It is a large number," he acknowledges, and that will make it harder to develop therapies that will benefit a large fraction of patients. "Given the number of genes that might cause autism, one shouldn't expect that one treatment is going to cure them all," says Wigler.
State's team made an intriguing finding in a segment of chromosome 7. Deletion of the region is associated with Williams–Beuren Syndrome, a condition that is linked to hypersocial behaviour. Duplication of the same region, they found, is associated with autism, which is linked to antisocial behaviour.
The region spans many genes, and for now it is unclear which might be responsible for the effects. "But there's clearly something there that's highly relevant to social behaviour," says State. "The neurobiology of that region is going to be extraordinarily interesting."
Working together
Wigler also teamed up with Dennis Vitkup, a computational biologist at Columbia University in New York City, to learn more about the neurobiology of the rare variants that his analysis had uncovered. The team analysed the relationships among spontaneously mutated genes that were likely to be involved in brain function, and found that many clustered into a large network that governs the creation and activity of connections between nerve cells.
Vitkup's team is now trying to determine whether the network that they have discovered could be used to construct a diagnostic test for autism.
Overall, the results have dramatically lengthened the list of genes that may have a role in causing autism, says Scherer. "This gives us a lot more data that we can use to start to pin autism down," he says.
One finding that will be pursued further is that girls are somehow shielded from the effects of mutations that are linked to autism in boys. Wigler's team found that autistic girls tended to have deletions or duplications in more genes than autistic boys.
That, says Scherer, suggests that one approach to developing therapies may lie in determining what protects the female brain from autism — and then activating those pathways in boys. "If you want to think about an approach to therapeutic intervention," he says, "perhaps the lessons to be learned are in the females."
