骁龙620:研究发现孤独症基因组：基因拷贝数控制大脑结构和行为

研究发现孤独症基因组：基因拷贝数控制大脑结构和行为2

ScienceDaily (Oct. 3, 2011) — Scientists at Cold Spring Harbor Laboratory (CSHL) have discovered that one of the most common genetic alterations in autism -- deletion of a 27-gene cluster on chromosome 16 -- causes autism-like features. By generating mouse models of autism using a technique known as chromosome engineering, CSHL Professor Alea Mills and colleagues provide the first functional evidence that inheriting fewer copies of these genes leads to features resembling those used to diagnose children with autism

《科学日报》2011年10月3日报道

"Children normally inherit one copy of a gene from each parent. We had the tools to see whether copy number changes found in kids with autism were causing the syndrome," explains Mills. In 2007, Professor Michael Wigler, also at CSHL, revealed that some children with autism have a small deletion on chromosome 16, affecting 27 genes in a region of our genomes referred to as 16p11.2. The deletion -- which causes children to inherit only a single copy of the 27-gene cluster -- is one of the most common copy number variations (CNVs) associated with autism.

“儿童通常从父母双方分别遗传一份基因。我们通过实验发现孤独症儿童的基因拷贝数是导致他们出现孤独症症状的重要原因。”Mills教授解释道。在2007年，CSHL的另外一位教授Michael Wigler发现一些儿童患者的16号染色体上的一些基因的缺失影响了16p11.2基因区域上的27个基因。这一基因缺失使得患者只从这个27个基因的基因组中遗传了一份基因，而另一份基因的缺失导致这些儿童患上的孤独症。

"The idea that this deletion might be causing autism was exciting," says Mills. "So we asked whether clipping out the same set of genes in mice would have any effect."

After engineering mice that had a chromosome defect corresponding to the human 16p11.2 deletion found in autism, Mills and her team analyzed these models for a variety of behaviors, as the clinical features of autism often vary widely from patient to patient, even within the same family.

由于孤独症患者的症状和行为个体差异非常大，即使是来自同一个家庭的患者也会有很大不同，Mills教授和她的团队对和孤独症患者出现同样基因缺失（即16p11.2基因组上的基因缺失）的老鼠进行了分析，把他们不同患者的临床症状和各种行为进行对比。

"Mice with the deletion acted completely different from normal mice," explains Guy Horev, a Postdoctoral Fellow in the Mills laboratory and first author of the study. These mice had a number of behaviors characteristic of autism: hyperactivity, difficulty adapting to a new environment, sleeping deficits, and restricted, repetitive behaviors.

Interestingly, mice that had been engineered to carry an extra copy, or duplication, of the 16p11.2 region did not have these characteristics, but instead, had the reciprocal behaviors. For each behavior, the deletion had a more dire consequence than the duplication, indicating that gene loss was more severe. This might explain why 16p11.2 duplications are detected much more frequently than deletions within the human population, and why patients with 16p11.2 deletions tend to be diagnosed earlier than those with duplications.

有趣的是，那些具有双份16p11.2基因（即在这个基因区域不缺少基因），或者拥有已有16p11.2基因的复制的老鼠并无上述表现。缺失基因的老鼠在行为上比具有复制基因的老鼠极端得多，而这或许能解释为什么人类患者基因缺失的那部分人群比具有复制基因的患者更早被诊断出来。

The mouse models also revealed a potential link between 16p11.2 deletion and survival, as about half the mice died following birth. Whether these findings extend to the human population might be answered by future studies that investigate the link between this deletion and unexplained cases of infant death.

那些实验鼠的数据还体现出16p11.2基因缺失和存活率之间的关联--这些老鼠中大概一半在出生后就死亡了。但是要想知道同样的情况是否在人类中也存在，还得看将来对婴儿死亡率和这个基因缺失是否有关的研究结果。

The researchers also used MRI to identify specific regions of the brain that were altered in the autism models, revealing that eight different parts of the brain were affected. The group is now working to identify which gene or group of genes among the 27 that are located within the deleted region is responsible for the behaviors and brain alterations observed.

这些研究人员还用MRI去辨认这些实验鼠大脑中具体那些区域发生了变化，结果他们发现了八处变化。他们目前正在研究那27个基因中哪些基因分别对应着这些变化，以及这些变化怎样对患者行为产生影响。

"Alea Mills has created a valuable resource for everyone engaged in autism research. The technical skill is extraordinary in creating mouse models bearing a human genetic variant that has been associated with autism," says Dr. Gerald Fischbach, Director of Life Sciences and Simons Foundation Autism Research Initiative (SFARI).

“Alea Mills的这项研究为这个领域提供了宝贵的资源。从技术上说，这些实验鼠具有和人类患者同样的基因变异。”塞蒙斯孤独症研究基金和生命科学(SFARI)项目主任Gerald Fischbach说。

These mice will be invaluable for pinpointing the genetic basis of autism and for elucidating how these alterations affect the brain. They could also be used for inventing ways to diagnose children with autism before they develop the full-blown syndrome, as well as for designing clinical interventions.

这些老鼠对于从基因角度判定孤独症起因和解释这些基因变异对人类大脑的影响有着非常重要的作用。而且研究人员也可以因此在患者完全病发之前作出诊断并作临床干预。

Collaborators on this work include a group of MRI specialists led by Dr. Mark Henkelman at the Hospital of Sick Children in Toronto. This study was funded by the Simons Foundation Autism Research Initiative (SFARI)

（该研究的合作者包括多伦多病童医院的Mark Henkelman医生领导下的MRI专家组。这个项目是由SFARI资助。）