Davis Jonathan M, Searles Veronica B, Anderson Nathan, Keeney Jonathon, Dumas Laura, Sikela James M
Department of Biochemistry & Molecular Genetics, Human Medical Genetics and Genomics Program & Neuroscience Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, United States of America.
Department of Biochemistry & Molecular Genetics, Human Medical Genetics and Genomics Program & Neuroscience Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, United States of America; Medical Scientist Training Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, United States of America.
PLoS Genet. 2014 Mar 20;10(3):e1004241. doi: 10.1371/journal.pgen.1004241. eCollection 2014 Mar.
One of the three most frequently documented copy number variations associated with autism spectrum disorder (ASD) is a 1q21.1 duplication that encompasses sequences encoding DUF1220 protein domains, the dosage of which we previously implicated in increased human brain size. Further, individuals with ASD frequently display accelerated brain growth and a larger brain size that is also associated with increased symptom severity. Given these findings, we investigated the relationship between DUF1220 copy number and ASD severity, and here show that in individuals with ASD (n = 170), the copy number (dosage) of DUF1220 subtype CON1 is highly variable, ranging from 56 to 88 copies following a Gaussian distribution. More remarkably, in individuals with ASD CON1 copy number is also linearly associated, in a dose-response manner, with increased severity of each of the three primary symptoms of ASD: social deficits (p = 0.021), communicative impairments (p = 0.030), and repetitive behaviors (p = 0.047). These data indicate that DUF1220 protein domain (CON1) dosage has an ASD-wide effect and, as such, is likely to be a key component of a major pathway underlying ASD severity. Finally, these findings, by implicating the dosage of a previously unexamined, copy number polymorphic and brain evolution-related gene coding sequence in ASD severity, provide an important new direction for further research into the genetic factors underlying ASD.
与自闭症谱系障碍（ASD）相关的三个最常被记录的拷贝数变异之一是1q21.1重复，它包含编码DUF1220蛋白结构域的序列，我们之前认为该蛋白结构域的剂量与人类脑容量增加有关。此外，患有ASD的个体经常表现出脑生长加速和脑容量增大，这也与症状严重程度增加有关。基于这些发现，我们研究了DUF1220拷贝数与ASD严重程度之间的关系，结果表明，在患有ASD的个体（n = 170）中，DUF1220亚型CON1的拷贝数（剂量）高度可变，呈高斯分布，范围从56到88个拷贝。更值得注意的是，在患有ASD的个体中，CON1拷贝数还以剂量反应方式与ASD的三种主要症状（社交缺陷（p = 0.021）、沟通障碍（p = 0.030）和重复行为（p = 0.047））的严重程度增加呈线性相关。这些数据表明，DUF1220蛋白结构域（CON1）剂量具有全ASD效应，因此可能是ASD严重程度潜在主要通路的关键组成部分。最后，这些发现通过表明一个先前未研究的、拷贝数多态且与脑进化相关的基因编码序列的剂量与ASD严重程度有关，为进一步研究ASD潜在遗传因素提供了一个重要的新方向。
