Iossifov Ivan, Levy Dan, Allen Jeremy, Ye Kenny, Ronemus Michael, Lee Yoon-Ha, Yamrom Boris, Wigler Michael
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; New York Genome Center, New York, NY 10013;
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;
Proc Natl Acad Sci U S A. 2015 Oct 13;112(41):E5600-7. doi: 10.1073/pnas.1516376112. Epub 2015 Sep 23.
We previously computed that genes with de novo (DN) likely gene-disruptive (LGD) mutations in children with autism spectrum disorders (ASD) have high vulnerability: disruptive mutations in many of these genes, the vulnerable autism genes, will have a high likelihood of resulting in ASD. Because individuals with ASD have lower fecundity, such mutations in autism genes would be under strong negative selection pressure. An immediate prediction is that these genes will have a lower LGD load than typical genes in the human gene pool. We confirm this hypothesis in an explicit test by measuring the load of disruptive mutations in whole-exome sequence databases from two cohorts. We use information about mutational load to show that lower and higher intelligence quotients (IQ) affected individuals can be distinguished by the mutational load in their respective gene targets, as well as to help prioritize gene targets by their likelihood of being autism genes. Moreover, we demonstrate that transmission of rare disruptions in genes with a lower LGD load occurs more often to affected offspring; we show transmission originates most often from the mother, and transmission of such variants is seen more often in offspring with lower IQ. A surprising proportion of transmission of these rare events comes from genes expressed in the embryonic brain that show sharply reduced expression shortly after birth.
我们之前计算得出，患有自闭症谱系障碍（ASD）的儿童中具有从头（DN）可能基因破坏（LGD）突变的基因具有高易损性：这些基因（即易损自闭症基因）中的许多破坏性突变很可能导致ASD。由于ASD个体的生育力较低，自闭症基因中的此类突变将受到强烈的负选择压力。一个直接的预测是，在人类基因库中，这些基因的LGD负荷将低于典型基因。我们通过测量来自两个队列的全外显子序列数据库中的破坏性突变负荷，在一项明确的测试中证实了这一假设。我们利用有关突变负荷的信息表明，智商较低和较高的受影响个体可以通过其各自基因靶点中的突变负荷来区分，同时也有助于根据基因成为自闭症基因的可能性对基因靶点进行优先级排序。此外，我们证明，LGD负荷较低的基因中罕见破坏的传递更常发生在受影响的后代中；我们表明传递最常来自母亲，并且此类变异在智商较低的后代中更常出现。这些罕见事件的传递中有一个惊人的比例来自胚胎大脑中表达的基因，这些基因在出生后不久表达急剧下降。
