Convergence of genetic and gestational immune mechanisms in 16p11.2-related ASD

 描述(由申请人提供)：遗传学研究表明，自闭症和自闭症谱系障碍(ASD)是由复杂的遗传倾向引起的，这种遗传倾向与非遗传因素共同作用，改变大脑发育。常见的基因变异可能占ASD风险的50%，其余原因归因于其他因素1，2。即使是穿透性单基因突变也不足以单独导致所有携带这种改变的人患有自闭症 很明显，非遗传或“环境”因素必须与遗传学相互作用，以改变ASD的风险。由于美国的诊断率为1/68，因此开发反映基因-环境相互作用的动物模型对促进自闭症的发展至关重要。与自闭症最强的环境关联之一是怀孕早期的母体免疫事件9-11。这些效果并不需要胎儿感染，而简单地激活母体炎症反应与增加风险有关。尽管有强有力的证据表明遗传和免疫因素都与ASD有关，但很少有报道证实特定的基因改变与妊娠免疫事件相互作用，从而导致或加重ASD的严重程度。动物模型证实，仅母体先天免疫事件的激活就足以引起神经发育和行为的改变15。众所周知，免疫诱导的胎盘损害14，16或胎盘功能17的改变有助于这些影响。一些ASD风险基因与胎盘形成有关，我们认为怀孕早期某些类型的疾病或免疫激活暴露将与遗传风险协同收敛，危及胎盘和发育中的胎儿。在这里，我们提供的证据表明，染色体16p11.2上与ASD相关的微缺失或复制在机制上与胎盘和发育中的脑中的免疫相关机制收敛。在这项建议中，在小鼠和人类多能干细胞上进行的实验将确定环境免疫风险和16p11.2拷贝数变异是否协同作用，以更严重地影响神经发育和导致ASD的功能。

 DESCRIPTION (provided by applicant): Genetic studies indicate that Autism and Autism spectrum disorders (ASD) result from a complex genetic predisposition that acts with non-genetic factors to alter brain development. Common genetic variation may account for up to 50% of ASD risk with remaining causes attributed to other factors 1,2. Even penetrant single gene mutations are not alone sufficient to cause autism in all individuals who carry the alteration and it is clear that non-genetic or "environmental" factors must interact with genetics to modify risk of ASD. With diagnoses at 1 in 68 in the United States8, it has become vital to develop animal models that reflect gene-environment interactions that contribute to the development of ASDs. One of the strongest environmental associations with ASD is a maternal immune event during early pregnancy9-11. Infections of the fetus are not required for these effects and simple activation of a maternal inflammatory response is associated with increased risk9. Despite strong evidence that that both genetic and immune factors contribute to ASD, there are very few reports confirming that specific genetic alterations interact with a gestational immune events to cause or worsen the severity of ASD. Animal models confirm that activation of an innate maternal immune event is alone sufficient to cause alterations in neurodevelopment and behavior 15. It is also known that immune-induced placental damage14,16 or alterations in placental function 17 contribute to these effects. Some ASD risk genes are involved in placentation and we propose that certain types of illness or immune-activating exposures during early pregnancy will synergistically converge with genetic risk to endanger the placenta and developing fetus. Here we provide evidence that microdeletions or duplications on chromosome 16p11.2 that are associated with ASD mechanistically converges with immune-related mechanisms in both the placenta and developing brain. In this proposal, experiments in mice and with human pluripotent stem cells will determine whether environmental immune risk and 16p11.2 copy number variation synergize to more severely impact neurodevelopment and function to cause ASD.