A MULTI-FACETED SEARCH FOR AUTISM DISEASE GENES

在申请RCDA （K08）时，候选人希望获得分子遗传学方面的专业知识，并将这些专业知识应用于自闭症的研究。该候选人是一名精神病学家，最近在精神健康临床研究中心完成了一项研究奖学金，在那里他最初进行了精神分裂症现象学和神经生物学的研究。然而，在研究期间，由于对神经发育性精神疾病分子遗传学的潜在兴趣，他开始对精神分裂症和自闭症进行基因研究。他现在已经加入了他所在机构的研究团队，在该奖项的支持下，他将领导和开展对这些疾病的分子遗传基础的独立调查。自闭症的特点是儿童时期开始出现刻板的、重复的行为和严重的社会交往和沟通缺陷。目前尚无有效的治疗方法。自闭症在很大程度上是遗传的，人们正在努力识别自闭症疾病基因，尽管还没有发现任何基因。候选人的研究计划使用两种方法来尝试识别这些基因：1)从15号染色体异常的自闭症受试者中创建体细胞杂交，以便分离异常染色体，对其进行分子表征，并更严格地定义潜在的疾病基因窝藏区域；2)在传统连锁分析的基础上，利用全基因组共享片段分析方法，对孤独症高渗透扩展家系进行连锁检测。通过这些方法确定的连接或缩小的区域将筛选候选基因，一旦确定，将使用适当的分子技术进行评估。候选人也有机会分析和比较来自其他类型家庭结构的遗传数据，并检查自闭症表型新定义的影响。候选人的分子指导将由爱荷华大学的Howard Hughes遗传学家提供，并将由统计遗传学，遗传计算生物信息学，自闭症遗传学和表型以及细胞遗传学方面公认的专家进行补充指导，并通过严格的，组织良好的一系列教学课程。总的来说，培训计划和研究计划提供了广泛的培训，有意义的发现的潜力，并支持建立一个独立的研究生涯。

In this application for a RCDA (K08), the candidate proposes to obtain expertise in molecular genetics, applying this expertise to the investigation of autism. The candidate is a psychiatrist who recently completed a research fellowship at a Mental Health Clinical Research Center, where he initially performed research in the phenomenology and neurobiology of schizophrenia. Midway through his fellowship, however, driven by his underlying interest in the molecular genetics of neurodevelopmental psychiatric disorders, he began genetic investigations of both schizophrenia and autism. He has now joined the research faculty at his institution and is in a position, with the support of this award, to move towards leading and conducting independent investigations into the molecular genetic basis of these disorders. Autism is characterized by the childhood onset of stereotyped, repetitive behaviors and severe deficits in social interaction and communication. No effective treatment currently exists. Autism is largely heritable, and increasing effort is being expended to identify autism disease genes, though none have yet been discovered. The candidate's Research Plan uses two approaches to attempt to identify such genes: 1) Creating somatic cell hybrids from autistic subjects with chromosome 15 anomalies in order to isolate the abnormal chromosomes, characterize them molecularly, and more narrowly define a potential disease gene harboring region; and 2) Using the genome wide shared segment analysis approach, as well as traditional linkage analysis, to test for linkage in a number of extended pedigrees highly penetrant for autism. Linked or narrowed regions identified through these approaches will be screened for candidate genes, which, once identified, will be evaluated using appropriate molecular techniques. There is also opportunity for the candidate to analyze and compare genetic data from other types of family structures and to examine the effect of novel definitions of the autism phenotype. The candidate's molecular mentoring will be provided by a Howard Hughes geneticist at the University of Iowa, and will be supplemented by mentoring from recognized experts in statistical genetics, genetic computational bioinformatics, the genetics and phenotype of autism, and cytogenetics, and by a rigorous, well- organized series of didactic coursework. Taken together, the training plan and research proposal provide for a breadth of training, the potential for meaningful discovery, and support for the establishment of an independent research career.