Investigation of DUF1220 Domains in Human Brain Function and Disease

摘要 我们已经确定了编码一个新的蛋白质结构域的人类基因组序列， DUF1220基因在人类谱系中高度扩增(200个拷贝，而在小鼠/大鼠中为1个拷贝)，并可能是 在人类特有的认知功能中很重要。大多数DUF1220域位于 1q21.1，人类基因组最复杂的区域之一，充满缺口和 分段复制。1q21.1区域的拷贝数变异(CNV)现已 与许多与认知功能障碍有关的疾病有关，例如自闭症、精神障碍 发育迟缓、精神分裂症、小头畸形和巨头畸形。这些发现可能表明 新的反复重排并反映了一种新的认知相关综合征 1q21.1区域。 为了更准确地确定CNV边界和致病基因 对于患者，将使用单倍体BAC文库来生成该区域的完整序列图。 将从水合物(单倍体)摩尔文库中进行1q21.1 BAC的测序 与里克·威尔逊博士在华盛顿大学的合作。在圣路易斯基因组中心 生成跨区域的单一单倍型路径。将使用完成的1q21.1序列 为了精细绘制已经确定的与自闭症、精神发育迟滞、 小头畸形和巨头畸形，通过与埃文·艾希勒博士的实验室合作 还有詹姆斯·卢普斯基。将为完成的1q21.1生成高密度自定义平铺阵列 区域，并用于阵列CGH以精细定位这些患者的CNV断裂点并识别 候选基因。此外，DUF1220结构域拷贝数在自闭症中的作用将是 使用DUF1220特异性引物对自闭症患者进行QPCR分析。 研究DUF1220结构域在哺乳动物DUF1220--中的功能 我们已经产生的小鼠(DUF1220功能的第一个动物模型)将受到 行为学测试评估DUF1220结构域缺失对学习和记忆的影响。

SUMMARY We have established that human genome sequences encoding a novel protein domain, DUF1220, are highly amplified in the human lineage (>200 copies vs. 1 in mouse/rat) and may be important in human-specific cognitive function. The majority of DUF1220 domains are located at 1q21.1, one of the most complex regions of the human genome and filled with gaps and segmental duplications. Copy number variations (CNVs) in the 1q21.1 region have now been implicated in numerous diseases associated with cognitive dysfunction, e.g. autism, mental retardation, schizophrenia, microcephaly and macrocephly. These findings may be indicative of a novel recurrent rearrangement and reflect a new cognition-related syndrome specific for the 1q21.1 region. In order to more precisely identify the CNV boundaries and causal disease genes in these patients, a haploid BAC library will be used to generate a finished sequence map of the region. Sequencing of 1q21.1 BACs from a Hydatiform (haploid) mole library will be carried out in collaboration with Dr. Rick Wilson at the Washington Univ. at St. Louis Genome Center to generate a single haplotype path across the region. The finished 1q21.1 sequence will be used for fine mapping of already identified disease-associated CNVs for autism, mental retardation, microcephaly and macrocephaly, through collaborations with the laboratories of Drs. Evan Eichler and James Lupski. High-density custom tiling arrays will be generated for the finished 1q21.1 region and used for array CGH to fine map CNV breakpoints in these patients and identify candidate genes. In addition the role of DUF1220 domain copy number in autism will be investigated by QPCR analysis of individuals with autism using DUF1220-specific primers. To investigate the function of DUF1220 domains in a living mammal, DUF1220-minus mice we have generated (the first animal model for DUF1220 function) will be subjected to behavioral testing to assess the affect of DUF1220 domain loss on learning and memory.