Investigation of DUF1220 Domains in Human Brain Function and Disease

描述（由申请人提供）：我们已经确定，编码新型蛋白质结构域 DUF1220 的人类基因组序列在人类谱系中高度扩增（> 200 个拷贝，而小鼠/大鼠中为 1 个拷贝），并且可能对人类特定的认知功能很重要。大多数 DUF1220 结构域位于 1q21.1，这是人类基因组最复杂的区域之一，充满了间隙和片段重复。 1q21.1 区域的拷贝数变异 (CNV) 现在与许多与认知功能障碍相关的疾病有关，例如认知功能障碍。自闭症、智力低下、精神分裂症、小头畸形和大头畸形。这些发现可能表明一种新的复发性重排，并反映了 1q21.1 区域特有的一种新的认知相关综合征。为了更精确地识别这些患者的CNV边界和致病基因，将使用单倍体BAC文库生成该区域的完整序列图。来自 Hydatiform（单倍体）葡萄胎库的 1q21.1 BAC 测序将与华盛顿大学的 Rick Wilson 博士合作进行。在圣路易斯基因组中心生成跨越该地区的单一单倍型路径。通过与 Drs. 的实验室合作，完成的 1q21.1 序列将用于对已识别的自闭症、智力低下、小头畸形和大头畸形疾病相关 CNV 进行精细定位。埃文·艾希勒和詹姆斯·卢普斯基。将为完成的 1q21.1 区域生成高密度定制平铺阵列，并用于阵列 CGH 来精细绘制这些患者的 CNV 断点并识别候选基因。此外，将使用 DUF1220 特异性引物通过对自闭症个体进行 QPCR 分析来研究 DUF1220 结构域拷贝数在自闭症中的作用。为了研究 DUF1220 结构域在活体哺乳动物中的功能，我们生成的 DUF1220-minus 小鼠（第一个 DUF1220 功能的动物模型）将接受行为测试，以评估 DUF1220 结构域缺失对学习和记忆的影响。公共卫生相关性：除了为科学界提供这一复杂基因组区域最完整的基因组图谱之外，这些研究还应有助于更好地了解 1q21.1 区域中的哪些基因（包括编码 DUF1220 结构域的基因）是已被证明与该区域 CNV 相关的特定认知疾病的基础。此外，使用 DUF1220-minus 小鼠进行的行为研究应该能够初步了解活体哺乳动物中这些域可能的认知功能。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: In addition to providing the scientific community with the most complete genome map for this complex genomic region, these studies should lead to a better understanding of which genes in the 1q21.1 region, including those encoding DUF1220 domains, underlie the specific diseases of cognition that have been shown to be associated with CNVs in this region. In addition, the behavioral studies using DUF1220-minus mice should generate the first insights into the possible cognitive function of these domains in a living mammal.