Investigation of DUF1220 Domains in Human Brain Function and Disease

描述(由申请人提供)：我们已经证实，编码一个新的蛋白质结构域DUF1220的人类基因组序列在人类谱系中得到了高度扩增(200个拷贝，而在小鼠/大鼠中为1个)，可能在人类特有的认知功能中具有重要作用。大多数DUF1220结构域位于1q21.1，这是人类基因组中最复杂的区域之一，充满了间隙和节段性复制。1q21.1区域的拷贝数变异(CNV)与许多与认知功能障碍相关的疾病有关，如自闭症、精神发育迟滞、精神分裂症、小头畸形和巨头畸形。这些发现可能预示着一种新的反复重排，并反映了1q21.1区域特有的一种新的认知相关综合征。为了更准确地确定这些患者的CNV边界和致病基因，将使用单倍体BAC文库来生成该区域的完整序列图。将与华盛顿大学的里克·威尔逊博士合作，对水母(单倍体)鼹鼠文库中的1q21.1 BAC进行测序。在圣路易斯基因组中心，以产生跨越该地区的单一单倍型路径。完成的1q21.1序列将通过与埃文·艾希勒博士和詹姆斯·卢普斯基博士的实验室合作，用于精细绘制已经确定的与自闭症、智力低下、小头畸形和巨头畸形相关的疾病相关CNV的图谱。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，以精细定位这些患者的CNV断裂点，并识别候选基因。此外，将通过使用DUF1220特异性引物对自闭症患者进行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，我们建立了DUF1220基因缺失的小鼠(第一个DUF1220功能的动物模型)，并将进行行为测试，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外，这些研究还应有助于更好地理解1q21.1区域的哪些基因，包括那些编码DUF1220结构域的基因，这些基因是特定的认知疾病的基础，这些疾病已被证明与该区域的CNV相关。此外，使用DUF1220基因缺失的小鼠进行的行为研究应该会首次深入了解这些区域在活着的哺乳动物中可能的认知功能。

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.