Investigation of DUF1220 Domains in Human Brain Function and Disease

描述（由申请人提供）：我们已经确定，编码新蛋白质结构域DUF 1220的人类基因组序列在人类谱系中高度扩增（>200个拷贝对小鼠/大鼠中的1个拷贝），并且在人类特异性认知功能中可能是重要的。DUF 1220的大部分结构域位于1q21.1，这是人类基因组中最复杂的区域之一，充满了缺口和片段重复。1q21.1区域中的拷贝数变异（CNVs）现在已经涉及与认知功能障碍相关的许多疾病，例如自闭症、精神发育迟滞、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，并反映了一种新的认知相关综合征特异性的1q21.1区域。为了更精确地鉴定这些患者中的CNV边界和致病基因，将使用单倍体BAC文库来生成该区域的成品序列图。将与华盛顿大学圣路易斯基因组中心的Rick Wilson博士合作，对来自棘状（单倍体）鼹鼠文库的1q21.1 BAC进行测序，以产生跨该区域的单一单倍型路径。通过与Evan Eichler和James Lupski博士的实验室合作，完成的1q21.1序列将用于自闭症，智力低下，小头畸形和大头畸形的疾病相关CNV的精细定位。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，以精细绘制这些患者的CNV断点并鉴定候选基因。此外，DUF 1220结构域拷贝数在自闭症中的作用将通过使用DUF 1220特异性引物对自闭症个体进行QPCR分析来研究。为了研究DUF 1220结构域在活的哺乳动物中的功能，将对我们产生的DUF 1220缺失小鼠（DUF 1220功能的第一个动物模型）进行行为测试，以评估DUF 1220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个复杂基因组区域的最完整的基因组图谱外，这些研究还应该更好地了解1q21.1区域中的哪些基因，包括编码DUF 1220结构域的基因，是已被证明与该区域的CNV相关的特定认知疾病的基础。此外，使用DUF 1220-minus小鼠进行的行为研究应该会首次深入了解这些域在活体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.