Investigation of DUF1220 Domains in Human Brain Function and Disease

DUF1220 结构域在人脑功能和疾病中的研究

• 批准号: 8429513
• 负责人: JAMES M SIKELA
• 金额: $ 36.15万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-02 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8429513
• 关键词: Affect; Animal Model; Autistic Disorder; Behavioral; Biological Markers; Brain; Candidate Disease Gene; Cognition; Cognition Disorders; Cognitive; Collaborations; Communities; Complex; Copy Number Polymorphism; Custom; DNA; DNA Sequence Rearrangement; Data; Disease; Exhibits; Genes; Genome; Genome Mappings; Genomics; Goals; Haploidy; Haplotypes; Head circumference; Human; Human Genome; Impaired cognition; Individual; Investigation; Knockout Mice; Laboratories; Lead; Learning; Letters; Libraries; Life; Link; Macrocephaly; Mammals; Maps; Memory; Mental Retardation; Microcephaly; Mole the mammal; Mus; Oligonucleotides; Paper; Patients; Pilot Projects; Rattus; Recurrence; Reporting; Role; Sampling; Schizophrenia; Syndrome; Tertiary Protein Structure; Testing; Universities; Washington; base; behavior test; cognitive function; density; design; disability; genome sequencing; insight; mouse model; novel

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.

总结 我们已经确定，人类基因组序列编码一种新的蛋白质结构域， DUF 1220在人类谱系中高度扩增（>200个拷贝，小鼠/大鼠中为1个拷贝）， 对人类认知功能很重要。大多数DUF 1220域位于 1q21.1是人类基因组中最复杂的区域之一，充满了缺口， 节段性复制1q21.1区域的拷贝数变异（CNVs）现在已经被发现。 涉及与认知功能障碍相关的许多疾病，例如自闭症、精神障碍、 发育迟缓、精神分裂症、小头畸形和大头畸形。这些发现可能表明 新的复发性重排，反映了一种新的认知相关综合征， 1q21.1区域。 为了更精确地鉴定这些细胞中的CNV边界和致病基因， 在患者中，将使用单倍体BAC文库来生成该区域的完成的序列图。 将在以下条件下对来自棘状（单倍体）鼹鼠文库的1q21.1 BAC进行测序： 与华盛顿大学圣路易斯基因组中心的里克·威尔逊博士合作， 在整个区域产生单一单倍型路径。将使用完成的1q21.1序列 对于已经确定的自闭症，精神发育迟滞， 通过与Evan Eichler博士的实验室合作，研究小头畸形和大头畸形 还有詹姆斯·卢普斯基将为完成的1q21.1生成高密度定制平铺阵列 区域并用于阵列CGH以精细绘制这些患者中的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是 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结构域在活体哺乳动物中的功能，DUF 1220-minus 我们已经产生的小鼠（DUF 1220功能的第一个动物模型）将经受 行为测试以评估DUF 1220结构域缺失对学习和记忆的影响。

项目成果

Generation of mice lacking DUF1220 protein domains: effects on fecundity and hyperactivity.

• DOI: 10.1007/s00335-014-9545-8
• 发表时间: 2015-02
• 期刊: MAMMALIAN GENOME
• 影响因子: 2.5
• 作者: Keeney, J. G.;O'Bleness, M. S.;Anderson, N.;Davis, J. M.;Arevalo, N.;Busquet, N.;Chick, W.;Rozman, J.;Hoelter, S. M.;Garrett, L.;Horsch, M.;Beckers, J.;Wurst, W.;Klingenspor, M.;Restrepo, D.;de Angelis, M. Hrabe;Sikela, J. M.
• 通讯作者: Sikela, J. M.