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: 8248795
• 负责人: JAMES M SIKELA
• 金额: $ 37.67万
• 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/8248795
• 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.

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