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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

基本信息

批准号：
9313332
负责人：
JAMES M SIKELA
金额：
$ 38.75万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9313332
关键词：
1q21 Address Affect Alleles Autistic Disorder Biological Assay Brain Brain Diseases CRISPR/Cas technology Cell Proliferation Chromosomes Cognition Disorders Collaborations Copy Number Polymorphism DNA DNA copy number Data Data Set Development Disease Dose Evolution Exhibits Family Family member Genetic Genome Genome Mappings Genomic DNA Genomics Growth Haploidy Human Human Genome Individual Investigation Label Link Macrocephaly Maps Mass Spectrum Analysis Measurement Measures Methods Microcephaly National Institute of Mental Health Neurons Normal Statistical Distribution Open Reading Frames Optics Pathologic Pathway interactions Population Process Reporting Resolution Resources Risk Risk Factors Role Sampling Schizophrenia Series Severities Severity of illness Source Symptoms Technology Tertiary Protein Structure Testing Time Transfection Variant brain abnormalities brain size disorder risk dosage improved insight nerve stem cell novel novel strategies protein expression transcriptome sequencing whole genome

项目摘要

SUMMARY DUF1220 protein domains have undergone the largest human lineage-specific increase in copy number of any protein coding region in the genome (~290 copies in human haploid genome), and map primarily to 1q21, a region where copy number variations containing many DUF1220 copies have been repeatedly linked to autism, schizophrenia, micro- and macrocephaly. DUF1220 copy number exhibits a broad Gaussian distribution in human populations, and is a rich source of unexamined functional allelic variation. Previously we have implicated DUF1220 copy number (dosage) in human brain expansion and normal and pathological changes in brain size. Over the past year we have demonstrated that DUF1220 (CON1 subtype) dosage is linearly associated with increasing symptom severity of autism (now confirmed by a replication study) and also inversely with schizophrenia severity and risk. These findings are remarkable in that they imply that dosage variations within the same protein domain family (DUF1220) may be involved in human brain evolution, autism and schizophrenia, and that these processes may be genetically and mechanistically interrelated. Building on these significant findings, we will expand our study of DUF1220 copy number in autism and schizophrenia severity (Aim 1) and risk (Aim 2) and in micro-/macrocephaly (Aim 3) using methods we have used successfully (ddPCR, 1q21-targeted arrayCGH) as well as through application of novel methods that have the potential to significantly improve DUF1220 copy number analysis (Aim 4). For example, we have recently optimized and validated our sequence read-depth method for measuring DUF1220 copy number at high resolution and precision from whole genome sequence (WGS) data. We will apply this approach to WGS data from 1) the Autism 10K project in collaboration with Dr. Stephen Scherer, and 2) to several additional large WGS datasets that are emerging for autism and schizophrenia. In addition, we have established a subcontract with our collaborator, Dr. Pui Kwok, to apply Irys, an optical mapping method for automated genome mapping of long (>150kb) single DNA molecules, to assess DUF1220 copy number variation in these disorders. The Irys approach should be aided by our development of a CRISPR-Cas9 method which allows DUF1220-specific labeling of genomic DNA. These approaches, including our exploration of long-read sequencing technologies, will be facilitated by utilization of a new, more accurate and gap-free 1q21 assembly we recently helped generate. Finally, we will build on our recent progress linking DUF1220 function to increases in neuron number by testing whether DUF1220 promotes neural stem cell (H9-derived) proliferation in a dosage-dependent manner and identifying cellular pathways affected by progressively increasing DUF1220 dosage.

总结