Defining the gene regulatory roles of non-coding variants in the pathogenesis of autism
定义非编码变异在自闭症发病机制中的基因调控作用
基本信息
- 批准号:10537043
- 负责人:
- 金额:$ 5.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAddressAffectAstrocytesBinding SitesBrain regionCellsChildChromatinClustered Regularly Interspaced Short Palindromic RepeatsCodeComputational BiologyDNADataDatabasesDiagnosisDiagnosticDoctor of PhilosophyElectrophysiology (science)FamilyFellowshipFoundationsFutureGene ExpressionGenesGeneticGenetic DiseasesGenetic ServicesGenetic TranscriptionGenomeGenomic approachGenomicsGoalsHuman GeneticsHuman GenomeImpairmentIn VitroIndividualLinkLocationMediatingMedicalMedical GeneticsMembrane PotentialsMentorsMinority GroupsMolecularNeurodevelopmental DisorderNeurogliaNeurologyNeuronsNeurosciencesNucleic Acid Regulatory SequencesOutcomeParentsPathogenesisPathogenicityPatientsPhenotypePhysiciansPhysiologicalProcessPropertyRegulationRegulator GenesRegulatory ElementResearchRoleScientistSusceptibility GeneSystemTechniquesTestingTimeTissuesTrainingTranscriptional RegulationTranslatingUntranslated RNAVariantautism spectrum disorderautistic childrenbasebrain cellcareercell typecellular engineeringclinical diagnosticscohortde novo mutationdisease phenotypeexomegenetic variantgenome editinggenome sequencinghuman diseaseimprovedin vivoindividuals with autism spectrum disorderinduced pluripotent stem cellinsightlarge datasetsmemberneuroregulationoffspringpre-doctoralprobandprogramsstem cellssuccesssynaptogenesistooltranscription factortranscriptome sequencingwhole genome
项目摘要
ABSTRACT
In this Predoctoral Fellowship proposal, I will be trained for a future as a physician-scientist with my own
independent research program at the interface of genomics, computational biology, and neuroscience.
During my MD/PhD training, I will be co-mentored by two physician-scientists, Drs. John Greally (Medical
Genomics) and Pablo Castillo (Neurology), addressing a question that is timely with the imminent widespread
use of whole genome sequencing (WGS) in clinical diagnostics – how do we interpret variants in the non-
coding majority of the human genome when a patient presents with a medical problem?
I will focus on autism, as a condition that represents a substantial proportion of patients seen by medical
genetics services, for which there is extensive WGS information from thousands of families. Despite this wealth
of research sequencing, only a small minority of individuals with autism receive a positive outcome of
diagnostic exome or WGS. I propose that the currently limited diagnostic success rates are mostly due to our
inability to interpret pathogenic variants in the non-coding majority of the genome of these patients. By
improving our insights into non-coding variants, we will be able to offer diagnostic information to many more
families seeking answers than currently.
My strategy is to focus on de novo variants (DNVs) in offspring with autism born to unaffected parents. My
hypothesis is that DNVs can be pathogenic when they occur in the cis-regulatory regions of cell types
mediating autism. The project is therefore based on a computational genomics foundation, using WGS and
DNV calls from large datasets from thousands of families who have a member with autism. In my preliminary
data, I show that DNVs in individuals with autism are enriched at cis-regulatory loci in glial and neuronal cells in
particular, and at genes known to be causative for autism. In my project, I will test these associations more
rigorously, and will define a high-confidence set of DNVs for functional testing.
Two types of functional testing will be performed. One will test whether the DNVs alter molecular genomic
properties, including chromatin accessibility and gene expression. The second will test the physiological
properties of the cells. To generate the appropriate cells for testing, I plan to use induced pluripotent stem cells
(iPSCs) that are in vitro differentiated to GABAergic neurons and astrocytes. By performing CRISPR-mediated
genomic editing in the iPSCs, I can generate cells with the candidate pathogenic DNVs, and test whether they
have effects on cellular properties like dendritogenesis, synaptogenesis, and electrophysiology, increasing the
confidence that these DNVs have pathogenic effects.
I will have the privilege of getting training in sophisticated computational, stem cell and neuroscience
techniques, under the guidance of two leaders in their fields, as part of a comprehensive training plan that will
equip me to become the independent physician-scientist I aspire to be in my career.
摘要
项目成果
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