Human gene duplications in neurodevelopment and disease
Human gene duplications in neurodevelopment and disease
批准号:
10803027
负责人:
Megan Y Dennis
金额:
$69.48万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-09-20 至 2028-07-31
关键词:
BenchmarkingBioinformaticsBiologicalBiological AssayBiological ModelsBrainCandidate Disease GeneClustered Regularly Interspaced Short Palindromic RepeatsComplementComplexCopy Number PolymorphismCoupledDataData SetDevelopmentDevelopmental ProcessDiseaseEmbryoEtiologyEvolutionExhibitsEye DevelopmentFamilyGene DuplicationGenesGeneticGenetic DiseasesGenetic HeterogeneityGenetic RiskGenetic ScreeningGenetic VariationGenomeGenomicsHumanHuman GeneticsHuman GenomeImageKnock-outLeftLifeLocationMapsMessenger RNAMethodsModelingModernizationMorphologyMusMutationNeurodevelopmental DisorderNeurologicNeuronsOrthologous GenePhenotypePongidaePopulationPopulation ControlPrimatesProliferatingProteinsPublicationsPublishingRecurrenceRoleSRGAP2 geneSamplingSequence AnalysisSiblingsSignal TransductionSocietiesSourceSpecific qualifier valueTestingTimeVariantZebrafishautism spectrum disorderautistic childrenaxon guidancebioinformatics pipelinecausal variantcohortexperiencefallsfetalfrontierfunctional genomicsgene conservationgene functiongenetic variantgenomic locushuman pangenomehuman reference genomeimprovedindividuals with autism spectrum disorderinnovationinsightmutantneuralneurodevelopmentparalogous genepatient screeningprobandrare variantreference genomesingle-cell RNA sequencingsynaptic functionsynaptogenesistelomeretooltraittranscriptome sequencingwhole genome
中文摘要
项目概要/摘要
尽管在识别人类神经发育和疾病中重要的基因方面做出了重大努力,但大部分基因仍然存在。
基因和变异的比例仍然未被发现。基因组的重复部分主要是
由于参考和生物信息学管道中的历史错误,
基因组中的多个位置。随着最近发表的一个完整的端粒到端粒的人类
基因组、基因和变体可以在复杂的基因座上更有效地测定,但修改的计算
方法是必要的。拟议的研究将利用功能基因组学的各种专业知识
和人类遗传学来检验一个假设,即人类复制基因的一个子集都有助于
神经学特征,并导致现代人类独有的疾病。重复的基因
以前被证明在早期大脑发育中发挥作用,并在基因组热点富集,
复发性拷贝数变异与神经发育障碍有关。以开局就是
成千上万的人类重复基因的综合列表,在人类基因组中表达的基因子集的功能,
将使用直向同源物的CRISPR敲除和人旁系同源物的表达来测试人皮质生成,
斑马鱼,以确定其对一般形态,突触功能和大脑发育的影响。的
同时测试数十到数百个基因的能力,以及基本发育过程的保护,
神经增殖、轴突引导和突触发生--使斑马鱼成为测试这些功能的理想模型
基因.其次,将在人群队列中进行遗传筛查,以确定保守的
复制基因由于标准方法在许多复杂的基因组基因座上过滤变体,因此改进的方法可以在许多复杂的基因组基因座上过滤变体。
利用现有的测序技术,将设计和优化利用短读数据的生物信息学方法
基准。此外,保守的基因将筛选新生和罕见的变异,在自闭症患者
使用已发布的数据集。利用这一多方面的方法,将能够系统地评估
重复基因及其在人类神经系统特征和疾病中的假定作用。斑马鱼工具包将
通常适用于测定脑中重要的额外(非复制)基因的功能
开发,而改进的生物信息学方法将使额外的重复基因筛选,
其他疾病队列。这个项目不仅将提供重要的见解,了解什么是人类,但
它也有能力发现缺失的遗传风险,并阐明复杂的遗传神经系统疾病的病因。
特征和失调
英文摘要
PROJECT SUMMARY/ABSTRACT
Despite significant efforts to identify genes important in human neurodevelopment and disease, a large
proportion of genes and variants remain undiscovered. Duplicated parts of the genome are largely
understudied due to historical errors in the reference and bioinformatic pipelines that filter reads mapping to
multiple locations in the genome. With the recent publication of a complete telomere-to-telomere human
genome, genes and variants can be more effectively assayed across complex loci, but modified computational
approaches are necessary. The proposed study will leverage diverse expertise in functional genomics
and human genetics to test the hypothesis that a subset of human duplicated genes both contribute to
neurological features and cause disorders exclusive to modern-day humans. Duplicated genes have
previously been shown to play a role in early brain development and are enriched at genomic hotspots where
recurrent copy-number variants are associated with neurodevelopmental disorders. Starting with a
comprehensive list of thousands of human duplicated genes, functions of a subset of genes expressed during
human corticogenesis will be tested using CRISPR knockout of orthologs and expression of human paralogs in
zebrafish to determine their effects on general morphology, synaptic function, and brain development. The
ability to test tens to hundreds of genes in parallel and conservation of basic developmental processes—such
as neural proliferation, axonal guidance, and synaptogenesis—make zebrafish an ideal model to test these
genes. Second, a genetic screen will be performed in human population cohorts to identify conserved
duplicated genes. Since standard methods filter variants across many complex genomic loci, an improved
bioinformatics approach leveraging short-read data will be devised and optimized using available sequencing
benchmarks. Further, conserved genes will be screened for de novo and rare variants in autistic individuals
using published datasets. Leveraging this multifaceted approach will enable systematic assessment of
duplicated genes and their putative roles in human neurological traits and disorders. The zebrafish toolkit will
be generally applicable to assaying functions of additional (non-duplicated) genes important in brain
development, while the improved bioinformatics approach will enable additional screens of duplicated genes in
other disease cohorts. This project will not only provide important insights into what it means to be human, but
also it has the capability to discover missing genetic risk and elucidate the etiology of complex genetic neural
traits and disorders.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
Parallel assessment of neurodevelopment genes implicated in autism using zebrafish
-
批准号:10666213
-
项目类别:
-
资助金额:$23.97万
-
财政年份:2023
-
负责人:Megan Y Dennis
-
依托单位:
Parallel assessment of neurodevelopment genes implicated in autism using zebrafish
-
批准号:10842174
-
项目类别:
-
资助金额:$9.45万
-
财政年份:2023
-
负责人:Megan Y Dennis
-
依托单位:
Characterization of Human-Specific Duplicated Genes Implicated in Neurocognitive
-
批准号:9186571
-
项目类别:
-
资助金额:$24.82万
-
财政年份:2016
-
负责人:Megan Y Dennis
-
依托单位:
Characterization of Human-Specific Duplicated Genes Implicated in Neurocognitive
-
批准号:8565256
-
项目类别:
-
资助金额:$9.0万
-
财政年份:2013
-
负责人:Megan Y Dennis
-
依托单位:
Characterization of Human-Specific Duplicated Genes Implicated in Neurocognitive
-
批准号:8722642
-
项目类别:
-
资助金额:$9.0万
-
财政年份:2013
-
负责人:Megan Y Dennis
-
依托单位:
Genetic & Functional Analysis of Variants Associated with Neurocognitive Disorder
-
批准号:8254117
-
项目类别:
-
资助金额:$5.22万
-
财政年份:2012
-
负责人:Megan Y Dennis
-
依托单位:
Genetic & Functional Analysis of Variants Associated with Neurocognitive Disorder
-
批准号:8412056
-
项目类别:
-
资助金额:$3.67万
-
财政年份:2012
-
负责人:Megan Y Dennis
-
依托单位:
海外基金