Genetic and epigenetic architecture of natural telomere length variation
Genetic and epigenetic architecture of natural telomere length variation
批准号:
10046874
负责人:
Eugene V Shakirov
金额:
$29.3万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-08-01 至 2022-05-31
关键词:
AffectAgeAgingAllelesArabidopsisArchitectureBiochemicalBiologicalBiological AssayBiological MarkersBiologyCandidate Disease GeneCell CycleCell divisionCellsChromosomesCollectionComplexDNADNA MethylationDNA SequenceDataDevelopmentDiseaseEpigenetic ProcessEukaryotaExpression ProfilingFoundationsFrequenciesFundingGene ExpressionGene Expression ProfilingGenesGeneticGenetic EpistasisGenetic PolymorphismGenetic VariationGenomeGenomic SegmentGenomicsGenotypeGoalsHeritabilityHomeostasisHumanInbreedingIndividualKnock-outLeadLengthLinkLongevityMaintenanceMalignant NeoplasmsMapsMethylationModelingMolecularMouse-ear CressMutationNatureOrthologous GeneParentsPathway interactionsPhenotypePlant ModelPlantsPopulationPredispositionPremature aging syndromePrognostic MarkerProteinsQTL GenesQuantitative GeneticsQuantitative Trait LociRNA methylationRecombinantsRegulationRegulator GenesResourcesRoleSeriesSomatic CellTelomere Length MaintenanceTelomere Maintenance GeneTelomere ShorteningTestingTranscriptTransgenic OrganismsTumor MarkersVariantYeastsage relatedbasecancer cellcomparativeepigenetic variationexperimental studygenetic architecturegenome wide association studyhuman diseaseinsightinter-individual variationmultidisciplinarymutantnovelstem cellstelomeretooltranscriptome sequencingtranscriptomicstumorigenesis
中文摘要
项目总结
英文摘要
Project Summary
Telomeres are evolutionarily conserved protein-DNA complexes at the physical ends of
linear eukaryotic chromosomes. Telomeres shorten with age in most human cells, and their
initial length pre-determines cellular lifespan. Mutations in telomere maintenance genes lead to
cancer, premature aging and a number of age-related disorders. While mean telomere length in
humans shows considerable inter-individual variation and appears to be under strong genetic
control, the exact nature of factors establishing telomere length set point remains elusive. In our
preliminary results using the model plant Arabidopsis thaliana we identify a major effect QTL in
a recombinant inbred population that explains 48% of telomere length variation and map this
QTL to a candidate gene, NOP2A. Notably, expression of the human NOP2 ortholog is linked to
tumorigenesis and serves as a prognostic marker of tumor development. In this proposal, we
will utilize genetic, genomic, biochemical and epigenetic approaches to decipher the mechanism
of AtNOP2A function, and to uncover additional genetic and epigenetic factors involved in
telomere length control. In Aim 1, through a series of quantitative transgenic rescue experiments
we will identify the causal SNP and explore the mechanism by which NOP2A impacts telomere
length. We will also employ powerful Arabidopsis genetic, genomic and transcriptomic tools to
identify and characterize NOP2A-dependent genes and trans-regulators. In Aim 2, we will
perform GWAS in 1,001 Arabidopsis genotypes and fine-map additional QTL in a bi-parental
Arabidopsis RIL population to identify novel polymorphisms that affect telomere length. We will
then perform a series of knock-out and transgenic rescue experiments to functionally
characterize candidate genes and validate their role in telomere biology. In Aim 3, we will utilize
a unique A. thaliana epigenetic recombinant inbred population with almost identical DNA
sequences, but variable methylation and gene expression profiles, to fine-map two previously
identified large-effect epi-QTL governing telomere length, and analyze how heritable epigenetic
variation directly affects telomere length. Overall, the results of this study are expected to
significantly increase understanding of genetic differences underlying telomere length
polymorphism in natural Arabidopsis populations. Because modes of telomere regulation are
highly conserved, our data may also provide novel insight into the molecular basis for different
rates of aging and predisposition to diseases associated with telomere abnormalities in humans.
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Genetic and epigenetic architecture of natural telomere length variation
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批准号:10446527
-
项目类别:
-
资助金额:$31.35万
-
财政年份:2018
-
负责人:Eugene V Shakirov
-
依托单位:
Genetic and epigenetic architecture of natural telomere length variation
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批准号:9923707
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项目类别:
-
资助金额:$27.27万
-
财政年份:2018
-
负责人:Eugene V Shakirov
-
依托单位:
Genetic and epigenetic architecture of natural telomere length variation
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批准号:10626849
-
项目类别:
-
资助金额:$29.26万
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财政年份:2018
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负责人:Eugene V Shakirov
-
依托单位:
Identification and analysis of genetic determinants of natural telomere length variation
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批准号:9262152
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项目类别:
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资助金额:$7.83万
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财政年份:2016
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负责人:Eugene V Shakirov
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依托单位:
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