Fine mapping rheumatic disease variants using functional genomic sequencing
使用功能基因组测序精细绘制风湿病变异图谱
基本信息
- 批准号:10115944
- 负责人:
- 金额:$ 13.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-05-01 至 2022-02-28
- 项目状态:已结题
- 来源:
- 关键词:ATAC-seqAccountingAddressAllelesAntiviral ResponseAutoimmune ProcessAwarenessBayesian MethodBiologicalBiological AssayBiological ModelsBiologyCD4 Positive T LymphocytesCRISPR/Cas technologyCell LineCell modelCellsCellular biologyChromatinClustered Regularly Interspaced Short Palindromic RepeatsComputer ModelsComputer softwareComputing MethodologiesDNADataData SetDendritic CellsDevelopmentDiseaseEmerging TechnologiesEnhancersEtiologyEuropeanGenesGeneticGenetic DeterminismGenomeGenome engineeringIL2RA geneIndividualInterventionKnock-inKnock-outLeadLinkage DisequilibriumMapsMethodsModelingMolecularMolecular Mechanisms of ActionMolecular ProfilingOutcomePathway interactionsPhasePhenotypeProcessPublic HealthPublishingQuantitative Trait LociRNA SplicingReporterResolutionRheumatismRheumatoid ArthritisSchemeScienceSignal TransductionSingle Nucleotide PolymorphismSjogren&aposs SyndromeSystemSystemic Lupus ErythematosusT cell differentiationT-Cell ActivationT-LymphocyteTestingUntranslated RNAValidationVariantWritingXCL1 genebasecandidate validationcausal variantcell typecomputerized toolsdisease-causing mutationfunctional genomicsgenome editinggenome wide association studygenomic dataimprovedprogramssynthetic biologysynthetic constructtraittranscriptomics
项目摘要
PROJECT SUMMARY ABSTRACT
Here, we propose to develop a two-step computational strategy to improve the power and resolution of
identifying non-coding variants causal for autoimmune rheumatic disease by integrating functional genomic
data. The computational methods developed here address an important problem in disease biology:
pinpointing the precise disease-causing mutations implicated by genome-wide association studies (GWAS)
and understanding the biological mechanisms by which they act. We will develop our program using activated
CD4+ T cells as a model system because of their relevance to autoimmune rheumatic disease, the availability
of functional genomic data, and the ability to experimentally manipulate primary T cells and related cell lines.
The three overlapping aims are:
1. Leveraging allele-specific reads to increase the power of detecting functional genomic quantitative
trait loci (fgQTLs). We will (i) develop an approach to accurately quantify allele-specific reads from functional
genomic sequencing data while accounting for sequencing and mapping biases, (ii) develop a linear mixed
model (LMM) method to perform phase-aware association tests for functional genomic traits, and (iii) apply the
method to identify expression and chromatin accessibility QTLs in activated CD4+ T cells in ~100 individuals.
2. Nominate causal non-coding variants in autoimmune rheumatic disease-associated loci. We will (i)
develop a method that leverages functional genomic QTLs to fine map disease-causing variants in a locus, (ii)
apply the method to integrate expression and chromatin accessibility QTLs from Aim 1 with three autoimmune
rheumatic disease GWAS datasets to identify disease-causing variants most likely associated with CD4+ T cell
activation, (iii) computationally refine and annotate causal variants using orthogonal functional genomic data in
CD4+ T cells.
3. Validate predictions using synthetic biology and genome engineering. We will (i) use massively
parallel reporter assays (MPRAs) to test in activated Jurkats, ~500 synthetic constructs harboring predicted
causal variants from Aims 1 and 2 prioritized for GWAS loci, and use CRISPR/Cas9 to (ii) knock out 25
enhancers harboring causal variants (a subset of the MPRA hits) in Jurkats and CD4+ primary T cells and (iii)
knock-in 10 predicted causal variants in CD4+ primary T cells. We will observe the endogenous effects of
genome edits by profiling molecular and cellular phenotypes during CD4+ T cell activation and differentiation.
项目摘要
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Single-cell RNA-sequencing of peripheral blood mononuclear cells reveals widespread, context-specific gene expression regulation upon pathogenic exposure.
- DOI:10.1038/s41467-022-30893-5
- 发表时间:2022-06-07
- 期刊:
- 影响因子:16.6
- 作者:
- 通讯作者:
Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection.
- DOI:10.1101/gr.240390.118
- 发表时间:2018-12
- 期刊:
- 影响因子:7
- 作者:Ye CJ;Chen J;Villani AC;Gate RE;Subramaniam M;Bhangale T;Lee MN;Raj T;Raychowdhury R;Li W;Rogel N;Simmons S;Imboywa SH;Chipendo PI;McCabe C;Lee MH;Frohlich IY;Stranger BE;De Jager PL;Regev A;Behrens T;Hacohen N
- 通讯作者:Hacohen N
Combined Single Cell Transcriptome and Surface Epitope Profiling Identifies Potential Biomarkers of Psoriatic Arthritis and Facilitates Diagnosis via Machine Learning.
- DOI:10.3389/fimmu.2022.835760
- 发表时间:2022
- 期刊:
- 影响因子:7.3
- 作者:Liu J;Kumar S;Hong J;Huang ZM;Paez D;Castillo M;Calvo M;Chang HW;Cummins DD;Chung M;Yeroushalmi S;Bartholomew E;Hakimi M;Ye CJ;Bhutani T;Matloubian M;Gensler LS;Liao W
- 通讯作者:Liao W
Genetic determinants of co-accessible chromatin regions in activated T cells across humans.
- DOI:10.1038/s41588-018-0156-2
- 发表时间:2018-08
- 期刊:
- 影响因子:30.8
- 作者:Gate RE;Cheng CS;Aiden AP;Siba A;Tabaka M;Lituiev D;Machol I;Gordon MG;Subramaniam M;Shamim M;Hougen KL;Wortman I;Huang SC;Durand NC;Feng T;De Jager PL;Chang HY;Aiden EL;Benoist C;Beer MA;Ye CJ;Regev A
- 通讯作者:Regev A
Multiplexed droplet single-cell RNA-sequencing using natural genetic variation.
使用自然遗传变异的多重液滴单细胞RNA序列。
- DOI:10.1038/nbt.4042
- 发表时间:2018-01
- 期刊:
- 影响因子:46.9
- 作者:Kang HM;Subramaniam M;Targ S;Nguyen M;Maliskova L;McCarthy E;Wan E;Wong S;Byrnes L;Lanata CM;Gate RE;Mostafavi S;Marson A;Zaitlen N;Criswell LA;Ye CJ
- 通讯作者:Ye CJ
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Chun Jimmie Ye其他文献
How mutations express themselves in blood-cell production
突变如何在血细胞生成中表现出来
- DOI:
10.1038/d41586-019-02028-2 - 发表时间:
2019-07-03 - 期刊:
- 影响因子:48.500
- 作者:
Siddharth Raju;Chun Jimmie Ye - 通讯作者:
Chun Jimmie Ye
Demuxafy: improvement in droplet assignment by integrating multiple single-cell demultiplexing and doublet detection methods
Demuxafy:通过集成多个单细胞解复用和双联体检测方法来改进液滴分配
- DOI:
- 发表时间:
2022 - 期刊:
- 影响因子:0
- 作者:
Drew R Neavin;A. Senabouth;Jimmy Tsz Hang Lee;Aida Ripoll;L. Franke;Shyam Prabhakar;Chun Jimmie Ye;Davis J. McCarthy;Marta Melé;M. Hemberg;J. Powell - 通讯作者:
J. Powell
Mutations causing medullary cystic kidney disease type 1 (MCKD1) lie in a large VNTR in MUC1 missed by massively parallel sequencing
导致 1 型髓样囊性肾病 (MCKD1) 的突变位于 MUC1 的大 VNTR 中,大规模并行测序未发现该突变
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:30.8
- 作者:
Andrew W. Kirby;A. Gnirke;D. Jaffe;V. Barešová;N. Pochet;B. Blumenstiel;Chun Jimmie Ye;Daniel Aird;C. Stevens;James T. Robinson;M. Cabili;Irit Gat;E. Kelliher;R. Daza;M. DeFelice;H. Hulkova;J. Sovová;P. Vylet’al;C. Antignac;M. Guttman;R. Handsaker;Danielle L Perrin;S. Steelman;S. Sigurdsson;S. Scheinman;C. Sougnez;K. Cibulskis;Melissa Parkin;Todd Green;E. Rossin;M. Zody;R. Xavier;M. Pollak;S. Alper;K. Lindblad;S. Gabriel;P. Hart;A. Regev;C. Nusbaum;S. Kmoch;A. Bleyer;E. Lander;M. Daly - 通讯作者:
M. Daly
SingleQ: a comprehensive database of single-cell expression quantitative trait loci (sc-eQTLs) cross human tissues
SingleQ:跨人体组织的单细胞表达数量性状位点 (sc-eQTL) 的综合数据库
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Zhiwei Zhou;Jingyi Du;Jianhua Wang;Liangyi Liu;M. G. Gordon;Chun Jimmie Ye;J. E. Powell;Mulin Jun Li;Shuquan Rao - 通讯作者:
Shuquan Rao
Highly Parallel Discovery of Synthetic Knockin Sequences for Enhanced Cancer Immunotherapies
- DOI:
10.1182/blood-2022-158641 - 发表时间:
2022-11-15 - 期刊:
- 影响因子:
- 作者:
Franziska Blaeschke;Yan Yi Chen;Ryan Apathy;Zhongmei Li;Cody T. Mowery;William A. Nyberg;Angela To;Ruby Yu;Raymund Bueno;Min Cheol Kim;Ralf Schmidt;Daniel B. Goodman;Tobias Feuchtinger;Justin Eyquem;Chun Jimmie Ye;Eric Shifrut;Theodore L. Roth;Alexander Marson - 通讯作者:
Alexander Marson
Chun Jimmie Ye的其他文献
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{{ truncateString('Chun Jimmie Ye', 18)}}的其他基金
Mapping gene-by-environment interactions using multiplexed single cell RNA-sequencing
使用多重单细胞 RNA 测序绘制基因与环境相互作用图谱
- 批准号:
10409737 - 财政年份:2020
- 资助金额:
$ 13.27万 - 项目类别:
Mapping gene-by-environment interactions using multiplexed single cell RNA-sequencing
使用多重单细胞 RNA 测序绘制基因与环境相互作用图谱
- 批准号:
10645108 - 财政年份:2020
- 资助金额:
$ 13.27万 - 项目类别:
Mapping gene-by-environment interactions using multiplexed single cell RNA-sequencing
使用多重单细胞 RNA 测序绘制基因与环境相互作用图谱
- 批准号:
10028224 - 财政年份:2020
- 资助金额:
$ 13.27万 - 项目类别:
Genetic regulation and immunological function of ERAP2 haplotypes
ERAP2单倍型的遗传调控和免疫功能
- 批准号:
10470505 - 财政年份:2018
- 资助金额:
$ 13.27万 - 项目类别:
Genetic regulation and immunological function of ERAP2 haplotypes
ERAP2单倍型的遗传调控和免疫功能
- 批准号:
10428475 - 财政年份:2018
- 资助金额:
$ 13.27万 - 项目类别:
Genetic regulation and immunological function of ERAP2 haplotypes
ERAP2单倍型的遗传调控和免疫功能
- 批准号:
10155391 - 财政年份:2018
- 资助金额:
$ 13.27万 - 项目类别:
Fine mapping rheumatic disease variants using functional genomic sequencing
使用功能基因组测序精细绘制风湿病变异图谱
- 批准号:
9906757 - 财政年份:2017
- 资助金额:
$ 13.27万 - 项目类别:
Single-cell sequencing of peripheral blood cells in SLE patients
SLE 患者外周血细胞的单细胞测序
- 批准号:
9372979 - 财政年份:2017
- 资助金额:
$ 13.27万 - 项目类别:
Single-cell sequencing of peripheral blood cells in SLE patients
SLE 患者外周血细胞的单细胞测序
- 批准号:
9522104 - 财政年份:2017
- 资助金额:
$ 13.27万 - 项目类别:
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