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

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)
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:
Genomic Technology Core
基因组技术核心
  • 批准号:
    10685564
  • 财政年份:
    2016
  • 资助金额:
    $ 13.27万
  • 项目类别:

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