INSPIIRED: Quantification and Visualization Tools for Analyzing Integration Site Distributions

被引：59

作者：

Berry, Charles C. ^{[1
]}

Nobles, Christopher ^{[2
]}

Six, Emmanuelle ^{[3
,4
]}

Wu, Yinghua ^{[2
]}

Malani, Nirav ^{[2
]}

Sherman, Eric ^{[2
]}

Dryga, Anatoly ^{[2
]}

Everett, John K. ^{[2
]}

Male, Frances ^{[2
]}

Bailey, Aubrey ^{[2
]}

Bittinger, Kyle ^{[2
]}

Drake, Mary J. ^{[2
]}

Caccavelli, Laure ^{[5
,6
]}

Bates, Paul ^{[2
]}

Hacein-Bey-Abina, Salima ^{[5
,6
]}

Cavazzana, Marina ^{[5
,6
]}

Bushman, Frederic D. ^{[2
]}

机构：

[1] Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA

[2] Univ Penn, Perelman Sch Med, Dept Microbiol, 3610 Hamilton Walk, Philadelphia, PA 19104 USA

[3] Paris Descartes Sorbonne Paris Cite Univ, Imagine Inst, F-75015 Paris, France

[4] INSERM 24, Lab Human Lymphohematopoiesis, F-75015 Paris, France

[5] Necker Childrens Hosp, AP HP, Biotherapy Dept, F-75014 Paris, France

[6] Grp Hosp Univ Ouest, AP HP, INSERM, Biotherapy Clin Invest Ctr, F-75014 Paris, France

来源：

MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT | 2017年 / 4卷

基金：

欧洲研究理事会;

关键词：

SEVERE COMBINED IMMUNODEFICIENCY; GENE-THERAPY; VECTOR INTEGRATION; DNA INTEGRATION; HUMAN GENOME; INSERTIONAL MUTAGENESIS; HIV-1; INTEGRATION; MLV INTEGRATION; CELLS; SELECTION;

D O I：

10.1016/j.omtm.2016.11.003

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Analysis of sites of newly integrated DNA in cellular genomes is important to several fields, but methods for analyzing and visualizing these datasets are still under development. Here, we describe tools for data analysis and visualization that take as input integration site data from our INSPIIRED pipeline. Paired-end sequencing allows inference of the numbers of transduced cells as well as the distributions of integration sites in target genomes. We present interactive heatmaps that allow comparison of distributions of integration sites to genomic features and that support numerous user-defined statistical tests. To summarize integration site data from human gene therapy samples, we developed a reproducible report format that catalogs sample population structure, longitudinal dynamics, and integration frequency near cancer-associated genes. We also introduce a novel summary statistic, the UC50 (unique cell progenitors contributing the most expanded 50% of progeny cell clones), which provides a single number summarizing possible clonal expansion. Using these tools, we characterize ongoing longitudinal characterization of a patient from the first trial to treat severe combined immunodeficiency- X1 (SCID-X1), showing successful reconstitution for 15 years accompanied by persistence of a cell clone with an integration site near the cancer-associated gene CCND2. Software is available at https://github. com/BushmanLab/ INSPIIRED.

引用

页码：17 / 26

页数：10

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