Insights into the Mutational Burden of Human Induced Pluripotent Stem Cells from an Integrative Multi-Omics Approach

D’Antonio, Matteo; Benaglio, Paola; Jakubosky, David; Greenwald, William W.; Matsui, Hiroko; Donovan, Maureen D.; Li, He; Smith, Erin N.; D’Antonio‐Chronowska, Agnieszka; Frazer, Kelly A.

doi:10.1016/j.celrep.2018.06.091

Cited by 83 publications

(97 citation statements)

References 56 publications

(126 reference statements)

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“…This is faster than the overall procedure from somatic cells' reprograming to pluripotent state, that requires subsequent maturation to sensory neural differentiation of $21-30 days reprograming and another $14-28 days to achieve sensory neural differentiation based on the published protocols [37,38,63,[66][67][68]. This timeline for iPSC does not include the time for required for iPSC isolation, expansion, and to evaluate the genomic integrity of iPSC [69] or clone to clone variations [70,71].…”

Section: Discussionmentioning

confidence: 99%

Chemotherapy-Induced Neuropathy and Drug Discovery Platform Using Human Sensory Neurons Converted Directly from Adult Peripheral Blood

Vojnits

Mahammad

Collins

et al. 2019

Stem Cells Translational Medicine

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Chemotherapy‐induced peripheral neuropathy (PN) is a disorder damaging the peripheral nervous system (PNS) and represents one of the most common side effects of chemotherapy, negatively impacting the quality of life of patients to the extent of withdrawing life‐saving chemotherapy dose or duration. Unfortunately, the pathophysiological effects of PN are poorly understood, in part due to the lack of availability of large numbers of human sensory neurons (SNs) for study. Previous reports have demonstrated that human SNs can be directly converted from primitive CD34+ hematopoietic cells, but was limited to a small‐scale product of SNs and derived exclusively from less abundant allogenic sources of cord or drug mobilized peripheral blood (PB). To address this shortcoming, we have developed and report detailed procedures toward the generation of human SN directly converted from conventionally drawn PB of adults that can be used in a high‐content screening platform for discovery‐based studies of chemotherapy agents on neuronal biology. In the absence of mobilization drugs, cryogenically preserved adult human PB could be induced to (i)SN via development through expandable neural precursor differentiation. iSNs could be transferable to high‐throughput procedures suitable for high‐content screening applicable to neuropathy for example, alterations in neurite morphology in response to chemotherapeutics. Our study provides the first reported platform using adult PB‐derived iSNs to study peripheral nervous system‐related neuropathies as well as target and drug screening potential for the ability to prevent, block, or repair chemotherapy‐induced PN damage. stem cells translational medicine 2019;8:1180–1191

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Section: Discussionmentioning

confidence: 99%

Chemotherapy-Induced Neuropathy and Drug Discovery Platform Using Human Sensory Neurons Converted Directly from Adult Peripheral Blood

Vojnits

Mahammad

Collins

et al. 2019

Stem Cells Translational Medicine

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“…( Figure 1A, Table S1, Table S2). The samples were obtained by combining data from two large induced pluripoitent stem cell (iPSC) resources: 1) iPSCORE (273 individuals, mean WGS coverage 50X, range 36-126X) (D'Antonio et al, 2018;DeBoever et al, 2017;Panopoulos et al, 2017b) and 2) HipSci (446 samples from 204 individuals, mean WGS coverage 37X, range 35-78X) (Kilpinen et al, 2017b;Streeter et al, 2017) (Figure 1B, C). The 477 individuals include members of all five 1KGP superpopulations (Auton et al, 2015): 415 European, 34 East Asian, 15 Admixed American, 7 South Asian, and 6 African.…”

Section: The I2qtl Sample Setmentioning

confidence: 99%

“…Replication rates were calculated for each 8 SV separately among MZ twin pairs and fibroblast-iPSC pairs. The 25 MZ twin pairs were used to select filters because they have matched cell types and fewer somatic differences (D'Antonio et al, 2018) while the 152 matched fibroblasts-iPSC pairs were used to confirm the performance of these thresholds in the HipSci collection.…”

Section: Reproducibility Of Sv Calling Is Associated With Quality Metmentioning

confidence: 99%

“…In this study, as part of the i2QTL consortium, we profiled 719 whole genomes from iPSCORE (D'Antonio et al, 2018;DeBoever et al, 2017;Panopoulos et al, 2017b) and HipSci (Kilpinen et al, 2017a;Streeter et al, 2017) with five variant calling algorithms to capture a wide spectrum of CNVs as well as MEIs, reference MEIs (rMEI), inversions, unspecified breakends (BND), and STRs. We identified algorithm-specific quality metrics and SV characteristics associated with the reproducibility of SVs using 177 pairs of genetic replicates embedded in our collection (25 monozygotic twin pairs and 152 fibroblast-iPSC pairs) and devised filtering and processing approaches to obtain a highly accurate, non-redundant call set across variant classes and algorithmic approaches.…”

Section: Introductionmentioning

confidence: 99%

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Discovery and Quality Analysis of a Comprehensive Set of Structural Variants and Short Tandem Repeats

Jakubosky

Smith

D’Antonio

et al. 2019

Preprint

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Structural variants (SVs) and short tandem repeats (STRs) are important sources of genetic diversity but are not routinely analyzed in genetic studies because they are difficult to accurately identify and genotype. Because SVs and STRs range in size and type, it is necessary to apply multiple algorithms that incorporate different types of evidence from sequencing data and employ complex filtering strategies to discover a comprehensive set of high-quality and reproducible variants. Here we assembled a set of 719 deep whole genome sequencing (WGS) samples (mean 42x) from 477 distinct individuals which we used to discover and genotype a wide spectrum of SV and STR variants using five algorithms. We used 177 unique pairs of genetic replicates to identify factors that affect variant call reproducibility and developed a systematic filtering strategy to create of one of the most complete and well characterized maps of SVs and STRs to date.

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“…HipSci, Supplementary File 2). For the 215 iPSCORE individuals, fibroblasts were reprogrammed, an iPSC clone obtained and RNA-seq data generated and processed as previously described (D'Antonio-Chronowska et al, 2019;D'Antonio et al, 2018;DeBoever et al, 2017;Panopoulos et al, 2017). Briefly, sequenced RNA-seq reads were aligned to the Gencode V.19 transcriptome using STAR (2.5.0a) (Dobin et al, 2013;Harrow et al, 2012).…”

Section: Human Ipscs Used In Expression Studiesmentioning

confidence: 99%

In-depth genetic analysis of 6p21.3 reveals insights into associations between HLA types and complex traits and disease

D’Antonio¹,

Reyna²,

D’Antonio‐Chronowska³

et al. 2019

Preprint

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The MHC region is highly associated with autoimmune and infectious diseases. Here we conduct an in-depth interrogation of associations between genetic variation, gene expression and disease. We create a comprehensive map of regulatory variation in the MHC region using WGS from 419 individuals to call eight-digit HLA types and RNA-seq data from matched iPSCs. Building on this regulatory map, we explored GWAS signals for 4,083 traits, detecting colocalization for 180 disease loci with eQTLs. We show that eQTL analyses taking HLA type haplotypes into account have substantially greater power compared with only using single variants. We examined the association between the 8.1 ancestral haplotype and delayed

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Insights into the Mutational Burden of Human Induced Pluripotent Stem Cells from an Integrative Multi-Omics Approach

Cited by 83 publications

References 56 publications

Chemotherapy-Induced Neuropathy and Drug Discovery Platform Using Human Sensory Neurons Converted Directly from Adult Peripheral Blood

Chemotherapy-Induced Neuropathy and Drug Discovery Platform Using Human Sensory Neurons Converted Directly from Adult Peripheral Blood

Discovery and Quality Analysis of a Comprehensive Set of Structural Variants and Short Tandem Repeats

In-depth genetic analysis of 6p21.3 reveals insights into associations between HLA types and complex traits and disease

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