Large-Scale Profiling Reveals the Influence of Genetic Variation on Gene Expression in Human Induced Pluripotent Stem Cells

Cell Stem Cell

Volumn 20, Issue 4, 2017, Pages 533-546.e7

  DeBoever, Christopher ^a   Li, He ^a   Jakubosky, David ^a   Benaglio, Paola ^f   Reyna, Joaquin ^a   Olson, Katrina M ^b,c   Huang, Hui ^a,d   Biggs, William ^e   Sandoval, Efren ^e   D'Antonio, Matteo ^a   Jepsen, Kristen ^a   Matsui, Hiroko ^a   Arias, Angelo ^f   Ren, Bing ^a,d,g   Nariai, Naoki ^f   Smith, Erin N ^f   D'Antonio Chronowska, Agnieszka ^a   Farley, Emma K ^b,c   Frazer, Kelly A ^a,f  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

^c SECTION OF MOLECULAR BIOLOGY   (United States)

^d LUDWIG INSTITUTE FOR CANCER RESEARCH   (United States)

^e Human Longevity Inc   (United States)

^f RADY CHILDREN'S HOSPITAL   (United States)

^g UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

eQTL; expression quantitative trait loci; gene expression; regulation of gene expression; stem cell gene expression; stem cell genetics

Indexed keywords

OCTAMER TRANSCRIPTION FACTOR 4; TRANSCRIPTION FACTOR NANOG; TRANSCRIPTION FACTOR;

ADULT; ARTICLE; BINDING SITE; COPY NUMBER VARIATION; FEMALE; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GENE MAPPING; GENETIC ASSOCIATION; GENETIC TRANSCRIPTION; GENETIC VARIABILITY; GENETIC VARIATION; HUMAN; HUMAN CELL; HUMAN TISSUE; INDUCED PLURIPOTENT STEM CELL; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING; QUANTITATIVE TRAIT LOCUS; WHOLE GENOME SEQUENCING; X CHROMOSOME; GENETIC HETEROGENEITY; GENETICS; METABOLISM; MOLECULAR GENETICS; NUCLEAR REPROGRAMMING; PROCEDURES; REGULATORY SEQUENCE;

BINDING SITES; CELLULAR REPROGRAMMING; CHROMOSOMES, HUMAN, X; DNA COPY NUMBER VARIATIONS; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GENETIC HETEROGENEITY; GENETIC VARIATION; HUMANS; INDUCED PLURIPOTENT STEM CELLS; MOLECULAR SEQUENCE ANNOTATION; QUANTITATIVE TRAIT LOCI; REGULATORY SEQUENCES, NUCLEIC ACID; TRANSCRIPTION FACTORS;

EID: 85017100835     PISSN: 19345909     EISSN: 18759777     Source Type: Journal    
DOI: 10.1016/j.stem.2017.03.009     Document Type: Article

References (84)

1. Abitua, P.B., Gainous, T.B., Kaczmarczyk, A.N., Winchell, C.J., Hudson, C., Kamata, K., Nakagawa, M., Tsuda, M., Kusakabe, T.G., Levine, M., The pre-vertebrate origins of neurogenic placodes. Nature 524 (2015), 462–465.
2. Albert, F.W., Kruglyak, L., The role of regulatory variation in complex traits and disease. Nat. Rev. Genet. 16 (2015), 197–212.
3. Ashburner, M., Ball, C.A., Blake, J.A., Botstein, D., Butler, H., Cherry, J.M., Davis, A.P., Dolinski, K., Dwight, S.S., Eppig, J.T., et al., The Gene Ontology Consortium. Gene ontology: tool for the unification of biology. Nat. Genet. 25 (2000), 25–29.
4. Auton, A., Brooks, L.D., Durbin, R.M., Garrison, E.P., Kang, H.M., Korbel, J.O., Marchini, J.L., McCarthy, S., McVean, G.A., Abecasis, G.R., 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature 526 (2015), 68–74.
5. Avior, Y., Sagi, I., Benvenisty, N., Pluripotent stem cells in disease modelling and drug discovery. Nat. Rev. Mol. Cell Biol. 17 (2016), 170–182.
6. Banovich, N.E., Li, Y.I., Raj, A., Ward, M.C., Greenside, P., Calderon, D., Tung, P.Y., Burnett, J.E., Myrthil, M., Thomas, S.M., et al. Impact of regulatory variation across human iPSCs and differentiated cells. bioRxiv, 2016, 10.1101/091660.
7. Carbon, S., Ireland, A., Mungall, C.J., Shu, S., Marshall, B., Lewis, S. AmiGO Hub, Web Presence Working Group. AmiGO: online access to ontology and annotation data. Bioinformatics 25 (2009), 288–289.
8. Chang, C.C., Chow, C.C., Tellier, L.C., Vattikuti, S., Purcell, S.M., Lee, J.J., Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience, 4, 2015, 7.
9. Chiang, C., Ayyanathan, K., Snail/Gfi-1 (SNAG) family zinc finger proteins in transcription regulation, chromatin dynamics, cell signaling, development, and disease. Cytokine Growth Factor Rev. 24 (2013), 123–131.
10. Chiang, C., Layer, R.M., Faust, G.G., Lindberg, M.R., Rose, D.B., Garrison, E.P., Marth, G.T., Quinlan, A.R., Hall, I.M., SpeedSeq: ultra-fast personal genome analysis and interpretation. Nat. Methods 12 (2015), 966–968.
11. Chiang, C., Scott, A.J., Davis, J.R., Tsang, E.K., Li, X., Kim, Y., Damani, F.N., Ganel, L. GTEx Consortium, Montgomery, S.B., et al. The impact of structural variation on human gene expression. bioRxiv, 2016, 10.1101/055962.
12. Choi, J., Lee, S., Mallard, W., Clement, K., Tagliazucchi, G.M., Lim, H., Choi, I.Y., Ferrari, F., Tsankov, A.M., Pop, R., et al. A comparison of genetically matched cell lines reveals the equivalence of human iPSCs and ESCs. Nat. Biotechnol. 33 (2015), 1173–1181.
13. Christiaen, L., Wagner, E., Shi, W., Levine, M., Electroporation of transgenic DNAs in the sea squirt Ciona. Cold Spring Harb. Protoc., 2009, 2009, t5345.
14. Cingolani, P., Platts, A., Wang, L., Coon, M., Nguyen, T., Wang, L., Land, S.J., Lu, X., Ruden, D.M., A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 6 (2012), 80–92.
15. Conesa, A., Madrigal, P., Tarazona, S., Gomez-Cabrero, D., Cervera, A., McPherson, A., Szcześniak, M.W., Gaffney, D.J., Elo, L.L., Zhang, X., Mortazavi, A., A survey of best practices for RNA-seq data analysis. Genome Biol., 17, 2016, 13.
16. Dale, R.K., Pedersen, B.S., Quinlan, A.R., Pybedtools: a flexible Python library for manipulating genomic datasets and annotations. Bioinformatics 27 (2011), 3423–3424.
17. Delsuc, F., Brinkmann, H., Chourrout, D., Philippe, H., Tunicates and not cephalochordates are the closest living relatives of vertebrates. Nature 439 (2006), 965–968.
18. DePristo, M.A., Banks, E., Poplin, R., Garimella, K.V., Maguire, J.R., Hartl, C., Philippakis, A.A., del Angel, G., Rivas, M.A., Hanna, M., et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43 (2011), 491–498.
19. Dobin, A., Davis, C.A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., Gingeras, T.R., STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29 (2013), 15–21.
20. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489 (2012), 57–74.
21. Erives, A., Corbo, J.C., Levine, M., Lineage-specific regulation of the Ciona snail gene in the embryonic mesoderm and neuroectoderm. Dev. Biol. 194 (1998), 213–225.
22. Farley, E.K., Olson, K.M., Zhang, W., Brandt, A.J., Rokhsar, D.S., Levine, M.S., Suboptimization of developmental enhancers. Science 350 (2015), 325–328.
23. Gaffney, D.J., Veyrieras, J.B., Degner, J.F., Pique-Regi, R., Pai, A.A., Crawford, G.E., Stephens, M., Gilad, Y., Pritchard, J.K., Dissecting the regulatory architecture of gene expression QTLs. Genome Biol., 13, 2012, R7.
24. Gamazon, E.R., Stranger, B.E., The impact of human copy number variation on gene expression. Brief. Funct. Genomics 14 (2015), 352–357.
25. Gamazon, E.R., Nicolae, D.L., Cox, N.J., A study of CNVs as trait-associated polymorphisms and as expression quantitative trait loci. PLoS Genet., 7, 2011, e1001292.
26. Gene Ontology Consortium. Gene Ontology Consortium: going forward. Nucleic Acids Res. 43 (2015), D1049–D1056.
27. GTEx Consortium. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348 (2015), 648–660.
28. Handsaker, R.E., Van Doren, V., Berman, J.R., Genovese, G., Kashin, S., Boettger, L.M., McCarroll, S.A., Large multiallelic copy number variations in humans. Nat. Genet. 47 (2015), 296–303.
29. Harrow, J., Frankish, A., Gonzalez, J.M., Tapanari, E., Diekhans, M., Kokocinski, F., Aken, B.L., Barrell, D., Zadissa, A., Searle, S., et al. GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res. 22 (2012), 1760–1774.
30. Ji, X., Dadon, D.B., Powell, B.E., Fan, Z.P., Borges-Rivera, D., Shachar, S., Weintraub, A.S., Hnisz, D., Pegoraro, G., Lee, T.I., et al. 3D Chromosome Regulatory Landscape of Human Pluripotent Cells. Cell Stem Cell 18 (2016), 262–275.
31. Juven-Gershon, T., Cheng, S., Kadonaga, J.T., Rational design of a super core promoter that enhances gene expression. Nat. Methods 3 (2006), 917–922.
32. Kang, H.M., Sul, J.H., Service, S.K., Zaitlen, N.A., Kong, S.Y., Freimer, N.B., Sabatti, C., Eskin, E., Variance component model to account for sample structure in genome-wide association studies. Nat. Genet. 42 (2010), 348–354.
33. Kheradpour, P., Kellis, M., Systematic discovery and characterization of regulatory motifs in ENCODE TF binding experiments. Nucleic Acids Res. 42 (2014), 2976–2987.
34. Kilpinen, H., Goncalves, A., Leha, A., Afzal, V., Ashford, S., Bala, S., Bensaddek, D., Casale, F.P., Culley, O., Danacek, P., et al. Common genetic variation drives molecular heterogeneity in human iPSCs. bioRxiv, 2016, 10.1101/055160.
35. Kircher, M., Witten, D.M., Jain, P., O'Roak, B.J., Cooper, G.M., Shendure, J., A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46 (2014), 310–315.
36. Korhonen, J., Martinmäki, P., Pizzi, C., Rastas, P., Ukkonen, E., MOODS: fast search for position weight matrix matches in DNA sequences. Bioinformatics 25 (2009), 3181–3182.
37. Kronenberg, Z.N., Osborne, E.J., Cone, K.R., Kennedy, B.J., Domyan, E.T., Shapiro, M.D., Elde, N.C., Yandell, M., Wham: Identifying Structural Variants of Biological Consequence. PLoS Comput. Biol., 11, 2015, e1004572.
38. Kundaje, A., Meuleman, W., Ernst, J., Bilenky, M., Yen, A., Heravi-Moussavi, A., Kheradpour, P., Zhang, Z., Wang, J., Ziller, M.J., et al., Roadmap Epigenomics Consortium. Integrative analysis of 111 reference human epigenomes. Nature 518 (2015), 317–330.
39. Lappalainen, T., Sammeth, M., Friedländer, M.R., ‘t Hoen, P.A., Monlong, J., Rivas, M.A., Gonzàlez-Porta, M., Kurbatova, N., Griebel, T., Ferreira, P.G., et al., Geuvadis Consortium. Transcriptome and genome sequencing uncovers functional variation in humans. Nature 501 (2013), 506–511.
40. Larson, D., abelhj, Chiang, C., AbhijitBadve, Morton, D., and Eldred, J. (2016). svtools: svtools v0.2.0a1(Zenodo).
41. Layer, R.M., Chiang, C., Quinlan, A.R., Hall, I.M., LUMPY: a probabilistic framework for structural variant discovery. Genome Biol., 15, 2014, R84.
42. Leslie, R., O'Donnell, C.J., Johnson, A.D., GRASP: analysis of genotype-phenotype results from 1390 genome-wide association studies and corresponding open access database. Bioinformatics 30 (2014), i185–i194.
43. Lessing, D., Anguera, M.C., Lee, J.T., X chromosome inactivation and epigenetic responses to cellular reprogramming. Annu. Rev. Genomics Hum. Genet. 14 (2013), 85–110.
44. Li, B., Dewey, C.N., RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics, 12, 2011, 323.
45. Li, H., Durbin, R., Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25 (2009), 1754–1760.
46. Li, X., Battle, A., Karczewski, K.J., Zappala, Z., Knowles, D.A., Smith, K.S., Kukurba, K.R., Wu, E., Simon, N., Montgomery, S.B., Transcriptome sequencing of a large human family identifies the impact of rare noncoding variants. Am. J. Hum. Genet. 95 (2014), 245–256.
47. Li, X., Kim, Y., Tsang, E.K., Davis, J.R., Damani, F.N., Chiang, C., Zappala, Z., Strober, B.J., Scott, A.J., Ganna, A., et al. The impact of rare variation on gene expression across tissues. bioRxiv, 2016, 10.1101/074443.
48. Liao, Y., Smyth, G.K., Shi, W., featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30 (2014), 923–930.
49. Liu, X., Sun, H., Qi, J., Wang, L., He, S., Liu, J., Feng, C., Chen, C., Li, W., Guo, Y., et al. Sequential introduction of reprogramming factors reveals a time-sensitive requirement for individual factors and a sequential EMT-MET mechanism for optimal reprogramming. Nat. Cell Biol. 15 (2013), 829–838.
50. Love, M.I., Huber, W., Anders, S., Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol., 15, 2014, 550.
51. Lyon, M.F., Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190 (1961), 372–373.
52. Maurano, M.T., Haugen, E., Sandstrom, R., Vierstra, J., Shafer, A., Kaul, R., Stamatoyannopoulos, J.A., Large-scale identification of sequence variants influencing human transcription factor occupancy in vivo. Nat. Genet. 47 (2015), 1393–1401.
53. Mayba, O., Gilbert, H.N., Liu, J., Haverty, P.M., Jhunjhunwala, S., Jiang, Z., Watanabe, C., Zhang, Z., MBASED: allele-specific expression detection in cancer tissues and cell lines. Genome Biol., 15, 2014, 405.
54. McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M., DePristo, M.A., The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20 (2010), 1297–1303.
55. McKernan, R., Watt, F.M., What is the point of large-scale collections of human induced pluripotent stem cells?. Nat. Biotechnol. 31 (2013), 875–877.
56. Melé, M., Ferreira, P.G., Reverter, F., DeLuca, D.S., Monlong, J., Sammeth, M., Young, T.R., Goldmann, J.M., Pervouchine, D.D., Sullivan, T.J., et al., GTEx Consortium. Human genomics. The human transcriptome across tissues and individuals. Science 348 (2015), 660–665.
57. Pai, A.A., Pritchard, J.K., Gilad, Y., The genetic and mechanistic basis for variation in gene regulation. PLoS Genet., 11, 2015, e1004857.
58. Pala, M., Zappala, Z., Marongiu, M., Li, X., Davis, J.R., Cusano, R., Crobu, F., Kukurba, K.R., Reiner, F., Berutti, R., et al. Population and individual effects of non-coding variants inform genetic risk factors. bioRxiv, 2016, 10.1101/065144.
59. Panopoulos, A.D., D'Antonio, M., Benaglio, P., Williams, R., Hashem, S.I., Schuldt, B.M., DeBoever, C., Arias, A.D., Garcia, M., Nelson, B., et al. iPSCORE: A systematically derived resource of iPSC lines from 222 individuals for use in examining how genetic variation affects molecular and physiological traits across a variety of cell types. Stem Cell Reports, 2017, 10.1016/j.stemcr.2017.03.012 in press. Published online April 11, 2017.
60. Pasque, V., Plath, K., X chromosome reactivation in reprogramming and in development. Curr. Opin. Cell Biol. 37 (2015), 75–83.
61. Pers, T.H., Timshel, P., Hirschhorn, J.N., SNPsnap: a Web-based tool for identification and annotation of matched SNPs. Bioinformatics 31 (2015), 418–420.
62. Pollard, K.S., Hubisz, M.J., Rosenbloom, K.R., Siepel, A., Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 20 (2010), 110–121.
63. Quinlan, A.R., Hall, I.M., BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26 (2010), 841–842.
64. Robinson, M.D., Oshlack, A., A scaling normalization method for differential expression analysis of RNA-seq data. Genome Biol., 11, 2010, R25.
65. Rouhani, F., Kumasaka, N., de Brito, M.C., Bradley, A., Vallier, L., Gaffney, D., Genetic background drives transcriptional variation in human induced pluripotent stem cells. PLoS Genet., 10, 2014, e1004432.
66. Stegle, O., Parts, L., Durbin, R., Winn, J., A Bayesian framework to account for complex non-genetic factors in gene expression levels greatly increases power in eQTL studies. PLoS Comput. Biol., 6, 2010, e1000770.
67. Stolfi, A., Ryan, K., Meinertzhagen, I.A., Christiaen, L., Migratory neuronal progenitors arise from the neural plate borders in tunicates. Nature 527 (2015), 371–374.
68. Storey, J.D., Tibshirani, R., Statistical significance for genomewide studies. Proc. Natl. Acad. Sci. USA 100 (2003), 9440–9445.
69. Stranger, B.E., Forrest, M.S., Dunning, M., Ingle, C.E., Beazley, C., Thorne, N., Redon, R., Bird, C.P., de Grassi, A., Lee, C., et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315 (2007), 848–853.
70. Streeter, I., Harrison, P.W., Faulconbridge, A., Flicek, P., Parkinson, H., Clarke, L., The HipSci Consortium. The human-induced pluripotent stem cell initiative-data resources for cellular genetics. Nucleic Acids Res. 45:D1 (2017), D691–D697.
71. Sudmant, P.H., Rausch, T., Gardner, E.J., Handsaker, R.E., Abyzov, A., Huddleston, J., Zhang, Y., Ye, K., Jun, G., Hsi-Yang Fritz, M., et al., 1000 Genomes Project Consortium. An integrated map of structural variation in 2,504 human genomes. Nature 526 (2015), 75–81.
72. Tarasov, A., Vilella, A.J., Cuppen, E., Nijman, I.J., Prins, P., Sambamba: fast processing of NGS alignment formats. Bioinformatics 31 (2015), 2032–2034.
73. Tchieu, J., Kuoy, E., Chin, M.H., Trinh, H., Patterson, M., Sherman, S.P., Aimiuwu, O., Lindgren, A., Hakimian, S., Zack, J.A., et al. Female human iPSCs retain an inactive X chromosome. Cell Stem Cell 7 (2010), 329–342.
74. Thomas, S.M., Kagan, C., Pavlovic, B.J., Burnett, J., Patterson, K., Pritchard, J.K., Gilad, Y., Reprogramming LCLs to iPSCs Results in Recovery of Donor-Specific Gene Expression Signature. PLoS Genet., 11, 2015, e1005216.
75. Tischler, G., Leonard, S., biobambam: tools for read pair collation based algorithms on BAM files. Source Code Biol. Med., 9, 2014, 13.
76. Tsankov, A.M., Akopian, V., Pop, R., Chetty, S., Gifford, C.A., Daheron, L., Tsankova, N.M., Meissner, A., A qPCR ScoreCard quantifies the differentiation potential of human pluripotent stem cells. Nat. Biotechnol. 33 (2015), 1182–1192.
77. van de Geijn, B., McVicker, G., Gilad, Y., Pritchard, J.K., WASP: allele-specific software for robust molecular quantitative trait locus discovery. Nat. Methods 12 (2015), 1061–1063.
78. Van der Auwera, G.A., Carneiro, M.O., Hartl, C., Poplin, R., Del Angel, G., Levy-Moonshine, A., Jordan, T., Shakir, K., Roazen, D., Thibault, J., et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr. Protoc. Bioinformatics 43 (2013), 1–33.
79. Veyrieras, J.B., Kudaravalli, S., Kim, S.Y., Dermitzakis, E.T., Gilad, Y., Stephens, M., Pritchard, J.K., High-resolution mapping of expression-QTLs yields insight into human gene regulation. PLoS Genet., 4, 2008, e1000214.
80. Walter, K., Min, J.L., Huang, J., Crooks, L., Memari, Y., McCarthy, S., Perry, J.R., Xu, C., Futema, M., Lawson, D., et al., UK10K Consortium. The UK10K project identifies rare variants in health and disease. Nature 526 (2015), 82–90.
81. Wen, X., Luca, F., Pique-Regi, R., Cross-population joint analysis of eQTLs: fine mapping and functional annotation. PLoS Genet., 11, 2015, e1005176.
82. Yan, J., Enge, M., Whitington, T., Dave, K., Liu, J., Sur, I., Schmierer, B., Jolma, A., Kivioja, T., Taipale, M., Taipale, J., Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites. Cell 154 (2013), 801–813.
83. Zeng, Y., Wang, G., Yang, E., Ji, G., Brinkmeyer-Langford, C.L., Cai, J.J., Aberrant gene expression in humans. PLoS Genet., 11, 2015, e1004942.
84. Zhao, J., Akinsanmi, I., Arafat, D., Cradick, T.J., Lee, C.M., Banskota, S., Marigorta, U.M., Bao, G., Gibson, G., A Burden of Rare Variants Associated with Extremes of Gene Expression in Human Peripheral Blood. Am. J. Hum. Genet. 98 (2016), 299–309.