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8. Genome-Scale CRISPR-Cas9 Knockout Screening in Human Cells

Author

McGovern Institute for Brain Research at MIT, Shalem, Ophir, Sanjana, Neville E, Scott, David Arthur, Zhang, Feng, Hartenian, E., Shi, X., Mikkelsen, T. S., Heckl, D., Ebert, B. L., Root, D. E., Doench, J. G., McGovern Institute for Brain Research at MIT, Shalem, Ophir, Sanjana, Neville E, Scott, David Arthur, Zhang, Feng, Hartenian, E., Shi, X., Mikkelsen, T. S., Heckl, D., Ebert, B. L., Root, D. E., and Doench, J. G.

Abstract

The simplicity of programming the CRISPR (clustered regularly interspaced short palindromic repeats)–associated nuclease Cas9 to modify specific genomic loci suggests a new way to interrogate gene function on a genome-wide scale. We show that lentiviral delivery of a genome-scale CRISPR-Cas9 knockout (GeCKO) library targeting 18,080 genes with 64,751 unique guide sequences enables both negative and positive selection screening in human cells. First, we used the GeCKO library to identify genes essential for cell viability in cancer and pluripotent stem cells. Next, in a melanoma model, we screened for genes whose loss is involved in resistance to vemurafenib, a therapeutic RAF inhibitor. Our highest-ranking candidates include previously validated genes NF1 and MED12, as well as novel hits NF2, CUL3, TADA2B, and TADA1. We observe a high level of consistency between independent guide RNAs targeting the same gene and a high rate of hit confirmation, demonstrating the promise of genome-scale screening with Cas9., National Institutes of Health (U.S.) (Award 1DP1-MH100706), National Institutes of Health (U.S.) (1R01-DK097768)

Published
2017

9. A molecular network of the aging brain implicatesINPPL1andPLXNB1in Alzheimer’s disease

Author

Mostafavi, S., primary, Gaiteri, C., additional, Sullivan, S. E., additional, White, C.C., additional, Tasaki, S., additional, Xu, J., additional, Taga, M., additional, Klein, H., additional, Patrick, E., additional, Komashko, V., additional, McCabe, C., additional, Smith, R., additional, Bradshaw, E.B., additional, Root, D., additional, Regev, A., additional, Yu, L., additional, Chibnik, L.B., additional, Schneider, J.A., additional, Young-Pearse, T., additional, Bennett, D.A., additional, and De Jager, P.L., additional

Published
2017
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11. The diversification strategies of large South African contractors into southern Africa

Author

Olivier, J and Root, D

Subjects
diversification, South African construction industry southern Africa, strategy, large South African contractors
Abstract

This article presents the results of a study into the current diversification strategies of large South African contractors and the reasons for choosing southern Africa as a diversification strategy. It investigated the major risks involved in doing business in southern Africa, which of the southern African countries are more favourable to diversify into and the impact of diversification on performance. It also attempted to identify the major competitors in southern Africa and the source of their competitive advantage. The study consists of a literature review and utilised the data from the annual reports for the period 2007 to 2011 of nine selected large South African contractors, as well as relevant publicised news articles. All the data used in this study is already in the public domain. The research found that the countries of southern Africa present significant opportunities for South African construction companies. Southern Africa forms a definite part of the diversification strategies of large South African contractors; they are, however, mostly moderately diversified, and the 'big' players are highly diversified both operationally and geographically. The extent of diversification has an impact on performance, as undiversified is clearly associated with underperformance, and moderately diversified within a specialised field with outperformance. The research was inconclusive on the identities of the major competitors in southern Africa and the source of their competitive advantage. It was, however, found through the literature study that Chinese contractors are the major competitive force in southern Africa and in the rest of Africa, and their governmental support systems on policy and financial backing are the source of their competitive advantage.

Published
2014

12. Johnson, John (i)

Author

McGuire, C.E., Burgers, J.W.J., Root, D., Bohlman, P.V., Cross, J., Meconi, H., Roberts, J.H., and ASH (FGw)

Published
2014

17. Towards patient-based cancer therapeutics

Author

Discovery, C. T., Network, D., Schreiber, S. L., Shamji, A. F., Clemons, P. A., Hon, C., Koehler, A. N., Munoz, B., Palmer, M., Stern, A. M., Wagner, B. K., Powers, S., Lowe, S. W., Guo, X., Krasnitz, A., Sawey, E. T., Sordella, R., Stein, L., Trotman, L. C., Califano, A., Dalla Favera, R., Ferrando, A., Iavarone, A., Pasqualucci, Laura, Silva, J., Stockwell, B. R., Hahn, W. C., Chin, L., Depinho, R. A., Boehm, J. S., Gopal, S., Huang, A., Root, D. E., Weir, B. A., Gerhard, D. S., Zenklusen, J. C., Roth, M. G., White, M. A., Minna, J. D., Macmillan, J. B., and Posner, B. A.

Subjects
Biomedical Engineering, MEDLINE, Bioengineering, Antineoplastic Agents, Bioinformatics, Small Interfering, Applied Microbiology and Biotechnology, Article, Mice, Neoplasms, Drug Discovery, medicine, Animals, Humans, Gene Regulatory Networks, Precision Medicine, RNA, Small Interfering, Drug discovery, business.industry, Animal, Cancer, Individualized Medicine, Precision medicine, medicine.disease, National Cancer Institute (U.S.), United States, Neoplasm Proteins, Cancer drug discovery, Disease Models, Animal, Disease Models, Molecular Medicine, RNA, business, Biotechnology
Abstract

A new approach to the discovery of cancer therapeutics is emerging that begins with the cancer patient. Genomic analysis of primary tumors is providing an unprecedented molecular characterization of the disease. The next step requires relating the genetic features of cancers to acquired gene and pathway dependencies and identifying small-molecule therapeutics that target them.

Published
2010

23. Genome-wide functional screening identifies CDC37 as a crucial HSP90-cofactor for KIT oncogenic expression in gastrointestinal stromal tumors

Author

Mariño-Enríquez, A, primary, Ou, W-B, additional, Cowley, G, additional, Luo, B, additional, Jonker, A H, additional, Mayeda, M, additional, Okamoto, M, additional, Eilers, G, additional, Czaplinski, J T, additional, Sicinska, E, additional, Wang, Y, additional, Taguchi, T, additional, Demetri, G D, additional, Root, D E, additional, and Fletcher, J A, additional

Published
2013
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27. LAB-RADIOBIOLOGY

Author

Floyd, S. R., primary, Pacold, M. E., additional, Clarke, S. M., additional, Blake, E., additional, Fydrych, A., additional, Ho, R., additional, Lee, M. J., additional, Root, D. E., additional, Carpenter, A. E., additional, Sabatini, D. M., additional, French, C. A., additional, Bradner, J. E., additional, Chen, C. C., additional, Yaffe, M. B., additional, Le Rhun, E., additional, Massin, F., additional, Lefevre, A., additional, Bonneterre, J., additional, Bittencourt, M. d. C., additional, Faure, G., additional, Hiramatsu, R., additional, Kawabata, S., additional, Yamada, Y., additional, Miyatake, S.-I., additional, Kuroiwa, T., additional, Li, S., additional, Chou, A. P., additional, Chen, W., additional, Chen, R., additional, Deng, Y., additional, Phillips, H. S., additional, Faull, K. F., additional, Cloughesy, T., additional, Liau, L. M., additional, Lai, A., additional, Mori, K., additional, Ishikura, R., additional, Tomogane, Y., additional, Izumoto, S., additional, Arita, N., additional, Piao, J., additional, Auyeung, G., additional, Policarpio, E., additional, Tabar, V., additional, Yeung, T. P. C., additional, Morrison, L., additional, Hoffman, L., additional, Lee, T.-Y., additional, Bauman, G., additional, Yartsev, S., additional, Ryu, S., additional, Kolozsvary, A., additional, Lapanowski, M., additional, Jenrow, K., additional, Brown, S., additional, Kim, J. H., additional, Brown, R. J., additional, Love, J., additional, Warburton, D., additional, McBride, W., additional, Bluml, S., additional, Ren, X., additional, Vanderwaal, B., additional, Jaboin, J., additional, Baldock, A. L., additional, Anh, S., additional, Rockne, R., additional, Neal, M., additional, Clark-Swanson, K., additional, Sterin, G., additional, Trister, A. D., additional, Malone, H., additional, Ebiana, V., additional, Sonabend, A. M., additional, Mrugala, M., additional, Rockhill, J. K., additional, Silbergeld, D. L., additional, McKhann, G. M., additional, Bruce, J. N., additional, Rostomily, R., additional, Canoll, P., additional, Swanson, K. R., additional, Hawkins-Daarud, A., additional, Baldock, A., additional, Bridge, C., additional, Corwin, D., additional, Mrugala, M. M., additional, Yagle, K., additional, Born, D., additional, and Swanson, P., additional

Published
2012
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32. A GENE FOR EPISODIC ATAXIA/MYOKYMIA MAPS TO CHROMOSOME 12P13

Author

LITT, M, KRAMER, P, BROWNE, D, GANCHER, S, BRUNT, ERP, ROOT, D, PHROMCHOTIKUL, T, DUBAY, CJ, and NUTT, J

Subjects
CLONING, POTASSIUM CHANNEL GENE, KINDREDS, MYOKYMIA, ACETAZOLAMIDE, HEREDITARY PAROXYSMAL ATAXIA, LOCUS, LOCALIZATION, PERIODIC ATAXIA
Abstract

Episodic ataxia (EA) is a rare, familial disorder producing attacks of generalized ataxia, with normal or near-normal neurological function between attacks. Families with autosomal dominant EA represent at least two distinct clinical syndromes. One clinical type of EA (MIM 160120) includes individuals who have episodes of ataxia and dysarthria lasting seconds to minutes. In addition, myokymia (rippling of muscles, diagnosable by electromyography) is evident during and between attacks. Since Kf channel genes are candidate genes for EA, we tested markers near known Kf channel genes for linkage. Using a group of Genethon markers from one such region-chromosome 12p-we found evidence of linkage in four EA/myokymia families. A maximum combined lod score of 13.6 was obtained at theta = 0, with the marker D12S99. A human Ca++ channel gene, CACNL1A1, and three human K+ channel genes-KCNA5, KCNA6, and KCNAl-map close to D12S99, but the Ca++ channel gene is unlikely to be the site of the defect, because crossovers have been observed to occur between the disease gene and a CA-repeat marker located close to this gene. Studies of a large Ed family with a different clinical phenotype (MIM 108500), which lacks myokymia but is associated with nystagmus, have excluded the gene causing that disease from the chromosome 12p locus.

Published
1994

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