IDEAS home Printed from https://ideas.repec.org/a/plo/pcbi00/1008194.html
   My bibliography  Save this article

Discovering functional sequences with RELICS, an analysis method for CRISPR screens

Author

Listed:
  • Patrick C Fiaux
  • Hsiuyi V Chen
  • Poshen B Chen
  • Aaron R Chen
  • Graham McVicker

Abstract

CRISPR screens are a powerful technology for the identification of genome sequences that affect cellular phenotypes such as gene expression, survival, and proliferation. By targeting non-coding sequences for perturbation, CRISPR screens have the potential to systematically discover novel functional sequences, however, a lack of purpose-built analysis tools limits the effectiveness of this approach. Here we describe RELICS, a Bayesian hierarchical model for the discovery of functional sequences from CRISPR screens. RELICS specifically addresses many of the challenges of non-coding CRISPR screens such as the unknown locations of functional sequences, overdispersion in the observed single guide RNA counts, and the need to combine information across multiple pools in an experiment. RELICS outperforms existing methods with higher precision, higher recall, and finer-resolution predictions on simulated datasets. We apply RELICS to published CRISPR interference and CRISPR activation screens to predict and experimentally validate novel regulatory sequences that are missed by other analysis methods. In summary, RELICS is a powerful new analysis method for CRISPR screens that enables the discovery of functional sequences with unprecedented resolution and accuracy.Author summary: Non-coding genome sequences contain a disproportionate number of genetic variants associated with human traits and diseases, however, interpretation of non-coding genetic variants is difficult because the molecular function of most non-coding sequences is unknown. By perturbing the genome using CRISPR, the function of non-coding sequences can be tested. Here we develop a new computational tool, RELICS, for the analysis of high-throughput CRISPR screens in which thousands of genome sequences are perturbed in a single experiment. Using simulated data, we find that RELICS has higher accuracy and resolution than other analysis methods. We apply RELICS to existing datasets to discover novel functional sequences and verify these predictions with experiments. In summary, RELICS is a powerful new analysis method for the discovery of functional sequences from CRISPR screens.

Suggested Citation

  • Patrick C Fiaux & Hsiuyi V Chen & Poshen B Chen & Aaron R Chen & Graham McVicker, 2020. "Discovering functional sequences with RELICS, an analysis method for CRISPR screens," PLOS Computational Biology, Public Library of Science, vol. 16(9), pages 1-23, September.
  • Handle: RePEc:plo:pcbi00:1008194
    DOI: 10.1371/journal.pcbi.1008194
    as

    Download full text from publisher

    File URL: https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1008194
    Download Restriction: no

    File URL: https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1008194&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pcbi.1008194?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Matthew C. Canver & Elenoe C. Smith & Falak Sher & Luca Pinello & Neville E. Sanjana & Ophir Shalem & Diane D. Chen & Patrick G. Schupp & Divya S. Vinjamur & Sara P. Garcia & Sidinh Luc & Ryo Kurita &, 2015. "BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis," Nature, Nature, vol. 527(7577), pages 192-197, November.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Inês A. M. Barbosa & Rajaraman Gopalakrishnan & Samuele Mercan & Thanos P. Mourikis & Typhaine Martin & Simon Wengert & Caibin Sheng & Fei Ji & Rui Lopes & Judith Knehr & Marc Altorfer & Alicia Lindem, 2023. "Cancer lineage-specific regulation of YAP responsive elements revealed through large-scale functional epigenomic screens," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Arianna Moiani & Gil Letort & Sabrina Lizot & Anne Chalumeau & Chloe Foray & Tristan Felix & Diane Clerre & Sonal Temburni-Blake & Patrick Hong & Sophie Leduc & Noemie Pinard & Alan Marechal & Eduardo, 2024. "Non-viral DNA delivery and TALEN editing correct the sickle cell mutation in hematopoietic stem cells," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    3. Jing Guo & Luyao Gong & Haiying Yu & Ming Li & Qiaohui An & Zhenquan Liu & Shuru Fan & Changjialian Yang & Dahe Zhao & Jing Han & Hua Xiang, 2024. "Engineered minimal type I CRISPR-Cas system for transcriptional activation and base editing in human cells," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Tomoyuki Ohno & Taichi Akase & Shunya Kono & Hikaru Kurasawa & Takuto Takashima & Shinya Kaneko & Yasunori Aizawa, 2022. "Biallelic and gene-wide genomic substitution for endogenous intron and retroelement mutagenesis in human cells," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    5. Deborah E. Daniels & Ivan Ferrer-Vicens & Joseph Hawksworth & Tatyana N. Andrienko & Elizabeth M. Finnie & Natalie S. Bretherton & Daniel C. J. Ferguson & A. Sofia. F. Oliveira & Jenn-Yeu A. Szeto & M, 2023. "Human cellular model systems of β-thalassemia enable in-depth analysis of disease phenotype," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. Jiaoyang Liao & Shuanghong Chen & Shenlin Hsiao & Yanhong Jiang & Yang Yang & Yuanjin Zhang & Xin Wang & Yongrong Lai & Daniel E. Bauer & Yuxuan Wu, 2023. "Therapeutic adenine base editing of human hematopoietic stem cells," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    7. Colin McGaw & Anthony J. Garrity & Gabrielle Z. Munoz & Jeffrey R. Haswell & Sejuti Sengupta & Elise Keston-Smith & Pratyusha Hunnewell & Alexa Ornstein & Mishti Bose & Quinton Wessells & Noah Jakimo , 2022. "Engineered Cas12i2 is a versatile high-efficiency platform for therapeutic genome editing," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:plo:pcbi00:1008194. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: ploscompbiol (email available below). General contact details of provider: https://journals.plos.org/ploscompbiol/ .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.