Identification of genetic mechanisms for tissue-specific genetic effects based on CRISPR screens

Elad Dvir, Shahar Shohat, Jonathan Flint, Sagiv Shifman

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

A major challenge in genetic studies of complex diseases is to determine how the action of risk genes is restricted to a tissue or cell type. Here, we investigate tissue specificity of gene action using CRISPR screens from 786 cancer cell lines originating from 24 tissues. We find that the expression pattern of the gene across tissues explains only a minority of cases of tissue-specificity (9%), while gene amplification and the expression levels of paralogs account for 39.5% and 15.5%, respectively. In addition, the transfer of small molecules to mutant cells explains tissue-specific gene action in blood. The tissue-specific genes we found are not specific just for human cancer cell lines: we found that the tissue-specific genes are intolerant to functional mutations in the human population and are associated with human diseases more than genes that are essential across all cell types. Our findings offer important insights into genetic mechanisms for tissue specificity of human diseases.

Original languageAmerican English
Article numberiyac134
JournalGenetics
Volume222
Issue number3
DOIs
StatePublished - Nov 2022

Bibliographical note

Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press on behalf of Genetics Society of America. All rights reserved.

Keywords

  • CRISPR screens
  • essential genes
  • genes intolerant to mutations
  • paralogs
  • tissue specificity

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