Genotype to phenotype: Crispr gene editing reveals genetic compensation as a mechanism for phenotypic disjunction of morphants and mutants

Cristy M. Salanga, Matthew C. Salanga

Research output: Contribution to journalReview articlepeer-review

2 Scopus citations

Abstract

Forward genetic screens have shown the consequences of deleterious mutations; however, they are best suited for model organisms with fast reproductive rates and large broods. Further-more, investigators must faithfully identify changes in phenotype, even if subtle, to realize the full benefit of the screen. Reverse genetic approaches also probe genotype to phenotype relationships, except that the genetic targets are predefined. Until recently, reverse genetic approaches relied on non-genomic gene silencing or the relatively inefficient, homology-dependent gene targeting for loss-of-function generation. Fortunately, the flexibility and simplicity of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas system has revolutionized reverse genetics, allowing for the precise mutagenesis of virtually any gene in any organism at will. The successful integration of insertions/deletions (INDELs) and nonsense mutations that would, at face value, produce the expected loss-of-function phenotype, have been shown to have little to no effect, even if other methods of gene silencing demonstrate robust loss-of-function consequences. The disjunction between outcomes has raised important questions about our understanding of genotype to phenotype and highlights the capacity for compensation in the central dogma. This review describes recent studies in which genomic compensation appears to be at play, discusses the possible compensation mechanisms, and considers elements important for robust gene loss-of-function studies.

Original languageEnglish (US)
Article number3472
JournalInternational Journal of Molecular Sciences
Volume22
Issue number7
DOIs
StatePublished - Apr 2021

Keywords

  • CRISPR/Cas
  • Genetic compensation
  • Genetic plasticity
  • Morpholino
  • Nonsense-mediated mRNA decay
  • Reverse genetics
  • Transcription activator-like effector nucleases (TALENs)
  • Zebrafish

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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