Functional Genetic Variants Revealed by Massively Parallel Precise Genome Editing
Open accessAbstract
A major challenge in genetics is to identify genetic variants driving natural phenotypic variation. However, current methods of genetic mapping have limited resolution. To address this challenge, we developed a CRISPR-Cas9-based high-throughput genome editing approach that can introduce thousands of specific genetic variants in a single experiment. This enabled us to study the fitness consequences of 16,006 natural genetic variants in yeast. We identified 572 variants with significant fitness differences in glucose media; these are highly enriched in promoters, particularly in transcription factor binding sites, while only 19.2% affect amino acid sequences. Strikingly, nearby variants nearly always favor the same parent's alleles, suggesting that lineage-specific selection is often driven by multiple clustered variants. In sum, our genome editing approach reveals the genetic architecture of fitness variation at single-base resolution and could be adapted to measure the effects of genome-wide genetic variation in any screen for cell survival or cell-sortable markers.
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Alternatives to DNA cleavage-induced editing include base editing, prime editing, and CRISPRi/CRISPRa.
“Alternatives to DNA cleavage-induced editing include using CRISPR-Cas9 for direct chemical sequence alteration (base editing) 25,26 , providing RNA templates for gene alteration (prime editing) 27,28 , and for transcriptional control (CRISPR interference, CRISPRi; CRISPR activation, CRISPRa) 29,30 (Fig. 3).”
From The promise and challenge of therapeutic genome editing (2020) · cites this paper as [27]
The citation is attached to the sentence’s claim about CRISPRi/CRISPRa for transcriptional control. The Introduction and Results describe Cas9 cleavage followed by donor-directed repair, not CRISPRi or CRISPRa; searches for those terms and transcriptional control found no passage addressing that claim. The References mention base editing, but do not establish the claim for which this citation is offered. (LLM, conf=0.75)
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The promise and challenge of therapeutic genome editing
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“…al., 2014, 2018), which relies on homology-directed repair (HDR), has been used to screen all possible variants in several exons of BRCA1; while HDR approaches are effective in yeast (Sharon et al., 2018), the low efficiency of HDR in human cells has restricted its use to rare near-haploid lines.”
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- Authors
- Sharon, E., Chen, S.-A. A., Khosla, N. M., Smith, J. D., Pritchard, J. K., & Fraser, H. B.
- Affiliations
- Howard Hughes Medical Institute (US)
- Stanford University (US)
- Corresponding author
- Sharon, Eilon
- Fraser, Hunter B.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 175
- Issue
- 2
- Pages
- 544-557.e16
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6563827
- OpenAlex
- W2890432440
- Cited by
- 225
- References
- 106
- Citations by year
- 2026: 20 · 2025: 29 · 2024: 44 · 2023: 24 · 2022: 29 · 2021: 28 · 2020: 28 · 2019: 19 · 2018: 4
- FWCI
- 7.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- the European Molecular Biology Organization (LTF 646-2014)
- the National Institutes of Health (5T32GM007276-42, 2R01GM097171-05A1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- functional variants, CRISPR/Cas9 genome editing, high-throughput genome editing, yeast, natural genetic variation, promoter polymorphism, transcription factor binding sites, lineage-specific selection
- MeSH terms
- Gene Editing, Chromosome Mapping, Genetic Vectors, Saccharomyces cerevisiae, Genetic Variation, Yeasts, Genome, High-Throughput Nucleotide Sequencing, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR-Cas Systems
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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