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High-throughput PRIME-editing screens identify functional DNA variants in the human genome.
Ren, Xingjie; Yang, Han; Nierenberg, Jovia L; Sun, Yifan; Chen, Jiawen; Beaman, Cooper; Pham, Thu; Nobuhara, Mai; Takagi, Maya Asami; Narayan, Vivek; Li, Yun; Ziv, Elad; Shen, Yin.
Affiliation
  • Ren X; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Yang H; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Nierenberg JL; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
  • Sun Y; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Chen J; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Beaman C; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Pham T; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
  • Nobuhara M; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
  • Takagi MA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Narayan V; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • Li Y; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA; Department of Computer Science, University of North Carolina, Chapel Hill, NC, USA.
  • Ziv E; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA; Division of General Internal Medicine, Department of Medicine, and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
  • Shen Y; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. Electronic addr
Mol Cell ; 83(24): 4633-4645.e9, 2023 Dec 21.
Article in En | MEDLINE | ID: mdl-38134886
ABSTRACT
Despite tremendous progress in detecting DNA variants associated with human disease, interpreting their functional impact in a high-throughput and single-base resolution manner remains challenging. Here, we develop a pooled prime-editing screen method, PRIME, that can be applied to characterize thousands of coding and non-coding variants in a single experiment with high reproducibility. To showcase its applications, we first identified essential nucleotides for a 716 bp MYC enhancer via PRIME-mediated single-base resolution analysis. Next, we applied PRIME to functionally characterize 1,304 genome-wide association study (GWAS)-identified non-coding variants associated with breast cancer and 3,699 variants from ClinVar. We discovered that 103 non-coding variants and 156 variants of uncertain significance are functional via affecting cell fitness. Collectively, we demonstrate that PRIME is capable of characterizing genetic variants at single-base resolution and scale, advancing accurate genome annotation for disease risk prediction, diagnosis, and therapeutic target identification.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Genome, Human / Genome-Wide Association Study Limits: Humans Language: En Journal: Mol Cell / Mol. cell / Molecular cell Journal subject: BIOLOGIA MOLECULAR Year: 2023 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Genome, Human / Genome-Wide Association Study Limits: Humans Language: En Journal: Mol Cell / Mol. cell / Molecular cell Journal subject: BIOLOGIA MOLECULAR Year: 2023 Type: Article Affiliation country: United States