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Author Correction: Evaluating drug targets through human loss-of-function genetic variation
- Source :
- Nature
- Publication Year :
- 2021
- Publisher :
- Nature Publishing Group UK, 2021.
-
Abstract
- Naturally occurring human genetic variants that are predicted to inactivate protein-coding genes provide an in vivo model of human gene inactivation that complements knockout studies in cells and model organisms. Here we report three key findings regarding the assessment of candidate drug targets using human loss-of-function variants. First, even essential genes, in which loss-of-function variants are not tolerated, can be highly successful as targets of inhibitory drugs. Second, in most genes, loss-of-function variants are sufficiently rare that genotype-based ascertainment of homozygous or compound heterozygous 'knockout' humans will await sample sizes that are approximately 1,000 times those presently available, unless recruitment focuses on consanguineous individuals. Third, automated variant annotation and filtering are powerful, but manual curation remains crucial for removing artefacts, and is a prerequisite for recall-by-genotype efforts. Our results provide a roadmap for human knockout studies and should guide the interpretation of loss-of-function variants in drug development.
- Subjects :
- Drug
Heterozygote
media_common.quotation_subject
MEDLINE
tau Proteins
Computational biology
Biology
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Prion Proteins
Target validation
Automation
Consanguinity
Text mining
Gene Frequency
Loss of Function Mutation
Genetic variation
Humans
Molecular Targeted Therapy
Author Correction
Loss function
media_common
Huntingtin Protein
Multidisciplinary
Genes, Essential
business.industry
Published Erratum
Homozygote
Reproducibility of Results
Neurodegenerative Diseases
Genomics
Exons
Gain of Function Mutation
Gene Knockdown Techniques
Sample Size
business
Artifacts
Subjects
Details
- Language :
- English
- ISSN :
- 14764687 and 00280836
- Volume :
- 590
- Issue :
- 7846
- Database :
- OpenAIRE
- Journal :
- Nature
- Accession number :
- edsair.doi.dedup.....bdb7b91308d3a6ab36e0018ddbe2158a