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Start Over Author "Neal JT" Topic genetic variation
2 results on '"Neal JT"'

1. An Atlas of Variant Effects to understand the genome at nucleotide resolution.

Author

Fowler DM, Adams DJ, Gloyn AL, Hahn WC, Marks DS, Muffley LA, Neal JT, Roth FP, Rubin AF, Starita LM, and Hurles ME

Subjects
Humans, Genome, Human, High-Throughput Nucleotide Sequencing, Precision Medicine, Genetic Variation, Genomics
Abstract

Sequencing has revealed hundreds of millions of human genetic variants, and continued efforts will only add to this variant avalanche. Insufficient information exists to interpret the effects of most variants, limiting opportunities for precision medicine and comprehension of genome function. A solution lies in experimental assessment of the functional effect of variants, which can reveal their biological and clinical impact. However, variant effect assays have generally been undertaken reactively for individual variants only after and, in most cases long after, their first observation. Now, multiplexed assays of variant effect can characterise massive numbers of variants simultaneously, yielding variant effect maps that reveal the function of every possible single nucleotide change in a gene or regulatory element. Generating maps for every protein encoding gene and regulatory element in the human genome would create an 'Atlas' of variant effect maps and transform our understanding of genetics and usher in a new era of nucleotide-resolution functional knowledge of the genome. An Atlas would reveal the fundamental biology of the human genome, inform human evolution, empower the development and use of therapeutics and maximize the utility of genomics for diagnosing and treating disease. The Atlas of Variant Effects Alliance is an international collaborative group comprising hundreds of researchers, technologists and clinicians dedicated to realising an Atlas of Variant Effects to help deliver on the promise of genomics., (© 2023. The Author(s).)

Published
2023
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2. Massively parallel assessment of human variants with base editor screens.

Author

Hanna RE, Hegde M, Fagre CR, DeWeirdt PC, Sangree AK, Szegletes Z, Griffith A, Feeley MN, Sanson KR, Baidi Y, Koblan LW, Liu DR, Neal JT, and Doench JG

Subjects
Alleles, BRCA1 Protein genetics, BRCA2 Protein genetics, Base Sequence, Catalytic Domain, Cell Line, Tumor, Humans, Loss of Function Mutation, Mutagenesis genetics, Myeloid Cell Leukemia Sequence 1 Protein genetics, Point Mutation genetics, Poly(ADP-ribose) Polymerases chemistry, Poly(ADP-ribose) Polymerases genetics, Reproducibility of Results, Selection, Genetic, bcl-X Protein genetics, Gene Editing, Genetic Variation, High-Throughput Nucleotide Sequencing
Abstract

Understanding the functional consequences of single-nucleotide variants is critical to uncovering the genetic underpinnings of diseases, but technologies to characterize variants are limiting. Here, we leverage CRISPR-Cas9 cytosine base editors in pooled screens to scalably assay variants at endogenous loci in mammalian cells. We benchmark the performance of base editors in positive and negative selection screens, identifying known loss-of-function mutations in BRCA1 and BRCA2 with high precision. To demonstrate the utility of base editor screens to probe small molecule-protein interactions, we screen against BH3 mimetics and PARP inhibitors, identifying point mutations that confer drug sensitivity or resistance. We also create a library of single guide RNAs (sgRNAs) predicted to generate 52,034 ClinVar variants in 3,584 genes and conduct screens in the presence of cellular stressors, identifying loss-of-function variants in numerous DNA damage repair genes. We anticipate that this screening approach will be broadly useful to readily and scalably functionalize genetic variants., Competing Interests: Declaration of interests J.G.D. consults for Agios, Maze Therapeutics, Microsoft Research, and Pfizer and consults for, and has equity in, Tango Therapeutics. D.R.L. is a consultant and co-founder of Prime Medicine, Beam Therapeutics, Pairwise Plants, and Editas Medicine, companies that use genome editing, and has previously filed patents on base editing technology. The interests of J.G.D. and D.R.L. were reviewed and are managed by the Broad Institute in accordance with its conflict of interest policies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Published
2021
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