Document Type
Article
Publication Date
6-24-2025
Original Citation
Xue H,
Mishra M,
Liu Y,
Liu P,
Grzybowski M,
Pandey R,
Usa K,
Vanden Avond M,
Bala N,
Alli A,
Cowley A,
Qiu Q,
Greene A,
Rao S,
O'Meara C,
Geurts A,
Liang M.
Physiological role and mechanisms of action for a long noncoding haplotype region. Cell Rep. 2025;44(6):115805.
Keywords
JMG, Humans, Haplotypes, Polymorphism, Single Nucleotide, Animals, Induced Pluripotent Stem Cells, Blood Pressure, Gene Editing, Mice, CRISPR-Cas Systems
JAX Source
Cell Rep. 2025;44(6):115805.
ISSN
2211-1247
PMID
40493452
DOI
https://doi.org/10.1016/j.celrep.2025.115805
Grant
This work was supported by National Institutes of Health grants HL149620 and DK129964.
Abstract
Direct targeting of noncoding genomic regions harboring common sequence variants associated with human traits through in vivo animal model studies and precise genome editing in human cells is essential for closing the critical gap between genetic discoveries and physiological understanding. However, such investigation has been impractical for many of these variants as they are in haplotypes containing multiple single-nucleotide polymorphisms (SNPs) spanning thousands of base pairs and have small effect sizes. We developed an integrated approach to address this challenge, combining an efficient two-step technique to precisely edit large haplotypes in human induced pluripotent stem cells and orthologous region deletion in phenotypically permissive animal models. As proof of principle, we applied this approach to examine a blood pressure-associated locus with a noncoding haplotype containing 11 SNPs spanning 17.4 kbp. We found a robust blood pressure effect of nearly 10 mmHg and identified the physiological and molecular mechanisms involved.
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.