| Title: |
Evaluating transportability of in vitro cellular models to in vivo human phenotypes using gene perturbation data |
| Authors: |
Howe, Laurence J.; Aulchenko, Yurii S.; Davey Smith, George; Davies, Neil M.; Esparza-Gordillo, Jorge; Johnson, Toby; Liu, Jimmy Z.; Richardson, Tom G.; Sanseau, Philippe; Scott, Robert A.; Seaton, Daniel D.; Sharma, Ashwini; Cortes, Adrian |
| Source: |
Howe, L J, Aulchenko, Y S, Davey Smith, G, Davies, N M, Esparza-Gordillo, J, Johnson, T, Liu, J Z, Richardson, T G, Sanseau, P, Scott, R A, Seaton, D D, Sharma, A & Cortes, A 2026, 'Evaluating transportability of in vitro cellular models to in vivo human phenotypes using gene perturbation data', Nature Communications, vol. 17, no. 1, 513. https://doi.org/10.1038/s41467-025-67199-1 |
| Publication Year: |
2026 |
| Collection: |
University of Bristol: Bristol Reserach |
| Subject Terms: |
/dk/atira/pure/core/keywords/population_health_SRI; name=Bristol Population Health Science Institute |
| Description: |
Gene perturbation screens (e.g. CRISPR-Cas9) assess the impact of gene disruption on in-vitro cellular phenotypes (e.g., proliferation, anti-viral response). In-vitro experiments can be useful models for in-vivo (organismal) phenotypes (e.g., immune cell anti-viral response and infectious diseases). However, assessing whether an in-vitro cellular model effectively captures in-vivo biology is challenging. An in-vitro model is ‘transportable’ to an in-vivo phenotype if perturbations impacting the in-vitro phenotype also impact the in-vivo phenotype with mechanism-consistent directionality and effect sizes. We propose a framework; Gene Perturbation Analysis for Transportability (GPAT), to assess model transportability using gene perturbation effect estimates from perturbation screens (in-vitro) and loss-of-function burden tests (in-vivo). In hypothesis-driven analyses, GPAT provides evidence for model transportability of higher lysosomal cholesterol accumulation in-vitro to lower human plasma LDL-cholesterol (P = 0.0006), consistent with the known role of lysosomes in lipid biosynthesis. In contrast, there was limited evidence for other putative in-vitro models. In hypothesis-free analyses, we find evidence for transportability of cancer cell line proliferation to in-vivo human plasma cellular phenotypes (e.g. erythroleukemia proliferation and plasma lymphocyte percentage). Here we show that perturbation data can be used to evaluate transportability of in-vitro cellular models, informing assay prioritisation and supporting novel hypothesis generation. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/41390353; info:eu-repo/semantics/altIdentifier/hdl/https://hdl.handle.net/1983/eeb26b85-b64b-493b-a256-c866319787d6 |
| DOI: |
10.1038/s41467-025-67199-1 |
| Availability: |
https://hdl.handle.net/1983/eeb26b85-b64b-493b-a256-c866319787d6; https://research-information.bris.ac.uk/en/publications/eeb26b85-b64b-493b-a256-c866319787d6; https://doi.org/10.1038/s41467-025-67199-1 |
| Rights: |
info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.1E5F41E9 |
| Database: |
BASE |