437: Cell villages and Dirichlet modeling map human cell fitness genetics

Hanson C et al., The American Journal of Human Genetics - Hanson et al. combine pooled multi-donor human neural progenitor cell "villages" with Townlet, a hierarchical Dirichlet regression model, to estimate donor-specific proliferation and treatment responses from Census-seq. They identify 16p11.2 deletion–associated NPC hyperproliferation and nominate common variants near ZFHX3 for proliferation and an ARNT2-linked locus for lead (Pb) sensitivity. Key terms: cell villages, Dirichlet regression, neural progenitor cells, 16p11.2 deletion, lead (Pb) sensitivity. Study Highlights:The authors developed and validated cell villages of 12–39 donor-derived NPC lines and Townlet, a Dirichlet regression framework, to analyze compositional time-series Census-seq data and estimate donor proliferation and treatment effects. Using this system they detected hyperproliferation of NPCs carrying the 16p11.2 deletion, mapped a common variant near ZFHX3 associated with proliferation, and identified ARNT2-linked variants associated with differential sensitivity to lead. Villages preserved donor-intrinsic growth rates while reducing technical variation, and Townlet outperformed standard models in simulations and empirical benchmarks. Conclusion:Pooled multi-donor NPC villages combined with the Townlet Dirichlet model provide a scalable, reproducible platform to map genetic and gene–environment effects on human cell fitness, nominating 16p11.2, ZFHX3, and ARNT2 as contributors to NPC proliferation and Pb sensitivity. Music:Enjoy the music based on this article at the end of the episode. Article title:Cell villages and Dirichlet modeling map human cell fitness genetics First author:Hanson C Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.07.005 Reference:Hanson C., Derebenskiy T., Rodriguez Vega A., et al. Cell villages and Dirichlet modeling map human cell fitness genetics. The American Journal of Human Genetics. 2026;113:1–21. doi:10.1016/j.ajhg.2026.07.005 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01☕ One-time donation: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 More at basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/cell-villages-dirichlet-modeling-human-cell-fitness QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-09. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing Townlet and cell villages, validation against array cultures, 16p11.2 deletion hyperproliferation, GWAS identifying ZFHX3-associated proliferation variants, and lead (Pb) resistance modifiers linked to ARNT2; also reviewed environmental exposome implications and limitations di- transcript topics: Cell villages concept and Townlet model; Census-seq and compositional data challenges; Village vs array validation and donor-intrinsic proliferation; 16p11.2 deletion NPC hyperproliferation in villages; GWAS in villages identifying ZFHX3 locus and rs34470044; Lead (Pb) exposure and ARNT2-associated Pb resistance QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims:...