Paper

Multiplex-edited mice recapitulate woolly mammoth hair phenotypes

Cantarel, Brandi L, Mastracci, Anthony, Lamm, Ben, Wilson, Raphael, Beebe, Jessie, Bhide, Ketaki, Sullivan, Jacob, Bow, Austin, Qin, Yiren, Rafael Vilar Sampaio, Coquelin, Melissa L, Oglesby, Rorie, James, Matt, Church, George M, Shapiro, Beth, Weston, Jacob, Abrams, Michael E, Papizan, James, Love Dalén, Van Der Valk, Tom, Chen, Rui, Ganji, Rakesh, Mathews, Jeremy, Srirattana, Kanokwan, Kehler, James, Ledesma, Alba, Chao, J Chris, Menon, Mitra

2025

Overview

The woolly mammoth (Mammuthus primigenius) possessed a thick woolly coat and other cold-adaptive traits that enabled survival in harsh Arctic environments. Current de-extinction efforts focus on genetically modifying the closely related Asian elephant to express woolly mammoth traits. In this study, we establish a multiplex-edited mouse model with modifications in genes associated with hair morphology and lipid metabolism, enabling insights into traits involved in developing woolly hair and cold tolerance. Our optimized workflows achieved high editing efficiencies and produced genetically modified mice with simultaneous editing of up to seven different genes. Selected modifications include loss-of-function mutations in Fgf5, Tgm3, and Fam83g, among others. The resulting mice display exaggerated hair phenotypes including curly, textured coats, and golden-brown hair. This study establishes a rapid platform for testing mammoth-centric genetic variants while advancing methods for complex genetic model generation. These approaches inform de-extinction efforts and research into the genetic basis of mammalian hair development and cold adaptation.Competing Interest StatementThe authors have filed a patent application based on the results of this work. All authors are current or former employees, or scientific advisors/consultants for Colossal Biosciences and/or Form Bio, and may hold stock and/or stock options in these companies. G.M.C. is a founder and shareholder of Colossal Biosciences and others - full disclosure for G.M.C. is available at http://arep.med.harvard.edu/gmc/tech.html.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Cold tolerance / Fibroblast growth factor 5 / Genetic diversity / Genetics / Hair / Lipid metabolism / Patent applications / Phenotypes / Polar environments