By editing seven genes simultaneously, scientists at Colossal Biosciences were able to successfully create mice that have a coat color, texture, and thickness similar to the woolly mammoth’s core phenotypes. Full details are provided in a new bioRxiv paper titled, “Multiplex-edited mice recapitulate woolly mammoth hair phenotypes.”
According to the company, the woolly mice were generated by expressing traits crucial for mammoth de-extinction in living mice. They learned these traits by analyzing 59 woolly, Columbian, and steppe mammoth genomes ranging from 3,500 to over 1,200,000 years old. Specifically, Colossal’s mammoth team explored data from 121 mammoth and elephant genomes, including internally generated reference genomes for Asian and African elephants. Their goal was to identify genes that impact hair and other cold-adaptation traits.
They began by focusing on a suite of genes in which mammoths had evolved fixed differences compared to the closely related Asian elephant. Next, they refined the list to include ten genes related to hair length, thickness, texture, and color as well as lipid metabolism that were compatible with expression in a mouse. They then combined three editing technologies to edit the mouse genome—RNP-mediated knockout, multiplex precision genome editing, and precision homology-directed repair. They used these methods to simultaneously make eight edits in seven genes.
The resulting mice all have an edit that causes loss of function in the FGF5 gene, which alters hair growth cycles and causes hair growth as much as three times longer than wild type. The edited mice also had loss of function edits in FAM83G, FZD6, or TGM3, which impacted hair follicle development and structure resulting in woolly hair texture, wavy coats, and curled whiskers. As a result of a nonfunctional TGFA gene and a mutation in the KRT27 gene, the mice display a wavy coat phenotype that is similar to that of the woolly mammoth.
Engineered mice also have lighter coat colors due to a modified version of the MC1R gene, which regulates melanin production resulting in golden hair rather than the black/agouti wild type mouse coat color. Colossal woolly mice also have a truncated version of the FABP2 gene, seen in woolly mammoths, which is associated with lipid metabolism and fatty acid absorption.
Colossal believes its research will have far-reaching effects. Besides being the first living animal engineered to express multiple cold-adapted traits using mammoth gene orthologs, these mice also serve as living models for studying cold-climate adaptations in mammals.
“The Colossal Woolly Mouse demonstrates remarkable progress we’ve made in precise genome engineering,” said George Church, PhD, professor of genetics at the Wyss Institute and Harvard Medical School and Colossal co-founder. “We are showing that we can now rationally design and construct complex genetic adaptations, with profound implications for the future of multi-gene de-extinction and engineering.”
