Engineering elephant models of cold-adaptation and cancer resistance

Proboscideans have developed a suite of genetic changes including those responsible for tumor suppression and environmental adaptation. Here we examine a handful of woolly mammoth-specific deletions, and their potential contributions to arctic adaptation, as well as the expanded TP53 genetic repertoire in elephants. We use CRISPR-Cas9 to introduce mammoth-specific noncoding deletions as well as knockouts of TP53, all 29 TP53 retrogenes, or both in combination in Asian elephant cell lines, and examine the transcriptomic response. We find that many of the mammoth-specific deletions likely contribute to various arctic phenotypes including vascular development, metabolism and thermogenesis, and hair and skin adaptations. We also find that while there is considerable overlap in DNA damage responses of the TP53 and retrogene knockouts, retrogenes knockouts also exhibit strong enrichment of many extracellular pathways suggesting they may play a role in the tumor microenvironment and mitigating metastatic growth.