Genetic basis of ruminant headgear and rapid antler regeneration

Phylogeny and characteristics of ruminants Ruminants are a diverse group of mammals that includes families containing well-known taxa such as deer, cows, and goats. However, their evolutionary relationships have been contentious, as have the origins of their distinctive digestive systems and headgear, including antlers and horns (see the Perspective by Ker and Yang). To understand the relationships among ruminants, L. Chen et al. sequenced 44 species representing 6 families and performed a phylogenetic analysis. From this analysis, they were able to resolve the phylogeny of many genera and document incomplete lineage sorting among major clades. Interestingly, they found evidence for large population reductions among many taxa starting at approximately 100,000 years ago, coinciding with the migration of humans out of Africa. Examining the bony appendages on the head—the so-called headgear—Wang et al. describe specific evolutionary changes in the ruminants and identify selection on cancer-related genes that may function in antler development in deer. Finally, Lin et al. take a close look at the reindeer genome and identify the genetic basis of adaptations that allow reindeer to survive in the harsh conditions of the Arctic. Science, this issue p. eaav6202, p. eaav6335, p. eaav6312; see also p. 1130 The genes underlying the development of bony antlers and horns in ruminants are examined. INTRODUCTION All pecoran families, except the Moschidae, have cranial appendages or headgear, a unique structure among mammals that has a different morphology in each family (ossicones in girafﬁds, pronghorns in pronghorn, antlers in cervids, and horns in bovids). Moreover, the deer antler is the only completely regenerable organ found in mammals, thus providing a unique model for regenerative biology. Antlers also have extremely rapid growth rates (~1.7 cm/day in red deer), with rates of cell proliferation that surpass even cancerous tissue growth. Cervids also have low cancer rates. The relation between a tight regulation of antler growth and inhibition of oncogenesis in deer may provide insights for cancer prevention and therapy in humans and other organisms. RATIONALE We obtained 221 transcriptomes from bovids and cervids and sequenced three genomes representing the two pecoran lineages that convergently lack headgear. Comparing the data with a large set of ruminant genomes, including nine cervids, we detect genetic changes (lineage-specific positively selected genes and conserved elements) in pecorans with headgear (PWH), particularly cervids. Using the observed genetic changes and gene expression in headgear, we explore the genomic basis of ruminant headgear origin and antler regeneration. RESULTS We find that highly or specifically expressed genes in horns and antlers are most frequently coexpressed in bone, skin, nerve tissues, and testis. Many genes under positive selection in PWH (e.g., OLIG1, OTOP3), PWH-specific genes associated with highly conserved elements (e.g., HOXD gene cluster, SNAI2, TWIST1, SOX9), and genes highly or specifically expressed in headgear (RXFP2, SOX10, NGFR) are involved in neural functions. In addition, RXFP2, which is specifically expressed in headgear and testis, was convergently pseudogenized in the headgearless lineages of Moschidae and Hydropotinae. The expression profile of antler is more correlated with osteocarcinoma than with normal bone tissue expression profiles. A number of proto-oncogenes (FOS, REL, FAM83A) and tumor suppression genes have been positively selected in cervids, especially several cofactor genes (PML, NMT2, and CD2AP) and regulator genes (ELOVL6, S100A8, ISG15, CNOT3, and CCDC69) of the p53 tumor suppressor, suggesting that these adaptive changes may enhance cancer resistance in deer. CONCLUSION Together, the phylogeny, gene expression profiles, and convergent headgear losses support a single evolutionary origin of the ruminant headgear. Pecoran headgear likely share a common cellular origin from neural crest stem cells, and the determination of the chondrogenic and neural lineages is important for headgear development. In addition, cervid-specific genetic changes in tumor suppressor and proto-oncogenes imply that the regenerative properties of antler tissue exploit oncogenesis pathways. Our study reveals genetic mechanisms underlying the evolutionary, developmental, and histological origin of ruminant headgear, as well as antler regeneration. The identified genes and their unique mutations provide guidelines for future functional studies of headgear development, regeneration of mammalian organs, and oncogenesis. Neural crest cellular origin of ruminant headgear and the tight control of rapid antler regeneration and low cancer risk in cervids. (Left) Phylogenomic relationships of the six ruminant families. Anatomic features of family-specific headgear are depicted, showing that headgear of ruminants share tissue and cellular origins. (Upper right) The gene expression profile of antler correlates more strongly with osteocarcinoma than with normal bone tissue. (Lower right) The balance between rapid antler regeneration, which depends on genes in the oncogenic pathway, and reduced cancer risk, which may involve adaptive evolution of tumor suppressor genes. Ruminants are the only extant mammalian group possessing bony (osseous) headgear. We obtained 221 transcriptomes from bovids and cervids and sequenced three genomes representing the only two pecoran lineages that convergently lack headgear. Comparative analyses reveal that bovid horns and cervid antlers share similar gene expression profiles and a common cellular basis developed from neural crest stem cells. The rapid regenerative properties of antler tissue involve exploitation of oncogenetic pathways, and at the same time some tumor suppressor genes are under strong selection in deer. These results provide insights into the evolutionary origin of ruminant headgear as well as mammalian organ regeneration and oncogenesis.