Classical guinea pig coat phenotypes are associated with variants in FGF5 and CELSR1

Classical Mendelian coat phenotypes in the domestic guinea pig, Cavia porcellus, were central to early studies of mammalian genetics, yet their molecular bases remain unresolved. Long fur is characterized by elongated hair, and rough coat by whorled patterns of fur orientation. Here, we performed genome-wide association mapping using exome and whole-genome sequencing data to identify the genetic basis of both phenotypes. Mapping of long fur identified a locus containing FGF5 and resolved the association to a premature stop codon, independently confirming a previously proposed candidate variant. Mapping of rough coat identified a locus containing CELSR1, an atypical cadherin and core component of the planar cell polarity (PCP) pathway, resolving the association to an in-frame proline insertion in its extracellular domain. The variant is associated with a dominant rough-coat phenotype, unlike previously characterized recessive mouse Celsr1 alleles, which produce a similar hair-patterning phenotype only when homozygous. The mouse alleles are also associated with severe developmental abnormalities, including open neural tube, which are not observed in rough-coat guinea pigs. This dominant, tissue-specific phenotype suggests that the insertion alters CELSR1 function in a previously undescribed manner. Consistent with this possibility, the rough-coat variant localized normally to cell-cell junctions in cultured mouse keratinocytes and retained its ability to recruit Fzd6 and Vangl2, demonstrating preserved molecular interactions involved in PCP junction assembly. These findings resolve the molecular basis of two classical guinea pig coat phenotypes and identify a naturally occurring, dominant CELSR1 allele associated with a mode of PCP disruption distinct from previously characterized alleles.