A deletion at the X-linked ARHGAP36 gene locus is associated with the orange coloration of tortoiseshell and calico cats

• Published in: Current biology Vol. 35; no. 12; pp. 2816 - 2825.e3
• Main Authors: Toh, Hidehiro, Au Yeung, Wan Kin, Unoki, Motoko, Matsumoto, Yuki, Miki, Yuka, Matsumura, Yumiko, Baba, Yoshihiro, Sado, Takashi, Nakamura, Yasukazu, Matsuda, Miho, Sasaki, Hiroyuki
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 23.06.2025
• Subjects: Animals; ARHGAP36; calico cat; Cats - genetics; Cats - physiology; DNA methylation; Female; Genes, X-Linked; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Hair Color - genetics; Humans; melanin; Mice; orange coat color; Pigmentation - genetics; RNA sequencing; Sequence Deletion; Skin Pigmentation - genetics; tortoiseshell cat; ultraconserved element; X Chromosome Inactivation; RNA sequencing; calico cat; tortoiseshell cat; melanin; X chromosome inactivation; ultraconserved element; DNA methylation; ARHGAP36; orange coat color
• ISSN: 0960-9822; 1879-0445; 1879-0445
• DOI: 10.1016/j.cub.2025.03.075

The X-linked orange (O) locus in domestic cats controls an unknown molecular mechanism that causes the suppression of black-brownish pigmentation in favor of orange coloration. The alternating black-brownish and orange patches seen in tortoiseshell and calico cats are considered classic examples of the phenotypic expression of random X chromosome inactivation (XCI) occurring in female mammals. However, the O gene in the cat genome has not been identified, and the genetic variation responsible for the orange coloration remains unknown. We report here that a 5.1-kilobase (kb) deletion within an intron of the X-linked ARHGAP36 gene, encoding a Rho GTPase-activating protein, is closely and exclusively associated with orange coloration. The deleted region contains a highly conserved putative regulatory element, whose removal is presumed to alter ARHGAP36 expression. Notably, ARHGAP36 expression in cat skin tissues is linked to the suppression of many melanogenesis genes, potentially shifting pigment synthesis from eumelanin to pheomelanin. Furthermore, we find evidence that the gene undergoes XCI in female human and mouse cells and XCI-dependent CpG island methylation consistent with random XCI in female domestic cats. The 5.1-kb deletion seems widespread in domestic cats with orange coat coloration, suggesting a single origin of this coat color phenotype. [Display omitted] •X-linked ARHGAP36 is identified as the gene responsible for the orange coat of cats•A deletion at this locus alters ARHGAP36 expression, leading to pigment-type switch•Evidence suggests that ARHGAP36 is subject to random X chromosome inactivation•The deletion seems widespread in cats, suggesting a single origin of this phenotype The X-linked orange locus is responsible for the orange coat color of domestic cats, including tortoiseshell and calico cats, and is proposed to be subject to random X chromosome inactivation. Here, Toh, Au Yeung, Unoki, et al. identify a genomic deletion that alters ARHGAP36 expression as the causative genetic variant.