Molecular and genetic characterization of sex-linked orange coat color in the domestic cat

Author:

Kaelin, Christopher B

McGowan, Kelly A

Trotman, Joshaya C

Koroma, Donald C

David, Victor A

Menotti-Raymond, Marilyn

Graff, Emily C

Schmidt-Küntzel, Anne

Oancea, Elena

Barsh, Gregory S
Author Address

Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA., Department of Neuroscience, Division of Biology and Medicine, Brown University, Providence, RI 02912, USA., Laboratory of Genomic Diversity, National Cancer Institute, Frederick, MD 21701, USA., Department of Pathobiology and Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA., Laboratory of Genomic Diversity, National Cancer Institute, Frederick, MD 21701, USA; Cheetah Conservation Fund, Otjiwarongo, Namibia., Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA. Electronic address: gbarsh@stanford.edu.,

Abstract:

The Sex-linked orange mutation in domestic cats causes variegated patches of reddish/yellow hair and is a defining signature of random X inactivation in female tortoiseshell and calico cats. Unlike the situation for most coat color genes, there is no apparent homolog for Sex-linked orange in other mammals. We show that Sex-linked orange is caused by a 5-kb deletion that leads to ectopic and melanocyte-specific expression of the Rho GTPase Activating Protein 36 (Arhgap36) gene. Single-cell RNA sequencing (RNA-seq) studies from fetal cat skin reveal that red/yellow hair color is caused by reduced expression of melanogenic genes that are normally activated by the melanocortin 1 receptor (Mc1r)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway, but Mc1r and its ability to stimulate cAMP accumulation is intact. Instead, we show that expression of Arhgap36 in melanocytes leads to reduced levels of the PKA catalytic subunit (PKAC); thus, Sex-linked orange is genetically and biochemically downstream of Mc1r. Our findings resolve a longstanding comparative genetic puzzle, provide in vivo evidence for the ability of Arhgap36 to inhibit PKA, and reveal a molecular explanation for a charismatic color pattern with a rich genetic history. Copyright © 2025 Elsevier Inc. All rights reserved.

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