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

The 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 in other mammals. We show that the is caused by a 5 kb deletion that leads to ectopic and melanocyte-specific expression of the ( ) gene. Single cell 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 the gene and its ability to stimulate cAMP accumulation is intact. Instead, we show that increased expression of in melanocytes leads to reduced levels of the PKA catalytic subunit (PKA ); thus, is genetically and biochemically downstream of . Our findings solve a comparative genomic conundrum, provide evidence for the ability of Arhgap36 to inhibit PKA, and reveal a molecular explanation for a charismatic color pattern with a rich genetic history.