In most mammals, including humans, red hair is caused by mutations in one cell surface protein, Mc1r, that determines whether skin cells called melanocytes produce a dark pigment or a lighter red-yellow pigment in skin or hair... But the gene encoding Mc1r didn’t seem explain where cats’ orange fur came from. It isn’t located on the X chromosome in cats or any other species—and most orange cats don’t have Mc1r mutations.
... [the scientists] didn’t find any mutations in the DNA that encodes the Arhgap36 protein. Instead, they found the orange cats were missing a nearby stretch of DNA that didn’t affect the protein’s amino acid components but might be involved in regulating how much of it the cell produced. Scanning a database of 188 cat genomes, Barsh’s team found every single orange, calico, and tortoiseshell cat had the exact same mutation... A separate study, also posted to bioRxiv this month, confirms these findings... Moreover Arhgap36 genes in mice, cats, and humans acquire chemical modifications that silence them on one of the two X chromosomes in females, Sasaki’s team documented, suggesting the gene is subject to X inactivation.
No one previously knew Arhgap36 could affect skin or hair coloration—it is involved in many aspects of embryonic development, and major mutations that affect its function throughout the body would probably kill the animal, Barsh says. But because the deletion mutation appears to only affect Arhgap36 function in melanocytes, cats with the mutation are not only healthy, but also cute.
I'm surprised I didn't catch this news when i came out two months ago. Not mentioning the fact that no one knew how orange fur in cats worked, this is also curious gene regulatory mechanism (deletion of an intronic region in an otherwise critical developmental gene)...
The two associated manuscripts, both are on bioRxiv and are not yet peer-reviewed:
- A deletion at the X-linked ARHGAP36 gene locus is associated with the orange coloration of tortoiseshell and calico cats Hidehiro Toh, Wan Kin Au Yeung, Motoko Unoki, Yuki Matsumoto, Yuka Miki, Yumiko Matsumura, Yoshihiro Baba, Takashi Sado, Yasukazu Nakamura, Miho Matsuda, Hiroyuki Sasaki bioRxiv 2024.11.19.624036; doi: https://doi.org/10.1101/2024.11.19.624036
- Molecular and genetic characterization of sex-linked orange coat color in the domestic cat Christopher B. Kaelin, Kelly A. McGowan, Joshaya C. Trotman, Donald C. Koroma, Victor A. David, Marilyn Menotti-Raymond, Emily C. Graff, Anne Schmidt-Küntzel, Elena Oancea, Gregory S. Barsh bioRxiv 2024.11.21.624608; doi: https://doi.org/10.1101/2024.11.21.624608