Scientists have finally identified the gene responsible for the orange, calico, and tortoiseshell patterns in cats, resolving a decades-long mystery.

For over 60 years, researchers puzzled over why most orange cats are male, while almost all calico and tortoiseshell cats are female. Despite extensive investigations, the genetic basis for these striking color variations remained elusive. Now, two independent research teams have discovered the long-sought mutation and identified a protein that affects fur color in a previously unknown way.

In most mammals, including humans, red or orange hair is typically caused by mutations in the Mc1r gene. This gene encodes a cell surface protein that regulates whether skin cells, called melanocytes, produce dark or light pigment. Mutations that reduce Mc1r activity often lead to lighter pigmentation. However, the Mc1r gene wasn’t responsible for orange fur in cats. Unlike in other species, most orange cats lack mutations in Mc1r, leaving scientists perplexed.

Greg Barsh, a geneticist at Stanford University, described this enigma as a long-standing genetic puzzle. To solve it, Barsh’s team collected skin samples from four orange and four non-orange cat fetuses at spay clinics. By analyzing RNA production in individual skin cells, the researchers identified the genes being expressed. They found that melanocytes in orange cats produced 13 times more RNA from a gene called Arhgap36 compared to non-orange cats. Since Arhgap36 is located on the X chromosome, it emerged as a strong candidate for the elusive orange fur gene.

Surprisingly, when the researchers sequenced the Arhgap36 gene in orange cats, they found no mutations in the coding region. Instead, the genetic anomaly was located nearby — a missing DNA segment that regulates the gene’s expression. Further analysis of 188 cat genomes confirmed that all orange, calico, and tortoiseshell cats shared this mutation. The findings were reported on the bioRxiv preprint server.

A second study from Kyushu University in Japan independently confirmed these results. Developmental biologist Hiroyuki Sasaki and his colleagues analyzed the genomes of 24 wild and domestic cats from Japan and 258 cats from around the world. They also detected the same genetic deletion and found higher levels of Arhgap36 RNA in the orange fur patches of calico cats compared to black or brown patches.

Additionally, the researchers documented a process called X inactivation, where one of the two X chromosomes in female mammals is silenced. In cats, this leads to the characteristic patchwork fur of calico and tortoiseshell cats. Arhgap36 was found to be subject to this inactivation, further solidifying its role in fur color determination.

The discovery has excited geneticists. Leslie Lyons, a cat genetics expert at the University of Missouri, described it as a long-awaited breakthrough. She emphasized that this new molecular pathway offers valuable insights into how fur color is regulated in mammals. Lyons also expressed curiosity about the mutation’s origins, noting evidence of orange cats in ancient Egypt.

Beyond fur color, this research could provide broader insights into how environmental factors influence gene expression. As Lyons remarked, “You can learn everything you need to know about genetics from your cat.”

Source: https://www.science.org/content/article/gene-behind-orange-fur-cats-found-last