Genetic Differences make Orange Cats Unique among Mammals, and New Research Explains the Reason
In a groundbreaking study published in 2025, geneticist Chris Kaelin at Stanford Medicine, along with a team of colleagues, discovered the genetic mutation that causes the distinctive orange coat colour in domestic cats. This finding, published in the esteemed journal Current Biology, sheds light on a longstanding question in the feline world.
The mutation, it turns out, affects a gene named Arhgap36, located on the X chromosome. In male cats, having one copy of the orange gene results in an orange coat. However, for female cats, the situation is more complex. They need both copies of the orange gene to appear fully orange, but most end up displaying a mosaic of orange and black due to a genetic process called random X inactivation.
The mutation alters gene activity instead of disrupting the gene itself. In orange cats, the activation of Arhgap36 in pigment cells blocks a late step in the melanin production pathway, resulting in a bright orange coat. This is unlike anything seen in any other mammal, making the calico cat mutation a unique and fascinating scientific tool for understanding how genes function and interact.
Interestingly, the mutation responsible for orange coat color in cats is not found in the same genes that cause orange or yellowish fur in most mammals. The mutation's ancient origins are evident, with depictions of calico cats appearing in 12th-century medieval paintings.
The researchers found no difference in Arhgap36 expression between orange and non-orange cats in non-skin tissues such as kidney, heart, brain, and adrenal gland. Arhgap36 is also linked to certain neuroendocrine tumors in humans and plays a role in cell signaling during development.
Kaelin believes this discovery resolves a longstanding question about why the orange color trait occurs only in domestic cats. The study offers a textbook example of how new biological traits can arise through unexpected pathways. The exact location of the mutation in the feline X chromosome was previously elusive, but Kaelin's team was able to find it using advanced genomic tools.
The findings were originally published in May 2025 and were updated with new information. The study was conducted by Kaelin and a team of colleagues, and the results have opened up a new avenue for further research into the genetics of cat coat colour and other feline traits.
