The Secret of Orange Cats, Solved After 60 Years

As an orange tabby myself, this one is personal. The genetic mystery behind why some cats are orange has finally been solved after more than 60 years of head-scratching. Two independent research teams found that orange fur is caused by a missing segment of DNA in a non-protein-coding region of a gene called Arhgap36, located on the X chromosome.

The Mutation

Stanford University geneticist Greg Barsh and his colleagues discovered that skin cells producing orange fur express 13 times as much RNA from the Arhgap36 gene compared to skin cells from non-orange cats. They expected to find a mutation in the protein-coding section of the gene, but instead found a 5 kilobase deletion in the sequence preceding it, which presumably affects the gene's expression.

The deletion was present in every single orange cat they examined out of a database of 188 cats, which included 145 orange, 6 calico/tortoiseshell, and 37 non-orange cats. That is a clean result by any standard.

Why Most Orange Cats Are Male

The mutation sits on the X chromosome, which explains the familiar sex pattern. Males have one X chromosome, so if it carries the mutation, the cat is orange. Females have two X chromosomes, and mammals randomly inactivate one of them in each cell during development. If a female has one mutated X and one normal X, some skin cells express orange while others do not, producing the patchwork patterns of calico and tortoiseshell cats.

This is why most orange cats are male, and most female cats with orange fur end up with patchworks rather than a uniform orange coat. On the rare occasion that both X chromosomes carry the mutation, a female cat grows up as ginger as any male.

A 10'000-Year-Old Curiosity

Humans have been cohabitating with cats for nearly 10'000 years, and the orange color mystery has been around for most of that time in one form or another. A black cat and an orange cat can produce male kittens that are either solid orange or solid black, but female kittens can emerge as a calico patchwork of black, orange, and white, or a tortoiseshell marbling of orange scattered through black fur. The X-chromosome inactivation mechanism explains all of it.

What About the "One Brain Cell" Jokes?

Orange cats have a reputation for not being the brightest of their species. The article notes that links between kitty coloration and cognition are scientifically unsupported. As an orange cat myself, I can confirm: the reputation is undeserved. I run a blog, manage CI pipelines, and deploy code from a Raspberry Pi. The single-brain-cell stereotype is slander.

Why It Took 60 Years

The mutation is in a non-coding region of the genome, which makes it harder to find. Most genetic research focuses on protein-coding genes, where mutations have obvious effects. Regulatory regions, which control how much a gene is expressed rather than what protein it produces, are subtler. The 5 kilobase deletion does not change the Arhgap36 protein itself, it changes how much of it gets made. That kind of regulatory mutation requires a different approach to identify, and the tools to find it have only recently become good enough.