Scientists find the meow-tation that makes cats orange

Have you ever wondered why all pretty calico and tortoiseshell kitties are female, while ginger tabbies, like the lasagne-loving Garfield, are overwhelmingly male?

Scientists have long suspected that the orange gene behind cats’ distinctive ginger fur must be sex linked, and on the X chromosome specifically, but they haven’t been able to identify it.

Now, 2 independent teams of biologists have cracked the mystery. They found the location of the mutation and in doing so revealed a new mechanism for making animals orange.

Both studies have been published simultaneously in the journal Current Biology.

“Identifying the gene has been a longtime dream, so it’s a joy to have finally cracked it,” says Professor Hiroyuki Sasaki, lead author of one of the studies from Kyushu University in Japan.

Lead author of the second study, Dr Christopher Kaelin of Stanford University in the US, says that the mutation probably arose early in the domestication process.

“We know that because there are paintings that date to the 12th century where you see clear images of calico cats. So, the mutation is quite old,” he says.

Male cats have XY sex chromosomes while female cats have XX, as is the case for most mammals. This is why a male cat only needs to inherit one copy of the orange mutation to be ginger.

Female cats must inherit the mutation on both X chromosomes to be completely orange, so they are much less common. But if they inherit only one copy, they develop a mottled pattern known as tortoiseshell, or patches of orange, black and white known as calico.

“These ginger and black patches form because, early in development, one X chromosome in each cell is randomly switched off,” says Sasaki.

“As cells divide, this creates areas with different active coat colour genes, resulting in distinct patches. The effect is so visual that it has become the textbook example of X-chromosome inactivation, even though the responsible gene was unknown.”

Both studies have now found that cats with orange fur share a small deletion mutation in the non-protein coding region of the gene ARHGAP36 on the X chromosome.

The ARHGAP36 gene, which is found across mammalian species, has never been connected to pigmentation before. It encodes a protein that has been implicated in neuronal development, bone formation, hair follicle development, and cancer.

The orange mutation doesn’t impact this protein’s structure but increases its expression instead.

“ARHGAP36 is not expressed in mouse pigment cells, in human pigment cells or in cat pigment cells from non-orange cats,” Kaelin says.

“The mutation in orange cats seems to turn on ARHGAP36 expression in a cell type, the pigment cell, where it’s not normally expressed.”

This high ARHGAP36 activity is linked to a reduced activity in many other genes involved in melanogenesis, the process that produces pigment in skin and hair.

Kaelin and collaborators found that ARHGAP36 activity in pigment cells specifically inhibits an intermediate step of the process which produces black-brownish pigmentation (eumelanin), but not that which produces pheomelanin – yellowish or reddish pigments.

This is the same process which occurs in other orange-coloured animals, such as tigers, golden retrievers, orangutans and red-headed humans. But typical orange mutations disrupt an earlier step in that pathway in those species. In cats, sex-linked orange disrupts a later step.

ARHGAP36 is active in many areas of the body, including in areas of the brain and hormonal glands. So, could it be responsible for the widely-held belief that an orange cats have particularly chaotic dispositions?

Kaelin is sceptical.

“The expectation, based on our observations, is this is highly specific to pigment cells,” Kaelin says. The team measured ARHGAP36 expression in several non-skin tissues – the kidney, heart, brain and adrenal gland – and found no differences between orange and non-orange cats.

“I don’t think we can exclude the possibility that there is altered expression of the gene in some tissue we haven’t tested that might affect behaviour,” Kaelin concedes. But he thinks orange cats’ reputation as friendly agents of chaos is more likely due to most of them being male. 

Sasaki is curious to determine the origins of the orange mutation.

 “One idea is to study ancient Egyptian cat paintings – or even to test DNA from mummified cats – to see if any cats back then were orange,” he says.

“It’s ambitious, but I’m excited to try.”