Ginger Cats

 My brother lives in Jerusalem. To amuse me he regularly snaps pictures of cats and texts them. In case you do not know, Jerusalem and all of Israel have a huge stray cat problem. According to the Times of Israel “there are an estimated 2 million feral cats in the streets of Israel, with 240,000 of them in Jerusalem alone.” I noticed that the pictures my brother was sending me were all of black and white cats. I asked him if there were only black and white cats in Jerusalem and he sent me a picture of a cat and asked me what color it was. (My brother is colorblind and had only been sending me what he could see.)

I texted back that it was a ginger (like his daughter’s hair) and told him that it was probably a male because it was ginger. I had heard that all gingers are male and all calicos and tortoiseshell cats are female. I decided to check that with google to make sure it was not an old wives’ tale and discovered that a recently published research study on just that topic which showed that cat color has lead scientist to a new understanding  of how physical traits in animals emerge. This is an example of how genes acquire new functions that allow for adaptation. All this from cat color.

The article below is largely excerpted from the research article and the press release from Stanford University where the lead researcher is a professor. Both are cited below:

Toh, Hidehiro et al. A deletion at the X-linked ARHGAP36 gene locus is associated with the orange coloration of tortoiseshell and calico cats; Current Biology, Volume 0, Issue 0

A deletion at the X-linked ARHGAP36 gene locus is associated with the orange coloration of tortoiseshell and calico cats: Current Biology

Scientists track down mutation that makes orange cats orange | Stanford Report

It turns out that orange/ ginger cat color is an X-linked trait as is red-green colorblindness. Traits that are determined by alleles carried on the X chromosome are referred to as X-linked.  Females will have two X-linked alleles (because females are XX), whereas males will only have one X-linked allele (because males are XY). Most X-linked traits in humans are recessive.

A  ginger cat in the old city

However, this is not true with cat orange/ ginger coloration. There is an alternative expression of the orange allele in females that creates a mosaic coloration pattern in female cats which we know as tortoiseshell or calico cats.

More than 60 years ago, it was suggested by Mary Lyon that one of the two X chromosomes in a female embryo is randomly selected and inactivated in each cell during early development. She suggested that the alternative black-brownish and orange patches of tortoiseshell cats are consistent with the random inactivation of some unidentified X-linked  orange/ ginger gene in heterozygous females. In this study, the scientists searched for that gene and genetic variation associated with the orange coloration by comparing the genomic sequences of cats with orange coat color, including tortoiseshell and calico cats, and control non-orange cats.

Despite the pictures that my brother sends, domestic cats display a wide variation in colors, and coat coloration patterns that result from interactions between multiple genetic loci, making them excellent models for studying gene function and regulation. For decades scientists knew from the preponderance of male orange cats that the mutation was somewhere on the X chromosome.

In cats like most mammals, females have XX while males have XY sex chromosomes. Any male cat with sex-linked orange will be entirely orange/ ginger, but a female cat needs to inherit sex-linked orange on both X chromosomes to be entirely orange/ ginger – a less likely occurrence. Which is why ginger or orange cats are usually male.

the late sweet Madeline

Female cats with one copy of sex-linked orange appear partially orange – with a mottled pattern known as tortoiseshell, or with patches of orange, black, and white known as calico. That’s due to a genetic phenomenon in females, called random X inactivation, in which one X chromosome is inactivated in each cell. The result is a mosaic of pigment cells, some that express sex-linked orange and others that do not.

The early genetic studies on the orange/ ginger phenotype of domestic cats helped to discover X-linked inheritance in mammals by Mary Lyon. Rare occurrence of the mosaic phenotype in males can be explained by sex chromosome aneuploidy (XXY), chimerism, mosaicism, or somatic mutations according to work by Moran et al.

“In a number of species that have yellow or orange pigment, those mutations almost exclusively occur in one of two genes, and neither of those genes are sex-linked,” said Christopher Kaelin, PhD, a senior scientist in genetics and lead author of the current study.  “This is something that arose in the domestic cat, probably early on 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.”

First, the scientists looked for variants on the X chromosome shared by male orange cats and found 51 candidates. They eliminated 48 of these, as they were also found in some non-orange cats. Of the three remaining variants, one stood out as likely having a role in gene regulation: It was a small deletion that increased the activity of a nearby gene known as Arhgap36.

Until this discovery Arhgap36 gene was not known to have any connection to pigmentation. The Arhgap36 gene, which is highly conserved in mammalian species, was being studied by researchers in cancer and developmental biology. Arhgap36 is normally expressed in neuro-endocrine tissues, where overexpression can lead to tumors. It was not known to do anything in pigment cells until now.

Kaelin and colleagues discovered, in orange/ ginger cats. “Arghap36 is not expressed in mouse pigment cells, in human pigment cells, or in cat pigment cells from non-orange cats,” Dr. Kaelin said. “The mutation in orange cats seems to turn on Arghap36 expression in a cell type, the pigment cell, where it’s not normally expressed.”

This rogue expression in pigment cells inhibits an intermediate step of a well-known molecular pathway that controls coat color – the same one that operates in other orange-shaded mammals. In those species, typical orange mutations disrupt an earlier step in that pathway; in cats, sex-linked orange disrupts a later step.

The scientists also looked to see if the orange mutation impacted anything else in cats. The researchers also 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 behavior,” Dr. Kaelin conceded. But orange cats’ reputation as friendly agents of chaos (Macvity in the Andrew Lloyd Webber musical and T. S. Eliot’s Old Possum’s Book of Practical Cats is a ginger)  is something that scientists have not yet been able to test for.