This is the first Genetics Committee Report on recent scientific research in genetics that relate to our cats. As it is the first we will be including some information from recent years, not just the past calendar year. This cannot be completely comprehensive as genomic technology is causing the information we have to increase enormously quickly, and writing an entire book every year is not really possible. Instead major findings relevant to the cat fancy will be presented, with background hopefully sufficient for interested non-geneticists.
Coat color: Agouti Modifiers.
A very hot topic this past year has been Corin mutation coat colors.
What is Corin? Corin came to light as a switch involved in coat color, among other things, some years ago. Back in 2008, which is quite old in genetics research time, Corin was discovered to affect the agouti pathway, producing “dirty blond” mice (Enshell-Seijffers et al. 2008), and some years later a mutation was identified in it that causes the golden markings in golden tigers (Xu et al. 2017). The mutation in mice was a total loss of function of Corin. The change in golden tigers was a much smaller change to the protein, but also caused a loss of function in term of color.
What does Corin do? Technically Corin is a protein, encoded by a gene (called CORIN), of a class called a membrane bound serine peptidase. What does that mean? It is a protein that is embedded in the cell membrane of specific cell types, and it can cut apart target proteins into smaller pieces. A peptidase can destroy the function of a target protein, but often it actually activates a target protein by clipping off parts that serve as a brake on the protein’s function. Cells need to activate and inactivate protein function according to circumstances. Peptidases often serve as these on/off switches.
Light “golden” and “bi-metallic” golden with silver undercoat cats had been showing up in Siberians for some years. They did not look like traditional shaded goldens, and the silvers definitely did not look like traditional shaded silvers. These cats had pale, wide-banded undercoats, rusty tabby markings (even on silvers to some extent), incomplete nose-liner, and a lot of white on the front of their faces and down their throats. They were referred to as “Sunshine” to differentiate them from traditional shaded goldens. They appeared to inherit as a simple recessive, unlike traditional golden Persians. In 2021 Marie Abitbol’s laboratory isolated the gene for this using genomics technology and it was a small change in the Corin gene. That same mutation was discovered in Kurilian Bobtails and Toybobs, all of which originate from Russia. A second mutation in the CORIN gene was also discovered that appeared to make a more extreme phenotype in combination with the first one (Beauvois et al. 2021).
How does Corin affect color? Its normal action shuts down the activity of the agouti signaling protein (ASIP), which is what makes a cat a tabby as opposed to a solid. We abbreviate the ASIP gene as A. Cat get two copies of this gene, as is the case for the vast majority of genes, one inherited from the mother and one from the father. A/A and A/a cats are tabbies, and a/a cats are solid colored. We are going to ignore red/cream here as red solids show their tabby patterns regardless of their A alleles. A good copy of the A gene makes ASIP which binds to a different membrane bound protein, MC1R, on pigment producing cells (melanocytes) and causes them to switch from making dark brown to black eumelanin, to making lighter yellow to red phaeomelanin. So a black based agouti cat starts making a hair colored black, then ASIP binds to MCR1 and the color switches to a light warm color. Under normal circumstances then Corin acts and shuts off the agouti protein causing the hair to go back to a dark band.
Heather Lorimer 2023
Beauvois et al. 2021
The MC1R gene can be mutated as well, causing a change in cat coat color. Amber in Norwegian Forest Cats is a mutation in the MC1R gene. MC1R is called E in animal coat color abbreviation e/e cats are amber.
More recently a distinctive color showed up in British Shorthairs. The cats were (and are) shown as shaded goldens. They also did not look like traditional shaded goldens. Their nose liner was gone. They had large amounts of white on their lower faces, extending down their chest. They also have white on the inside of their legs and on their toe tips so they look like they have extraordinarily even gloving pattern. Most of their coat color is a hot coppery color but the hairs have little black tips, their eye liner is black and so are their paw pads. They were called “copper” by some.
Their CORIN gene had a more extreme mutation, one that removes the peptidase part of the protein entirely (Abitbol et al. 2022). The versions of the genes have been named Wb for the normal version, wbSIB for the first Siberian version found, wbeSIB for the second Siberian version, and wbBSH for the British Shorthair version.
“Copper” British Shorthairs, Heather E. Lorimer. Note the lack of nose liner and white spot above the nose leather, as well as white fur on the ends of the toes.
These genes have no visible effect on a/a cats. However, it is important to remember that these peptidases serve as on/off switched for a number of target proteins, not just ASIP. Corin mutations are also associated with a series of physical and metabolic problems in mice and humans. Notably, loss of function of the protease is connected to salt sensitive hypertension that can lead to hypertrophic cardiomyopathy and heart failure. We need to be careful to observe blood pressure, heart function and longevity in Corin mutation cats, particularly in the BSH version which entirely loses its protease part of the protein.
Recent color research by Chris Kaelin’s group, and including our own Anthony Hutcherson, on Bengals has uncovered a series of Corin and MC1R mutations in Bengals that change their coat color. Remember that ASIP and Corin both bind to MC1R. This research is available as a preprint, not yet published in a scientific journal. (Kaelin et al. Preprint).
Pre-prints are written papers based on research, made publicly available by the researchers but not yet peer reviewed and accepted for publication by scientific journals. As such they are not considered to be thoroughly vetted out, not as solid as published, peer reviewed papers. The information can be good and thoughtful though.
Also of interest in the Kaelin preprint was his analysis of 38 charcoal Bengals. The large majority of them were heterozygous with solid, meaning that they had one copy of the Bengal version of the ASIP gene APB, and one copy of the defective nonagouti allele that makes solid colored cats when homozygous (a/a): “Five of 38 charcoal cats were homozygous for a leopard cat-derived Asip allele, and 27 were compound heterozygotes for a leopard cat-derived Asip allele and a domestic cat allele with a 2 bp coding sequence deletion, nonagouti (Asipa), that causes complete melanism when homozygous.” This adds to the data showing that many, perhaps most, obvious charcoal Bengals carry solid color.
Authors: TICA Genetics Committee (January 2024)
