This mutation is associated with Rho GtPase Activated Protein 36 (ARHGAP36). Research conducted by a team from Stanford University School of Medicine suggests that this anomaly occurs in genes of various mammals.
The orange mutation linked to sex in domestic cats results in various reddish/yellow patches in their fur, clearly demonstrating random X inactivation in female turtles and calico cats. Unlike most coat color genes, other mammals lack evident homologs for the orange associated with gender. Research by Kaelin et al. shows that this mutation results from a 5 kb deletion leading to ectopic and melanocyte-specific expression of the ARHGAP36 gene. Image credit: Kaelin et al., doi: 10.1016/j.cub.2025.04.055.
Various mammals exhibit orange shades—like tigers, golden retrievers, orangutans, and red-headed humans—but this is particularly prevalent in domestic cats (Felis catus). The orange coloration is sex-linked and is observed more frequently in males.
“In many species with yellow or orange pigments, these mutations almost exclusively occur in one of two genes, neither of which is sex-linked,” states Christopher Kaelin, PhD, a researcher at Stanford University School of Medicine and the HudsonAlpha Institute for Biotechnology.
Scientists have pinpointed typical mutations that stimulate skin pigment cells to generate yellow or orange pigments instead of the default brown or black; however, they only had vague notions about locating corresponding mutations in cats.
They were aware that the mutation, termed sex-linked orange, was located on the X chromosome due to the predominance of male orange cats.
Male cats with this sex-linked orange will exhibit a complete orange coat, while females must inherit the mutation from both X chromosomes to appear fully orange.
A female cat possessing one copy of the sex-linked orange will showcase a partially orange coat with a pattern known as Tortoiseshell, or with patches of orange, black, and white known as Calico.
This variability arises from a phenomenon in females called random X inactivation, where one X chromosome becomes inactive in each cell.
Consequently, a mosaic pattern of pigment cells develops, some expressing the sex-linked-orange and others not.
“I observed this genetic anomaly over 100 years ago,” Dr. Kaelin recalled.
“It was the genetic puzzles that sparked my interest in Sex Link Orange.”
Building on prior research that dissected segments of the X chromosome housing mutations, Dr. Kaelin and his team methodically concentrated on the sex-linked orange mutation.
“Our ability to do this was facilitated by the development of genomic resources for cats made available in the last five to ten years,” Dr. Kaelin explained.
“This includes a fully sequenced genome along with various cat breeds.”
The researchers also obtained DNA samples from cats at neutering and spaying clinics.
Initially, they searched for a variant of the X chromosome common among orange cats and identified 51 candidates.
They excluded 48 of the candidates as they were also present in several non-orange cats.
Among the remaining three variants, one was speculated to play a significant role in gene regulation: ARHGAP36.
“When we identified it, ARHGAP36 had no association with pigmentation,” Dr. Kaelin stated.
This gene, well-conserved across mammalian species, has drawn attention from cancer and developmental biology researchers.
ARHGAP36 is typically expressed in neuroendocrine tissues, where its overexpression can lead to tumors; however, its association with pigment cells remained unknown.
Notably, it was discovered in a pumpkin-colored cat by Dr. Kaelin and his colleagues.
“ARHGAP36 is not present in mouse, human, or non-orange cat pigment cells,” Dr. Kaelin noted.
“The orange cat mutation appears to induce ARHGAP36 expression within pigment cells, where it is normally not present.”
This irregular expression in pigment cells disrupts intermediate steps in known molecular pathways governing coat color.
In other species, typical orange mutations interrupt earlier stages in that pathway; however, in cats, sex-linked oranges confuse the latter stages.
“It’s certainly an unusual mechanism for gene alteration in specific cell types,” said Dr. Kaelin.
The team’s findings are detailed in a study published this week in the journal Current Biology.
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Christopher B. Kaelin et al. Molecular and genetic properties of sex-linked orange coat colors in domestic cats. Current Biology Published online on May 15th, 2025. doi:10.1016/j.cub.2025.04.055
Source: www.sci.news
