6 days ago
Orange Fur Created By A Unique Mutation In Domestic Cats
A small deletion within a gene on the X-chromosome has unique effects upon cats' fur color, creating orange male tabbies and orange patches in female tortoiseshell cats.
Tortoiseshell Cat. (Credit: Shutterstock, via Chris Kaelin)
It was long predicted that the source of domestic cats' distinctive pumpkin-orange fur coloring was genetic and was produced by a gene on the sex-determining X-chromosome because 80% of orange cats are male — so the trait's mystery gene came to be known as 'sex-linked orange'.
Male cats, like male humans, have an X- and a Y-chromosome. The genes on their lone X-chromosome are all expressed, giving rise to orange tabbies if they possess a copy of the orange fur color gene. Female cats have two X-chromosomes, one of which is randomly inactivated early in embryonic development on a cell-by-cell basis (figures 1 & 2), giving rise to tortoiseshell or calico fur color patterns. This pattern of inheritance suggests there is a gene that controls orange fur color on the X-chromosome, but identifying precisely which gene this is has eluded scientists for decades.
Incidentally, white patches seen in calicos, known as 'piebalding', are not encoded by a gene on the X-chromosome.
Figure 1: Graphical abstract, doi:10.1016/
'Cats have lived commensally with humans around the world for thousands of years, giving humans plenty of time to select and preserve unusual colors and color patterns,' lead author of the Stanford study, geneticist Christopher Kaelin, told me in email. Dr Kaelin is a senior scientist in genetics at Stanford Medicine who has been studying the genetics of coloration and color patterns in mammals for more than two decades.
Are cats the only domesticated mammal with a sex-linked fur color trait?
'Dogs also come in many color varieties. Some of the colors that are similar between dogs and cats are caused by different mutations in the same gene,' Dr Kaelin added. 'However, a sex-linked color trait has not been observed in dogs or other mammals, which suggests that orange cats could offer an opportunity to learn something new and insightful.'
Dr Kaelin has worked alongside two of the Stanford study's co-authors – Greg Barsh and Kelly McGowan – on the genetics of coloration and color patterns for more than 25 years. They all started at Stanford, but Dr Barsh accepted a leadership position at HudsonAlpha 15 years ago, at a critical time when these researchers could adapt some of the emerging technologies being developed for human genomic science and apply them to genetic studies in domestic cats.
'Kelly [McGowan] and I also accepted positions at HudsonAlpha but remained at Stanford, where we were best equipped to pursue other aspects of our research,' Dr Kaelin explained in email. 'Kelly [McGowan] and I are currently affiliated only with Stanford, while Greg maintains affiliations with both institutions.'
Additional collaborators on the Stanford study are based at Brown University, Auburn University, and at the National Cancer Institute.
A second group of scientists, based at Kyushu University, Kindai University, Azabu University, The University of Tokyo and the National Institute of Genetics in Japan, independently discovered the same molecular mechanism underlying ginger-colored fur in domestic cats: a small deletion mutation on the cats' X-chromosome. The Kyushu team, whose work was largely crowdfunded by cat lovers around the world, published its research alongside the Stanford study in the peer-reviewed journal, Current Biology.
'These ginger and black patches form because, early in development, one X-chromosome in each cell is randomly switched off,' senior author of the Kyushu study, geneticist Hiroyuki Sasaki, a professor at Kyushu University, explained in a statement.
'As cells divide, this creates areas with different active coat color genes, resulting in distinct patches,' Professor Sasaki said. 'The effect is so visual that it has become the textbook example of X-chromosome inactivation, even though the responsible gene was unknown.'
X-chromosome inactivation is a process whereby one copy of a female mammal's two X-chromosomes is rendered transcriptionally inactive. This phenomenon, sometimes known as Lyonization, was originally reported by British geneticist Mary Lyon who confirmed this theory in 1961 (ref). She discovered that female mammals' cells randomly silence one of the two X-chromosomes inherited from their parents. The inactivated chromosome can be seen under a microscope as a tiny dark Barr body compacted inside cells.
Figure 2: X-Chromosome Inactivation (XCI) and cat fur colors. In cats, the X-chromosome contains a ... More gene controlling the orange/black pigmentation of the fur. If the two X-chromosomes of a female carry the same version of this gene, the coat of the adult cat will be of a single, unified color (either fully orange or fully black). However, if a female carries one X-chromosome with the orange variant and the other X-chromosome with the black variant, the mosaicism of XCI occurring during embryonic development will be visible in the color pattern of the adult cat's fur. In other words, the cat's fur is a mosaic of colors that reflects the random X-chromosome inactivation, that happens during early development. As a side note, and in contrast to the orange and black coloring, the presence of additional white patches in calico cats is not under the control of the X-chromosome. This condition, called 'piebalding', causes unpigmented skin and fur, and is commonly found in both XX and XY cats. (Credit: Image modified from '6-year old tortoiseshell cat," by Michael Bodega (public domain).)
Originally, these two teams of scientists were investigating whether cats with orange fur were at a heightened risk for certain genetic disorders or health conditions, but along the way, they discovered that the cellular context (the tissue type, in this situation) of the gene's expression is what makes the difference.
'The orange mutation has not been linked to disease,' Dr Kaelin told me in email. 'In cats, the orange mutation occurs near a gene called Arhgap36 and activates it specifically in pigment cells.'
The Arhgap36 gene is also present and active in humans.
'A related type of mutation has been identified in a human patient with a fatal disease that caused abnormal bone growth in areas where bone does not normally exist,' Dr Kaelin added in email. 'In that case, Arhgap36 is also activated, but in a different tissue type. Orange cats are spared that fate because the nature of the mutation appears to limit its activity to pigment cells.'
Both Dr Kaelin and collaborators and the Kyushu study's team report that the missing section of DNA not only explains the unique sex-linked genetics of ginger fur in cats, but also points to an entirely new and so far unique mechanism for creating orange fur coloring in mammals.
This discovery came after both Dr Kaelin and collaborators and members of the Kyushu collaboration compared the DNA from dozens of cats with and without orange fur. They found that cats with ginger fur color were missing a section of DNA within the Arhgap36 gene. This result of this mutation is that the Arhgap36 gene is more active than normal, leading to the production of pumpkin-orange fur pigment.
Did this mutation for orange fur color arise just once?
'Orange cats are found all over the globe today, but our findings indicate that all orange cats can be traced back to a single orange (or tortoiseshell) cat,' Dr Kaelin replied to me in email. 'However, we still don't know when or where the original orange cat lived.'
How long ago did this mutation arise?
'The wild progenitors of domestic cats are not orange, so we can infer that the mutation occurred during or after cat domestication. We know the mutation is old because calico cats are depicted in Chinese art dating to the 12th century. Identifying the orange mutation could help scientists who study ancient DNA look further back into prehistory for evidence of orange cats.'
A Japanese woodblock print of calico cats in different poses and activities. Edo, Japan. NOTE: this ... More image was cropped from the original. (Credit: Utagawa Kuniyoshi (1798–1861); Japanese ukiyo-e painter / Public Domain.)
Strangely, what seems to cause orange fur in cats isn't so much an 'orange gene' as it is an 'orange mutation' within a still-unknown gene, according to Dr Kaelin.
Looking closer at the mutation, the researchers found that the deletion lies within a non-coding region of Arhgap36, so the resulting protein remains structurally unchanged.
'This is key,' Professor Sasaki explained. 'Arhgap36 is essential for development, with many other roles in the body, so I had never imagined it could be the orange gene. Mutations to the protein structure would likely be harmful to the cat.'
'The affected gene, Arhgap36, in orange cats is not typically a pigmentation gene,' Dr Kaelin explained in email. 'The unusual nature of the mutation represents a rare example of a gene acquiring a new function due to its accidental activation in a cell type where it is normally inactive. This process – where a gene acquires a new function – is thought to be important for evolution.'
A change in genetic function or activity can have powerful consequences. For example, humans and chimpanzees share the same set of genes, but those genes act differently during development.
'Our study identifies a case in which a genetic change has a highly specific effect on gene activity, and understanding how this occurs will contribute to a broader understanding of gene regulation,' Dr Kaelin told me in email.
Further analysis showed that high Arhgap36 activity is linked to reduced activity in many genes involved in melanogenesis, the process that produces pigment in skin and hair. Through an unknown mechanism, this change may alter pigment production away from dark eumelanin to lighter pheomelanin – orange.
What other roles does this gene normally have? Is it active in neurogenesis or brain development? (I ask these questions because ginger cats are alleged to share a single brain cell between all members of the orange cat community worldwide.)
'Orange cats have their owners convinced that they are friendlier, more mischievous, and perhaps dimmer than other cats. This may all be true – or not,' Dr Kaelin told me in email. 'Rigorous scientific studies linking orange coat color to behavior have yet to be conducted. Arhgap36 is active in certain brain areas; however, in our study, we did not observe altered activity of Arhgap36 in those brain regions in the same way we observed altered activity in pigment cells.'
Already, plans are underway to identify the orange gene's origins and additional cellular functions.
'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,' Professor Sasaki stated. 'It's ambitious, but I'm excited to try.'
Another plan is to develop cat cell cultures to decipher the molecular function of Arhgap36. In addition to understanding molecular function of this gene in cat neurogenesis, this study may have medical implications for humans because this gene is also active in humans and is linked to conditions like skin cancer and hair loss.
Hidehiro Toh, Wan Kin Au Yeun, Motoko Unoki, Yuki Matsumoto, Yuka Miki, Yumiko Matsumura, Yoshihiro Baba, Takashi Sado, Yasukazu Nakamura, Miho Matsuda & Hiroyuki Sasaki (2025). A deletion at the X-linked ARHGAP36 gene locus is associated with the orange coloration of tortoiseshell and calico cats, Current Biology | doi:10.1016/
Christopher B. Kaelin, Kelly A. McGowan, Joshaya C. Trotman, Donald C. Koroma, Victor A. David, Marilyn Menotti-Raymond, Emily C. Graff, Anne Schmidt-Küntzel, Elena Oancea & Gregory S. Barsh (2025). Molecular and genetic characterization of sex-linked orange coat color in the domestic cat, Current Biology | doi:10.1016/
Questions emailed to the senior authors of both studies, Hiroyuki Sasaki and to Gregory Barsh, and to the Kyushu study's co-lead author, Wan Kin Au Yeun, went unanswered.
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