July 20, 2008

The white horse is an icon for dignity which has had a huge impact on human culture across the world.
Pictured: Aurora Stud's Silver Omen

Researchers in Sweden have discovered that grey horses carry an identical mutation that can be traced back to a common ancestor that lived thousands of years ago.

An international team led by researchers at Uppsala University say this mutation also enhances the risk for melanoma. The paper is being published in the July issue of Nature Genetics.

Researchers say the great majority of white horses carry the dominant mutation 'greying with age'. A grey horse is born coloured (black, bay, brown or chestnut), but the greying process starts during its first year and they are normally completely white by six to eight years of age, but the skin remains pigmented. Thus, the process resembles greying in humans but the process is ultrafast in these horses. The research presented now demonstrates that all grey horses carry exactly the same mutation which must have been inherited from a common ancestor.

Today, about one horse in ten carries the mutation for greying with age.

The study was led by Leif Andersson.

The grey horse is also interesting from a medical point of view since the mutation also predisposes for development of melanoma. About 75% of grey horses older than 15 years of age have a benign form of melanoma that in some cases develops into a malignant melanoma. Thus, the study has also given new insight in a molecular pathway that may lead to tumour development.

"We propose that the Grey mutation stimulates growth of melanocytes and that this leads to a premature loss of the melanocyte stem cells needed for hair pigmentation whereas the mutation promotes an expansion of some of the melanocytes causing skin pigmentation," said Leif Andersson.

Domestic animals constitute extraordinary models for evolution of biological diversity as already recognized by Charles Darwin. The white horse is a beautiful illustration of the importance of regulatory mutations as a major underlying mechanism for phenotypic diversity within and between species. The Grey mutation does not change any protein structure but it affects the genetic regulation of two genes. The researchers found that the white horses carry an extra copy of a DNA segment located in one of these genes.

"Here we show that the grey phenotype is caused by a 4.6-kb duplication in intron 6 of STX17 (syntaxin-17) that constitutes a cis-acting regulatory mutation. Both STX17 and the neighboring NR4A3 gene are overexpressed in melanomas from grey horses. Grey horses carrying a loss-of-function mutation in ASIP (agouti signaling protein) had a higher incidence of melanoma, implying that increased melanocortin-1 receptor signaling promotes melanoma development in grey horses. The grey horse provides a notable example of how humans have cherry-picked mutations with favorable phenotypic effects in domestic animals," the researchers said.

"It is very likely that regulatory mutations like the one we found in these white horses constitute the dominating class of mutations explaining differences between breeds of domestic animals as well as between species like humans and chimpanzee," Andersson said.