What Every Rat Owner Should Know About High White and Megacolon

The wedge blaze on Mystery is a clue that he was likely high white.
His brother, Weasel (photo below), had even more signs of high white.

I normally don't care much about superficial rat traits like color, markings, ear type, and fur type. I admit that I do like to have variety, as it makes it a lot easier to tell the rats apart from a distance, but aside from that convenience, the physical characteristics of a rat are not that important to me. I have taken a passing interest in what the different marking mutations are, the different colors, the different fur types, etc, and some of the genetics behind them. But it is just an academic interest. I am never looking for a specific color, marking, or trait when I take in new rats. I take in the rats that need homes when I have a home to offer.

I have researched one specific trait, however, much more than the others. Despite all that research, my understanding of it remains incomplete and flawed. That trait is high white.

What is high white? High white is a term used to describe the color patterns that result when cell migration is delayed and the pigment cells do not reach their destination, resulting in patterns of white (unpigmented) fur. That sounds great, but what does it really mean? During fetal development, neural cells, including pigment cells, originate along the neural crest (a strip along the spine). From there, they migrate to other parts of the body as the embryo develops. If, for some reason, that migration is delayed, those cells start on their journey but may not reach their destination. In the case of the pigment cells, it means the cells that were designed to add pigment to the fur don't reach their destination and that destination area is left unpigmented, or white. So normally, the pigment cells start at the top of the back and migrate all the way down the sides toward the belly. But if they start a little late, they might make it only partially down the sides. The more the delay, the higher the white areas that will creep up the sides. High white markings can also affect the head, resulting in irregular white spots or blazes. This delayed migration can also affect pigment to the eyes, and sometimes results in the odd-eye phenotype (one eye is a different color than the other).



Weasel was almost certainly a high-white rat. He had odd-eyes (one Ruby, one black)
a lightning blaze, and white patches that crept up the sides farther than normal.

Does this mean that all rats with white on their sides or with blazes or other irregular white spotting are high white? No. There are some genes that cause white markings such as hooded, masked, Berkshire, bareback, dalmation, etc. These traits are usually associated with the hooded locus and are not high white markings. More often than not, blazes in the US are associated with high white markings. But there are other genes that can cause blazes that are not derived genetically from high white. As far as I know, odd eye is always associated with high white - although I could be mistaken. I have never heard of any other causes for odd-eye.

Gandolf and Sam (facing forward) are split-capped, which is a high white marking.
Their brother, Max (facing away) is a hooded like their mother.

Unfortunately, it can be very difficult to tell if a rat is genetically high white just by looking at it. Things like odd-eye, white running up the sides further than is normal for the standard markings, and blazes are clues that there is a higher likelihood of being high white. However, without a pedigree, it can be hard to know for sure.

So now comes the real question: Why do we care if a rat is high white or not? The answer to that is simple. High white rats come with a much increased risk for megacolon. What is megacolon? Megacolon is a condition where the proper cells that allow an animal to defecate do not reach the colon. Thus, the rat cannot defecate and fecal matter collects in the colon. The condition is always fatal. It is a very painful condition for which euthanasia is usually the only option. Most rats that develop megacolon die shortly after weaning. This is called early-onset megacolon. However, some rats with megacolon have enough functionality to survive normally into early adulthood, but eventually succumb to the megacolon and die at an early age. This is late-onset megacolon. Late onset megacolon is much more rare than early onset.

In many cases, when a physical characteristic like color/markings is associated with a condition, it is because the gene for the marking and the gene for the condition both appear on the same chromosome and thus both tend to get passed on together. The closer together on the chromosome the two genes are, the more likely they will get passed on together. Because of genetic transposition, a portion of one chromosome can sometimes break off and switch places with a portion of another chromosome, allowing traits on the same chromosome to be separated in the right circumstances. The closer two genes are together, the more likely they are to stay together (the break would have to be in just the right spot to separate them). Thus, traits that often show up together are more likely to appear close together on the same chromosome. In selective breeding, much work can be put into trying to separate the two traits (hoping for just the right transposition to occur). It can be difficult, but it is possible.

Unfortunately, it is not possible in the case of megacolon to separate high white from megacolon in this manner. That is because the gene combination that produces high white is also the same combination that can produce megacolon. Basically, the process that delays the pigment cells from reaching their destination, also delays the neural cells that stimulate the colon from reaching their destination. It is in fact the same genes that make high white possible that also make megacolon possible. You cannot selectively separate the two conditions because they are made possible by the same set of genes.

That said, most high white rats do not actually develop megacolon. The delaying of cell migration that causes high white marking patterns also can delay the neural cells from reaching the colon, but it is also possible and even likely that those specific cells will reach the colon just fine. It is very unpredictable. When breeding, you can predict with some accuracy whether the offspring may be high white by knowing the parents pedigrees. However, you cannot predict what the exact pattern of markings will look like in those high white rats. There is a lot of variability in how the high white is expressed and that variability is controlled by many other genetic factors. In the same manner, we cannot predict whether or not the needed neural cells will reach the colon in a high white rat. A greater delay in cell migration may produce more severe high white patterns and also may imply a greater risk for megacolon, and thus there may be high white lines where the risk is extreme and some high white lines where the risk is less, but the ability to predict whether or not megacolon will occur in any given high white is very difficult. The best you can do is look at pedigrees for patterns in the line.

There have been some genes that have been determined to be involved with megacolon. There is the Spotting Lethal gene (dominant is normal, recessive linked to megacolon). There is also the White Spotting gene (dominant linked to megacolon, recessive is normal). More recently, there have also been studies done showing a connection between the SOX10 gene and megacolon. But part of the problem with these genes is that they have incomplete penetrance. This means that while you might need the right genes to be present to actually have megacolon, the mere presence of those genes does not mean megacolon will develop. It just means the potential for megacolon is there. The actual inheritance of megacolon is polygenetic and the right conditions need to be produced for megacolon to develop. At least this is my understanding.

What does this all mean to the average rat owner? Basically, megacolon is a very nasty condition that we want to avoid at all cost. Most (but not all) rats that develop megacolon are high white rats. Does that mean we should never adopt high white rats because they are likely to die of megacolon? Absolutely not. That is a completely false assumption. Most high white rats are perfectly healthy. The ones that develop megacolon usually die in the first weeks after weaning. If they survive past the risky period, they most likely do not have megacolon and they are far more likely to die of other rat health issues like respiratory problems and tumors. There is very little risk adopting a rat with odd eyes or blazes or high white markings once they are past the risky early weeks.

However, there is a much higher risk associated with breeding high white rats. If you are going to purchase rats from a breeder, you should try to acquaint yourself with the signs of high white. Most reputable breeders will not breed high white rats. A breeder who is selling rats with high risk markings is likely not reputable and should be avoided. However, it is possible that similar markings are being bred from safer traits, so ask to see pedigrees to verify where those traits are coming from if you believe the breeder to be reputable. Some breeders have worked with high whites and have pedigrees showing that megacolon has not appeared in their lines. It is possible that they have selected out the most risky gene combinations to produce reliable breeding under their controlled setting. However, there is no guarantee that megacolon will not eventually show up in those lines and there is also high risk breeding those offspring to outside lines - especially with unreliable pedigrees, so casual breeders should never work with high white rats - even when obtaining stock from a more reliable source with pedigreed rats. And if you are a pet owner with rats with high white markings, you should take extra precaution to ensure they are never bred (spay/neuter or don't keep mixed sexes in the same home).

If you are interested in high whites or megacolon, I recommend the following sources, from which I have learned a lot. I don't promise my understanding of the issue is perfect, so if you have concerns or interests, please just use this post as a jumping off point, but refer to the sources below for more reliable information:

For info on the condition of Megacolon:
The Rat Guide's article on Megacolon

For info on identifying High White markings (note that this article is no longer on the web and is only available through the Internet Archives Way Back Machine):
High-White and High-Risk

For info on the connection between high white and megacolon in embryo development:
Why Do Some Rats Have White Blazes and Megacolon

For info on some of the genes that are tied to megacolon:
Mutations in Rat Coat Color
Curiosity Rats: Genetics