The Red Hair Gene

I've always wanted eye-catching, attention-getting, vibrant red hair. I've tried dyeing it several times, but my hair is so dark that the best I've ever managed is a few weak highlights. Eventually, I gave up. I now know the only color change my hair will ever go through is graying.

A few weeks ago, something rekindled my interest in red hair, though. I heard someone mention that red-haired women apparently have greater pain tolerance than people with other hair colors. It sounded pretty far-fetched, and at least one red-haired acquaintance said she had a very low pain tolerance. Biology is full of strange things, however, and I decided that this was worth investigating. It turns out that not all types of pain, or all pain killers, have the same effect on people with red hair. In order to better understand the studies that have been done on pain, however, we need to talk about genes—both in general and about the red hair gene in particular.

 

Genes

Genes are found on DNA, which can be thought of as long strings of letters. Think of all your DNA as a book. Each cell in your body has a copy of this book. Your DNA is divided into chromosomes the way a book is divided into chapters. Each gene is like a sentence—a string of letters with a beginning point and an end. Each word in the sentence is three letters long.

The machinery of the cell transcribes this sentence into a molecule called messenger ribonucleic acid, or mRNA, which is yet another string of letters. The mRNA then gets translated, word by word, into protein. For each word, a protein building block called an amino acid is added. The amino acids get strung together like beads. Once all of the amino acids have been added, the string of amino acid beads folds into a three dimensional shape. The protein then moves to the part of the cell where it does its work. In some cases, the protein will go outside of the cell. The protein can also join together with other proteins to make complex structures and complete complex tasks.

The three dimensional shape into which a protein folds is important for how the protein works—or if it works at all. A number of things can cause a protein to wind up in the wrong shape, including changes in the gene. In many cases, one letter in the gene sentence gets switched for another. That changes one of the words, and that often (but not always) changes one of the amino acids in the protein. Each amino acid has a different size, shape, chemistry and electrical charge, so the shape of the protein gets changed as well. Depending on how much the protein shape changes, it can work slightly differently, very differently, or not at all.

These one-letter changes in a gene are the smallest kind. Sometimes, if a letter or even several letters get added or deleted, it can affect every word that follows. That's because there are no spaces between words in a DNA sentence. The words are determined by counting off three letters at a time. When letters in the gene get added or deleted, the protein is often shorter or longer than it should be. The protein's shape is so different that it almost never works.

Problems can also arise if there are changes in the letters just before the gene. This area is called a promoter, and it's an important landing site for many of the enzymes involved in the process of making RNA and proteins from DNA.

 

Human Coloring

All human coloring results from the presence of a substance called melanin. Melanin is made in cells called melanocytes, which can be found in the skin and the irises of our eyes. There are two types of melanin. The brown/black type that most people are familiar with is called eumelanin. The other type is a red/yellow pigment called pheomelanin. There are several proteins involved in making melanin. Some of them are enzymes, which perform (or catalyze) chemical reactions on molecules until melanin is finally produced. Other proteins are signaling molecules that tell the melanocytes when to produce melanin and which type. Still other proteins, called receptors, sit on the outside of the melanocytes. When a signaling protein attaches to a receptor, the receptor passes on the message to the rest of the cell. That's normally how the melanocyte knows to start or stop making certain kinds of melanin.

Most people with red hair have at least one change in the gene for a receptor protein. That protein is called the melanocortin-1 receptor (abbreviated as MC1R). There are two signaling proteins that send messages to this receptor. One tells the cell to produce more brown/black melanin, while the other tells the cell to produce red/yellow melanin. Some changes in the MC1R gene cause the protein to always pass on a "make red/yellow melanin" message no matter which signaling proteins are around.

 

Old School Genetics

Long before people knew about DNA, they were studying genes. Early geneticists thought of genes as abstract units of inheritance. They knew that a child inherited two copies of each gene—one copy of the gene from each parent. Genes were studied by examining family trees and plotting out which members had the trait of interest. Red hair was studied this way long before MC1R was discovered. Based on these family tree studies, geneticists concluded that there was only one gene responsible for people having red hair. This was much simpler than traits like height, which seems to be determined by many genes, as well as factors in the environment.

Early geneticists also knew that genes came in different varieties. The gene associated with red hair also had a brown variant. In order to have red hair, a person had to have two copies of the red form of the gene. Having even just one copy of the brown form meant that a person would have brown hair. In a case like this, red hair is considered the recessive trait, while brown hair is considered dominant.

This one gene, recessive trait rule is pretty simple, which is probably why students are often taught the red hair example in high school biology classes. Newer research has shown that this is mostly but not completely true.

 

The Many Shades of MC1R

Researchers consider strawberry blond and auburn hair to be different from "real" or fiery red hair. About 90% of the time, it is indeed having two copies of variant MC1R that leads to having fiery red hair. However, there are a number of different variants of MC1R, only some of which lead to having red hair. One variant, for example, seems to lead to having fair (blond or light brown) hair.

Three variants of MC1R seem to strongly promote having red hair, and having two copies of these variants (in any combination) almost guarantees having fiery red hair. If a person has only one copy or no copies of the red hair variants, that usually means that the person will have either non-red hair, strawberry blond hair, or auburn hair. That fits in with the classic model of a recessive trait. However, if a person has one of those three strong variants plus the variant for fair hair, she will probably still have red hair. In this case, red hair acts as a dominant trait.

There are other twists in the MC1R story. A person usually needs two copies of the red hair variants of MC1R to have red hair. Some red-haired people, however, don't have two such variants. Some red-haired people don't have any. Researchers have found that even fraternal (not physically or genetically identical) twins who have the exact same combination of MC1R variants will have different hair colors. In these people, there must be some other gene or genes that determine whether or not they have red hair.

In a very small number of redheads, that gene is the POMC gene. The POMC gene produces a rather large protein, which eventually gets cut into smaller proteins. The larger protein doesn't have its own function, but several of the smaller ones are important signaling proteins, including signals for the production of the brown/black type of melanin. The other small proteins include an endorphin and a hormone made in the pituitary gland that stimulates the adrenal gland.

When the POMC gene is altered, people don't produce brown/black melanin, thus ending up with red hair. Unfortunately, because the proteins made by POMC perform so many other roles, these people also end up with early onset obesity and decreased levels of adrenal hormones.

The POMC gene doesn't explain all redheads without MC1R variations, however. Red hair still has some genetic mysteries.

 

Red Hair, Health, and Pain

People with red hair have to take special precautions with their health. Most people with red hair burn easily in the sun. They are also more likely to get skin cancer, including both melanomas and non-melanomas. Now it seems that people with red hair might want to be careful when they have to undergo medical procedures that may be painful and where anesthetic may be needed.

During my red hair research, I found four studies about red heads and pain. The first study tested how women with red hair and those without reacted to two kinds of pain: heat-induced pain and pain caused by lack of blood flow. They also examined a type of pain killer called the kappa-opioids. The researchers tested only women because kappa-opioids don't work in men, no matter what the hair color.

The researchers found that there was no difference in pain tolerance for either group of women. It turned out, however, that most—but not all—of the redheads needed less of the pain killer. The researchers also analyzed their results by skin tone. They found that women with light skin also needed less of the pain killer, and that it was easier to guess how much of the drug a woman would need by her skin than it was to guess by her hair color. However, the best way to tell if a woman would need less _-opioid was by looking at the MC1R gene. All of the women who had two red hair variants for the MC1R gene needed less kappa-opioid.

The findings were intriguing enough that three more studies by various groups of researchers were done on how red-haired people respond to pain killers. One study found that red-haired women (no men were studied) needed more desflurane, an inhaled general anesthetic, than their dark-haired counterparts.

Another study, again only of women, suggested that they had lower tolerance to heat-induced and cold-induced pain, but no difference in their tolerance to pain induced by electric current. These women also needed more lidocaine, a local anesthetic, especially if the lidocaine was injected below the skin.

The final study I found enrolled both men and women. In this study another, more commonly used class of opioids called the mu-opioids were tested. Unlike with the kappa-opioids, both men and women had the same response to the mu-opioids. Once again, however, the people with two red-hair variants of the MC1R gene needed less of the drug. Surprisingly, though, this study found that redheads were less sensitive to electric current-induced pain.

As you can see, pain and pain killers are tricky to study.

 

Confused? Me too.

So far, it's not clear why people with red hair respond differently to pain killers. One clue is that the MC1R protein is found in more than just skin and eyes. It is also found in some parts of the brain, and it may do more than we realize. As with most scientific research, the more we know, the more questions we find to ask.

There are some basic pieces of information to be taken away from all this research, however. Not all red-heads have the same genetics, so no rule is going to apply to them all. Still, if you have red hair, be careful when you're out in the sun. (That applies for everyone else, too, actually.) Finally, if you do need pain killers for some reason, you might want to ask your doctor adjust your dose based on how you feel.

Red hair, which seems to be so simple, turns out to be a fascinating and complex biological puzzle. It reminds us that while we know so much, there is still a lot left to learn.