A deep dive into red hair genetics

Those of you interested in red hair will probably also know something about its genetics. The genetics of red hair appear to be associated with the melanocortin-1 receptor gene (MC1R), which is found on chromosome 16.

This receptor, by controlling the production of melanin, determines the colour of hair, skin, and body hair. It is located on the plasma membrane of specialized cells known as melanocytes, which produce the pigment melanin through the process of melanogenesis. When this receptor functions normally, it produces brown-black eumelanin. However, MC1R can have a number of loss-of-function mutations (also called variants), which can result in the gene producing yellow-red phaeomelanin. If you are homozygous for these mutations (ie, both copies of the gene are nonfunctional) you may have red or blond hair, pale skin and freckles. Eighty percent of redheads have one or more MC1R gene mutations.

This is the simple explanation you can find on many blogs and websites. However, I recently had the opportunity to delve a little deeper into the topic and discovered some very interesting things, which I will now report to you.

 

Before going any further, it is important to understand that many human traits (both physical and behavioural) and even many diseases are not related to a single gene, but are polygenic, that is, they are due to the interaction of multiple genes. For example, hair, eyes and skin colour are polygenic, as well as height and weight. Furthermore, many traits can also be influenced by environmental factors and nutrition.

Those of you (like me) who are of a certain age 😁 may remember that in 1990, when the Human Genome Project began, geneticists expected to find a very large number of genes, from 80,000 to 140,000. In previous years, the genomes of very simple organisms had been sequenced, and it was discovered that, for example, the fruit fly (Drosophila melanogaster) possessed approximately 14,000 genes and the worm Caenorhabditis elegans approximately 20,000, so a complex organism like man was expected to possess many more. Instead, geneticists found out only approximately 22,300 protein-coding genes, the same range as in other mammals. Plants, on the contrary, have more genes than humans. This means that the great complexity of human beings does not depend on the number of genes, but on how these genes are used, so to speak (the same gene, for example, can produce multiple proteins).

 

MUTATIONS OF MC1R

The exact number of mutations in the MC1R gene is not clear (some researches report they are 77, otheres that they are 90), partly because geneticists continue to find new ones. This study, for example, was conducted in 2022 in Italy (more precisely, in central Italy, between Rome and my region, Abruzzo) and concluded with the identification of four novel variants.

This other study, also from 2002, also identified four novel MC1R variants in red-haired South African individuals of European descent.

Another study from 2015 reported three more variants in Puglia (South-Eastern Italy). and a study from 2004 found more novel variants in Liguria, Northern Italy.

This great amout of variants puzzles geneticists, who cannot explain their usefulness.

Mutations more linked to red hair are about 15 and I’m going to list them below. I will write first the name of the mutation, then its SNP (single-nucleotide polymorphism) with the standard adopted by dbSNP. I will mark with an “R” the mutaions with a high penetrance and with an “r” the low-penetrance mutations (although in some cases the penetrance is disputed). I will not include the novel variants found in Italy and South Africa, but you can read about them in the articles linked above.

 

 

MUTATION             SNP          PENETRANCE

D84E                     rs1805006              R            rare

R151C                    rs1805007              R           one of the most frequent

R160W                   rs1805008              R            one of the most frequent

D294H                     rs1805009             R            more common in northern Europe, but less than others

R142H                     rs11547464            R            rare

I155T                      rs1110400               R            rare  

V92M                      rs2228479               r             frequent in Asia

 V60L                   rs1805005                   r            more frequent in the Mediterranean area        

R163Q                      rs885479                  r            frequent in Asia  

Y152X                     rs201326893            R            rare     

R306H                      rs368507952            R                         

S83P                         rs34474212              R

T95M                         rs34158934             R

R213W                     rs200000734             R

I182Hfs                    rs555179612             R

The first ten are the most studied.

The main MC1R mutations (source)

One of the R variants may be sufficient to have red hair, although not with 100% certainty. For example, the Genome-wide study of hair colour in UK Biobank shows that sometimes even people with two variants may not have red hair. 

“MC1R only explains 73% of the SNP heritability for red hair in UK Biobank, and in fact most individuals with two MC1R variants have blonde or light brown hair. We identify other genes contributing to red hair, the combined effect of which accounts for ~90% of the SNP heritability.”

Also, it seems that sometimes R variants may cause red hair even if they are heterozygous. On the contrary, r variants alone are not enough, but (since hair colour is polygenic) they may result in red hair if their function is supported by other genes connected with pigmentation (that we will see in a moment).

In order to know if you have that particular variant, you need to check the genotype. There can be three types of genotype, expressed with pairs of letters A (adenine), C (cytosine), G (guanine) and T (thymine). Let’s make an example with R142H, which has SNP rs11547464. As you can see here, if your genotype for this variant is AA, you have the variant, but if it is either AG or GG you haven’t (with AG you are a carrier). AA and GG are homozygous, while AG is heterozygous.

 

THE OTHER GENES

Now, as I said, there are other genes associated to hair, skin and eyes pigmentation and I’m going to list them below. Since each one of them has got multiple SNPs, I won’t mention them, but you can find most of them on SNPedia.

 

OCA2: it provides instructions for making the protein called P protein, which is located in melanocytes (specialised cells that produce melanin), and in the cells of the retinal pigment epithelium.

HERC2: SNPs found within the HERC2 gene are strongly associated with iris colour variability in humans, through effects on the expression of the downstream gene OCA2.

ASIP: it is responsible for the distribution of melanin pigment in mammals. It interacts with the melanocortin 1 receptor to determine whether the melanocyte (pigment cell) produces phaeomelanin or eumelanin. ASIP is a competitive antagonist with alpha-Melanocyte-stimulating hormone (α-MSH) to bind with MC1R proteins. Activation by α-MSH causes production of the darker eumelanin, while activation by ASIP causes production of the redder phaeomelanin.

TYR: an oxidase that is the rate-limiting enzyme for controlling the production of melanin.

TYRP1: it is a melanocyte-specific gene product involved in melanin synthesis within melanosomes.

SLC45A2: it has been found to play a role in pigmentation in several species. In humans, it has been identified as a factor in the light skin of Europeans.

SLC24A5: associated with differences in skin pigmentation.

IRF4: it is strongly associated with pigmentation: sensitivity of skin to sun exposure, freckles, blue eyes, and brown hair color. A variant has been implicated in greying of hair.

KITLG: it is involved in the proliferation and survival of melanocytes, the cells that produce melanin.

 

So, if you have one (or more) of the r variants and most of these genes are coding for light-coloured hair, eyes and skin and for freckles, and especially if ASIP is causing the production of pheomelanin, you may have red hair, even without the R variants (it's a rather unusual occurrence, but it can happen). If you have only one R variant, these genes may make the red colour stronger.

Let’s make a couple of examples.

Here you cane see the page of HERC2 SNP rs12913832. If your genotype is GG, you probably have blue eyes, while if it’s AG or AA you probably have brown eyes.

Here’s the page for the SNP rs16891982 of SLC45A2: If your genotype is CC or CG you are more likely to have black hair, while if it’s GG you are more likely to have light skin.

Clearly, you can have at same time both genes coding for a darker pigmentation and genes coding for a lighter pigmentation. In these cases, the effect of a gene variant is masked by that of different genes. For example, a redhead may have genes coding for blond or dark hair, or a person with brown eyes may have genes coding for blue eyes. This may explain all the different shades we see not only in red hair, but in any other hair colour. A redhead with copper hair instead of carrot-y hair may have genes coding for dark hair. For the same reason, even a redhead may have genes coding for a decent ability to tan. This may explain why in Southern Europe redheads with an amber complexion (instead of a very pale one) are not uncommon, as well as redheads (like me) whose eyebrows are not nearly-white but dark blond.

 

NORTHERN EUROPE VS SOUTHERN EUROPE

As a matter of fact, there are studies showing differences between redheads from Northern Europe and Southern Europe.

Before going any further, though, we need to clarify the difference between synonymous (S) and non-synonymous (NS) mutations.

Synonymous mutations are DNA mutations that do not change the gene that is expressed, because the amino acid is not changed. Synonymous mutations are actually fairly common, but since they have no effect, they are not noticed.

On the contray, non-synonymous mutations usually do affect the amino acids that are coded for and change the resulting protein that is expressed. The severity of this kind of mutation depends on how early in the amino acid sequence it happens.

MC1R mutations resulting in red hair are non-synonymous, because they change eumelanin into pheomelanin.

 

I quote from the study Nucleotide diversity and population differentiation of the Melanocortin 1 Receptor gene, MC1R:

The greatest number of SNPs was present in individuals from Southern Europe (29 NS, 7 S) and Northern Europe (18 NS and 3 S). In particular: Italy~ 31 SNPs, with ~ 26 NS, Spain  ~17 SNPs with ~15 NS, Greece 12 SNPs with 10 NS.

So, in Southern Europe not only there are more NS variants of MC1R than in northern Europe (29 vs 18), but the total of variants too is higher in Southern Europe (36 vs 21).

Since we have said that MC1R mutations resulting in red hair are NS, one would expect more redheads in Southern Europe than in Northern Europe, but we know this is not the case. The reason is that most of the mutations in Southern Europe are either low-penetrance or intermediate, while in Northern Europe there are fewer mutations, but of the high-penetrance type. This means that, with the combined action of other “darkening” genes we have seen, redheads in Southern Europe may result a bit “darker” than in Northern Europe.

 

DNA TESTS

Now, if you are wondering where to find all your SNPs, genotypes, etc, the obvious answer is a DNA test.

In this article from 2021 you can find information about the different DNA tests available. Some of them (like LivingDNA, AncestryDNA or 23andMe) are more focused on ancestry, but along with the results they send a file with the raw data of part of your autosomal DNA: in this file you can find the SNPs of genes and variants and their genotype. You can either search this file by yourself or upload it to other sites more focused on health and traits. Other companies do both ancestry and health/traits, but this is more expensive. For example, this test from 23andMe also has, among the Trait reports, “Red hair”.

 

FURTHER READINGS

Please note that some of these articles/papers may be a bit dated. For example, the first one, by Valverde et al. (1995), is the first study to identify alleles on MC1R associated with red hair. In any case, even if old, these papers can give you an idea about the history of the research on red hair.

Variants of the melanocyte-stimulating hormonereceptor gene are associated with red hair and fair skin in humans

A Study in Scarlet: MC1R as the main predictor of red hair and exemplar of the flip-flop effect 

 The “Red Hair” Variants: rs1805007 and rs1805008               

Red Hair is the Null Phenotype of MC1R

Evidence for Variable Selective Pressures at MC1R

Variants of the melanocyte–stimulating hormonereceptor gene are associated with red hair and fair skin in humans

Understanding the Complex Genetics Behind Red Hair –From Ancient Origins to Modern Expressions

Hair melanins and hair color: Ultrastructural andbiochemical aspects

Hair color gene study sheds new light on roots of redheads' locks

Whole-exome sequencing confirmation of multiple MC1Rvariants associated with extensive freckles and red hair: Analysis of aMongolian family

Phenotypic Expression of Melanocortin-1 ReceptorMutations in Black Jamaicans

Association study of MC1R gene polymorphisms withfreckles in Chinese Han population from Chengdu

 Melanocortin 1 Receptor Variants in an Irish Population

Comprehensive evaluation of allele frequencydifferences of MC1R variants across populations

Pleiotropic effects of the melanocortin 1 receptor(MC1R) gene on human pigmentation

Modeling MC1R Rare Variants: A Structural Evaluationof Variants Detected in a Mediterranean Case–Control Study

The melanocortin-1-receptor gene is the major frecklegene

Genetic association and cellular function of MC1Rvariant alleles in human pigmentation

Melanocortin-1 receptor gene variants in four Chineseethnic populations

National Library of Medicine

 

Rhesus Negative - So What Now?

I finally took a test to find out what blood group I am. I'm A negative. Rhesus negative.

I've always wondered about this, ever since I started coming across articles online linking it to red hair. "Am I rhesus negative?" I would wonder. Now I know.

I don't think there is any link to red hair in actuality (though I remain open to the idea), other than the general fact that RH negative is more common in Europeans, where red hair is also more common.

A decade ago now I wrote the following in Chapter Seven of my book, where I catalogued some of the weirder things out there on the internet about red hair.

Another variety of blood associated with redheads on-line is the rhesus negative blood type. Rhesus negative blood is linked to all sorts of weird and wonderful stuff on-line - aliens, magical abilities, grail bloodlines, pretty much everything. It's also often claimed that redheads are much more likely to possess rhesus negative blood than others.

Since then there hasn't really been too much progression of the topic. It's the same type of woo-woo stuff, but not really anything concrete. (Unless it's out there and I just haven't seen it yet.)

My Personal Feelings on the Test

[What now follows are my personal feelings on the topic. So it's anecdotal, and should be taken as such.]

I always felt that I would be rhesus negative. Obviously, this could just be bias - I had red hair, so I no doubt saw the online articles and thought, "Yes, I must be rhesus negative, too." Or, I saw the "special" personality traits associated with it and found the thought of being special appealing. So that can't be ignored, and it could just be a lucky, biased guess. However, nevertheless, I did have a good instinctive feeling based on the general information that was out there.

In fact, I actually guessed my entire blood group and not just the rhesus factor before I took the test. Though this was largely an estimated guess based on looking at the distribution of blood groups across world populations. A- seemed about right.

Another thing that was interesting was that I found out my father is A positive (I only found this out yesterday - me taking the test inspired the conversation). This is another thing that I felt I already knew anyway before the confirmation. I say this because my father doesn't have the personality associated with rhesus negative online. He's very practical. He definitely doesn't have a romantic soul.

For instance, to give a quick illustration, this image would mean nothing to him (and not just because it's red-haired).

He's just not the arty, poetic type. My mother, on the other hand, loves this sort of stuff. And, unlike him, she's red-haired as well (though there's red hair on both sides of the family), and I suspect she too would be rhesus negative, though we don't know her blood type (maybe something worth checking).

My father is practical and good with maths. He never reads books, ever. My mother loves art and books (but is hopeless with anything science or maths related). I always feel very lucky that I inherited both sides through the lottery of genetics, even if it did come with the curse of red hair. (Though people may argue my maths and science is failing me here, given I'm putting so much credence in what could be coincidence and anecdote.)

These honest feelings and observations interest me though. It's so interesting that people, even related people, can be so different. The contrast I see in my parents seems hardwired in their personalities (or biology). I don't think any amount of nurture could've made my mother a no-nonsense realist or my father a lover of flowery art. Likewise, the personality differences between me and my father, though I look very much like him, are all too apparent. I'm not saying this is down to a rhesus blood antigen - I'm sure there are plenty of rhesus positive people that look at the above image and find it as rich, beautiful and thought-provoking as I do. It's just curious to me, and worth noting.

It's also worth noting that tests can be wrong too, of course. Maybe the test I took yesterday was wrong and I'm sitting here with rhesus positive blood after all. (It was just a test I ordered off Amazon.) Plus, these things are never as simple in reality. As we've seen with the "red-haired gene," things are always much more complex and nuanced when you start digging down. These things are rarely a simple yes or no.

As I said at the end of the last blog post, more digging is needed. However, between the generic AI "official" science and the online woo it can be hard to get beyond what we already know.

Gingers Are Black TikTok Trend

A few months ago there was a trend on TikTok stating 'Gingers Are Black.' It was part joking, part serious (I think), and there was a fair bit of sentimentality from some redheads in response.

The following YouTuber gives a fairly good overview. She sees the silliness, but is also genuinely sympathetic.

Apparently Redheads Are Black Now? - Amala Ekpunobi

I mention it here as, obviously, it's redhead related, but also because it somewhat leans towards the theory that gingerness is a product of cultural melting pots. Where dark and light skin/hair tones end up in the gene pool. Though the various people making these gingers are black TikTok videos don't touch upon this idea. At least as far as I'm aware.

They do note the thickness of ginger hair though - the ginger-fro. So there's this sense that people are picking up on something that they can't quite put their finger on.

I've mentioned before the relatively high pheomelanin that redheads have, and how dark-haired people likewise possess this high pheomelanin - it's just masked by the high eumelanin that redheads lack. And that a good illustration of this comes when dark-haired people try to bleach their hair blonde only to end up with hair of an orangey-amber shade. As the bleach destroys the eumelanin more readily than it destroys the pheomelanin.

Anyway, the mention of the ginger-fro reminded me of the oft-repeated claim that redheads have fewer hair follicles on the head.

According to the Google search AI overview (yes, we're in the age of AI now), blondes have around 150,000 hair follicles; brunettes 110,000; black-haired 100,000; and redheads 90,000.

(My lazy AI search result)

That difference between blondes and redheads is really quite staggering, if accurate, and worthy of more investigation. Especially given how fair-skinned both groups are. Though blond hair does seem to be an outlier in general when compared to all groups.

I also (again, lazily) tried to find out how many hair follicles people of African descent have. The answer was 50,000 to 100,000.

Note that this AI overview gives a slightly lower figure of 86,000 for redheads. It also flips the figures for brunette and black hair around. Showing how unreliable these quick AI overviews can be.

I need to do a bit more digging.

Red hair in Latin

There are many references to red hair in Latin. Some of them are proverbs (probably from the Middle Ages) and for that reason they don’t have an original source. Others come from literary works.

 

- Si ruber est fidelis, diabolus est in coelis 

If the redhead is faithful/loyal, the devil is in heaven

This proverb is only mentioned by Italian folklorist Giuseppe Pitrè in the 1st volume of his collection Proverbi siciliani. He writes it is a Medieval proverb, but doesn’t cite the source where he found it (if it is a Medieval proverb, I guess he found it in a Medieval text). 

 

- Martial (between 38 and 41 AD – between 102 and 104 AD), Epigram LIV, Book XII – To Zoilus

Crine ruber, niger ore, brevis pede, lumine laesus, rem magnam praestas, Zoile, si bonus es. (source) 

With red hair, a black face, a cloven foot, and blear eyes, you show the world a prodigy, Zoilus, if you are an honest man. (source) 

 

Ruodlieb is a fragmentary romance in Latin verse written by an unknown southern German poet who flourished about 1030. He was almost certainly a monk of the Bavarian Tegernsee Abbey. The poem is one of the earliest German romances of knightly adventure, and its vivid picture of feudal manners gives it a certain value as a historical document.

At one point, the main character Ruodlieb meets a man with red hair, arrogant and violent, who ends up killing another man. In the Latin text he is called Rufus, while in the English translation he is called “the red-head”. The stanza below is one of the twelve teachings the king gives Ruodlieb before letting him go.

From Fragment V, stanza 450 (here Latin and English)

Non tibi sit rufus umquam specialis amicus.

Si fit is iratus, non est fidei memoratus;

Nam vehemens dira sibi stat durabilis ira.

Tam bonus haut fuerit, aliqua fraus quin in eo sit,

Quam vitare nequis, quin ex hac commaculeris;

Nam tangendo picem vix expurgaris ad unguem.

 

Never let a red-headed man be your special friend!

When such a one becomes angry, he is not mindful of good faith,

for his wrath is vehement and terrible, and will last.

He will not be so good that there will be no guile in him,

and you will be unable to avoid it or keep from soiling yourself by it.

For after touching pitch, you will scarcely get clean down to your nails.

 

The proverbs below come from the book The Dialogue of Salomon and Saturnus, that we have seen here.

-  Raro breves humiles, longos vidi sapientes.

Albos audaces, rufos sine prodicione.

Cum fusco stabis, cum nigro tela parabis.

Rarely I saw an humble short man, a wise tall man,

a brave white-haired man, a faithful red-haired man.

With the brown-haired man you can stay, with the black-haired man prepare your weapons.

 

- In rufa pelle vix est animus sine felle.

In a red skin there is hardly a soul without poison/hate.

 

- Raro breves humiles uidi, longos sapientes,

albos audaces, nigros rufosque fideles.

Rarely I saw short humble men, wise tall men,

brave white-haired men, faithful black- and red-haired men.

 

- Per rubram barbam debes cognoscere nequam,

Multi non rubram sed habent cum crimine nigram.

By the red beard you must know the wicked,

many criminals are not red-haired, but black-haired

 

- Rufus habet speciem post Sathanae faciem.

Xts plasmauit rufum Sathanamque vocauit,

Sic laus hic dixit seruus per secula sic sit.

The redhead looks like Satan.

Christ shaped the redhead and called him Satan,

Thus the servant said, let it be praised for ever.

 

- Quia rufus esset, quae species malignam naturam designaret,

iuxta hunc versum,

Raro breues humiles uidi, rufos que fideles.

Because he was red-haired, which appearance denotes a malignant nature,

according to this verse,

seldom have I seen a humble short man, or a faithful red-haired man

 

The proverbs below come from the collection in 6 volumes Proverbia sententiæque latinitatis Medii Aevi,gesammelt und herausgegeben (by Hans Walther, Göttingen: Vandenhoeck & Ruprecht, 1963-1969)

-  In rubea pelle non est animus sine felle / si tibi dicat avevelut ab hoste cave

Under the skin of a redhead there is no soul which is not bilious; if he says hello to you, beware of him as an enemy. 

 

- Intus et exterius ruffus est felle repletus, idcirco socium numquam quaeras tibi ruffum!

The red-haired man is full of bile, inside and outside; for that reason, beware of making friends with a redhead. 

 

- Sub rossa barba latet fiducia parva / in domo rufi numquam sumas tibi pausam

Under a red beard hides a very poor reliability / never rest in the house of a redhead

 

And these are proverbs without a source. 

- Rufus homo raro bonus, sed si bonus, valde bonus

A red-haired man is rarely good, but when it is, he is very good. 

 

- Rufum et barbatam a longe saluta. 

Say hello from a distance to redheards and bearded men