How inbreeding killed off a line of kings

Blogging on Peer-Reviewed ResearchOn November 1st, 1700, an entire dynasty of kings came to a crashing end with the death of Charles II of Spain. Charles had neither a pleasant life nor a successful reign. He was physically disabled, mentally retarded and disfigured. A large tongue made his speech difficult to understand, he was bald by the age of 35, and he died senile and wracked by epileptic seizures. He had two wives but being impotent, he had no children and thus, no heirs. Which is what happens after 16 generations of inbreeding.

i-f414434b49438248c19ec65c8a0282fe-CharlesII.jpgCharles II was the final king of the Spanish Habsburg dynasty (see family tree), part of a house that ruled over much of Europe for centuries and which took Spain to the height of its international power. Concerned with corralling their heritage within their bloodlines, the Spanish Habsburgs married heavily between each other. Most of their 11 marriages were between blood relatives, including several matches between first cousins and two between uncles and nieces. Charles's own mother was the niece of his father, and his grandmother was also his aunt.

Historians have often speculated that this inbreeding was the dynasty's downfall and contributed to Charles II's numerous health problems. The more closely related a child's parents are, the greater the odds that they will be dealt a dud genetic hand. We inherit one copy of almost every gene from our father and one from our mother. Some will be defective, but chances are that a second working copy will compensate for this. But if parents are related, they may already share many of the same genes and they risk of passing down an identical pair of faulty ones to their children. That can lead to genetic disorders or birth defects, like those that afflicted poor Charles.

Through a fascinating piece of historical genetics, Gonzalo Alvarez from the University of Santiago de Compostela has confirmed that inbreeding caused the extinction of this dynasty. He traced the pedigree of the entire line back through 16 generations, including over 3,000 people.

For each person, he calculated a figure called the "inbreeding coefficient", symbolised by the letter F. It measures the probability that a person with two identical copies of a gene inherited both from the same ancestor. For example, a child born to cousins has an F value of 0.0625, but it becomes much higher if the parents come from a long line of inbred couples. The higher the value, the greater the degree of inbreeding in that lineage.

Alvarez found that the first Spanish Habsburg king, Philip I, had a relatively low F-value of 0.025. But after just five generations, his descendant Charles II had an F-value of 0.254, more than ten times that of his great-great-great-grandfather. This figure is even twice as high as the expected value for the child of an uncle-niece marriage, which reflects just how pervasive inbreeding was in this family tree. It also means that Charles II would have carried identical copies for more than quarter of his genes (his genome was 25% homozygous, in the parlance of geneticists).


These figures help to explain why Charles II had such ill health. In fact, Alvarez speculates that Charles's entire panoply of symptoms could be explained by two genetic disorders, both caused by inheriting two copies of faulty recessive genes.

The first is combined pituitary hormone deficiency, caused by mutations in a gene called PROP1. The disorder affects about 1 in 8,000 people and is caused by a lack of important hormones from the pituitary gland. People who have it tend to be short, uninterested in their surroundings, and have weak muscles, infertility, impotence and digestive problems. The second disorder, distal renal tubular acidosis, is caused by mutations in two genes - ATP6V0A4 and ATP6V1B1. It hampers the kidneys' ability to get rid of acid through urine, and can lead to bloody urine, weak muscles, rickets and a large head relative to one's body size. 

This array of symptoms is a good match for those that Charles II suffered through this childhood and adult life. Of course, Alvarez realises that his suggested diagnosis is incredibly speculative, but it is compelling nonetheless. It would normally be very unlikely that someone suffered from two rare genetic disorders at the same time, but Charles's inbred heritage makes that a much more likely proposition.

Alvarez's analysis also suggests how their inbreeding sealed the fate of the Spanish Habsburgs. For a start, it wreaked havoc on the health of their babies, a massive proportion of whom died at an early age. Of 34 children, half died before their tenth birthday, and 10 died before their first. Even villagers, most of whom led much poorer lives, only lost one in five babies.

By looking at death records for the family, Alvarez found that babies were much less likely to survive for 10 years if they were born to kings with high F-values. The growing degree of inbreeding in the family meant that fewer and fewer children made it to adulthood, leaving the entire line resting on the infertile genitals of a handicapped and short-lived king.

Update: Razib at Gene Expression has a majestic post that goes into a lot more detail about the genetics of inbreeding. Go check it out.

Reference: Alvarez, G., Ceballos, F., & Quinteiro, C. (2009). The Role of Inbreeding in the Extinction of a European Royal Dynasty PLoS ONE, 4 (4) DOI: 10.1371/journal.pone.0005174

More on inbreeding:

Sidenote: On researching this article, I learned that the Spanish Habsburg dynasty started with a marriage between Philip I, also known as Philip the Fair, and Joanna I, also known as Joanna the Mad. I can only think that either Joanna's nickname came after the marriage, or that Philip didn't read the personal ad carefully enough...

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I get a 404 on --(see family tree)--

It does bear mentioning that the Hapsburgs were more than a little inbred by the time they acquired Spain (through marriage), having been the dominant dynasty within the (not)Holy (not)Roman (not)Empire for several centuries.

Poor J the M (b. 1495 to that Ferdinand & Isabella) was, as described by Geoffrey Parker in Philip II:

... a whimpering lunatic locked up in Tordesillas castle from 1506 until her death in 1555, whipped and beaten into submission by her keepers (with the express approval of her son, Charles V [himself a noted melancholiac).

According to Parker, Carlos II (calling him Charles helps confuse him with the English & French Charleses) was ancestrally deprived:

... instead of eight great-grandparents he only had four, and instead of sixteen great-great-grandparents he only had six!

As to how Joanna's son could be "Charles" (I prefer Karl) V while her great-great (I think) grandson was "Charles" (Carlos) II - well, European royal geneaology gets quite complex...

By Pierce R. Butler (not verified) on 14 Apr 2009 #permalink


Drop the " target=" from the url.

Ed, very interesting article. Thanks!

I so enjoyed reading this. It brought back my childhood fascination with European kings and queens prior to constitutions and parliaments with real power. But why was Philip IV's f factor lower than either Philip III or II?

Thanks Ed! The family tree url is broken.

Charles II was a disfigured freak of nature, and was kept on the throne as a compromise--His death caused a war of succession.

Also: royalty portraits don't reflect reality much. Imagine, if that portrait is the nicest looking thing even resembling Charles II...

The family tree should be working now.

Pierce - agreed. Note that Alvarez based his inbreeding calculations using 16 generations of ancestry, which goes well beyond the start of the Spanish Habsburg lineage. He explicitly found that it takes at least 10 generations to achieve a good accuracy for these calculations, so yes, Charles's conditions were the result of centuries of inbreeding going back well before Philip I.

zpmorgan - I take your point about the portraits, but I'm told that this point in history reflected a shift towards more accurate royal portraiture as opposed to over-beautifying the subject.

Great stuff! I love me some history. Interestingly, you can see in the photograph that another inheritance of the Hapsburgs (made worse by the inbreeding, I'm sure) was the incredibly prominent jaw. It was noted on Philip II (the one who married Mary I "Bloody Mary" of England), and he wore a beard to cover it, but it just kept getting worse. By the time of Charles II of Spain it was so bad that his mouth hung open all the time.

Of course, no matter WHAT he looked like or acted like, he would have been described as "the most fair prince, totally awesome, really a genius, and wonderfully handsome".

Actually, Why IS Philip III's F factor lower? His father was Philip II, and his mother was Anne of Austria, who was Philip's niece.

So Philip IV's F-value was lower than many of the kings surrounding him because his parents were first cousins once removed, and thus more distantly related than the parents of either Philip II (first cousins), Philip III (uncle-niece) or Charles II (uncle-niece).

While Philip III and Charles II were both the product of uncle-niece unions, presumably Charles's F-value is slightly higher simply because he's a few generations of inbreeding down from Philip (who's his grandfather).

Wait, so is this thick-tongued, slow-witted Charles the one that put the lisp in the Castilian Spanish still spoken today?

By IgnatiusJReilly (not verified) on 15 Apr 2009 #permalink

I'd guess there was infanticide, some due to politics, others due to worse (but possible survivable) physical defects.

Ignatius - Wikipedia tells me that's a myth. So I believe you are mythtaken...

For the record, Joanna the Mad wasn't nearly so mad before her husband died. She was probably a bit unstable, maybe what we would call manic-depressive, and was also profoundly in love with her famously handsome (and age-matched) husband. Unfortunately, he was apparently also kind of an asshole and took advantage of her adoration of him, plus her reputation for being a bit loony, to usurp a lot of her power. When he died, she really went round the bend and reportedly carried his corpse with her everywhere, which was enough for her father to declare her incompetent and confine her. It was a pretty sad story really.

IIRC, her Wikipedia page is pretty good. Worth reading.

Ed, where does the Cathtilian lithp really come from then? I've been curious for a while.

where does the Cathtilian lithp really come from then?

From a sound shift that affected one of the two [s] sounds (one of which was derived from [ts], spelled c and z because of its own origins). In Andalusia, the two sounds merged instead, and that's where the Latin American pronunciation comes from.

Incidentally, Basque still has two, one spelled s and the other spelled z... Basque also shares several other sound-system features with Spanish, despite having origins that could hardly be more different.

By David MarjanoviÄ (not verified) on 15 Apr 2009 #permalink

Hmmm... as someone who started balding at 18, and has been making steady progress since, I wonder if you would class Carlos' baldness among his disabilities or as a mere disfigurement :-)
At any rate it seems to have been the least of his problems...

Er, yes, quite. Should probably have thought that through. So between the baldness and the lisping, does anyone else have a physical tic I can crassly make fun of? ;-)

When I saw the title of this post, I assumed that it was about the Ptolemies of Egypt.

I have taken an interest in Spanish history lately, but so far it has been during the period of Columbus and the discovery of the Americas. Interesting post.

Some research this. Should they have consulted Carlos the Bewitched by John Nada, published in 1962 by Jonathan Cape, they might have found that an earlier writer already reached this conclusion. The end papers contain Carlos' maternal and paternal lines and as part of the description of his heredity, reference is made to some of the forebears of Queen Isabella of Castille, including King Enrique IV (d 1474), who displayed physical and mental traits which were similar to those of Carlos II.

By Richard T (not verified) on 16 Apr 2009 #permalink

I wonder how the author takes into account cuckoldry. Maybe it's not prevalent enough, in that particular context, to change the results much.

By Nathan Myers (not verified) on 16 Apr 2009 #permalink

"Elizabeth of Castile" on the fam tree should in fact read "Isabella of Castile" as the mother of J the M. She and Ferdy were the "Ferdinand and Isabella" who funded Columbus. It's perhaps a blessing that so many of the royal marriages were childless; imagine how much more complicated it would be if, say, Philip II had had children with Mary Tudor ("Bloody Mary"), who, in keeping with family tradition, was his first cousin. Philip II also tried to marry Mary's half-sister, Elizabeth I, then later tried to get her to marry his son! He also tried to promote her marriage with a "prince of Portugal," who may have been an uncle or cousin or his, or his son.

Figuring out the pedigrees of European royalty can be like untangling knitting mistakes ...

On a side note, there is literature by Christine E. Garver-Apgar (2006) that there are immediate effects of genetic similarity (MHC genes) on sexual responsitivity, extrapair partners, and attractiveness of alternative mates in women.

Some research this. Should they have consulted Carlos the Bewitched by John Nada, published in 1962 by Jonathan Cape, they might have found that an earlier writer already reached this conclusion.

It's been speculated upon/assumed by many, for a long time.

This research nails down the degree of shared genes Charles got from his mother and father, it's the quantification that's interesting.