On 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.

Charles 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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