Monday, October 19, 2009

Scientists weigh in on inbred Spanish royals

Remember my series of posts on inbreeding earlier this year? What's that? You didn't read those? Well, anyway a study was published this spring which adds scientific support to the theory that the decline and fall of Spain's Habsburg dynasty was due to excessive inbreeding. This hypothesis, along with the suggestion that King Carlos II's varied health problems were due to inbreeding depression, has long been espoused by historians, but this is the first time that the claims have been analyzed based on genetic data.

In April, the online scientific/medical journal PLoS One published a paper submitted by three biologists from La Coruña, Spain (in Galicia) entitled "The Role of Inbreeding in the Extinction of a European Royal Dynasty."  Scientists first reconstructed a genealogy of the Spanish Habsburgs, including 3,000 individuals across 16 generations, in order to determine the inbreeding coefficient for each of the Habsburg Kings of Spain. Next, they looked at the incidence of late-term miscarriage, stillbirth and infant/childhood mortality (defined here as death before the age of 10) in the family between 1527 and 1661. Finally, the biologists catalogue Carlos II's physical and mental shortcomings and hypothesize that these might have been due to his affliction with two rare genetic diseases.

How inbred were they?

9 out of the 11 marriages entered into by the Habsburg kings were marriages between close relatives (third cousins or closer): these include two uncle-niece marriages, one double first cousin marriage, and one first cousin marriage. How inbred an individual is can be measured by calculating his "inbreeding coefficient," which is defined as the probability of a zygote obtaining identical copies of the same gene because its parents are related. The inbreeding coefficient of the kings studied ranges from .025 for Philip I (Felipe el hermoso, 1478-1506), the dynasty's founder, to .254 for Carlos II (1661-1700), the last Habsburg King of Spain.

This means that Carlos II's inbreeding coefficient is actually HIGHER than that for the offspring of a parent-child or brother-sister union (.25), and it would mean that there was at least a 25.4% chance of Carlos II having received identical copies of any given gene from each parent. Several other members of the family also had inbreeding coefficients over .20 including King Philip III (1578-1621) and Don Carlos, Prince of Asturias (1545-1568), the child of Philip II and his first wife Maria Manuela of Portugal. Don Carlos had his own physical and psychological complaints which might be attributable to inbreeding.

The kings' average inbreeding coefficient was .129 (higher than the coefficient for the offspring of uncle-niece or half-brother/half-sister unions). How is this possible? The paper explains that these high coefficients were as much due to ancestral inbreeding among multiple remote ancestors as they were to unions between close relatives among an individual's parents and grandparents. Thus, one has to go back 10 or more generations in order to get a complete picture of how inbred these people were.

Infant mortality rate

Between 1527 (the year of Philip II's birth) and 1661 (the year of Carlos II's birth) the Habsburg kings and queens produced 34 children, of whom 10 died before completing their 1st year and 17 (50%) died before their tenth birthday. This is significantly higher than the 20% infant mortality rate observed in Spanish villages around this time. The latter statistic, moreover, includes poorer families whose children were adversely affected by malnutrition or limited access to medical treatment, whereas these factors would not have been an issue for the royal family.

The scientists also examined a separate set of data: looking at the pregnancies recorded by historical sources in 8 marriages (the marriages of the Spanish kings from Ferdinand and Isabella up to the two marriages of Carlos II's father Philip IV, excluding the first two marriages of Philip II that produced only one child between them). Out of 51 reported pregnancies, 5 ended in late-term miscarriage or stillbirth, 6 produced babies who died within a month, 14 more produced children who died before age 10, and 26 children who survived infancy. When statistically analyzing this data together with inbreeding coefficients, the study found a significant correlation between the inbreeding coefficient and deaths before the age of 10. This would suggest that excessive inbreeding may have had a negative effect on infant mortality in the families of the Habsburg Kings of Spain. Further bolstering this theory are other studies which show a correlation between infant mortality and unions between closely related individuals (e.g. first cousins).

This makes me think of what I found out about Carlos II's sister Margarita Teresa (1651-1673) when researching the first post. The infanta, who married her uncle Leopold I and who died at the age of 21, had four children: three who died before the age of 2 and one daughter Maria Antonia (1669-1692) who lived to be 23. None of Maria Antonia's three children with her husband Maximillian Emanuel of Bavaria survived to adulthood.

What was wrong with Carlos II?

The paper did a good job of cataloging Carlos' symptoms based on historical sources. We're told Carlos II was a "weak breast-fed baby" and that he had a disproportionately large head. He didn't manage to speak until age 4 or to walk until age 8, and he grew up to be short, weak and thin. The biologists characterize his personality as "abulic" (apparently meaning that he was uninterested in his environment and apathetic). As for reproductive problems, we all know Carlos II had no offspring: his first wife complained of premature ejaculation and his second said he was impotent. Carlos also suffered from occasional hematuria (blood in urine) and gastro-intestinal problems (diarrhea, vomiting). At 30, we're told he looked prematurely old and that parts of his lower body and face were swollen from edema. In later life, Carlos could barely stand on his own and he was afflicted with hallucinations and convulsions. He died at the age of 39 after an illness characterized by fever, abdominal pain, breathing difficulty and coma.

The possible explanation for Carlos' problems offered in the paper is that he may have suffered from two rare conditions: combined pituitary hormone deficiency (CPHD) and distal renal tubular acidosis (dRTA). CPHD refers to impaired production of growth hormone and other hormones produced by the anterior pituitary gland. It is associated with short stature, hypotonia (low muscle tone), apathetic personality, gastrointestinal problems, and infertility/impotence. The condition is also exacerbated by physical stress which can result in abdominal pain and fever. dRTA, on the other hand, is the condition which results when the kidneys are not removing acid from the blood normally. Symptoms include muscular weakness, rickets, hematuria and a disproportionately large head.

It is only a hypothesis that Carlos II suffered from these two conditions, and the paper's authors are careful to point out that both disorders can be caused by environmental factors as well as genetics. Moreover, in a comment on the paper, a group of doctors dispute the claim that Carlos II suffered from dRTA as unlikely. Nevertheless, Carlos' high inbreeding coefficient makes it much more likely that he may have inherited a recessive genetic disorder, rarely occurring in the population as a whole. In order to inherit a recessive genetic disorder one must receive "bad copies" of the same gene from both parents, and as we said above Carlos' inbreeding coefficient tell us that he had a 25.4% chance of receiving identical copies from both parents for any given gene. What's more, another study shows that genetic homozygosity (i.e. possessing two identical forms of the same gene) for related individuals is often even greater than their pedigree suggests (probably because unrelated or distantly related individuals in the gene pool also have identical copies of the same gene sometimes). This would make the chances even greater.


So, to sum up: the Habsburg Kings of Spain became much more inbred than the population as a whole, and their families were affected by an unusually high infant mortality rate (50% of their children died before age 10). A statistical analysis in this and other studies shows a significant correlation between inbreeding and infant mortality. Thus, one could theorize that the high incidence of inbreeding adversely impacted the Habsburg children's chances of surviving to adulthood.

Spain's last Habsburg king, Carlos II, was even more inbred than the child of a brother-sister union, and thus his chances of having inherited a recessive genetic disorder were greatly increased. He was also mentally and physically handicapped, and he died childless at age 39. Based on his symptoms as recorded by historians, scientists hypothesize that he may have suffered from something like combined pituitary hormone deficiency and/or distal renal tubular acidosis -- two rare conditions sometimes caused by inherited genetic defects.
Now I would really like to see scientists study this man's DNA to better determine how homozygous his genes were and what genetic conditions he may have suffered from.

Images: Portrait of  Don Carlos by Alonso Sánchez Coello and portrait of Margarita Teresa by Jan Thomas van Ieperen both on display at Vienna's Kunsthistorisches Museum and both found on wikipedia.


nola32 said...

so i feel like there should be a post about how inbred the brit royals are (i know they got a mention in an earlier post but i feel like there's so much more that can be said). can we also discuss how complicated it gets when you get into hre names vs spanish names? (this makes me think of charles V hre/charles I spain)

Meeg said...

Yeah Charles V was Charles I of Spain. Also Philip the Fair or whatever you want to call him (Juana la loca's husband) was Philip I, I guess, but I don't feel like he was really the King of Spain.

nola32 said...

no, i don't think he really was. ahh, juana la loca. she deserves a post of her very own.