Inbreeding, Genetic Disease and the Royal Wedding

Today is, of course, the day of the Royal Wedding, with new blood entering the British royal line, and the hope of new heirs to our throne. And of course the question on the lips of all British geneticists is: will there be any new royal genetic diseases in this crop? The European royal lines have always been prone to the odd loss-of-function mutation. An unlucky mutation in Queen Victoria’s Factor IX gene caused a nasty case X-linked Haemophilia B in her male descendants (a mutation that was only mapped in 2009 by sequencing the bones of the murdered Romanov branch). Luckily for them, this mutation hasn’t been observed in any of Victoria’s descendants lately; while it can hide undetected in women, this obviously doesn’t apply to William. More systemic genetic problems have been the result of heavy inbreeding; Charles II of Spain, with his distressingly bushy family tree (left), suffered from severe Habsburg jaw, along with a host of other genetic complaints.

In terms of inbreeding, there has been a bunch of digging around in the press to find the closest common ancestor of William and Kate: Channel Four turned up fourteen and fifteenth cousinships, and the Daily Mail managed to find a eleventh cousinship. For comparison, William’s parents Diana and Charles were also 11th cousins, and the Queen and Prince Philip were a far more regal 2nd cousins once removed. Eleventh cousins share on average 60-parts-per-billion of DNA, or about 180bp (although with wide variation due to the spotty nature of meiotic recombination: in fact, 99.5% of 11th cousins will share no stretches of DNA through recent descent at all, while the remaining 0.5% will typically share tens of thousands of bases). Given that the average person harbours about 10 recessive diseases, this gives about a 1 in 1.6 million chance of Kate and Will’s offspring developing a royal disease due to a piece of DNA shared between them. So, not very likely then.

In fact, eleventh cousins is a pretty low degree of relatedness, by the standard of these things. A study of inbreeding in European populations found that couples from the UK are, on average, as genetically related as 6th cousins (the study looked at inbreeding in Scots, and in children of one Orkadian and one non-Orkadian. No English people, but I would be very suprised if we differed significantly). 6th cousins share about 0.006% of their DNA, and thus have about a 0.06% chance of developing a genetic disease via a common ancestor. Giving that the Royal Family are better than most at genealogy, we can probably conclude that the royal couple are less closely related than the average UK couple, and thus their children are less likely than most to suffer from a genetic disease. Good news for them, bad news for geneticists, perhaps?

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11 Responses to “Inbreeding, Genetic Disease and the Royal Wedding”


  • Nice post. A few months back, in wake of Tut genome, I wrote a story for National Geographic on the history of royal incest, including the benefits which made it attractive. Readers may be interested. It’s at http://j.mp/mOzOkG

  • There was actually a deCODE study that looked at fertility as a function of kinship. They found that fertility peaked if the parents were related at the level of third or fourth cousins.

    http://www.sciencemag.org/content/319/5864/813.full

  • Actually, there’s evidence for hereditary porphyria in the British Royal family as well: http://www.sussex.ac.uk/press_office/bulletin/25jun99/article1.html

    Salient quote:
    ” “The Queen’s cousin, William of Gloucester, who died in a plane crash in 1972, was clinically diagnosed with the same type of porphyria by three different doctors in three parts of the world”, says John. “We’re only at the beginning. Only last week, someone wrote to us and gave us permission to examine the heart of James II.” As his research continues, the point at which the disease entered into the family can be established. It is currently believed to have originated with Mary Queen of Scots, whose son, James I, described his urine as being “the colour of Alicante wine”.”

  • My view is the snobbish gene of Williams is joinng the playful and free open genes of Kate.Epigenetics of Williams is not that encouraging with touchy Diana and the secluded and isolated Charles in earlier years.But Kate with playful human interactions is a good and hybrid match for Williams.If Williams controls his “nakrahs”(~snobbish) of royalty and if Kate increases her accommodation without too much control on Williams and spends more time time with him the epigenetics may turn into a positive upsurge of happiness.If they read this they will understand the situation
    genetically

  • Why did Charles never marry Camilla when he was younger, did it have something to do with one of Camilla’s relatives having a fling with one of Charles’ early Kings? Plus did these two have any children? As I wondered if Camilla is more like a distant cousin to Charles & sharing in his genes? Tricky situation eh? With the Porphyria gene in their blood. It goes back further than ‘The maddness of king George 111′ I read the book ‘The Purple Secret’ & this problem goes back as Henry V1 (1421-71)So it would be interesting to fill in the blanks of who was missed out!

  • The book that revealed that George VI’s brother was diagnosed with porphyria, showed that the tests failed to adequately distinguish which form of metabolic porphyria he had. Variegate porphyria and hereditary coproporphyria look very similar on the tests for levels of assorted porphyrins that were done. What needed to be done was specific assays for two different enzymes; protoporphyrinogen oxidase and coproporphyrinogen oxidase, to determine which was present at only half its normal level (because of having one nonfunctioning copy of the gene). This was not done. The same author sequenced most but not all of the gene for protoporphyrinogen oxidase in somebody he expected to have the royal porphyria, and did not find it. The gene for coproporphyrinogen oxidase was never searched.

    Hereditary coproporphyria is characateristically milder than variegate porphyria, so would more often be expected to be silent or mild and vague. It is well recognized that through George VI’s generation, royalty did things that aggravated porphyria, from heavy metals in the paint to same in their wine to same in their medicines. People with metabolic porphyria actually can’t take many drugs because heme enzymes are needed to metabolize them, and some block the production of these enzymes. The royal family themselves believed that whatever ailed George VI and his brothers was caused by starvation, dosing with alcohol, and poor cleanliness, all parts of abusive care by their nurse, and all of that would have aggravated genetic metabolic porphyria.

    George VI’s repeated attacks of acute digestive symptoms and extreme nervousness were far more characteristic of a typical attack of porphyria than George III’s more severe attacks, that probably were aggravated by his medical care. One time he escaped, went to the seashore, ate porridge, and got well, which pretty much is the strategy that used to work on one of these genetic mutations that has become common in a part of Scandinavia. When these people started going to hospitals they started getting much sicker and dying. Evidently, by the time George VI was in the navy, the royal doctors had absorbed the information that whatever else you do, you do NOT give this family medicine. They kept prescribing rest and milk toast. His attacks were likely caused by conditions on board naval vessels. At the same time as they removed his appendix, he withdrew from the navy, and I guess he never had another acute attack, though his nerves and bad temper were the stuff of legend.

    Dora

  • One other thing; children born with two bad copies of the genes for protoporphyrinogen oxidase and coproporphyrinogen oxidase make very little of the affected enzyme of the heme biosynthetic pathway (the heme from which is used for metabolic enzymes; hemoglobin is made by its own genes). They are characteristically very sickly and undersized, often neurologically damaged, and they very often don’t live very long. Since porphyria has been traced in the royal lines to the Spanish, French, English and Habsurg lines in the 15th century, and these lines were extremely inbred, they were having alot of children with homozygous porphyria, and that fact explains much. I think that Henry VIII and Catherine of Aragon actually had fifteen children, certainly a large number of them, including several sons, but only Mary survived. William of Orange was badly stunted in growth and had severe neurological damage, probably to his respiratory nerves among other things. He was raised in a simple Protestant household; kept very clean and fed simple food and no alcohol, and his doctors tended to avoid medicine; that enabled him to survive.

  • One other thing. George VI had a fifth brother, who was sickly and neurologically damaged, and kept having seizures, and only lived to be 15. He was eventually isolated in a house at Sandringham because the king and queen didn’t want people to be aware of him. I think he was eventually buried there.

  • Something else I forgot to mention. VERY important. Minus exacerbating factors, like a steady diet of red wine laced with lead, walls lined with lead paint, etc., children who were never washed, severe inbreeding in a family that carries the gene, etc., etc., genetic metabolic porphyria is absolutely silent in 90% of people who have it. Blood work usually reveals a characteristic deficiency of the affected enzyme, but the heme biosynthetic pathway has considerable excess capacity in normal healthy people who don’t have heavy metal poisoning and whatever. Most of the people who DO get acute attacks of porphyria, other things being normal, have a difference in the way they metabolize certain kinds of hormones that the body normally makes, which is shaped around the time people are born.

    However. Most people with genetic metabolic porphyria have characteristic defects that show up on certain brain scans, like holes in the basal ganglia, and are characteristically intense and nervous – similar to someone with a bipolar temperament.

    During the dark ages, the other word for bipolar disorder was feudal warlord temperament. Most warlords came to power by being ambitious and obsessive and mad enough to frighten people. Those whose families held power didn’t for instance suffer repeated attacks of madness like someone with severe bipolar disorder. One tends to suspect that genetic metabolic porphyria selected itself into the royal lines. Most royal lineages lived simply, in ways that would not have aggravated porphyria into acute attacks, during their first several generations. Morover, repeated bouts of illess that resembled George VI’s were characteristic of, for example the kings of Wessex, and they just lived with them. The Merovingian kings had repeated attacks of madness, sometimes accompanied by peripheral paralysis. These high aristocratic lines fed into each other, even when the connections can’t be traced.

  • Dora, you know a lot about this! And your conclusions are really interesting. It IS possible that the royal family of England-France-Etc. had more than one porphyria mutation. If tested properly, however, the problem would have shown up, the unfortunately this illness is hard to test, partly because labs and doctors don’t do enough of it to know all the in’s and out’s, and some doctors do not consider a person to have porphyria at relatively low, but significant levels on lab tests. Some kinds of porphyria don’t seem to show up well on tests unless a person is “caught” in acute attack.
    Like testing a week after an attack, if problems are resolving, may not show hereditary coproporphyria, which you mention as the interesting alternative to varigate porphyria in this family.

    I imagine the whole family is aware of “triggers” and avoids them as much as possible, making it possible for even those who have the porph gene to live relatively normal, but cautious, lives. the tragedy is not theirs, it is that of the “commoners” who do not get their high level of knowledge and care. The family had many offspring, both legitimate and non-legitimate; in fact in medieval Scotland it was very common for rulers to have a whole list of illegitimate children, even ones accepted by clergy who were swooned over the mystical significance of royalty.

  • Compare photographs. Camilla looks remarkably like the now-deceased Queen Mother, who was mother of the current Queen Elizabeth.

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