In royal/commoner marriage, a happy mix of genetic diversity

While opinion leaders in Britain debate whether Prince William's impending marriage to a commoner will diminish the royal family's public image, geneticists see only an upside to the pairing.

"From a genetic perspective, mixture is good," said Francisco Ceballos, a biologist at the Universidad de Santiago de Compostela in Spain. Ceballos is involved with an ongoing study of the Habsburg family, a once-powerful royal dynasty that appears to have inbred itself into extinction.

Inbreeding, which can increase the likelihood of genetic defects, is still one of the most complex areas of evolution and population genetics, he said. Some groups of plants and animals can withstand more than others before harmful effects surface. In the badly depleted Florida panther population, geneticists determined that inbreeding had led to various birth defects, including malformed testicles and heart deformities - and that without intervention, the big cats were nearly certain to go the way of the Habsburgs.

About 10 percent of humans worldwide are the product of some inbreeding, and the potential dangers were little understood as recently as 150 years ago, when Charles Darwin did some of the earliest research on inbreeding, in plants. Since he was married to his first cousin, historians say, some of his interest was driven by concerns about his own children's health.

Ceballos and other scientists are hoping to gain a better understanding of the varied effects of inbreeding by looking at royal families, where the practice has reached extremes in the past.

In the British royal family, Prince Charles is a product of slight inbreeding, said Ceballos: His parents are related as third cousins through Victoria and Albert, and also fourth cousins once removed, through King George II and Queen Charlotte.

But by marrying unrelated Princess Diana, he produced sons who are not inbred. Still, Ceballos said, it can't hurt for William to be adding more diversity to the royal gene pool.

Friday's wedding certainly will make it less likely for the Windsor family to meet the fate of the Habsburgs - the royal dynasty that arose in the 1500s and controlled the Spanish Empire at its height. By the late 1600s, the last Habsburg king, Charles II, suffered chronic muscle weakness, abnormally short stature, intestinal problems, mental retardation, impotence, and infertility. He married twice, but died childless at age 39.

So numerous were his maladies that he was sometimes called Charles the Hexed. Until now, however, there was no direct evidence that inbreeding was the cause.

By looking far back into his family tree, the Spanish researchers determined that Charles II was the product of a number of cousin marriages, as well as uncle-niece pairings. The scientists used a mathematical technique to calculate the level of inbreeding that went into the unfortunate king. They use a number, called F, that quantifies the level of inbreeding. It's 0.25 for children born of brothers and sisters, and 0.0625 for the offspring of first cousins.

The effects are cumulative. So Charles II, thanks to multiple cousin and uncle-niece marriages in his ancestry, had an inbreeding coefficient of .254 - slightly higher than that of children produced by full siblings.

Yet Charles II's sister, the equally inbred Margareta of Austria, was considered a beautiful woman and suffered no obvious abnormalities.

It's an odds game, which makes sense in light of today's understanding of genetics.

The problem with inbreeding is that it allows harmful mutations to accumulate. Everyone inherits some mutations. Since we get two copies of almost all our genetic material - one from each parent - we usually have a healthy gene as backup to a mutated version.

That's why many people are carriers of genetic diseases such as cystic fibrosis without realizing it. When the healthy copy can override the mutated one, the disorders are called recessive. (When a single gene has the power to override the other copy, the resulting trait or disease is called dominant.)

But the more inbreeding in your ancestry, the more likely you are to have identical copies of the same genes - and that raises the odds that some of those double copies will contain defects.

Ceballos and his colleagues theorize that Charles II suffered from double doses of two harmful recessive genes - one pair that causes a disease called combined pituitary hormone deficiency, and another that leads to distal renal tubular acidosis.

Charles II also suffered from an extreme version of a protruding jaw - a family trait known as the "Habsburg lip." So far, the researchers haven't been able to pin this on his genetic inheritance, but they are continuing to investigate the phenomenon.

Ceballos also cowrote a study published last year that suggested inbreeding may have had an impact on the health of the large Darwin family. Charles Darwin married his first cousin Emma Wedgwood. After the death of their daughter, Annie, he began worrying about the effects this might have on his growing family.

The leader of the new study, Ohio State University biologist and Darwin biographer Tim Berra, said that Annie died of tuberculosis at the age of 10, while his youngest son died in childhood from scarlet fever. Susceptibility to infectious disease has been connected to inbreeding, Berra said, as has unexplained infertility.

Six of Darwin's children had long marriages, but only three had children. "Is that where unexplained infertility is raising its head?" Berra said.

One of Darwin's sons actually studied cousin marriages himself. George Darwin was a brilliant and accomplished mathematician, said Berra. He surveyed mental hospital patients and found that the percentage of those who were products of cousin marriages was no greater than that in the general population.

Charles Darwin must have gotten some solace from this, said Berra, but he still knew from his research in plants that inbreeding could be harmful. "In his own experiments, he saw that crossbreeding was much more effective than inbreeding," Berra said.

That seems to have proved true for the endangered Florida panthers, which had dwindled to about 40 animals by the early 1990s. Geneticist Stephen O'Brien, who spoke last week at Philadelphia's Wagner Free Institute of Science, said many had been stricken with viruses, including feline immunodeficiency virus and feline leukemia virus.

O'Brien, who works for the National Cancer Institute, said a DNA analysis had shown that genetic diversity was badly depleted and that this population was almost certain to go extinct.

In 1995, in a last-ditch effort to save them, conservationists brought in eight new panthers from different subspecies. Last fall, O'Brien and colleagues reported that the Florida population had grown to more than 100 and that the animals were healthier.

While the British royal family isn't endangered, it can't hurt to bring in more outside genes, said Ceballos. "When you mix it up, good things happen."

Go online to discuss evolution with Faye Flam at www.philly.com/evolutionEndText