Unwanted results of human inbreeding

Sickle-cell anemia illustrates how natural selection can, paradoxically, maintain a disease in a population. We’ll now look at another way diseases can emerge in a population: by bringing together rare deleterious mutations through inbreeding. There are many examples to choose from, among humans and nonhuman species alike. Probably the most spectacular example concerns the fall of the Spanish Empire.

Charles II belonged to the great Hapsburg dynasty, which took over Spain in 1516 and dramatically expanded its sphere of power. When Charles II became king of Spain in 1665, the Spanish Empire was the greatest power on the planet. In the New World, its power reached from California down to the tip of Tierra del Fuego. In Europe, Spain possessed half of Italy. It held sway over much of the Caribbean as well as the Philippines. But all that would soon end.

Charles II was crowned at age four, and from the start it was clear that the boy was an unfortunate monarch. He had a host of deformities, including a jaw that was so large it left him unable to chew and a tongue so big that people could hardly understand his speech. He did not walk until he was eight, and he was such a poor learner that he was never formally educated. He vomited and suffered from diarrhea all his life. By age 30 he looked like an old man. All this suffering earned Charles II the name El Hechizado—“the Hexed”—because he was widely believed to be the victim of sorcery.

Spain suffered under Charles’s reign. Its economy shrank as it fought a host of small but draining wars. And worst of all, it became increasingly clear that Charles II would not produce an heir. The Hapsburgs had long feared such an outcome; to hold onto Spanish rule, they had taken to marrying within their family. Charles II not only failed to produce an heir with his two wives but also lacked any brothers or other Hapsburgs who could succeed him. And so, when Charles II died in 1700 at the young age of 39, he left the throne to Philip, a French duke who was the grandson of his half sister and King Louis XIV of France.

Philip was not just the king of Spain now. He was also in the line of succession to the French throne. There was a real chance that he might eventually become king of a united France and Spain—a prospect that terrified the rest of Europe. Soon England, the Netherlands, the Holy Roman Empire, and other European powers declared war to stop Philip from creating a superempire. They battled not just in Europe, but in their colonies as well. The English in the Carolinas waged war with the Spanish of Florida; in Canada, they battled the French and their Indian allies.

The War of the Spanish Succession had claimed hundreds of thousands of lives by the time it ended in 1714. Spain and France were defeated and forced to sign away substantial parts of their empires. Philip forsook the French throne. Spain fell into decline, while England started its rise to become the most powerful empire on the planet.

Any major historical event like the War of Spanish Succession has many causes. But one of the most important of them involved population genetics—specifically, how the genes of Spanish kings made their way down through the generations of the Hapsburg dynasty. Like many royal dynasties, the Hapsburgs tended to marry within their extended family. It was quite common for first cousins to marry, for example, and uncles even married nieces. Marrying relatives kept power within the dynasty, but it had an unfortunate side effect known as inbreeding.

Rare recessive alleles can be preserved in large populations, even if they’re deleterious, because the more common dominant alleles overshadow them. In an inbreeding population, however, rare deleterious alleles can become unmasked in homozygotes. That’s because parents in these populations tend to be closely related and are thus much more likely to share rare alleles than are two people picked at random from a large population. The more closely the parents are related to each other, the greater the odds that their children will be homozygous for recessive alleles, including alleles that are deleterious. And often, as was the case for Charles II, they will suffer fitness consequences from their resulting phenotypes.

On its own, inbreeding does not change the frequency of alleles in a population. It simply rearranges alleles such that homozygotes for rare recessive alleles become more common. This means that inbreeding on its own is not a mechanism of evolution. But it can create the conditions for evolution to take place. When deleterious rare alleles are combined in homozygotes, they can cause genetic disorders that lower fitness. Selection can then reduce the frequency of these rare alleles, reducing the genetic variation in the population.

In 2009, Gonzalo Alvarez, a geneticist at the University of Santiago in Spain, and his colleagues measured the impact of inbreeding on the Hapsburgs—and Charles II in particular— by building a detailed genealogy of the dynasty (Alvarez et al. 2009). They charted the kinship of three thousand of Charles II’s ancestors and other relatives. To calculate the probability that Charles II was homozygous at any of his loci, Alvarez and colleagues worked their way through his ancestry. His father, King Philip IV, was the uncle of his mother, Mariana of Austria. And Philip and Mariana themselves were also the product of a long history of inbreeding, going back to the early 1500s. As a result, Charles II was far more inbred than you’d expect if his parents were an uncle and his niece. In fact, Charles II was more inbred than the children of a brother and sister.

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