The PRNP gene: One reason not all of us make good cannibals

original-fore-tribe-papua-kuruThe story starts in the eastern highlands of New Guinea, back in the 1940s-1950s. A fatal disease called kuru blazed through many villages, and women and children were especially affected. It started with a few months of head and body aches. This was followed by trouble standing and walking. Eventually tremors began, and sufferers lost the ability to get around entirely. Finally, euphoria set in (kuru is sometimes called the “laughing death”). By the late 1950s, more than 200 new cases a year were being reported, and, all told, over 3,000 deaths resulted (in a population that numbered only about 12,000). In some places, few young women were left.

Figuring out what was responsible for kuru was not an easy task. According to the Fore, the group hardest hit by the disease, it had first appeared in the 1920s and spread rapidly.  Researchers noticed that often multiple people in a family were affected, so they started building kuru pedigrees. Complicated genetic causes were proposed. But eventually the strange distribution of the disease (it primarily affected women and young children) shed light on the true culprit: cannibalism. When someone died (say, of kuru) the women and children in the family would prepare their body for the funeral. Part of this preparation involved eating their loved one’s body, in a feast that signified respect for the deceased. The brain, which was the most infectious body part, was eaten by women and children. And the infectious entity wasn’t a bacterium or virus. Instead, it was something entirely different: a prion, or a protein folded in a strange way. Once prions enter the body, they cause other proteins to misfold, until there are enough faulty proteins to cause real problems. The gene that encodes the prion protein is called PRNP, and changes in this gene have since been linked to other prion diseases like variant Creutzfeldt-Jakob disease (aka mad cow disease), fatal familial insomnia, and Gerstmann-Sträussler-Scheinker disease. Kuru and similar diseases are called transmissible sponge encephalopathies, because of the sponge-like effect they have on the brain (shown in the picture below).

BrainSectionsWhile nobody knows for sure how the epidemic started, the current theory is that someone among the Fore happened to develop variant Creutzfeldt-Jakob disease early in the 20th century. When his or her loved ones performed the mortuary feast, they ingested the prion and developed kuru. When they died, the chain continued, and the disease spread across the Eastern highlands. In the 1950s, the Australian government instituted strict, new laws that outlawed cannibalism. After this, the disease started to lose steam. A trickle of new cases continued to appear, however, well into the 2000s. Although the average time from participation in a fateful mortuary feast to the onset of kuru is 12 years, it turns out that the incubation time for kuru can be anywhere from 4 years to over 50! What accounts for that variation? And why did some people who participated in mortuary feasts get kuru, while others did not?

It turns out that the story is not so simple! Those early attempts to link kuru to genes were not so far off after all. At the 129th amino acid residue in the PRNP protein, people either have a methionine (M) or a valine (V). Since we all have two versions of the PRNP protein (one from mom, and one from dad), a person can either be an MM, an MV, or a VV. It turns out that being an MM makes you especially susceptible to kuru. MVs and VVs are both less likely to develop kuru AND if they do develop it, the incubation time is longer. But being an MV is the absolute best. After the kuru epidemic ended, there was a deficiency of MM individuals among the Fore, because so many of them had died of kuru. And it turns out that the finding that MM individuals are susceptible to kuru is relevant beyond New Guinea. Patients who develop variant Creutzfeldt-Jakob disease have also invariably turned out to be MMs!

In 2003, an attention-grabbing paper on the PRNP gene came out in Science. Scientists had already established that, among the Fore, MVs were the most likely to survive the kuru epidemic. When the best genotype to have is one that combines two different types of alleles, it is called balancing selection. Natural selection will often end up keeping both types of alleles in a population; the success of individuals with both versions will result in a “balance” being struck between the two. In the Science paper, a group of researchers said they had also found evidence of balancing selection in the PRNP gene worldwide. What could this mean? The authors speculated that maybe a long history of exposure to prion diseases spread from animals (like mad cow disease) could account for selection that favored MVs. Or MAYBE it was a long history of human cannibalism! This study has been a controversial one. Not everyone agrees with the way the analysis was performed, for example. But it’s pretty interesting.

In short, MMs don’t make good cannibals–or maybe even meat eaters, since they are also more susceptible to mad cow disease. As it happens, you can figure out your genotype using 23andme! If you’ve been genotyped, you can go to the browse raw data page and enter rs1799990It will tell you your DNA sequence at the relevant part of the gene: An “A” corresponds to the M version of the protein, and a “G” corresponds to the V version. I found out I have two As, which means I’m an MM. I’m not cut out to be a cannibal, and maybe I should consider becoming a vegetarian too! That’s the breaks, I guess.