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Genetic Linkage

When Mutation Counters Infection: From Sickle Cell to Ebola

Balanced polymorphism retains mutant genes in populations when they protect against other conditions.
While pharmaceutical companies focus on drug discovery for Ebola virus disease, a powerful clue is coming from a rare “Jewish genetic disease” that destroys the brain. People with Niemann-Pick C1 disease can’t get Ebola, adding to the list of disease pairs that arise from a fascinating form of natural selection.

Balanced polymorphism, aka heterozygote advantage, is a terrific illustration of ongoing evolution. And it pits the human body against all sorts of invaders – prions, viruses, bacteria, protozoa, and fungi.

The textbook example of balanced polymorphism is the protection that being a carrier for sickle cell disease confers against malaria, published in 1954.

The blood of a person with full-blown sickle cell disease is too thick to accommodate the malaria parasite, and the red blood cells too bent to house them. A carrier has enough sickled cells to quell the parasite, but not enough to block circulation and cause the pain and anemia of the inherited disease. Alpha thalassemia, hemoglobin C and G6PD deficiency are other single-gene diseases that affect red blood cells in ways that lower risk of malaria.

The link between genetic disease and Ebola virus disease dates from 2011, when Thijn Brummelkamp, PhD and co-workers, at the Whitehead Institute for Biomedical Research, reported in Nature that cells of people with the rare single-gene Niemann-Pick C1 disease keep out Ebola. The gene that is mutant in Niemann-Pick C1 encodes a transporter protein that normally binds cholesterol -- and it’s also the receptor for Ebola virus. Carriers of the inherited disease, with half the normal number of transporters, might have some protection against the viral disease. (A recent article in the Wall Street Journal discussed the carrier situation, but oddly didn't mention the sickle cell standard case – commenters did.)

The tango between us and our pathogens is more complex than illnesses that cancel each other out. The poor clotting of hemophilia shields against dangerous blood clotting; the extremely low serum cholesterol level of Smith-Lemli-Opitz syndrome, which causes intellectual disability and a host of strange birth defects, counters cardiovascular disease due to high cholesterol. These don’t involve a second party.

Examples of balanced polymorphism are like mystery stories, beginning with the clue of why a seemingly harmful recessive genetic disease hangs around. New mutation is one answer, but more common is the protection that the heterozygous state offers. Here are some of the stories.

In cholera a bacterial toxin opens chloride channels in small intestine cells, and salt and water pour out in a torrent of diarrhea. The misfolded CFTR protein behind many cases of cystic fibrosis, which is a chloride channel, does the opposite, failing to reach the cell surface and trapping salt and water inside cells, drying secretions on the outside. A person with full-blown CF won’t get cholera, while a CF carrier, with enough working chloride channels to breathe okay, but not enough to welcome toxin-spewing pathogens, suffers neither disease.

The cholera epidemics that have swept through human history favored individuals who carry or have CF. But geography and history suggest that the story goes farther back, because CF arose in western Europe and cholera in Africa. Perhaps a different diarrheal infection, typhoid fever, triggered the initial favoring of mutant CF alleles that perhaps arose from mutation.

The bacterium responsible for typhoid fever, Salmonella typhi, enters small intestine cells — through CFTR channels. In people with severe CF the channels are too mangled to reach the cell surface, and bacteria can’t enter. Cells of CF carriers only let in a few bacteria. Protection against infections that produce the runs may therefore have kept CF around.

Testing for phenylketonuria – PKU – ushered in the era of newborn screening with the Guthrie test, invented in 1957 and one of my favorite genetics stories. It tests blood from a newborn’s heel so that dietary intervention can prevent the profound intellectual disability that would transpire.

PKU is a classic “inborn error of metabolism.” A missing enzyme causes the amino acid phenylalanine to build up, devastating the nervous system. Carriers have excess phenylalanine -- not enough to damage their brains, but enough to counter the effects of a fungal poison called ochratoxin A that causes spontaneous abortion.

In 1986, PKU guru L. I. Woolf published a brief letter in the American Journal of Human Genetics explaining how a fungus could maintain a rare inherited disease of humans.

Ochratoxin A is a derivative of phenylalanine that binds to the enzyme that places phenylalanine into proteins as they form. With one of the 20 amino acid types blocked from joining proteins, the embryo stops developing – unless the pregnant woman’s body makes excess phenylalanine, which counters the effects of the toxin. That happens in PKU carriers. Thanks to newborn screening PKU is caught early enough today to be treated. However, ochratoxin is still around. It causes a kidney disease in Eastern Europe called Balkan endemic nephropathy.

It isn’t coincidence that PKU is most prevalent in Ireland and Scotland. In the dampness of those lands, the Aspergillis and Penicillium fungi that produce the toxin grow on grains, which people were forced to eat during times of famine. Because pregnant PKU carriers were more likely to have healthy children than non-carriers, who suffered miscarriage due to the fungal toxin, the PKU mutation increased in the population. That’s natural selection. Evolution.

Prions are proteins that can fold into infectious forms that cause transmissible spongiform encephalopathies. The most familiar are those that come from eating the proteins, such as mad cow disease. The classic example is kuru, which caused brain degeneration among the Foré people in Papua New Guinea in women and children eating the brains of honored dead relatives. The Australian government halted the practice in the mid-1950s.

We also make our own prion protein – the gene that encodes it is on chromosome 20. Normal prion protein is abundant in the brain, and likely plays a role in synaptic plasticity in early development. The prion story is more complicated than those of Ebola, CF, and PKU, because the same protein comes from inside and outside the body, and it is the protein, in abnormal form, that is the pathogen. Prion protein is a shape-shifter, able to assume the infectious form right inside ourselves.

Back to New Guinea. Some of the female Foré brain eaters are still alive, and an investigation of the prion protein gene among 30 of them revealed that 23 are heterozygotes for the prion protein gene on chromosome 20. They have two slightly different versions of the gene. Population genetics statistics predicted only 15 of them should have been so.

The carriers have the amino acid valine at amino acid position 129 on one chromosome 20 and a methionine on the other. And this somehow prevents the infectious misfolding. Plus, everyone in the UK who developed mad cow disease (variant Creutzfeldt-Jakob disease) had only methionine at position 129.

Cannibalism may have fueled the overrepresentation of carriers of the infectious form of prion protein. Protected, the carriers slowly accumulated in the population.

For many years, the central dogma reigned: DNA encodes RNA which encodes protein. Our genomes were thought to little else, although people hypothesized vague “controls” amongst our regular genes.

Then introns (non-protein-encoding parts of genes) came along in 1977 and turned our simplistic view on its head. Most of us in genetics never thought the “rest” of the genome was “junk.” If I remember correctly, that was an unfortunate utterance from Francis Crick that the media ran with, and it stuck.

Today we know that the human genome comes complete with all manner of controls. Some are indeed embedded in the non-protein encoding sequences that make up most of the genome. Other controls are in short RNAs that fold themselves up in ways that turn off certain genes, and in the numbers of short repeated sequences that pepper genomes. The human genome is a little like a fancy TV with a zillion remotes that somehow knows how to control itself without the user knowing how it all works.

Balanced polymorphism is yet another form of genetic information. It reveals a story, a subtext to our genes written by our own actions throughout history, and the scourges that felled some of our ancestors, enabling individuals carrying particular mutations to survive to reproduce, perpetuating those mutations.

Making sense of the intriguing pairings of genetic and infectious diseases can reveal ways to fight those infections. Let’s hope this approach works for Ebola virus disease.
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