Why We Can’t Get Rid of Disease-Causing Genes

A mouse leukemia virus (yellow) buds from an immune system cell. / Credit: Elizabeth Fischer and Kim Hasenkrug, NIH

We carry among us the seeds of our own destruction. Immune-system genes that were supposed to save us from disease instead invite it in. Why we hang on to such flawed genes has been a biological mystery. The possible answer, published this week, may hold a key to protecting us from drug-resistant bacteria.

The genes trigger our immune system to fight against invading germs like malaria and hepatitis viruses. But some versions of the genes are too weak to ward off the attackers.

You’d think that evolution would weed out the bad seeds. People who carry them get sick and die, while those with good genes thrive and have more children—shouldn’t their genes crowd out the bad ones? But no. Instead, there is an astounding diversity of those genes, which belong to a group called the Major Histocompatibility Complex, or (luckily) MHC for short.

“There are hundreds of varieties of MHC genes in most vertebrate species,” says Wayne K. Potts, a professor of biology at the University of Utah. “One gene has 2,300, which holds the record.” And since the weaker varieties persist, so does vulnerability to disease.

Those poor defenders hang around, says Mr. Potts, because of a continuing arms race with germs. In a clever experiment described this week in the Proceedings of the National Academy of Sciences, he and several of his colleagues infected three groups of mice with the same kind of mouse-leukemia virus. Each mouse group, though, had a different MHC variant, called a genotype. Some initially performed well against the virus, and some did not. But some of the viruses adapted to evade the defenders, sickened their host mice, and multiplied in number.

Then the researchers mixed things up. They infected mice from one group with viral particles taken from another group. “And we found there was a trade-off,” Mr. Potts says. “If a virus adapts to one MHC genotype, it does less well against another organism’s MHC genotype.” So the viral change that led to disease in one mouse left that virus vulnerable to the different MHC in the second mouse—and Mouse No. 2 would live to have babies that carried that same genotype. Do this lots of times with lots of mice and lots of viruses, and you get a huge number of MHCs in the population.

From the mouse-population perspective, this great diversity in MHCs keeps any single disease from wiping all the creatures out. From the virus-population perspective, diversity means a virus will always find a weak point, some animal in which it can survive and adapt and thrive. It’s an arms race that always leaves some attackers and defenders around to fight another day.

More milk, and more disease vulnerability too. / Credit: Kabsik Park under a Creative Commons license.

George Gilchrist, acting deputy director of the division of environmental biology at the National Science Foundation—the NSF financed the research—points out that not only does this explain the forces driving diversity, it has implications for how we practice agriculture in ways that can affect human health. The use of a lot of antibiotics in meat and dairy cows, for instance, is a result of breeding to reduce genetic diversity. Changing this to add new MHC varieties could cut down on the reliance on drugs.

When livestock are bred to make more cows that give more milk, for instance, that shrinks genetic diversity. But as the “less milk” genes are bred out, so are the MHCs that were in those animals. So the remaining monolithic milk-heavy herd is prone to diseases. Farmers use antibiotics as crutches to replace the missing MHCs. But “that is a major source of antibiotic resistance in bacteria,” says Mr. Potts. And those bacteria infect people too.

“We could back off the antibiotics if we bred back in some MHC diversity,” he says. Range cattle still have it, and could be bred into dairy herds. Of course, range-cattle MHCs may be accompanied by genes that don’t produce as much milk. Farmers may be reluctant to cut their sales, and consumers may be unwilling to pay higher milk prices. That’s another kind of arms race: economics and health.

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