Typically, mutations that silence genes are bad for your health. But that's not the case with caspase-12. When this gene doesn't work anymore, the immune system goes into high gear. Geneticists now think that this aberration survived because it protected early humans against serious infections that arose from more crowded living conditions.
In its normal form, caspase-12 curtails the production of regulatory proteins called cytokines, which help mount an immune response against bacterial infection. People with a so-called "nonsense" mutation in this gene make a shortened form of the caspase-12 protein. In 2004, researchers discovered that this defect helps to protect against potentially lethal infections because it can no longer control cytokine activity. People with two copies of the mutated gene are eight times more likely to avoid severe sepsis, which leads to kidney, gut, lung, and liver failure. And when sepsis does develop, they are three times more likely to survive than those with the original gene.
Geneticist Chris Tyler-Smith from the Wellcome Trust Sanger Institute in Hinxton, U.K., and his colleagues decided to find out how the mutated gene spread around the world. They surveyed 1000 people representing 52 populations and took a more intensive look at caspase-12 in 77 people from China, Africa, and Utah. The genetic variations of those populations had been extensively cataloged as part of the HapMap project (ScienceNOW, 26 October 2005).
The researchers found that the original caspase-12 gene has disappeared or is very rare almost everywhere. The exception is sub-Saharan Africa, where it's found in 28% of the population and 60% of the Pygmies there, the group reports in the April issue of the American Journal of Human Genetics.
Based on the similarity in the DNA sequences located near the caspase-12 gene, Tyler-Smith and his colleagues estimate that the nonsense mutation occurred about 500,000 years ago in Africa. But it didn't start to become common until within the last 100,000 years. That's about when people began migrating out of Africa and interacting more with each other. Individuals better equipped, genewise, to fight off pathogens had the upper hand, says Tyler-Smith. As a result, the mutation became more prevalent over time.
The findings corroborate a study in this month's PLoS Biology by Jinzhi Zhang, a geneticist at the University of Michigan, Ann Arbor, and his colleagues. That group also concluded that the increased risk of sepsis caused the defective variant to replace the original gene.
"It's a very compelling case for the importance of evolutionary pressures in controlling the magnitude of the immune response," says Kevin Tracey, an immunologist and head of the Feinstein Institute for Medical Research in Manhasset, New York.