Tuberculosis has killed more people in the past 2,000 years than any other disease and has become much sicker, including those patients who rested in front of the UK’s Houses of Parliament in 1936.
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By Ann Gibbons
Think of the worst plagues of mankind, and the Black Death, the Spanish flu and COVID-19 come to mind. Millions died in these deadly pandemics, but their number is small compared to that of tuberculosis (TB), which has killed more than 1 billion people in the past 2,000 years – and still kills 1.5 million people worldwide every year . But how and when tuberculosis became so deadly has long been a mystery.
Now, by tracking the evolution of a variant of the gene that makes people more susceptible to the disease, researchers have been able to track the rise and fall of tuberculosis over the past 10,000 years – and show how it has reshaped the immune systems of people living in Iron Age in Europe. “We are [all] the descendants of people who survived previous epidemics, ”says author Lluis Quintana-Murci, a population geneticist at the Pasteur Institute and the College of France. This article helps to identify “what are the real pathogens that changed our DNA and made us more resilient”.
The first evidence of tuberculosis comes from skeletons buried in the Middle East 9,000 years ago, shortly after the invention of agriculture. But the variant that kills humans today –Mycobacterium tuberculosis– appeared 2,000 years ago, when people lived in denser villages next to domesticated animals, usually reservoirs for tuberculosis
Two years ago, graduate student at the University of Paris Gaspard Kerner discovered that people were at a much greater risk of becoming seriously ill when infected with tuberculosis if they inherited two copies of a rare variant of the immune gene TKY2, called P1104A. He realized that by tracking the frequency of this variant in 1,013 European genomes over the past 10,000 years, he had a “golden” tool for detecting how the immune gene coevolved with tuberculosis, says Quintana-Murci, who hired Gaspard as a postdoctoral fellow at the Institute Pasteur.
The researchers found that the P1104A mutation was ancient – they identified it in the DNA of a farmer who lived 8,500 years ago in Anatolia (what is now Turkey) and calculated that the mutation appeared at least 30,000 years ago. Anatolian farmers and Yamnaya herders spread this variant of the gene as they moved to Central Europe. By studying changes in the frequency of the variant over time, the researchers estimated that about 3% of the population carried the gene until about 5000 years ago. In the middle of the Bronze Age, about 3,000 years ago, 10% of Europeans had the characteristic. But since then, its frequency has plummeted to 2.9% – the same rate among Europeans today.
The sharp drop coincides with the emergence of the modern variant of tuberculosis, according to ancient DNA studies. Quintana-Murci and his team did computer simulations of how population size and migration influenced the frequency of the gene. They propose that tuberculosis killed or seriously ill a fifth of those with two copies of the variant, few of whom had children who survived after the end of the Bronze Age, 2,000 years ago. As a result, natural selection acted strongly and quickly to eliminate the deadly gene variant to low levels, the researchers report today in The American Journal of Human Genetics.
“Infectious diseases are the strongest evolutionary pressure that humans have to face,” says Quintana-Murci. Molecular anthropologist Anne Stone of Arizona State University in Tempe agrees. Having both copies of the gene variant, she says, “would not be good if tuberculosis was in town.”
Stone and other outside researchers say the timing for selection in humans and the emergence of modern tuberculosis fits in perfectly. “It’s cool and exciting to see two very different data lines producing similar results,” says paleogeneticist Kirsten Bos, from the Max Planck Institute for Evolutionary Anthropology.
Given new databases like the UK Biobank and other old DNA samples around the world, this could be “just the beginning” of studies that track the frequency of variants to understand how our immune system co-evolved with specific pathogens, says Sebastien Gagneux , microbiologist at Swiss Tropical and Instituto de Saúde Pública, who did not participate in the study.
But there is an urgent need to know how widespread the P1104A variant is, says Kerner. It is rare in populations tested in India, Indonesia, China and parts of Africa where tuberculosis is endemic. But about one in 600 Britons in the UK’s Biobank database carries two copies of the variant. They are at a high risk of serious illness or death if they are exposed to tuberculosis, says Kerner.