Laid low. A cholera ward in Dhaka, Bangladesh, a country where nearly half the people are infected with the cholera bacterium by
age 15.

Mark Knobil/Creative Commons

Cholera Is Altering the Human Genome

Cholera kills thousands of people a year, but a new study suggests that the human body is fighting back. Researchers have found evidence that the genomes of people in Bangladesh—where the disease is prevalent—have developed ways to combat the disease, a dramatic case of human evolution happening in modern times.

Cholera has hitchhiked around the globe, even entering Haiti with U.N. peacekeepers in 2010, but the disease's heartland is the Ganges River Delta of India and Bangladesh. It has been killing people there for more than a thousand years. By the time they are 15 years old, half of the children in Bangladesh have been infected with the cholera-causing bacterium, which spreads in contaminated water and food. The microbe can cause torrential diarrhea, and, without treatment, "it can kill you in a matter of hours," says Elinor Karlsson, a computational geneticist at Harvard and co-author of the new study.

The fact that cholera has been around so long, and that it kills children—thus altering the gene pool of a population—led the researchers to suspect that it was exerting evolutionary pressure on the people in the region, as malaria has been shown to do in Africa. Another hint that the microbe drives human evolution, notes Regina LaRocque, a study co-author and infectious disease specialist at Massachusetts General Hospital, Boston, is that many people suffer mild symptoms or don't get sick at all, suggesting that they have adaptations to counter the bacterium.

To tease out the disease's evolutionary impact, Karlsson, LaRocque, and their colleagues, including scientists from the International Centre for Diarrhoeal Disease Research in Bangladesh, used a new statistical technique that pinpoints sections of the genome that are under the influence of natural selection. The researchers analyzed DNA from 36 Bangladeshi families and compared it to the genomes of people from northwestern Europe, West Africa, and eastern Asia. Natural selection has left its mark on 305 regions in the genome of the subjects from Bangladesh, the team reveals online today in Science Translational Medicine.

The researchers bolstered the case that cholera was the driving force behind the genomic changes by contrasting DNA from Bangladeshi cholera patients with DNA from other residents of the country who remained healthy despite living in the same house as someone who fell ill with the disease. Individuals who were susceptible to cholera typically carried DNA variants that lie within the region that shows the strongest effect from natural selection.

One category of genes that is evolving in response to cholera, the researchers found, encodes potassium channels that release chloride ions into the intestines. Their involvement makes sense because the toxin spilled by the cholera bacterium spurs such channels to discharge large amounts of chloride, leading to the severe diarrhea that's characteristic of the disease.

A second category of selected genes helps manage the protein NF- kB, the master controller of inflammation, which is one of the body's responses to the cholera bacterium. A third category involves genes that adjust the activity of the inflammasome, a protein aggregation inside our cells that detects pathogens and fires up inflammation. However, the researchers don't know what changes natural selection promotes in these genes to strengthen defenses against the cholera bacterium.

Researchers have identified other examples of infectious diseases driving human evolution, such as malaria in Africa favoring the sickle cell allele, a gene variant that provides resistance to the illness. But they are just starting to search the entire genome for signs of disease effects, and this study is the first to use such methods for cholera.

"I think it's a great example of the impact infectious diseases have had on human evolution," says infectious disease specialist William Petri of the University of Virginia School of Medicine in Charlottesville, who wasn't involved with the study. "It's ambitious, fairly extensive, and very well done," adds medical microbiologist Jan Holmgren of the University of Gothenburg in Sweden. One strength of the work is that it flags genes, such as those involved with the inflammasome, that researchers have implicated in other intestinal illnesses such as inflammatory bowel disease, says genetic epidemiologist Priya Duggal of the Johns Hopkins Center for Global Health in Baltimore, Maryland. "Overall, they make a very nice case."

The findings probably won't lead to new cholera treatments, says LaRocque, because current measures—which rapidly replace the water and electrolytes patients lose—work very well. "The real issue with cholera," she says, "is how do we prevent it," a difficult problem in areas without clean water supplies. But understanding how humans have evolved in response to cholera might help researchers devise more potent vaccines that would provide better protection against this killer, she says.

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