A child fishes in the Ganges river. People living in this region have developed a natural genetic resistance to cholera over the last 5,000 to 30,000 years. Credit Sanjay Kanojia/Agence France-Presse — Getty Images

People living in the Ganges Delta, where cholera is an ancient, endemic and often lethal disease, have adapted genetically to the scourge through variations in about 300 genes, say researchers who have scanned their genomes for the fingerprints of evolution.

The researchers also found unexpected changes in genes that protect against arsenic, suggesting that arsenic exposure in Bangladesh is not just a modern problem associated with deep tube wells but may have ancient roots.

These instances of natural selection probably took place within the last 5,000 to 30,000 years, the researchers say, and show how evolution has continued to mold human populations through the relatively recent past.

Pinpointing the genes responsible for natural resistance to cholera will help the development of better vaccines, said Dr. Regina C. LaRocque, an infectious disease expert at the Massachusetts General Hospital and an author of the study, published Wednesday in the journal Science Translational Medicine. Vaccines now in use do not stay effective for long and must constantly be readministered in regions where the disease is endemic.

The genes that showed fingerprints of natural selection were identified by two other authors of the study, Elinor K. Karlsson and Dr. Pardis C. Sabeti, computational biologists at Harvard, in the genomes of Bengalis, the majority population in Bangladesh.

The selected genes offer a road map to how the body defends itself against cholera. Toxin from the bacterium binds to cells in the victim’s intestine, prizing open the channels through which chloride ions leave the cell and forcing the cells to excrete volumes of water and electrolytes — up to two liters an hour. The diarrhea benefits the organism, which can reach drinking water and spread further, but can be lethal for the host if unchecked.

One set of selected genes in the Bengalis affects control of the innate immune system, the body’s first line of defense against microbes. Another set of genes affects the channels that control the flow of potassium ions in and out of cells. It is not yet known exactly how the variations in any of the selected genes affect the biology of resisting cholera. But variations in the potassium channel genes, for instance, could help reverse the outward flow of water caused by the cholera toxin’s attack on the chloride channels.

These findings fit the expected biology of cholera but upset other predictions. Cystic fibrosis is caused by a mutation in a gene that controls the movement of chloride in and out of cells. Since the cholera toxin requires this gene to be in working order, the mutation might be protective against it. But the researchers found no evidence of selection on the cystic fibrosis gene in the Bengali population.

People with blood group O are particularly susceptible to cholera, and indeed few Bengalis have blood group O. In scanning blood group genes, the researchers were not able to pick up any negative selection against the O group genes. But they unexpectedly found evidence of natural selection having favored a minor blood type known as the Kell blood group. The genes of this group have no known connection with cholera but seem to offer a defense against arsenic. The poison contaminates the groundwater of Bangladesh, having been released by the tube wells dug to secure clean water to protect against cholera. The presence of protective genes in the Bengali population, if verified, would suggest arsenic is not just a modern problem but has been unleashed by monsoons or other natural phenomena for thousands of years.

As a necessary preliminary to testing for natural selection, the researchers looked at the racial composition of the Bengali population and found that they are an Indian population with a 9 percent admixture of East Asian genes, probably Chinese. The admixture occurred almost exactly 52 generations ago, according to statistical calculation, or around A.D. 500, assuming 29 years per generation. The Gupta empire in India was in decline at this time, but it is unclear whether the intermarriage with East Asians took place through trade or conquest. “We can now go back to the historians and see what happened then,” Dr. Karlsson said.

John Mekalanos, a cholera expert at the Harvard Medical School, said the new finding was one of several that “are starting to give a strong impression that the human genome has been dramatically shaped by responses to microorganisms.” The discovery that Bengalis enjoy special resistance to cholera may help explain why much stronger doses of vaccine are needed to immunize them than are required for North American populations, Dr. Mekalanos said. The difference is usually attributed to differences in gut bacteria, but genetics now offers an alternative explanation.

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