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Natural Selection in a Bangladeshi Population from the Cholera-Endemic Ganges River Delta

Natural selection in a Bangladeshi population from the cholera-endemic Ganges River Delta has targeted genes associated with cholera resistance and an innate immunity pathway activated by Vibrio cholerae. Modern Lessons from an Ancient Disease A history of natural selection favoring resistance to an infectious disease should drive the emergence of underlying genetic variants that can be readily detected. In a new study, Karlsson et al. show this for cholera, an ancient, often fatal disease that likely exerted selection pressure on Bangladeshi populations living in the Ganges River Delta where cholera is endemic. The authors combine a selection scan with an association study of cholera susceptibility, and translate the resulting genetic discoveries into clinically relevant biology. They performed whole-genome scans of Bangladeshi families to identify 305 genomic regions of selection. These regions are highly enriched for potassium channel genes and genes in the NF-κB pathway, a master regulator of inflammation and immunity that is also involved in protecting the lining of the gut. They show, by comparing cholera-affected and healthy individuals, that top selected genes correlate with cholera susceptibility. These genes regulate an innate immune signaling pathway that is activated by Vibrio cholerae, the pathogen that causes cholera, and is repeatedly targeted by selection. This combined selection and association approach identifies genes not previously implicated in the cholera host response and highlights the role of innate immunity and intestinal homeostasis in disease pathogenesis. This approach of leveraging ancient history in genetic studies is applicable to many other ancient infectious diseases still circulating in the population today. As an ancient disease with high fatality, cholera has likely exerted strong selective pressure on affected human populations. We performed a genome-wide study of natural selection in a population from the Ganges River Delta, the historic geographic epicenter of cholera. We identified 305 candidate selected regions using the composite of multiple signals (CMS) method. The regions were enriched for potassium channel genes involved in cyclic adenosine monophosphate–mediated chloride secretion and for components of the innate immune system involved in nuclear factor κB (NF-κB) signaling. We demonstrate that a number of these strongly selected genes are associated with cholera susceptibility in two separate cohorts. We further identify repeated examples of selection and association in an NF-κB/inflammasome–dependent pathway that is activated in vitro by Vibrio cholerae. Our findings shed light on the genetic basis of cholera resistance in a population from the Ganges River Delta and present a promising approach for identifying genetic factors influencing susceptibility to infectious diseases.