Science Translational Medicine
3 July 2013 vol 5, issue 192
http://stm.sciencemag.org/content/current

Research Article – Genomics
Natural Selection in a Bangladeshi Population from the Cholera-Endemic Ganges River Delta
Elinor K. Karlsson¹,²,*, Jason B. Harris³,⁴, Shervin Tabrizi¹,², Atiqur Rahman³,⁵,†, Nick Patterson², Colm O’Dushlaine², Stephen F. Schaffner²,⁶, Sameer Gupta⁷, Fahima Chowdhury⁵, Alaullah Sheikh⁵,‡, Ok Sarah Shin³,§, Crystal Ellis³, Christine E. Becker⁸, Lynda M. Stuart²,⁸, Stephen B. Calderwood³,⁹,¹⁰, Edward T. Ryan³,⁶,⁹, Firdausi Qadri⁵,¶, Pardis C. Sabeti¹,²,⁶,*,¶ and Regina C. LaRocque³,⁹,*,¶

Abstract
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.