Hypothesis: Possible respiratory advantages for heterozygote carriers of cystic fibrosis linked mutations during dusty climate of last glaciation Vladimir Borzan a , Boris Tomašević b , Sven Kurbel c,n a Osijek University Hospital, Dept. of Internal Medicine, Osijek, Croatia b Zagreb University Hospital, Dept. of Anesthesiology, Zagreb, Croatia c Osijek Medical Faculty, Dept. of Physiology, Osijek, Croatia HIGHLIGHTS  Airway fluid is lost through evaporation, particularly when breathing cold and arid air.  Fluid reabsorption depends on active CFTRs that allow ENaCs to absorb salt and water.  The cystic fibrosis (CF) mutation is common in north Europe and probably near 52 ky old.  Between 50 and 10 kya, the European climate was arid, cold, with a dust-laden atmosphere.  Individuals with one CF mutation due to slower fluid reabsorption might have better clearance of inhailed dust. article info Article history: Received 2 January 2014 Received in revised form 4 August 2014 Accepted 9 August 2014 Available online 21 August 2014 Keywords: ENaC function CFTR function Mucus transport Membrane potential Airways abstract This paper puts forward a new hypothesis to interpret the high carrier frequency of CFTR mutations in individuals of European descent. The proposed heterozygote advantage factor is related to the specific climate conditions in Europe during the last 50 ky that might have heavily compromised the respiratory function of our ancestors in Eurasia. A large part of the last 50 ky was cold, and the coldest period was the Last Glacial Maximum (LGM) (26.5 to 19 kya). The global climate was dry with a dust-laden atmosphere (20 to 25 times more dust than the present level). High levels of atmospheric dust started more than 40 kya and ended less than 10 kya. Secretion of airway fluid is usually related to the submucosal tissue hydration, while salt reabsorp- tion relies on activation of CFTRs that allow ENaCs to absorb salt and water. The water loss by evaporation depends on the air humidity and flow rate. Salt accumulation in the mucus is normally prevented by reabsorption of Na þ and Cl  by epithelial cells if the presence of functional CFTRs is normal. If one gene for CFTR is mutated, the number of functional CFTRs is reduced and this limits the capacity of salt reabsorption by epithelial cells. This means that evaporation makes the airway fluid more hypertonic, and osmotic forces bring more water from the interstitial space, thus leading to a new balance in mucosal fluid traffic. Increased osmolarity and volume of airway fluid can be more moveable in cases when evaporation and dust exposure is increased. If both CFTR genes are mutated, low number of functional CFTRs diminishes salt resorption of epithelial cells. Salt accumulated in the mucous fluid within respiratory ducts, as previously described. The hypertonic ductal content forces more water and some electrolytes to enter the airway fluid from the interstitial fluid, and evaporation leads to further concentration of thick immobile mucus. The proposed interpretation is that CFTR mutations have spread among our ancestors that roamed the central Eurasia after the LGM. The heterozygote individuals might have benefitted from the limited water resorption in their respiratory mucosa that allowed improved airway cleansing. & 2014 Elsevier Ltd. All rights reserved. 1. Introduction A puzzling question is what makes the prevalence of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) mutations Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/yjtbi Journal of Theoretical Biology http://dx.doi.org/10.1016/j.jtbi.2014.08.015 0022-5193/& 2014 Elsevier Ltd. All rights reserved. n Corresponding author to: Osijek Medical Faculty, J Huttlera 4, 31000 Osijek, Croatia. Tel.: þ385 31 512800; fax: þ385 31 512833. E-mail address: sven@jware.hr (S. Kurbel). Journal of Theoretical Biology 363 (2014) 164–168