An evolutionary approach to the high frequency of the Delta F508 CFTR mutation in European populations
Introduction
Cystic fibrosis (CF) is the most common autosomal recessive disorder in European Caucasian populations associated with substantial morbidity and high case-fatality. CF is a disease characterized by the production of abnormally thick secretions of mucus and elevated sweat electrolytes by the exocrine glands of the epithelia, often resulting in progressive respiratory and gastrointestinal problems [1]. CF is known to be caused by over 800 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, situated at the long arm of chromosome 7 in the 7q22–7q31 interval [2], [3], and its prevalence at birth in Europeans ranges from 1/2000 to 1/4000 [4]. The most common mutation in CF patients is a three base pairs (3 bp) deletion at codon 508, called Delta F508 [5].
A number of studies have reported lower frequencies of the Delta F508 mutation and a greater mutation heterogeneity in southern European populations compared with northern Europeans. Likewise, restriction fragment length polymorphism (RFLP) haplotype analyses using XV2c and KM19 probes closely linked to the CFTR gene have shown a lower degree of association between CF and the Delta F508 mutation in southern European countries, suggesting that this mutation could have penetrated more recently into northern Europe than into southern Europe [6]. Based on these findings, some research groups have conjectured that the Delta F508 mutation could have spread in Europe by the migratory waves of the early farmers from the Middle East, according to the Neolithic demic diffusion model [7]. However, current thinking is that the introduction of agriculture did not lead to a major change in the European gene pool, as it did not entail any significant gene flow between human populations: it was rather a process of learning and acquisition of a more advanced culture transmitted between adjacent populations (acculturation model) [8], [9]. Furthermore, age estimates of the Delta F508 mutation based on the reconstruction of the original microsatellite haplotype in which the mutation arose, as well as based on the genealogy of the microsatellite haplotypes with the 3 bp deletion at codon 508 both strongly support the notion that the Delta F508 mutation was not disseminated across Europe by the Indo-European invasions, but was already present since the Paleolithic era [10], [11].
Applying the Darwinian principles of natural selection to address questions concerning the ultimate causation of human diseases constitutes the main goal of evolutionary medicine [12], [13]. Frequently, the hypothesized scenarios to account for the origin of a human disease involve genetic adaptations to an ancient environment, which have become maladaptive in modern environments [12], [14]. The past benefits of these alleles in terms of survival and reproduction would explain their high frequency in contemporary populations despite their associated disease states. Thus, the presence of geographic structuring in the frequency distribution of disease-associated alleles has been considered as a genetic footprint of prior selective pressures [15].
The relatively high frequency of CFTR in European and European-derived populations is unusual for a lethal gene. In explaining this phenomenon, several authors have postulated a variety of mechanisms, based on the distribution of the Delta F508 mutation in specific human populations, the different spectrum of mutations causing the disease in different regions of Europe and the estimated age for the Delta F508 mutation. These include random genetic drift, high mutation rate, multiple loci and selective advantages due to heterozygote resistance to cholera and to other intestinal infectious diseases [4], [16].
With the spread of the Neolithic in Europe, animal domestication promoted the emergence and transmission of new pathogenic agents to humans, most likely resulting in striking changes of the population mortality patterns. This Neolithic epidemiological transition was mainly characterized by elevated mortality rates due to infectious diseases [17].
Section snippets
Hypothesis
The diffusion of the cattle pastoralism across Europe during the Neolithic period was probably accompanied by the emergence and spread of diverse contagious diseases that were unknown in the Paleolithic and that could have affected the frequency of genes directly or indirectly associated with differential susceptibility to infectious pathogens. We therefore propose that the high frequency of the CFTR gene and in particular the common Delta F508 allele mutation in European populations might be
Evaluation of the hypothesis
One of the most important events in human development in the last 10,000 years was undoubtedly the acquisition of the ability to domesticate animals and plants. This landmark event marked the beginning of the Neolithic revolution, which led to enormous cultural and socioeconomic changes as human populations gained access to a surer, more abundant source of food than could be found by hunting and gathering. As a result, population density increased greatly and large population nuclei became
Conflicts of interest statement
None declared.
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Was the Last Ice Age dusty climate instrumental in spreading of the three “Celtic” diseases (hemochromatosis, cystic fibrosis and palmar fibromatosis)?
2019, Medical HypothesesCitation Excerpt :Among the already proposed advantages of being a CFTR mutation heterozygote carrier, several of them are based on the local climate in Eurasia at that time: Improved resistance to cholera toxin and other diarrheal disorders, including lactose intolerance [18], typhoid fever [19], possibly related to the cattle pastoralism and migratory routes [20]. Limited water resorption in respiratory mucosa of heterozygotes might allow improved airway cleansing [21] during dusty atmosphere of the Last Ice Age.
Comparison of geographic distributions of Irritable Bowel Syndrome with Inflammatory Bowel Disease fail to support common evolutionary roots: Irritable Bowel Syndrome and Inflammatory Bowel Diseases are not related by evolution
2018, Medical HypothesesCitation Excerpt :Subsequently rates of 8 “western” diseases (5 cancers CD, UC and multiple sclerosis) based on limited available national data were also found to be inversely related to LNP [50,51]. The hypothesized explanation of these observations is that evolutionary pressures which led to the LP/LNP divide may have also led to the evolution of different genes to accommodate consumption of milk [12–17]. Some credence to this notion is offered by the observations that genes found to be linked with IBD are also detected in some 2 dozen autoimmune and non-autoimmune diseases considered to be predominantly linked with “western” geography [52].
Geographic associations between lactase phenotype, multiple sclerosis, and inflammatory bowel diseases; Does obesity trump geography?
2016, Medical HypothesesCitation Excerpt :A likely connection then could be novel genetic traits hypothesized to accompany the emergence of the dominant LP status and evolved to counteract possible infections associated with drinking unpasteurized milk. These genes included the NOD2/CARD15 system [27], the CFTR sodium transporter [28,29] as well as the HLA system [29,30]. So shared genetic alterations may lead to variation in development of different diseases.
Mitochondrial DNA genetic diversity and LCT-13910 and deltaF508 CFTR alleles typing in the medieval sample from Poland
2015, HOMOCitation Excerpt :The indicated periods cover the time of cattle domestication in Europe, which has been confirmed by archeological findings (Bollongino et al., 2006). Some authors also suggest that the most common mutation leading to cystic fibrosis (Kerem et al., 1990), i.e., deletion of 3 bp (deltaF508) within the CFTR gene (cystic fibrosis transmembrane conductance regulator) could have undergone coevolution, similarly to LCT-13910, as a consequence of milk introduction to the human diet during the last 10 Ka in Europe (Alfonso-Sanchez et al., 2010). People carrying one mutated CFTR allele (deltaF508 heterozygote) demonstrate a reduced number of chloride channels (50%) within cell membranes, which is thought to protect them against diarrhea (loss of water and ions), i.e., the main of the lactose intolerance effects facilitating acquisition of milk nutrients (Modiano et al., 2007).
Hypothesis: Possible respiratory advantages for heterozygote carriers of cystic fibrosis linked mutations during dusty climate of last glaciation
2014, Journal of Theoretical BiologyCitation Excerpt :Besides that, the heterozygotes seem to have better resistance to typhoid fever (Pier et al., 1998). Another interesting proposition is that the distribution of CF genes results from the development of the cattle pastoralism in the recent Neolithic period (Alfonso-Sánchez et al., 2010). These combined seasonal migrations of men and their cattle helped spreading of infectious disease that imposed a new survival pressure favoring certain traits, possibly even the CF related genes in heterozygote individuals.
Cystic fibrosis in adult age
2014, Revista Clinica Espanola