FeverTime · SELECTION VERSUS DRIFT IN THE RISE OF DELETERIOUS MUTATIONS: THE CASE OF FAMILIAL MEDITERRANEAN FEVER

SELECTION VERSUS DRIFT IN THE RISE OF DELETERIOUS MUTATIONS: THE CASE OF FAMILIAL MEDITERRANEAN FEVER

Familial Mediterranean Fever (FMF) is the most prevalent monogenic autoinflammatory disorder worldwide, caused by mutations in the MEFV gene. These mutations are particularly common in Mediterranean populations and their diasporas, with carrier rates reportedly reaching up to 20%. This raises a compelling question that remains unresolved: what evolutionary forces have led to the emergence and persistence of such a substantial genetic burden across this broad region? The phenomenon of balancing selection is famously exemplified by the relationship between malaria resistance and hemoglobin disorders, a landmark example of how selective pressure can shape the human genome. By analogy, it has been proposed that MEFV mutations might confer a survival advantage against historical infectious diseases such as tuberculosis, smallpox, cholera, or plague. Despite the appeal of this idea, definitive evidence to support it is lacking and a comprehensive analysis of the interplay between selection and genetic drift in driving the regional prevalence of MEFV mutations is needed. FeverTime sought to leverage ancient genomics to establish a new benchmark example of how evolutionary mechanisms shape the genetic architecture of human disease, outlining the following objectives: Reconstructing the demographic history of the Armenian Highland. Changes in the frequency of deleterious alleles can be influenced by demographic processes, making it crucial to accurately model the demographic history of the Armenian population to make correct inferences about the role of evolutionary forces in the local mutation load. To achieve the most thorough demographic reconstructions over time, time-series data from this geographically and genetically continuous region, spanning many millennia, were generated. Detecting the role of selection and random drift in the drive of local MEFV mutation burden. FeverTime investigated the possibility that selection pressure on MEFV variants has changed through time, considering major cultural and technology shifts as well as detailed climate reconstructions as possible explicit drivers. Estimating the age of selected MEFV alleles. FeverTime evaluated the age of MEFV alleles and examined whether the local increase in the frequency of disease-causing alleles was driven by a founder effect or recurrent mutations.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз