Allele Age Estimation for Genetic Loci Associated with Autoinflammatory Diseases in Anatolia: Insights from Ancient and Modern DNA Analysis

Autoinflammatory diseases are immune system disorders that arise from abnormalities in the innate immune system. With the advent of genome sequencing, several distinct genetic loci associated with different types of autoinflammatory diseases have been identified. However, the evolutionary history of these variants, such as the age of the alleles, has not been fully explored in human populations. In this study, we focus on Anatolia, a region with a rich and dynamic prehistory, serving as a hub for human migration and genetic interactions. We explore the age of mutations associated with autoinflammatory diseases that are prevalent in present-day Anatolia, including Familial Mediterranean Fever, Tumor Necrosis Factor Receptor Associated Periodic Fever Syndrome, and Behçet’s Disease. We use RELATE and analyze genomic data from six low-to-medium coverage (0.74 - 6.02X) ancient (1500 BCE - 7955 BCE) and 16 modern individuals from Anatolia to estimate the ages of 26 SNPs associated with these autoinflammatory disorders. Our results show that allele ages range from 981.452 to 74080.4 generations. We find that Behçet’s Disease is the earliest to have appeared in Anatolia, followed by Tumor Necrosis Factor Receptor Associated Periodic Fever Syndrome and Familial Mediterranean Fever. We assessed the allele ages of 26 SNPs associated with three autoinflammatory diseases in Anatolia using both modern and ancient samples to improve the accuracy of our estimates. The Familial Mediterranean Fever SNP (rs61732874) age range of 8,050 to 17,929.8 generations, suggests that the origin of Familial Mediterranean Fever disease in Anatolia may date back further than previously thought. This is the first time that Tumor necrosis factor receptor-associated periodic syndrome SNP (rs4149584) age was calculated as 3,263.58 to 8,160.29 generations. In summary, understanding the age of these alleles is crucial, as it provides valuable insights into the historical prevalence of mutations linked to rare diseases in Anatolia and their role in the genetic landscape of the region.