Spatio-temporal dynamics of pathogenic variants associated with monogenic disorders reconstructed with ancient DNA.

Genetic disease burden in ancient communities has barely been evaluated despite an ever expanding body of ancient genomes becoming available. In this study, we inspect 2729 publicly available ancient genomes (100 BP-52000 BP) for the presence of pathogenic variants in 32643 disease-associated loci. We base our subsequent analyses on 19 variants in seven genes-PAH, EDAR, F11, HBB, LRRK2, SLC12A6 and MAOA, associated with monogenic diseases and with well-established pathogenic impact in contemporary populations. We determine 230 homozygote genotypes of these variants in the screened 2729 ancient DNA samples. Eleven of these are in the PAH gene (126 ancient samples in total), a gene associated with the condition phenylketonuria in modern populations. The variants examined seem to show varying dynamics over the last 10000 years, some exhibiting a single upsurge in frequency and subsequently disappearing, while others maintain high frequency levels (compared to contemporary population frequencies) over long time periods. The geographic distribution and age of the ancient DNA samples with established pathogenic variants suggests multiple independent origin of these variants. Comparison of estimates of the geographic prevalence of these variants from ancient and contemporary data show discontinuity in their prevalence and supports their recurrent emergence. The oldest samples in which a variant is established might give an indication of their age and place origin, and an EDAR gene pathogenic variant was established in a sample estimated to be 33210-32480 calBCE. Knowledge about the historical prevalence of variants causing monogenic disorders provides insight on their emergence, dynamics and spread.