Genomic signatures of increasing disease burden in recent prehistory

One of the strongest selection pressures experienced by human populations is that driven by diseases on immune-related genomic regions. While it has been hypothesized for some time that disease burdens increased with the shift to agricultural and urbanized lifestyles, direct evidence for this hypothesis is lacking. Here, we capitalize on the accumulation of ancient genomic data to study changes in disease burden in human populations over the past 12,000 years. We investigated changes in genetic diversity and balancing selection in two distinct geographical and cultural centers in Southwest Eurasia and Eastern Asia, and found that not only is the major histocompatibility complex (MHC) the genomic region with the most substantial increases in diversity in terms of enrichment of genes and rates of increase, but that the rates of changes for individual genes are highly correlated between the two cultural centers, indicating similar selection pressures. We identify periods of time with substantial peaks in MHC diversity increase that primarily correspond to periods with settlement intensification, increased connectivity, and the expansion of animal domestication, which suggest that the most intensive disease burden occurred following the transition to sedentary lifestyle but prior to urbanization. These findings demonstrate the potential of our approach in uncovering the interplay between cultural shifts and selection, and provide strong support to the hypothesis that the levels of disease burden have substantially increased in recent prehistory following changes in lifestyle, connectivity and the introduction of domesticated animals.