Analysis of Genomic DNA from Medieval Plague Victims Suggests Long-Term Effect of Yersinia pestis on Human Immunity Genes

Abstract

Pathogens and associated outbreaks of infectious disease exert selective pressure on human populations, and any changes in allele frequencies that result may be especially evident for genes involved in immunity. In this regard, the 1346-1353 Yersinia pestis-caused Black Death pandemic, with continued plague outbreaks spanning several hundred years, is one of the most devastating recorded in human history. To investigate the potential impact of Y. pestis on human immunity genes, we extracted DNA from 36 plague victims buried in a mass grave in Ellwangen, Germany in the 16th century. We targeted 488 immune-related genes, including HLA, using a novel in-solution hybridization capture approach. In comparison with 50 modern native inhabitants of Ellwangen, we find differences in allele frequencies for variants of the innate immunity proteins Ficolin-2 and NLRP14 at sites involved in determining specificity. We also observed that HLA-DRB1*13 is more than twice as frequent in the modern population, whereas HLA-B alleles encoding an isoleucine at position 80 (I-80+), HLA C*06:02 and HLA-DPB1 alleles encoding histidine at position 9 are half as frequent in the modern population. Simulations show that natural selection has likely driven these allele frequency changes. Thus, our data suggest that allele frequencies of HLA genes involved in innate and adaptive immunity responsible for extracellular and intracellular responses to pathogenic bacteria, such as Y. pestis, could have been affected by the historical epidemics that occurred in Europe.

Keywords: HLA; Yersinia pestis; aDNA; ancient DNA; human immunity; natural selection; plague.

Fig. 1.

Mass burials discovered at Ellwangen. (A) Location of Ellwangen in Germany. (B) Location of the marketplace, where the mass burials were discovered during an excavation in 2013–2015. (C) Mass grave 549 showing several individuals being buried together.

Fig. 2.

The 16th century plague victims and modern inhabitants of Ellwangen form a continuous population. (A) PCA showing the 16th century (red) and modern (blue) Ellwangen populations in the context of 65 modern-day populations from West-Eurasia based on 1,233,013 genome-wide SNPs (Lazaridis et al. 2014; Haak et al. 2015; Fu et al. 2016). (B) Admixture modeling based on four ancestral components (K = 4) of the same 65 modern West Eurasian populations including 16th century (Ellwangen plague) and modern Ellwangen (Ellwangen modern) populations. The K = 4 model was chosen due to the lowest cross-validation error.

Fig. 3.

Natural selection drives HLA allele frequency changes. Density plots showing the distributions of allele frequencies from SLIM3 model simulations with (dark grey) or without (light grey) natural selection. The starting frequency for simulations was the observed frequency in the 16th century population. Selection coefficients for the models with natural selection were −0.1 for HLA-B*51:01 and HLA-C*06:02 and 0.2 for DRB1*13:01 (supplementary fig. 5, Supplementary Material online). The 2.5% extremes are shown in blue illustrating where the P value cutoff of 0.05 would occur. Red points represent the frequency in the modern-day population.