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

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.     

Support of unrelated stem cell donor searches by donor center-initiated HLA typing of potentially matching donors

Large registries of potential unrelated stem cell donors have been established in order to enable stem cell transplantation for patients without HLA-identical related donors. Donor search is complicated by the fact that the stored HLA information of many registered donors is incomplete. We carried out a project that was aimed to improve chances of patients with ongoing donor searches to find an HLA-matched unrelated donor. For that purpose, we carried out additional donor center-initiated HLA-DRB1 typing of donors who were only typed for the HLA loci A and B so far and were potential matches for patients in need of a stem cell transplant. In total, 8,861 donors were contacted for donor center-initiated HLA-DRB1 typing within 1,089 donor searches. 12 of these donors have donated stem cells so far, 8 thereof for their respective target patients. We conclude that chances of patients with ongoing donor searches to find an HLA-matched unrelated donor can indeed be improved by donor-center initiated typing that is carried out in addition to the standard donor search process. Our results also raise questions regarding the appropriate use of incompletely typed donors within unrelated donor searches.     

Evaluating the potential of fluorinated tyrosines as spectroscopic probes of local protein environments: a UV resonance Raman study

Ultraviolet resonance Raman (UVRR) studies designed to test the utility of fluorinated tyrosines as spectroscopic probes of the local environment are presented. Specifically, resonance Raman spectra of 2-fluoro-L-tyrosine and 3-fluoro-L-tyrosine (3-Y(f)) obtained with 229 nm excitation are reported. In contrast to the modest environmental dependence of the tyrosine resonance Raman spectrum, the spectrum of 3-Y(f) is found to be extremely dependent on the hydrogen bonding strength of the surrounding environment. Preliminary ab initio studies suggest that this behavior is due to normal modes having dominant contributions from the C-OH and C-F internal coordinates. Hydrogen bonding to the solvent perturbs the internal coordinate energetics and/or couplings, thereby altering the character of the normal modes and the corresponding transition frequencies and/or intensities. In addition to the solvent studies, 3-Y(f) is site specifically incorporated into the influenza hemagglutinin (HA) 100-107 peptide which binds to the Fv fragment of the 17/9 anti-HA(98-108) peptide antibody. These studies demonstrate that the spectrum of 3-Y(f) can be monitored in the presence of native tyrosine. In summary, the studies presented here demonstrate that 3-Y(f) holds exceptional promise as a probe of the protein environment.