No abstract

The highly polymorphic genes of the major histocompatibility complex (MHC) play a key role in adaptive immunity. Divergent allele advantage, a mechanism of balancing selection, is proposed to contribute to their exceptional polymorphism. It assumes that MHC genotypes with more divergent alleles allow for broader antigen-presentation to immune effector cells, by that increasing immunocompetence. However, the direct correlation between pairwise sequence divergence and the corresponding repertoire of bound peptides has not been studied systematically across different MHC genes. Here, we investigated this relationship for five key classical human MHC genes (human leukocyte antigen; HLA-A, -B, -C, -DRB1, and -DQB1), using allele-specific computational binding prediction to 118,097 peptides derived from a broad range of human pathogens. For all five human MHC genes, the genetic distance between two alleles of a heterozygous genotype was positively correlated with the total number of peptides bound by these two alleles. In accordance with the major antigen-presentation pathway of MHC class I molecules, HLA-B and HLA-C alleles showed particularly strong correlations for peptides derived from intracellular pathogens. Intriguingly, this bias coincides with distinct protein compositions between intra- and extracellular pathogens, possibly suggesting adaptation of MHC I molecules to present specifically intracellular peptides. Eventually, we observed significant positive correlations between an allele’s average divergence and its population frequency. Overall, our results support the divergent allele advantage as a meaningful quantitative mechanism through which pathogen-mediated selection leads to the evolution of MHC diversity.

Pathogen-mediated balancing selection is regarded as a key driver of host immunogenetic diversity. A hallmark for balancing selection in humans is the heterozygote advantage at genes of the human leukocyte antigen (HLA), resulting in improved HIV-1 control. However, the actual mechanism of the observed heterozygote advantage is still elusive. HLA heterozygotes may present a broader array of antigenic viral peptides to immune cells, possibly resulting in a more efficient cytotoxic T-cell response. Alternatively, heterozygosity may simply increase the chance to carry the most protective HLA alleles, as individual HLA alleles are known to differ substantially in their association with HIV-1 control. Here, we used data from 6,311 HIV-1-infected individuals to explore the relative contribution of quantitative and qualitative aspects of peptide presentation in HLA heterozygote advantage against HIV. Screening the entire HIV-1 proteome, we observed that heterozygous individuals exhibited a broader array of HIV-1 peptides presented by their HLA class I alleles. In addition, viral load was negatively correlated with the breadth of the HIV-1 peptide repertoire bound by an individual’s HLA variants, particularly at HLA-B. This suggests that heterozygote advantage at HLA-B is at least in part mediated by quantitative peptide presentation. We also observed higher HIV-1 sequence diversity among HLA-B heterozygous individuals, suggesting stronger evolutionary pressure from HLA heterozygosity. However, HLA heterozygotes were also more likely to carry certain HLA alleles, including the highly protective HLA-B*57:01 variant, indicating that HLA heterozygote advantage ultimately results from a combination of quantitative and qualitative effects in antigen presentation.

Leprosy, a chronic infectious disease caused by Mycobacterium leprae (M. leprae), was very common in Europe till the 16th century. Here, we perform an ancient DNA study on medieval skeletons from Denmark that show lesions specific for lepromatous leprosy (LL). First, we test the remains for M. leprae DNA to confirm the infection status of the individuals and to assess the bacterial diversity. We assemble 10 complete M. leprae genomes that all differ from each other. Second, we evaluate whether the human leukocyte antigen allele DRB1*15:01, a strong LL susceptibility factor in modern populations, also predisposed medieval Europeans to the disease. The comparison of genotype data from 69 M. leprae DNA-positive LL cases with those from contemporary and medieval controls reveals a statistically significant association in both instances. In addition, we observe that DRB1*15:01 co-occurs with DQB1*06:02 on a haplotype that is a strong risk factor for inflammatory diseases today.

The Wartberg culture (WBC, 3500-2800 BCE) dates to the Late Neolithic period, a time of important demographic and cultural transformations in western Europe. We performed genome-wide analyses of 42 individuals who were interred in a WBC collective burial in Niedertiefenbach, Germany (3300-3200 cal. BCE). The results showed that the farming population of Niedertiefenbach carried a surprisingly large hunter-gatherer ancestry component (34–58%). This component was most likely introduced during the cultural transformation that led to the WBC. In addition, the Niedertiefenbach individuals exhibited a distinct human leukocyte antigen gene pool, possibly reflecting an immune response that was geared towards detecting viral infections.