Variabilität des Haupthistokompatibilitätskomplexes auf verschiedenen Ebenen - Eine evolutionäre Perspektive
Evolution, Anthropology
Final Report Abstract
The human leukocyte antigen (HLA) represents an exceptionally gene-dense region in the human genome, containing some of the most polymorphic human genes known to date. These genes code for cell surface molecules that are key factors of the adaptive immune system and present pathogen-derived antigens to immune effector cells to initiate a pathogen-specific immune response. Consequently, it is assumed that the extreme polyrmophism in these genes is the result of an ongoing coevolution between the human as a host and its pathogens. Here we investigated specifically the evolutionary consequences of pathogen-mediated selection in the HLA region. In a first project, using theoretical simulations and an unprecedented level of sequence information about the distribution and frequency of functional mutations in the human genome, we could show that the constant adaptation to coevolving pathogens can indirectly lead to an unexpected accumulation of deleterious genetic variation. These results highlight the advantage of genetic recombination, and thus ultimately help explaining the evolution of sexual reproduction. Furthermore, this phenomenon explains how some heritable diseases are not purged but instead occur at considerable frequencies in the human population. In a second project, we investigated the effect of higher genetic diversity (heterozygosity) at the HLA genes with respect to the risk for autoimmune diseases. Here we found that individuals with two different alleles at the HLA locus on average have a higher risk to develop autoimmunity, but that the extent of the predisposition and the type of potentially resulting autoimmune disease depends on the specific combination of the two different HLA alleles. This suggest that there is an evolutionary trade-off between the ability to recognize coevolving infectious pathogens and the necessity to minimize damage to the own tissue through selfreactive immunity. By bridging the fields of human genetics and evolutionary medicine, this work addresses fundamental aspects of human evolution and medicine, such as the co-evolution between humans and their pathogens, the maintenance of genetic diversity in human populations, but also potential changes in the selection regime in modern societies. The acquired results will contribute to our understanding of individual differences in pathogen resistance and immunity, and therefore potentially contribute to the improvement of personalized medical care and therapy.
Publications
- (2013). Divergent allele advantage at MHC-DRB through direct and maternal genotypic effects and its consequences for allele pool composition and mating. Proceedings of the Royal Society B: Biological Sciences, 280(1762), 20130714
Lenz, T.L., Mueller, B., Trillmich, F., & Wolf, J.B.W.
(See online at https://doi.org/10.1098/rspb.2013.0714) - (2013). Evaluating patterns of convergent evolution and trans-species polymorphism at MHC immunogenes in two sympatric stickleback species. Evolution, 67(8), 2400-2412
Lenz, T.L., Eizaguirre, C., Kalbe, M., & Milinski, M.
(See online at https://doi.org/10.1111/evo.12124) - (2013). Exploring local immunological adaptation of two stickleback ecotypes by experimental infection and transcriptome-wide digital gene expression analysis. Molecular Ecology, 22(3), 774-786
Lenz, T.L., Eizaguirre, C., Rotter, B., Kalbe, M., & Milinski, M.
(See online at https://doi.org/10.1111/j.1365-294X.2012.05756.x) - Onengut-Gumuscu S., Han B., Chen W.-M., Howson J.M., Todd J.A., de Bakker P.I.W., Rich S.S., Raychaudhuri S. (2015) Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk. Nature Genetics, 47: 898-905
Hu X.Y., Deutsch A.J., Lenz T.L.
(See online at https://doi.org/10.1038/ng.3353) - Widespread non-additive and interaction effects within the HLA modulate the risk of autoimmune diseases. Nature Genetics, 2015 Sep;47(9):1085-90
Lenz T.L., Deutsch A.J., Han B., Hu X.Y., Okada Y., Eyre S., Knapp M., Zhernakova A., Huizinga T.W.J., Abecasis G., Becker J., Boeckxstaens, G.E., Chen W.-M., Franke A., Gladman D.D., Gockel I., Gutierrez-Achury J., Martin J., Nair R.P., Nöthen M.M., Onengut-Gumuscu S., Rahman P., Rantapää- Dahlqvist S., Stuart P.E., Tsoi L.C., Van Heel D.A., Worthington J., Wouters M.M., Klareskog L., Elder J.T., Gregersen P., Schumacher J., Rich S.S., Wijmenga C., Sunyaev S.R., de Bakker P.I.W., Raychaudhuri S.
(See online at https://doi.org/10.1038/ng.3379)
